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Volume 11 Issue 5


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets


North Africa, An Underestimated Region With Huge Potential For Clinical Trials EU Clinical Trials Regulation And Protection of Personal Data Giving Diseases a Gut Punch Microbiome Applications in Clinical Trials Effective Optimisation and Cost Management In Clinical Trial Logistics






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



Ensuring Inspection Readiness at Clinical Facilities

The principles of Good Clinical Practice (GCP) serve to ensure the protection of trial participants and the integrity of the data recorded. Katrien Lemmens at SGS Clinical Research explains why regulations require that all clinical trials be designed, conducted and reported in accordance with these GCP guidelines in order to be acceptable upon submission for marketing approval. 8

Digesting the Alphabet Soup of Data Standards

Harmonisation of data standards has been a popular topic recently at the US Food and Drug Administration (FDA) and other regulatory organisations. Governmental regulation attracts acronyms, and data standards are no exception. In case these mysterious jumbles of letters are unclear, Julie Odland at Clarivate Analytics has put forward a handy guide to terms discussed at recent FDA public workshops. 10 Successful Oncology Trials Need Intelligent Supply Management As clinical trials become more complex, so does the task of ensuring the right supplies are in the right place at the right time. Protocol changes, undefined doses, unexpected recruitment rates, batch failures and raw material shortages are just some of the challenges facing sponsors and CROs when managing their supply chain. Jason Dean at Signant Health explains why it’s time to bring clinical forecasting and planning into the 21st century. 12 Planning for Early Access Programmes Early access programmes are becoming more common and more sophisticated, requiring greater attention and resources from sponsors. The FDA’s pilot programme is designed to help physicians as they seek access to unapproved, yet promising oncology medications for individual patients who have a poor prognosis and few treatment alternatives. Noolie Gregory at Real World & Late Phase Research explores the US Food and Drug Administration’s (FDA’s) new pilot programme, Project Facilitate. 14 Living in the Data Stream: Real-time Access to Patient Data and Study Metrics Clinical research is changing rapidly alongside the growing prevalence of “smart” technology. Data is being generated beyond traditional clinical settings – originating in disparate locations such as in clinics, from homes, on mobile devices and on telemedicine platforms. Michael Murphy at Worldwide Clinical Trials examines how studies have become increasingly complex, both in structure and in the number of measures tracked.

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 11 Issue 5 September 2019 PHARMA PUBLICATIONS

16 Are Regulatory Service Providers Overestimating AI’s Potential Impact on Process Transformation? Within the next three years, the pharma and biotech industries will be at a point of deploying AI and machine learning to transform the pace and productivity of routine regulatory processes, according to Deloitte. By 2022, automated writing of clinical study reports will be happening as standard, using natural language processing. Alan White CEO of Arriello questions whether there is a danger that the industry is being oversold on the promise of AI. 18 Adjust in Time: Beware of the Challenges Annex VI Brings for Labelling Five years after Clinical Trial Regulation (EU) first came into force, development of the clinical trials portal and database that will

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Contents trigger its official application is about to begin. Subsequently the pharmaceutical industry is at the brink of new regulations that will bring added complexity to the labelling of clinical trial supplies. Gordon Alexander & Simon Jones at PRISYM ID explain why the new regulations will need companies to rethink their clinical trial supply processes.

as drugs. Kinari Shah, a Research Fellow at DIA, scrutinises how a deeper knowledge of the biology of the microbiome may ultimately help us to use the microbiome effectively in clinical trials in a way that will impact health outcomes overall.


43 Optimise Your eTMF Strategy

20 EU Clinical Trials Regulation and Protection of Personal Data

Given the critical role that the TMF plays in ensuring data integrity and the safety of human subjects and the challenges with maintaining a cost-effective solution, an optimised eTMF strategy is an excellent investment. Chet Shemanski at Ennov appraises the merits of a a successful strategy which will encompass regulatory compliance, quality, and cost-effectiveness.

Personal data concerning health should include all data pertaining to the health status of a data subject which reveal information relating to the past, current or future physical or mental health status of the data subject. Vincenzo Salvatore at BonelliErede gives us an insight into EU Clinical Trials Regulations and how the introduction of GDPR can protect personal data. 22 The Public’s Growing Appetite for Product Data As momentum builds anew towards ISO IDMP compliance, life sciences companies could be forgiven for a lacklustre response, after a series of delays. Most organisations have already jumped through so many regulatory hoops to meet each new set of guidelines. Frits Stulp at Iperion Life Sciences Consultancy examines how there is another far more important factor at play here, and that is the public’s growing appetite for access to medicinal product data. MARKET REPORT 24 North Africa, An Underestimated Region with Huge Potential for Clinical Trials North Africa is the region covering the northern part of the African continent, and can be defined as the area covering Morocco, Algeria, Tunisia, Libya, Egypt and Sudan. Mariem Melliti Smaali, et al at Arianne Consulting Inc shows why more attention should be paid to Algeria, Tunisia and Egypt as a strategic choice to host clinical trials, with its large extensive medical infrastructures. 32 Collaboration is Essential for Successful Clinical Trial Outsourcing By 2020, close to three-quarters of clinical trials may be performed by professional contract research organisations (CROs). Ramya Sriram at Kolabtree illustrates how CROs have already proven successful for pharmaceutical companies carrying out clinical trials, whilst also questioning if freelance scientists can add to their expertise as the clinical trial service market grows. THERAPEUTICS 36 Alzheimer’s in Clinical Trials – Is there a Way Out of Ongoing Failures? The attempt to develop a causal treatment against the progression of Alzheimer’s disease is an unparalleled series of nearly two decades of failures in drug development. However, the failures also allowed much better insights in the the design of a future development programme for anti-Alzheimer medications. Peter Schueler at ICON Clinical Research investigates how these insights are to be used to end the series of failures with novel targets and molecules.


46 LIMS in Clinical Trials Sample Management In the 1980s, during the nascent era of laboratory information management systems (LIMS), major analytical instrument manufacturers figured that producing software to help acquire information from those devices while managing lab samples might leverage sales of those high-margin instruments. Since that time, many so-called “Pure Play” LIMS vendors have emerged. Shonali Paul at ISBER demonstrates how LIMS has evolved in clinical trials sample management over the years. LOGISTICS AND SUPPLY CHAIN MANAGEMENT 49 The Role of the Clinical Supplies Manager in Averting Unplanned Costs and Delays Patient recruitment and protocol design receive much attention when planning a clinical trial; however, it is all too easy to neglect another factor critical to a trial’s success: the availability of clinical supplies. Ian Webb at Catalent expresses how an early conversation between the sponsor, contract research organisation (CRO), and clinical supplies manager (CSM) will set out a plan and timeframe for the study. 52 Effective Optimisation and Cost Management in Clinical Trial Logistics Historically, clinical trial distribution was focused on product protection and patient safety at any cost. More recently, there has been a significant shift within the clinical trial sector, which is adopting more cost-effective processes. Kevin Lawler at Peli BioThermal explains how the sector as a whole seems to be looking much more closely at optimisation and cost management. 54 What is Artificial Intelligence, and How is it Beneficial for the Healthcare Industry Artificial intelligence (AI) is the branch of computer sciences that emphasises the development of intelligence machines, thinking and working like humans. Adhiti Sharad Kumar in the Healthcare and Government Sector argues that contrary to popular belief, AI or machine learning is not the future – it is the present.

40 Giving Diseases a Gut Punch: Microbiome Applications in Clinical Trials The community of microbiota (microorganisms such as bacteria, yeast, fungi, and viruses) in our body (the microbiome) is an important part of human health. It affects immunity, organ system interactions, and the metabolism of nutrients and substances foreign to the body, such 2 Journal for Clinical Studies

Volume 11 Issue 5


ADVANCED CLINICAL RESEARCH SOLUTIONS LIFE INSPIRED, QUALITY DRIVEN SGS is providing clinical research and bioanalytical testing with a specific focus on early stage development and biometrics. Delivering solutions in Europe and in the Americas, SGS offers clinical trial (Phase I to IV) services encompassing drug development consultancy, clinical project management and monitoring, biometrics, PK/PD modeling and simulation, and regulatory and medical affairs services. Clients benefits from our wealth of expertise in First-In-Human studies, human challenge testing, biosimilars and complex PK/PD studies with a high therapeutic focus in infectious diseases, vaccines, and respiratory therapeutics. Stay ahead in your drug development plan, contact us for reliable and adaptive clinical trial solutions.





Foreword Summer has come and gone and here at JCS we welcome the change of seasons, with our fifth edition of the year. We’ve curated leading research and industry developments from across the world, with the national flower of Egypt, the Lotus, being featured on our front cover. As part of our exclusive market report feature, Cellia Habita at Arianne Consulting Inc has delved into why Algeria, Tunisia and Egypt, as part of the populous North African region, is a strategic choice to host clinical trials. Titled ‘North Africa, An Underestimated Region with Huge Potential for Clinical Trials’ Habita explores healthcare, regulatory processes readily available to date, and integral points of the region as a definitive choice for clinical studies in various settings including rare diseases, the advantages and challenges that the region faces and its potential future. Whilst the North African countries share a common cultural and linguistic identity, it is their collectively large medical infrastructure that has changed scientific perception of the region, with Egypt taking concentrated efforts to improve its public and private sector. She looks at how Egypt is on the verge of issuing the first law regulating the conduct of clinical trials in the country, ensuring the inclusion of all parties in formulating the law and ensuring its alignment with the global and regional regulations whilst addressing all good clinical practice pillars are included without complicating the process. In our Regulatory section, we have an excellent article by Vincenzo Salvatore at BonelliErede discussing ‘EU Clinical Trials Regulation and Protection of Personal Data’ . Salvatore explores how personal data concerning health should include all data pertaining to the health status of a data subject which reveal information relating to the past, current or future physical or mental health status of the data subject, giving us an insight into EU Clinical Trials Regulations and how the introduction of GDPR can protect personal data. The article topically examines the intersection of General Data Protection Regulation and Clinical Trials Regulation, concluding that although we are still in the early days of interaction between CTR and GDPR we have already experienced many uncertainties in identifying the proper legal basis to ensure a lawful data processing of data collected. There are still many knots to be untied and additional interpretative support and guidance from regulatory and data protection authorities both at national and European level would be more than welcome and would help in navigating this complex matter in the context of clinical trial operations. For Therapeutics, we have featured a piece on ‘Giving Diseases a Gut Punch: Microbiome Applications in Clinical Trials’ by Kinari Shah, a Research Fellow at DIA. The study looks at how the community of

JCS – Editorial Advisory Board • Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA • Bakhyt Sarymsakova – Head of Department of International

Cooperation, National Research Center of MCH, Astana, Kazakhstan

• Catherine Lund, Vice Chairman, OnQ Consulting

microbiota (microorganisms such as bacteria, yeast, fungi, and viruses) in our body (the microbiome) is an important part of human health, determining that it affects immunity, organ system interactions, and the metabolism of nutrients and substances foreign to the body, such as drugs. Shah demonstrates how the study of the microbiome in pharmaceutical drug interactions is known as pharmacomicrobiomics, covering efficacy, toxicity, pharmacokinetics, and pharmacodynamics. Within this relatively new field, the concepts of pharmacometabolomics and pharmacometabonics describe the application of metabolomic technology and the analysis of metabolite interactions with drugs, respectively. Consequently, the authors findings reveal how Pharmaceuticals and gut microbiota interact in a variety of ways, with clinical researchers looking into how altering the microbiome of patients with certain diseases may offer new treatment options beyond traditional therapies or prevent the disease entirely. Shonali Paul at ISBER looks at ‘LIMS in Clinical Trials Sample Management’ in our technology section. She has evaluated the evolution of Laboratory information Management Systems from the nascent era in the 1980’s to present day, determining that major analytical instrument manufacturers figured that producing software to help acquire information from those devices while managing lab samples might leverage sales of those high-margin instruments. Since that time, many so-called “Pure Play” LIMS vendors have emerged, demonstrating how LIMS has evolved in Clinical Trials Sample Management over the years, with many consumers actively coveting the cash-rich pharmaceutical and biotechnology accounts seeking to achieve competitive advantages through increasing productivity. The writer concludes with a discussion of how the marriage of clinical and conventional LIMS in clinical trials accelerates the pace and quality of research from inception through production and is a viable solution for companies wishing to remain competitive. Finally, in Logistics & Supply Chain Management, we have a fantastic article by Kevin Lawler at Peli BioThermal on ‘Effective Optimisation and Cost Management in Clinical Trial Logistics’. He explains how historically, clinical trial distribution was focused on product protection and patient safety at any cost, which has trascended into a significant shift within the clinical trial sector and is adopting more cost-effective processes. He concludes that the sector as a whole seems to be looking much more closely at optimisation and cost management. That rounds off our fifth edition of the year – we hope you enjoy autumn and look forward to bringing some pre-festive cheer in our November issue. Ana De-Jesus, Editorial Co-Ordinator Journal for Clinical Studies

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

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

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

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

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

• Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety

of Europe

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

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

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

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

Recruitment & Retention

• Francis Crawley, Executive Director of the Good Clinical Practice

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

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

• Georg Mathis, Founder and Managing Director, Appletree AG

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

• Hermann Schulz, MD, Founder, PresseKontext

• T S Jaishankar, Managing Director, QUEST Life Sciences

4 Journal for Clinical Studies

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spanning the globe. China: strategic partner Teddy Clinical Research Laboratory since 2019. North America: well established partnership with Cenetron since 2015. Europe: full coverage through MLM Medical Labs since 2012.

MLM Medical Labs is one of the leading central labs for clinical trials in Europe. For 25 years we have been supporting clinical trials phase I-IV with full laboratory services, kit building and logistics. For further information please contact Dr. Katja Neuer at or visit us at

MLM Medical Labs GmbH Dohrweg 63 41066 Mรถnchengladbach Journal for Clinical Studies 5 Germany

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Ensuring Inspection Readiness at Clinical Facilities The principles of Good Clinical Practice (GCP) serve to ensure the protection of trial participants and the integrity of the data recorded. Regulations require that all clinical trials be designed, conducted and reported in accordance with these GCP guidelines in order to be acceptable upon submission for marketing approval. Any site involved in a clinical trial may be subject to GCP inspection by regulatory authorities, including the investigator sites, laboratories, the sponsor’s premises, and the contract research organisations acting under arrangements with a sponsor. Clinical research is global, meaning it is increasingly important for sites to pass both FDA and EMA GCP inspections. These may be conducted on a routine basis or occur in response to a specific trigger, and can be related to ongoing or completed studies. Additionally, the inspections may or may not be announced. The objectives of GCP inspections are to: • verify that quality assurance arrangements exist, in compliance with regulatory requirements and GCP; • ensure the safety of human subjects is preserved and ethical standards are being applied; • confirm that clinical trial data and results are scientifically valid and accurate. During an inspection, an inspector must be able to wholly reconstruct the clinical trial to confirm that all steps have been performed in accordance with the guidelines, that patients’ rights and safety were protected at all times, and that all data is reliable. For clinical teams undergoing inspection, the process brings with it the burden of administrative tasks and checklists. A common and recurring issue for a site is that getting ready for an inspection is regarded as a preparatory activity that starts only after notification of an upcoming inspection. This means that the team, headed by the quality assurance department, must ensure that all documentation is accessible, accurate and complete by the time the inspector visits the site, often leading to time pressure. To overcome these last-minute activities leading up to an inspection, facilities can adopt a state of “inspection readiness” whereby the objective is to operate every day at a quality level ready for inspection, and is achieved by developing a culture of compliance. Inspection readiness entails the following activities: 1. development of a solid quality management system, consisting of robust standard operating procedures (SOPs) that cover the required measures to maintain high quality standards; 2. adopting a proactive quality control process that not only checks activities but also aims for continuous improvement. 6 Journal for Clinical Studies

The implementation of digital solutions for data, document and quality management supports this process; 3. carrying out regular, routine internal mock audits and inspections. To foster a culture of compliance, the quality management process installs a set of procedures and policies which are monitored and evaluated to highlight where there may be room to improve. Trial activities and collected data are verified against protocol requirements, GCP and Good Distribution Practice (GDP) regulations and internal procedures, as well as digitisation of these data allows for much simpler review. The verification can be undertaken on all trial data which results in a 100% quality check; however, a more efficient approach may be to spot check only the crucial activities identified during an upfront risk analysis. The checks need to be reported and interpreted, and whenever a flaw in a system or procedure is detected, its cause needs to be analysed (root cause analysis) to see if any action is needed to correct the fault or to prevent the situation happening again. This corrective and preventive actions (CAPA) process allows for improvement of the facility’s overall quality, and its ability to be inspection ready at all times. The cornerstone of a solid quality control approach is described by the Shewart Cycle (adapted by William E. Demming): • Plan: look at the way of working, define how things can improve and set clear objectives; • Do: implement the planned improvements; • Check: measure results and evaluate if objectives were met; • Act: apply actions for improvement if needed. Internal mock audits and inspections are good tools to evaluate whether the quality system is working as intended, and if the team is indeed inspection ready. These types of self-compliance checks provide valuable opportunities for the identification of deficiencies in documentation or processes long before an inspector arrives, and additionally, help people to be clear, concise and confident when being interviewed.

Dr Katrien Lemmens Dr Katrien Lemmens joined SGS as Medical Director Early Phase in 2016. She started her medical career in clinical cardiology, during which she obtained her PhD. After a FWO post-doctoral position, Dr Lemmens went on to join Janssen Pharmaceuticals, where she was Medical Director of its Clinical Pharmacology Unit in Merksem, before rejoining the University of Antwerp as Associate Professor of Pathophysiology and Pharmacology, and later SGS.

Volume 11 Issue 5

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Digesting the Alphabet Soup of Data Standards Harmonisation of data standards has been a popular topic recently at the US Food and Drug Administration (FDA) and other regulatory organisations. Governmental regulation attracts acronyms, and data standards are no exception. In case these mysterious jumbles of letters are unclear, here is a handy guide to terms discussed at recent FDA public workshops. ADaM: Analysis Data Model, one of the required standards for data submission to the FDA and Japan’s PMDA. ADaM facilitates reviewer analysis of sponsors’ clinical data. BCO: BioCompute Object, a computational record of specific steps in the bioinformatics pipeline that contains all the information necessary to repeat an entire pipeline, from FASTQ file format to result. A BCO is a tool intended to communicate bioinformatic workflows clearly and transparently, allowing for reproducibility and verification. BTRIS: Biomedical Translational Research Informatics System, a protocol created by the US National Institutes of Health (NIH) and designed to enable platform-supporting clinical research and patient care.

information, and IT support: electronic-submissions-gateway

CDASH: Clinical Data Acquisition Standards Harmonization, a standardised method of collecting data consistently across studies and sponsors so that data collection formats and structures provide clear traceability of submission data. The FDA does not require the use of CDASH, but at recent workshops, FDA panelists said they will accept it.

FHIR: Fast Healthcare Interoperability Resources is a framework from Health Level Seven International (HL7) “to exchange information using a set of resources that can be assembled to meet various data exchange requirements – including those in the regulatory domain” (International Medical Device Regulators Forum Data Exchange Guidelines, 2017).

CDISC: Clinical Data Interchange Standards Consortium. A collective of >450 member organisations that compiles a suite of standards applicable throughout the clinical research process. Website:

INFORMED: Information Exchange and Data Transformation, a program developed by the FDA and Flatiron Health. Characterised as a holistic approach to regulatory science, the program converts raw data to drug-development tools using algorithmic analytics.

CTMS: Clinical Trial Management System, used to manage critical functions of the research site (e.g., patient recruitment, study tracking, financial accounting, scheduling, reporting).

RWD: Real-world data are data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources. The 21st Century Cures Act, passed by the US Congress in 2016, places additional focus on the use of these types of data to support regulatory decision making, including approval of new indications for approved drugs: https://www.fda. gov/regulatory-information/selected-amendments-fdc-act/21stcentury-cures-act

eCTD: Electronic common technical document, the standard format for submitting applications, amendments, supplements, and reports to the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). In January 2019, the FDA published Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (Revision 6) (Final). The FDA has identified six strategic goals that comprise the data standards strategy (see inset). ESG: Electronic Submissions Gateway, the central transmission point for electronic submissions to the FDA, intended to facilitate secure submissions of pre-market and postmarket information for agency review. The FDA maintains an ESG website that provides sponsors with a user guide, policy 8 Journal for Clinical Studies

RWE: Real-world evidence is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD. In-depth definitions of RWD and RWE are listed in a white paper, A Framework for Regulatory Use of Real-World Evidence, developed by the Robert J. Margolis, MD, Center for Health Policy at Duke University, funded in part by the FDA: files/rwe_white_paper_2017.09.06.pdf SDSP: Study Data Standardization Plan, a template developed by the FDA that sponsors can use to document key data Volume 11 Issue 5

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Source: FDA public workshop presentation slides, 12 June 2019.

information, analysis strategies, and technology choices that will support the submission of standardised study data to support applications. SDTM: Study Data Tabulation Model, to develop standardised review strategies and methods; sponsors use this tool to store, display, and analyse information for tabulated clinical data. SEND: Standard for Exchange of Nonclinical Data. According to CDISC, SEND is an implementation of the SDTM standard for nonclinical studies that specifies a way to collect and present nonclinical data in a consistent format. SMQs: Standardized MedDRA queries, tools developed to facilitate retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development. SMQs are validated, predetermined sets of MedDRA terms grouped after extensive review, testing, analysis, and expert discussion.

SUPPQUAL: Supplemental qualifiers, a special SDTM dataset that contains nonstandard variables that cannot be represented in the existing SDTM domains. According to the FDA, SUPPQUAL should be used only when key data cannot be represented in SDTM domains. TAUGs: Therapeutic Area User Guides. An FDA panellist at a recent workshop stated that if TAUGs are supported and noted in the technical conformance guide, there is an expectation that they will be used. TCG: Technical conformance guide, provides specifications, recommendations, and general considerations on how to submit standardised study data using FDA-supported data standards located in the FDA Data Standards Catalog. FDA Data Standards Strategic Goals

Julie Odland Julie Odland is a writer and editor with more than two decades of experience in publishing. She joined Clarivate Analytics in 2017 and specialises in pharmaceutical regulatory affairs as a medical and regulatory writer for the Cortellis database and AdComm Bulletin. Email:

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Successful Oncology Trials Need Intelligent Supply Management As clinical trials become more complex, so does the task of ensuring the right supplies are in the right place at the right time. Protocol changes, undefined doses, unexpected recruitment rates, batch failures and raw material shortages are just some of the challenges facing sponsors and CROs when managing their supply chain. The challenges are magnified in the increasingly competitive world of oncology, which has seen the globalisation of studies and rising investigational product costs. Combined with the growing obligation to reduce waste, it means effective supply management systems are more important than ever. It’s time to bring clinical forecasting and planning into the 21st century with modern, specialised supplies management software that allow for the visualisation of the entire supply chain. Ensuring everyone has the materials they need, when they need them, reduces costs, maintains safety and ensures compliance across territories. Enabling clarity in the demand on the supply chain leaves life sciences companies free to concentrate on developing the next generation of life-changing cancer drugs. Immature Clinical Supply Chains The life sciences industry is well known for having immature clinical supply chains that often lack the sophistication of their commercial counterparts. Further challenges also include an increased variability in the factors that impact supply and demand in the clinical space. Current tools in the hands of study planners are apt to be based on spreadsheets and manual calculations, meaning clinical supply decisions can be impulsive, error-prone, and the forecasts become little more than guesswork. With a lack of visibility to the supply chain, sponsors tend to find themselves fire-fighting material-related problems rather than collecting the data they need to improve the lives of people living with cancer. Increasing Visibility and Traceability Purpose-built software solutions can increase the visibility and traceability of clinical supplies by taking forecasting and planning off of manual processes and plugging them into the overarching end-to-end clinical trial management system. Integrated supply management software provides life sciences companies with the tools they need to effectively forecast, plan, label, distribute, manage and reconcile clinical supplies. Forecasting and Planning Accurately forecasting clinical supply and demand is critical. However, it is often complicated by issues including protocol 10 Journal for Clinical Studies

changes, undefined doses, unexpected recruitment rates and batch failures. Forecasting too little of material leads to struggles with sponsors having to manage unexpectedly high enrolment rates, resulting in material delivery delays. Forecasting too much product results in an abundance of material that will ultimately need to be destroyed prior to subject assignment, but only after incurring significant manufacturing, labelling and storage costs for those unused products. When faced with the choice of delaying a trial start or absorbing the costs of surplus product, most supply managers will overestimate the buffer. This can prove to be an expensive decision for sponsors. Modern purpose-built clinical supplies software can take the guesswork out of trial forecasting. It can be used to dynamically predict and graphically represent supply demand across an entire programme or compound level. The advantages to this are multiple. A more accurate forecast allows for a more accurate buffer of product that can shift between studies. This results in a substantial reduction in the product needed to support a programme, cutting supply wastage and associated costs. Linking the Supply Chain and the IRT As the growing complexity of oncology trials has made tracking and monitoring product development, distribution and reconciliation difficult, more sponsors have adopted interactive responsive technology (IRT) platforms to manage their clinical supply chain. Such systems, though, tend to focus only a singular protocol, rather than using a programme-wide viewpoint. This isn’t conducive to the management of today’s complex, international oncology studies which require asset level planning and visibility throughout the material genealogy. One solution has been the introduction of stand-alone inventory management systems that oversee lot and country Volume 11 Issue 5

Watch Pages releases, as well as protocol-level approvals. These systems are prohibitively complex and require ongoing, manual data entry in order to line up with real-world availability of materials. What’s more, such systems often need reprogramming every time a new protocol comes online in order to ensure all components and variables from each protocol are accounted for. This leads to disjointed systems that are not globally harmonised over time. It’s worth considering what can be achieved when the full power of end-to-end supply management is harnessed by integrating systems. By moving depot-level supply management out of the IRT and into an overarching clinical supplies management system (CMS), supplies for the whole programme gain greater visibility. Drug supply managers are able to gain much greater visibility throughout the supply chain back to drug substance and excipient manufacturing for their compounds and beyond. There are two clear benefits to this way of working. Crucially, it allows for a flexible pooled inventory model within the IRT. This results in substantial buffer reductions per trial and associated cost savings across the programme, even when new protocols are introduced.

Linking supply management software to trial planning, monitoring, and distribution systems gives sponsors full audit control capability. This ensures supplies are released to the appropriate location from the right depot and has the correct expiry information.

Furthermore, it eliminates the need to manage depot inventories across multiple contract manufacturing organisations (CMOs) and trials run by various IRT vendors, simplifying the whole process for clinical supply teams.

Ultimately, integrated solutions can reduce costs by 10 per cent and even more, while keeping participants safe and ensuring location-specific compliance and appropriate stock levels at every node.

End-to-end Considerations When fully integrated into clinical trial systems, supply software packages can use live enrolment figures to model supply and demand with the latest information.

Summary Oncology research is expanding at an incredible rate, making it an exciting yet competitive field to be working in. Maximising ROI and expediting progress on costly cancer drug treatments has, arguably, never been more important.

Supply planning considers factors such as expiry dating, expected yields, lead times, and asset capacities. This allows for intelligent, risk-based manufacturing and packaging throughout the programme and for each trial, ensuring stock levels are maintained at optimum levels. Integrated systems can generate time-phased demand schedules, which can be easily shared throughout the organisation. This allows for clearer communication with drug supply managers and leads to better informed decisions with regard to internal and external operations.

Integrating supply chain software into trial management systems can help organisations significantly reduce costs by managing supplies efficiently, and with minimal risk, over an entire clinical programme or compound. In a time of ever-complicated oncology trials, the system can also simplify processes for study teams, leading to increased efficiencies. Clinical trials stand or fall on patients having the drugs they need, when they need them – and intelligent supply chain software can be used to ensure that this happens.

Jason Dean Jason Dean, Director of CMS Software Solutions at Signant Health has spent his full career managing validated software solutions in regulated environments in a variety of roles. Jason joined Signant Health’s Clinical Management Systems team in 2006. He has led several successful projects in implementing forecasting and inventory management applications for life science organisations. He holds Bachelor of Science degrees in Business Management and Computer Engineering from the University of Maine.

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Planning for Early Access Programmes

Early access programmes (EAPs) are becoming more common and more sophisticated, requiring greater attention and resources from sponsors. And should the US Food and Drug Administration’s (FDA’s) new pilot programme, Project Facilitate, be adopted into practice, sponsors might see an influx of patient requests, requiring them to think about, and plan for, “named-patient” supply differently – both in clinical and operational terms. The FDA’s pilot programme, which was announced in June 2019, is designed to help physicians as they seek access to unapproved, yet promising oncology medications for individual patients who have a poor prognosis and few (if any) treatment alternatives. Traditionally the process has been confusing and cumbersome for physicians, necessitating detailed conversations with sponsors and regulatory agencies. Through Project Facilitate, the FDA’s Oncology Center of Excellence is staffing a call centre to answer healthcare professionals’ questions and assist them in completing the steps needed to secure supplies of an investigational product. Undoubtedly this will save physicians’ time, but likely won’t reduce the time that sponsors spend in discussing individual cases with physicians. Indeed, if the project is adopted more widely, sponsors will be devoting more, not less, time to the process. Outside of the US, the situation is even more burdensome for all parties, as there is no support to help physicians navigate country-specific regulations that entail different processes and expectations. The FDA intends to follow up on individual requests, gathering data on their disposition (and if access was denied, why that was the case) as a way to gauge how the process is benefiting patients. This added oversight could potentially put sponsors under more pressure to grant access to named patients – a decision that is already difficult to make objectively given the poignancy of patient situations. On a positive note, the FDA is signalling with the pilot that early access has a place in the clinical development programme, which could lead to a greater use of the evidence EAPs can generate. Lutathera®, for example, was approved on the basis of two studies, one of which was led by an investigator who conducted research with patients who were receiving the product through an EAP. Note that data collection via EAPs is viewed differently in different regions; whereas the UK is very open to it, other areas discourage it because of the added burden it places on physicians. Recommendations for Sponsors Should Project Facilitate form a blueprint for a more permanent and widespread approach by the FDA, it will be even more critical for sponsors to adopt the best practices for managing EAP programmes that have been in use around the world: •

Developing a strategic plan. Companies should determine how they will integrate EAPs into their clinical development plan. This is of particular importance for cohort EAPs, which serve

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as a bridge for patients between the close of clinical trials and marketing approval. Careful consideration should be given to providing early access if any clinical trials remain open, as doing so could hinder patient recruitment. •

Establishing clear, defensible policies to guide decisions. Decisions around granting access should be made on the basis of a sound rationale founded on the data and supporting science. Drafting early access policies is more straightforward for cohort programmes than for named patients; in the latter case, it can be hard to predict the indications for which requests may be made, and there may be little data to consult.

Articulating the policy. Sponsors should develop a communication package to articulate their public position on early access so that they can manage expectations and offer patients and physicians a clear route to pursue access. This is an important step in protecting a company’s reputation and insulating it from criticism.

Ensuring sufficient product supply. EAP requests – particularly for the named patient route – are unpredictable in that they can encompass multiple indications and regions, making it challenging to plan for the manufacture and supply of required products.

Developing an exit plan. Sponsors must plan how and when they will close EAPs. This is clear cut when a product comes to market, but far less so when early access is granted to a named patient in an indication for which there are no commercialisation plans. In these cases, the sponsor, regulators, and treating physicians need to establish the best route of supply – one of which might be off-label use once the product is commercialised.

The FDA’s initiative in Project Facilitate reflects the agency’s commitment to expanding access for oncology patients and may be an approach worth replicating elsewhere. Sponsors should be thinking proactively about how early access will fit into their clinical development programme and be prepared to handle requests that are not part of a product’s clinical development pathway.

Noolie Gregory Noolie Gregory, Executive Director, Real World & Late Phase Research, spent more than 14 years in a large pharmaceutical company before joining Syneos Health. She works closely with medical affairs teams to fill medical evidence gaps via real-world and late-phase projects. She has written and operationalised early access programme policies and SOPs. Email:

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Living in the Data Stream: Managing Patient and Study Metrics Clinical research is changing rapidly alongside the growing prevalence of “smart” technology. Data is being generated beyond traditional clinical settings – originating in disparate locations such as in clinics, from homes, on mobile devices and on telemedicine platforms. Studies have become increasingly complex, both in structure and in the number of measures tracked. As far back as 2008, an evaluation conducted by the Tufts Center for the Study of Drug Development revealed a steady rise in the complexity of protocol designs.1 Thus, typical studies today follow more measures in more detail from more origination points. The result: torrents of trial data swirling around sponsors, CROs, investigators and others. Effectively managing this data stream is essential to study success. While some technology vendors advocate the use of single-suite solutions to ease data management tasks, that idea seldom matches reality. A best-of-breed technology approach often enables sponsors and CROs to accommodate preferred partnerships and integrates enterprise systems that span multiple studies or sponsors. The question, therefore, is how to integrate and access disparate data in as close to real time as possible – all while balancing clinical, operational and regulatory demands. The answer may entail standardising builds where possible, setting up consistent data structures, and aggregating in a vendor-agnostic enterprise system. To achieve an effective solution, however, one must understand the data needs underlying each individual trial. A Sponsor’s Perspective Sponsors’ data access requirements generally fall into two broad buckets, namely study metrics and patient-level information. Under the “study metrics” umbrella, key performance indices (KPIs) provide a baseline indicator of how well a study is progressing. For example, commonly measured start-up metrics might include days from site qualification to executed contract, or percentage of sites activated vs. projected number of sites to activate. Likewise, sponsors must be able to follow key quality indices (KQIs) such as the percentage of significant protocol violations vs. total violations. Yet while knowing KPI/KQI status is good and probative, sponsors ideally should emphasise metrics with predictive value. Some lagging indicators – such as site activation, for example – offer leading indicators of other factors such as overall recruiting, first patient in (FPI), last patient last visit (LPLV), etc. Therefore, the quality of KPIs/KQIs defined and monitored should take precedence over the quantity. Focusing on a dozen or so exceptionally key indicators rather than trying to manage up to 50 metrics of varying value supports a more mature risk-management strategy. It helps avoid data overload and “analysis paralysis”. Given that investors often judge decisions and stakeholders based on how well a study meets its KPIs/KQIs, it might behoove 14 Journal for Clinical Studies

sponsors to encourage educational efforts as well. Explain to investors what each KPI really means and why it is important. Define the failure mode for essential aspects such as endpoints and technologies, as well as when and how the sponsor and partners will react. When it comes to patient-level data, sponsors require nothing less than a detailed, 360-degree view of every patient. Orphan disease and other trials in which each data point is especially critical accentuate the necessity. The problem is that aggregation of data points is not enough to deliver the desired insights. Achieving value compels a proactive approach to ensure suitable upfront design of the anticipated data (attributes and values), and implementation of a disciplined review process. Sponsors also want quick access to data – preferably in real time. Codified data provided months after the fact is of limited use. While new technologies certainly can play a pivotal role in enabling faster access, they also introduce new challenges. By definition, new devices and unique approaches are nonstandard. They can give rise to problems such as the need to assure compliance in a non-traditional design (e.g., wearables). With potentially multiple conditions creating multiple failure modes, it’s all too common to layer technology upon technology to “fix the fix” – and in so doing escalate complexity, cost and risk. Once again, a preemptive approach that entails good data and reporting design, data definitions and mastering may be preferable. An upfront evaluation of the flaws, weaknesses, risk profiles and failure modes of the various technologies used can help sponsors and CROs develop a more effective risk management and compliance strategy. Similarly, designing studies to carefully separate roles and define who can review which data points can reduce the potential for unblinding, especially in small study populations. Integrated Solutions A CRO must safeguard study integrity. Although most CROs possess some sort of cloud-based technology backbone to ease data entry, issues can arise integrating multiple data sources and maintaining accuracy and veracity. That is why CROs must grant access rights with the proper controls in place to prevent unintentional harm – including inadvertently compromising database integrity or violating regulatory compliance. Moreover, real-time data also raises an expectation for real-time intervention. The question must be asked: Is an organisation and its systems ready and able to monitor and respond in real time to patient safety risks? Better reporting and visibility can aid in such endeavours but are not foolproof. Other ways CROs and sponsors can work together to better live in the data stream include ensuring: •

Strong data governance. Creating clear data definitions, mastering, and fully understanding failure modes for technologies that generate clinical or operational data can go Volume 11 Issue 5

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a long way toward alleviating challenges. Define appropriate roles and responsibilities, and promote consistent, disciplined and open review. •

Completed business requirements. Define and agree upon KPIs/KQIs and other data targets upfront, understand how they will be used, and ensure they are tracked at the determined frequency via the tools available.

Straightforward data access. Aggregate clinical and operational metrics into dashboards (for a “read and react” view) and into analytics (for deeper data dives). Balance features such as standard printouts with the flexibility to modify and manipulate data.

Comprehensive staff training. As study complexity grows, so does the need for staff to understand which data capabilities are more vs. less important. The same holds for sponsors, executives, and members of the marketing and finance teams. The entire team (e.g., clinicians/project manager/operational lead/data management-statistics lead) must decide how to appropriately tier efforts into “must-have” and “nice-to-have” data and access capabilities. Appropriate technology use. Technology may be the lubricant that eases data interactions, but its drawbacks must be recognised. If it’s too complex for sites or patients to use correctly, for instance, it might negatively impact use and the patient journey. It is vital to train sites, data managers, statistics leads, project managers and CRAs to use technologies appropriately, as well as to aggregate and integrate data appropriately. Conflict adjudication skill. Where possible, avoid conflicts altogether through good design. Often, potential conflicts can be eased through good definitions of the expected use and value of each particular measurement, data point and technology.

Effectively Channel the Current As the number and variety of data points continue to grow, study success increasingly will depend on how effectively sponsors

and CROs live in the ever-swelling data stream. This includes standardising builds where possible, setting up consistent data structures, and aggregating in a vendor-agnostic enterprise system. However, there is no one-size-fits-all solution. An experienced, proactive approach to channelling the data current will be necessary to accommodate the unique nuances of each individual trial. REFERENCES 1.

Getz, Kenneth A., Campo, Rafael A, Kaitin, Kenneth I. “Variability in Protocol Design Complexity by Phase and Therapeutic Area.” Drug Information Journal. 2011 45:4; p. 413-420. https://journals.sagepub. com/doi/abs/10.1177/009286151104500403, visited on 13 Aug 2019.

Michael Murphy Michael Murphy, M.D., Ph.D., is Chief Medical and Scientific Officer, Worldwide Clinical Trials. He emphasizes translational research and strategic consultation regarding methodologies for interventional and observational research. He is boarded in adult psychiatry, with a pharmacology doctorate. He trained at Tulane University, Stanford University, and Mt. Sinai School of Medicine. Email:

Ted Finlan Ted Finlan is Senior Vice President of Project Planning and Administration, Worldwide Clinical Trials. He is actively engaged in shaping operational changes that drive efficient growth, transparency, and datadriven management across the enterprise – including standardizing project launch and ensuring common project management and delivery processes. Email:

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Are Regulatory Service Providers Over-estimating AI’s Potential Impact on Process Transformation? Advanced digital tools are certain to play a pivotal role in the redesign of labour-intensive regulatory processes, but there is a danger that AI’s potential contribution is being over-hyped to life sciences firms. Alan White, CEO of Arriello, warns that the key to ROI is in the application. Within the next three years, the pharma and biotech industries will be at a point of deploying AI and machine learning to transform the pace and productivity of routine regulatory processes, according to Deloitte1. By 2022, automated writing of clinical study reports will be happening as standard, using natural language processing – industrialising the conversion of structured study data into text narratives. Meanwhile leading firms will have automated up to 95 per cent of regulatory filing, saving up to a year in their launch cycles, it claims. But is there a danger that the industry is being over-sold on the promise of AI? Where manufacturers are outsourcing routine processes to external solutions and services companies, and being promised the earth in terms of smart automation, they must be clear about what exactly they are being promised and what measurable, visible impact any proposed new innovation will have on their operations. This is particularly the case for mid-range pharma companies and smaller biotech firms, which may not benefit to the same degree from automated process efficiencies as Big Pharma, because their needs are not of the same scale. It’s all too easy to set unrealistic expectations of how quickly AI-enabled improvements will filter through to the bottom line. In the meantime, procurement managers and department heads need to be able to demonstrate improved value and efficiency in the here and now. The good news is that technology-enabled transformation can happen on a much more modest and focused scale, and still have a big impact – today. Indeed, the more focused and specific the target use case and its mapping to a known ‘pain point’, the greater the chance at making a significant difference in a reasonable timeframe, and without major disruption to the status quo. Targeting PV Pain Take pharmacovigilance (PV) and the role drug companies’ sales people are expected to play in reporting any adverse reactions experienced by patients linked to any of their organisation’s products (for instance, if such information is relayed during faceto-face or phone-based client meetings). If this reporting task is left to chance, happens manually and/or (because sales people are human) left until some later point, the quality and value of the sales agent’s input is likely to be relatively poor. They may scribble some notes for someone else to transcribe later, and/or forget to capture the fuller details that are needed for a complete PV report. They know they have a responsibility to pass on this feedback, but for a busy on-the-road sales rep this just isn’t a priority. 16 Journal for Clinical Studies

But what if a simple yet clever software tool could make light work of PV reporting for those frontline teams? What if they could simply input and dictate all the required details straight into a secure mobile app, then move on? This would alleviate pressure on the sales rep, who has other more pressing tasks to attend to. It would also save on painstaking follow-up work by PV/safety teams and contract service providers, who ordinarily would have to try to verify any ambiguity and fill any gaps after the event – and at a point when it might be difficult to track down the clinician or pharmacist with the original case notes. The intelligence in a software solution like this could be in the smart workflow, prompts and auto-filling of information fields, and the ability to link voice notes to a file containing additional case data. It would also be in the tool’s ability to capture some of this data in a structured way as part of the recording process. Small is Often Most Impactful It is in specific applications of advanced software tools that business process service providers can really add value for their life sciences clients, especially for smaller-scale operations that can’t readily spare staff’s time for manual form-filling and case follow-up. When manufacturers are being enticed by talk of AI and process automation, then, it is important that they are able to ground this in tangible everyday experiences – and understand the specific ways any new innovation will change their own workloads and resource use. If firms can have direct input into process improvements and where intelligent automation will be most useful, so much the better. Companies need to be careful, too, that they are not carried away by overly ambitious expectations, especially where the proposed application of AI is on a grander scale. This can happen when firms fall under the spell of hyper-scale cloudbased analytics services, which offer to slice and dice data in all sorts of novel ways to distil insights they might never have spotted otherwise. But, without the right controls and quality/ accuracy safeguards in place, firms might never really be able to fully rely on the findings, and deliver practical value from them. Alternatively, they may incur all sorts of additional work to get to that point, which ends up undermining the business case. From a PV perspective, even tools which ‘automatically’ read, extract and interpret text from documents, and put them into context – ostensibly to save a team of people from having to do it – could potentially create more work than they save, or certainly at this still-early point along AI’s maturity curve. And of course, doing powerful things with data all starts from an assumption that the source data is definitive and of robust quality… A better use of budget might be to use the technology to ensure that the right data is collected in the first place, as in the example above about transforming the way drug companies’ sales Volume 11 Issue 5

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reps provide adverse events information back to PV and safety teams.

Alan White

Certainly, AI is only valuable to organisations if it transforms painful processes for the better. In which case, life sciences manufacturers should assess their specific requirements and find a suitable partner that can help apply the right technology most effectively.

Alan White is CEO of Arriello, a specialist global provider of innovative, high-impact market access, regulatory affairs & pharmacovigilance solutions and services for pharma and biotech firms primarily in Europe and North America.


The future awakens: life sciences and health care predictions 2022 (Deloitte, November 2017)


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Adjust in Time: Beware of the Challenges Annex VI Brings for Labelling The pharmaceutical industry is on the brink of new regulations that will bring added complexity to the labelling of clinical trial supplies. Five years after Clinical Trial Regulation (EU) 536/2014 first came into force, development of the clinical trials portal and database that will trigger its official application is about to begin. Six months after it’s completed, the regulation will take full effect and the rules governing clinical trials will transform quickly although you will have a one-year transition period after that where you can continue to register a trial under the existing EU Clinical Trial Directive. The EMAs management board say that the regulation will come into effect in 2020. Their impact on labelling is profound. Annex VI of the new regulation mandates the inclusion of ‘period of use’ dates on both immediate and outer packaging, removing the option for companies to reference the information centrally via IRT or RTSM systems. Under the previous directive, the inner packaging needed an expiry date and if changed, did not need to be updated on the inner pack and could be updated on an IRT system. Whereas, Annex VI requirements state that if subject to change, the expiry date must be physically replaced on both the inner and outer packaging, which cannot be done by an IRT system. Although adding dates to labels is itself quite straightforward, changing those dates as IMP stability becomes clearer is much more problematic. For example, with biologics where stability is often difficult to determine up front, expiry date changes during clinical trials are becoming increasingly frequent. However, with repackaging needing to be carried out in a GMP-controlled environment and overseen by a qualified person (QP), the requirement to update period of use dates on primary and secondary packaging presents major challenges for products that have already been shipped in bulk. If the packaging is then sent to a site with no DMP environment, then repackaging can be difficult or even impossible. Many trial or distribution sites don’t have the facilities or infrastructure to relabel products in-country, increasing the risk of costly delays as supplies are reshipped to GMP-controlled environments for repackaging. In some instances, companies may be forced to scrap and remake expensive compounds. Conversely, failure to comply puts them in breach of clinical trial regulations and could invalidate a study. The potential implications are severe. Therefore, as the industry counts down to the official application of the new regulation, companies need to rethink their clinical trial supply processes and adopt agile technologies that unlock more efficient and responsive ways of working. Leading organisations are exploring a range of measures to ensure operations are fit for purpose. 1. Smart Packaging One option is to use ‘smart’ packaging, which allows labels to be updated without opening an outer pack. This reduces the risk of breaking tamper-proof packs and can be an elegant solution. However, there are costs associated with the adoption and validation 18 Journal for Clinical Studies

of new packaging while the options available are dependent on the IMP being trialled. Smart packaging is not always suitable. 2. Weather the Storm The uncertainty surrounding when the new regulations will become applicable has led some companies to take a pragmatic view, keeping a weather eye on emergent best practice rather than committing to a solution in advance. This approach is not without risk; once the portal and database finally go live, companies have six months (plus the option of an additional one-year transition period) to implement a workable solution. That’s still cutting it fine. 3. Leverage Partner Network A third option is to leverage existing CRO and CSO partnerships. Many industry partners have good in-country GMP facilities and are well-placed to help pharma meet the new labelling requirements. However, success is not just about a partner’s capabilities, it depends on the availability of their QPs to release products. Moreover, leveraging partner networks still requires pharma companies to change their labelling strategies and inevitably adds time and cost to clinical trial supplies. 4. Small Batch Production Some organisations are exploring new production models. One example is to produce smaller but more frequent batches of primary packaging. This approach requires no changes to existing processes and, since production volumes are smaller, minimises the likelihood that packs will carry incorrect expiry dates. The model, often incorrectly referred to as Just in Time, is well suited to early-phase trials involving lower volumes of patients and studies. However, at scale the approach can be inefficient. As volume increases, the number of batches required increases too, intensifying the QP effort to release products, particularly in later phases. 5. Just in Time Labelling Perhaps the best response is to take a Just in Time (JIT) approach. JIT is a procedure for printing, packing and shipping packs as and when supply plans state they’re required. A similar, nuanced option is ‘on demand labelling’, where printing is done in response to confirmed patient attendance at study sites. JIT is different in that printing, packing and shipping is done in line with a pre-existing plan so that levels of stock can be kept to a bare minimum, an approach which can Volume 11 Issue 5

Watch Pages In most cases, JIT is likely to be a good option – but it’s not without its challenges. To overcome them, organisations need a labelling solution that uses automation and integration to remove manual effort and reduce risk. Crucially, they need to apply the same level of automation around QP processes. Although the precise timing of the application of Regulation 536/2014 remains uncertain, a new era for clinical trials supply compliance in the EU is almost here. The smartest organisations are those that have recognised it takes time to roll out a new system and are partnering early with labelling solution experts to prepare for the change.

improve inventory turnover. In both models, labels are printed using the latest data – dosage and period of use dates – close to the time products are actually required. This also reduces the need to update inner or outer packaging, providing further flexibility to respond to future trial design changes or regulatory fluctuation. JIT and On Demand offer real potential for cost savings and efficiency gains.

It is important to be prepared during times of uncertainty. The strategy of waiting to analyse what competitors or partners do is risky as it takes time to integrate a new system. To adjust in time, it might just pay to think Just in Time.

JIT requires a labelling solution that can pull in data in real time and configure it into an approved format to be printed, validated and applied at speed. The best label management solutions leverage integration and automation, ensuring clinical supply teams aren’t required to calculate expiry dates or re-enter data that’s already in the system. Automation and integration are crucial for JIT; since expiry dates will change with greater frequency, teams cannot afford to rely on manual processes to change and validate data. Making the move to JIT may naturally increase a company’s QP requirements. With QPs potentially required to manage and sign off multiple runs – rather than large single batches – organisations will need to redesign and automate their QP processes accordingly. Once again, good labelling software can make a huge difference but it is not all you need. The smartest solutions include ‘vision inspection’, which automates the inspection of labels and provides reports (and audit trails) to help QPs validate the process. Next Steps Change is coming. As pharma awaits the dawn of new regulations, organisations must evaluate their existing processes to identify the best solution. The considerations will vary according to individual company needs; how often do you anticipate the period of use changing throughout your trial? Using your current processes, how much will it cost to make those changes and what’s the associated wastage? What impact will the new regulations have on your QP requirements? Does your planned solution support that QP effort and do enough to mitigate risk?

Gordon Alexander Gordon Alexander, Enterprise Pre-sales Engineering, PRISYM ID is involved in understanding customer needs and industry challenges to drive solutions to improve efficiency, minimise risk, address regulatory requirements and provide new approaches to business systems and processes. Gordon has 20 years of technical software experience with roles as industry consultant, business analyst, and pre-sales engineering.

Simon Jones Simon Jones, VP Global Products, PRISYM ID has 20 years of experience in delivering product strategies and product positioning which address market opportunities effectively. He is a subject expert in clinical trials labelling, researching this market, discussing the industry challenges with the PRISYM ID customers and remaining up to date on market trends, regulatory changes and technology alternatives.

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EU Clinical Trials Regulation and Protection of Personal Data According to Regulation (EU) 2016/679 of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (also known as General Data Protection Regulation or GDPR), personal data concerning health should include all data pertaining to the health status of a data subject which reveal information relating to the past, current or future physical or mental health status of the data subject. The latter includes information derived from the testing or examination of a body part or bodily substance, including from genetic data and biological samples; and any information on, for example, a disease, disability, disease risk, medical history, clinical treatment or the physiological or biomedical state of the data subject independent of its source, for example from a physician or other health professional, a hospital, a medical device or an in vitro diagnostic test. The GDPR also clearly states that the processing of personal data for scientific purposes should also comply with other relevant legislation, such as on clinical trials (Recital 157 GDPR), and that for the purpose of consenting to the participation in scientific research activities in clinical trials, the relevant provisions of Regulation (EU) No 536/2014 of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (i.e. the Clinical Trials Regulation or CTR) should apply. Conversely, the Clinical Trials Regulation which foresees the setting up and maintenance of both a EU portal (Article 80 CTR) and an EU database (Article 81 CTR) – the first of which is to function as a single entry point for the submission of all data and information relating to clinical trials and the second one as a single data and information repository – dictates that no personal data of data subjects participating in a clinical trial should be recorded in the EU database (Recital 67 CTR). The idea behind that is that all clinical trial information shall be recorded, processed, handled, and stored by the sponsor or investigator, as applicable, in such a way that it can be accurately reported, interpreted and verified. Nonetheless, the EU legislator is aware of the need and commits to protect the confidentiality of records and of personal data of the subjects involved in clinical trials, in accordance with the applicable law on personal data. For this purpose, the CTR requires appropriate technical and organisational measures to be implemented to protect information and personal data processed against unauthorised or unlawful access, disclosure, dissemination, alteration, or destruction or accidental loss, in particular where the processing involves the transmission over a network (Article 56 CTR). 20 Journal for Clinical Studies

In particular, the clinical trial protocol, authorised under the CTR, shall define the purposes and conditions for which the data of clinical trial subjects will be processed, and data subjects involved in the trial shall be properly informed on the processing of his/her personal data. In this regard, it is mandatory to include in every clinical trial protocol a description of measures that will be implemented to ensure confidentiality of records and personal data of subjects. In any case, as far as protection of personal data involved in clinical trials is concerned, one of the final provisions of the CTR (Article 93 CTR) establishes that processing of personal data pursuant by the CTR, carried out either in the EU Member States or carried out by the European Commission or the European Medicines Agency, is subject to compliance with the EU rules governing personal data, making explicit reference to EU Directive 95/46/EC and Regulation EC 45/2001, subsequently respectively repealed by the GDPR and by Regulation 2018/1725 on the protection of natural persons with regard to the processing of personal data by the Union institutions, bodies, offices and agencies, and on the free movement of such data. It follows that both the CTR and GDPR provisions apply simultaneously. In order to facilitate the correct interpretation of the relevant provisions quoted above and to ensure the proper interaction of the different rules at stake, on 10 April 2019 the European Commission published a Questions & Answers document (the Q&A) on the interplay between the GDPR, which entered into force on 25 May 2018, and the CTR, which after several postponements is currently expected to be applicable as of late 2020. The document consists of eleven questions and answers addressing respectively: (1) the general obligations set by the CTR with regard to personal data; (2) the identification of the subject responsible for determining the correct legal basis for personal data processing in the context of a clinical trial; (3) the legal basis for processing of personal data of clinical trial subjects in the context of a clinical trial (primary use); (4) the difference between informed consent within the meaning of the CTR and consent within the meaning of the GDPR; (5) the GDPR requirements concerning information that should be given to subjects participating in a clinical trial; (6) the legal consequences of withdrawal of the consent for participation in the clinical trial; (7) the use of personal data outside the protocol of the clinical trial (secondary use) within the scope of the GDPR; (8) the processing of personal data in the context of emergency clinical trials; (9) the applicability of EU data protection rules to sponsors established outside the EU; (10) data transfer outside the EU and, eventually (11) transitional measures with regard to clinical trials approved under Directive 2001/20/ EC, pending the applicability of the CTR. Volume 11 Issue 5

Regulatory Focusing on some of the main personal data protection challenges that sponsors and clinic-institutions of the investigators will have to face when conducting a clinical trial and relying on the guidance provided by the European Commission and by national Data Protection Authorities (DPAs), the following has to be noted. As a starting point, one should emphasise that the responsibility to determine the legal basis for processing of personal data lies with the data controller, i.e. with the natural or legal person determining the purposes and means of the processing of personal data in the context of the concerned clinical trial. And in addition, it is crucial to define the respective role of the sponsor(s) and the clinical trial centre(s) to which investigator(s) belong, and also to determine who should be considered the data processor, i.e. the natural or legal person who processes the data on behalf of the controller. Looking at the sponsor’s role, as mentioned in the guidelines issued by the Italian DPA (‘Garante per la protezione dei dati personali’) in 2008, it should be recalled that, prior to starting the trial, the sponsor selects the candidate centres by assessing the respective eligibility and interests; it subsequently draws up the trial protocol and provides the necessary guidance to the centres with regard to data processing – including retention and security mechanisms – along with instructions related to use of the IT systems deployed, which in some cases are made available to the individual centres. The sponsor verifies compliance by the centres with both the protocol and the respective internal procedures, via own collaborators; draws up the documents to be used for providing notice to the patients and obtaining their consent as also related to processing of their personal data; and finally, the sponsor notifies the centres that it is no longer necessary for them to keep the trial-related documents. On the other hand, considering the activities vested with the trial centre, as it has also correctly been noted by the Italian DPA in the context of the same guidelines, the individual trial centre is not under the sponsor´s control and it carries out the trial autonomously – albeit in compliance with the applicable protocol, the standard operational procedures, and the sponsor´s guidelines. In addition, it is up to the trial centre to provide the information notices to patients and obtains their consent, as also related to processing of the data concerning them; being also responsible for the safekeeping of the relevant documents. In the light of the above it can be concluded that both the sponsor and the trial centre should be regarded as either separate data controllers or joint data controllers. Another important distinction to be made as far as the legitimate use of personal data of subjects involved in clinical trials is concerned relates to the difference between primary and secondary use of data collected in the context of a clinical trial. Whilst primary use entails all processing operations related to a specific clinical trial protocol during its whole lifecycle, from the starting of the trial to deletion at the end of the archiving period, secondary use implies use of personal data concerning subjects involved in the clinical trial outside the clinical trial protocol and for future scientific purposes. The chosen legal basis may or may not differ from the legal basis of the primary use. That is to say that, as clarified by the European Commission, if a sponsor and/or an investigator would like to use the personal data gathered for any other purposes than the one defined by the clinical trial protocol (e.g. medical data collected to conduct a clinical trial on breast cancer used to run a study aiming to identify new biomarkers, but which was not foreseen in the clinical trial protocol), the processing of the relevant data would require a valid legal ground that cannot be provided by the CTR but it would rather have to be sought under Article 6 of the GDPR. Namely, according to Article 6(1)(a) of the GDPR, the legal basis for the processing of personal data for secondary use will have to

be found in the consent of the data subject. Consent of the data subject means any freely given, specific, informed and unambiguous indication of the data subject’s wishes by which he or she, by a statement or by a clear affirmative action, signifies agreement to the processing of personal data relating to him or her. Nonetheless, it is again crucial to distinguish between the consent to process personal data pursuant to the GDPR and the informed consent to be enrolled in a trial required by the CTR. The informed consent under CTR is the fundamental condition under which a person can be included into a clinical trial, but it is not and it cannot be conceived as an instrument to ensure data processing compliance. This means that, in principle, scientific research projects can only include personal data on the basis of consent if they have a well-described purpose. Further data processing operations may also be necessary in order to fulfil a legal obligation placed upon the sponsor and/or the investigator. This is notably the case, for instance, for obligations relating to the performance of safety reporting under Articles 41 to 43 of the CTR, and obligations concerning the archiving of the clinical trial master file (25 years according to Article 58 CTR) and the medical files of subjects (which is to be determined by national law according to the same provision). The same applies to any disclosure of clinical trial data to the national competent authorities in the course of an inspection in accordance with relevant national rules (see Article 78 CTR). With regard to all the legal obligations listed above, the proper legal basis for the lawful data processing cannot be retrieved from the CTR but shall rather be identified under Article 9(2)(i) of the GDPR that, by way of derogation to Article 9(1), allows processing of special categories of data (i.e. sensitive data, such as those concerning health) when: “processing is necessary for reasons of public interest in the area of public health, such as [...] ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or member State law, which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy”. We are still in the early days of interaction between CTR and GDPR but we have already experienced many uncertainties in identifying the proper legal basis to ensure a lawful data processing of data collected with regard to the many and different activities carried out in the context of clinical trial operations. There are still many knots to be untied and additional interpretative support and guidance from regulatory and data protection authorities, both at national and European level, would be more than welcome and would definitely help in navigating this complex matter.

Vincenzo Salvatore Vincenzo Salvatore is counsel and leader of the Healthcare and Life Sciences Focus Team at BonelliErede. Full Professor of European Union Law, he joined BonelliErede in 2015, bringing his specific regulatory and compliance skills in terms of clinical trials, marketing authorisation procedures, pharmacovigilance, personal data protection, promotion and marketing of medical devices, inspections and enforcement. Vincenzo has gained significant experience in complex litigation representing public and private entities before the European Court of Justice based in Luxembourg, in EU law disputes. In addition, he was Head of the Legal Service at the European Medicines Agency from 2004 to 2012.

Journal for Clinical Studies 21


The Public’s Growing Appetite for Product Data Whatever international regulators’ demands might be, society’s expectations will ultimately dictate the need to prepare comprehensive, up-to-date product data that patients, clinicians and pharmacists can scrutinise on demand, says Frits Stulp of Iperion Life Sciences Consultancy. As momentum builds anew towards ISO IDMP compliance, life sciences companies could be forgiven for a lacklustre response, after a series of delays to its rollout. Most organisations have already jumped through so many regulatory hoops, bolstered teams and implemented IT systems and new processes, to meet each new set of guidelines and mandates that come along, seeing this as a condition of staying in the market and a necessary expense. They knew IDMP would be realised eventually, so the final preparations that lay ahead were always inevitable, but that doesn’t mean firms are embracing the latest implementation advice with enthusiasm. Yet there is another far more important factor at play here, and that is the public’s growing appetite for access to medicinal product data: not just the wider healthcare market, but consumers themselves. In the detail of specific regulatory mandates, it is easy to lose sight of why new measures are being introduced, but bringing the industry back to the original drivers for IDMP and other information-based regulations can help to reframe compliance initiatives with a more positive and strategically significant emphasis. After all, life sciences firms have hard-won reputations to protect – and being responsible for good patient outcomes, and upholding patients’ best interests, are high on their list of corporate pledges. This being the case, it is worth keeping patients, clinicians, pharmacists and the wider public front of mind when evaluating priorities and best next steps towards IDMP and other emerging international quality and safety standards.

Beyond Formats: Defining an Operating Model for Product Transparency Looking specifically at IDMP, which is now moving closer to becoming a reality, life sciences firms should now be looking to embrace evolving regulatory standards, to define a practical target operating model for managing their product data. The aim of this is to ensure that what is submitted to regulators is an accurate reflection of the current truth. While much of the advice around ISO IDMP preparations concerns how different categories of data must be categorised and formatted – the nitty-gritty of how to keep within the specific database parameters – the bigger picture surrounds how firms can get that data into the hands of those who need it – and quickly. This doesn’t just include the European Medicines Agency (EMA) and other international regulatory bodies, which before long will insist on accurate and complete data filings alongside traditional dossiers. It also includes the patients of medical products, and those prescribing or selling them. Patient-centricity Companies can become so caught up in their regulatory obligations that they lose sight of why compliance exists and is so important. Once product records are brought under control, and consolidated in a robust, credible and definitive living record (a single, up-todate version of the product truth), there are plenty of other keen consumers of that information besides the industry watchdogs. Certainly, in the digital age, it should not be taking months or years for the latest safety advice to filter through to patients, simply because patient information leaflets haven’t been updated. In future, we can expect to see QR codes (matrix barcodes, which when scanned open a relevant web page) being used as standard on medical products, as a means to providing links to the latest, revised instructions for use online. That is, access to complete, up-to-the-minute advice will be much more immediate and convenient than it is today. All of which comes back to the need for companies to have an accurate master data source, along with visibility of where this data is re-used and a way of managing interoperability between the central master and wherever information has been reproduced. Even keeping submitted regulatory dossiers and electronic data equivalents in sync will require appropriate controls, because information may continue to be updated after original documentation has been put together. A Call to Action It is undoubtedly unfortunate that the timelines around IDMP have been subject to delays over recent years, slowing down preparation of a definitive data truth about products that clinicians, pharmacies, patients and other stakeholders could benefit from today. But this should not be allowed to stymie all progress. For just a few hundred euros, any company today can buy the ISO IDMP specifications from their local standards organisation and begin working toward a target operating model for wider data exchange.

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It is worth remembering that 60 countries participated actively in proposing and setting these new ISO standards, and 160 countries have pledged to recognise and enforce them. That’s a strong endorsement to justify preparing and managing electronic product data in support of wider public access. Committing to this is an important step toward the democratisation of healthcare and medicine data, something respected industry players talked about a lot during the spring/early summer conference season. If society’s growing expectations are not enough of a driver for change (and they should be), consider this. A technological giant like Amazon may yet disrupt the life sciences industry, using as its leverage its superior grasp on information management to create new value around medicinal products for consumers. It is not beyond the bounds of credibility to imagine that if Amazon wanted to buy the intellectual property for a drug compound, along with the other operational elements to running a pharmaceutical business, it could establish a healthcare organisation with relative ease. In the life sciences industry, product information is vastly underestimated as a business asset, and if firms don’t want to leave themselves exposed to huge risk by failing to gain control of this, they must act now.

Frits Stulp Frits Stulp is the managing director of Iperion Life Sciences Consultancy. With over 20 years of experience in the life sciences industry, he has worked on multiple regulatory compliance projects, becoming an IDMP SME programme manager and adviser to several high-profile pharmaceutical companies, regulatory authorities and software suppliers. He is currently the project manager for the EU Substance Registration System (MEB/EMA); is an active member of the EMA ISO IDMP Task Force for Substances and Products; and is the IRISS Forum IDMP topic lead. He holds an MSc in pharmacochemistry from the Free University of Amsterdam. Frits recently spoke at AMPLEXOR’s 21st annual BE THE EXPERT industry forum in Provence, France, on how life sciences organisations can best prepare to deliver standardised data versions of their regulatory dossiers, which will ultimately form a public record of their product information – including the latest safety data. Email:

Journal for Clinical Studies 23

Market Report

North Africa; an Underestimated Region with Huge Potential for Clinical Trials North Africa is the region covering the northern part of the African continent, and can be defined as the area of Morocco, Algeria, Tunisia, Libya, Egypt and Sudan. Another definition limits it to the north western African region, which is Morocco, Algeria and Tunisia, known since the French colonisation as “Nord Afrique” and by the Arabs as “Maghreb region”. The most accepted definition includes the portion of the continent bordered by the Red Sea and Suez Canal to the east and the Atlantic shores of Morocco to the west. The countries encompassing this area are Egypt, Libya, Tunisia, Algeria and Morocco. The Sahara Desert cuts across the south of the region separating it from other Sub-Saharan countries of Africa. In addition to the five countries, several other territories are also considered to be part of the region; these include the Western Sahara, Canary, Pelagic islands and other Moroccan-claimed Spanish territories. The North African countries share a common cultural and linguistic identity which is unique to this region of the world. Berbers are the indigenous inhabitants of the Maghreb region, while Egyptians are native inhabitants of the eastern part (Egypt). Between A.D. 600s and 1000s, the region has known waves of Muslim conquest coming from the Middle East. Ever since, a process of Arabisation and Islamisation has begun, which now defines the cultural landscape of the region. The region is mainly Muslim with a Christian minority in Egypt, Tunisia, Algeria and Morocco and a Jewish minority in Tunisia and Morocco. This article will focus mainly on the three countries in the region which are the most active in clinical research. While we will start with a brief description of each country, its healthcare, and regulatory processes readily available to date, the article will then discuss the key points of the region as a strategic choice for clinical studies in various settings including rare diseases, the advantages and challenges that the region faces and its potential future. CPhI (Convention of Pharmaceutical Ingredients) reports that pharma sales have reached an impressive $32 billion across the Middle East and North Africa (MENA) pharma market, with North Africa accounting for $10.7 billion. Saudi Arabia remains the biggest pharma market in the region according to 2017 sales numbers at $7.5bn, with Egypt ($3.4bn) and the UAE ($3.17bn) following closely behind. However, overall the North Africa region is predicted to see the fastest growth rates in the next few years at 7.6% CAGR (compound annual growth rate). With a stabilised political situation and gentrifying populations, factors accounting for this leap include sizeable population growth, increased life expectancy, greater prevalence of lifestyle-related diseases such as diabetes, and a greater prioritisation of healthcare services among governments in the region. The Middle East and North Africa (MENA) region’s 24 Journal for Clinical Studies

pharmaceutical market is projected to reach a value of around USD 60 billion by 2025, according to Reporting from Trade Arabia. The most impressive growth is coming from the UAE, but North African giants Egypt and Algeria are also significant contributors.  Egypt, the region’s most populous nation, also boasts a pharma market on the up, growing at a CAGR of 17 per cent between 2011 and 2017 to reach a total market valuation of USD 2.9 billion in 2017. Despite a difficult economic and political situation between 2011 and 2014, stakeholders are once again recognising Egypt as a promising investment destination. First of all, its geographical location, with access to two seas; 18 airports; 65 seaports; proximity to the African market and easy access to the Gulf countries. Secondly, Egypt has many treaties with Arab countries, Latin America, Asia and especially Africa. The main one is COMESA, a treaty between Egypt and 19 East African countries that have 510 million inhabitants or potential consumers. Thirdly, its population: 98 million Egyptians. Egypt is also making moves towards implementing a universal healthcare system, and is upgrading its regulatory apparatus by establishing a new ‘Egyptian Drug Authority’. The healthcare sector in Algeria, Africa’s largest nation by landmass, has seen plenty of upheaval in recent years, including the economic fallout from the global oil price slump of 2014 and the imposition of import restrictions on pharmaceuticals and medical devices. Nevertheless, the USD 3.8 billion Algerian pharma market remains a high priority for multinational corporations investing in MENA (see Figure 1, Top 20 Pharmaceutical Companies in Algeria). Algeria is the second largest market on the African continent, but it is also a heavyweight when compared to other Middle Eastern markets. One of the characteristics that immediately stands out in Algeria is the sheer importance that the authorities place on securing access to healthcare for patients1.

Figure 1: Top 20 Pharmaceutical Companies in Algeria

Egypt Egypt lies in the heart of the Middle East and the ancient world, bringing both Africa and Asia together on its land. It is also considered Volume 11 Issue 5

Market Report the most populated country in the Middle East and the third in Africa, with more than 100 million people living in its land of 1 million m2 with more than 30% below the age of 15, though most of the population live around the River Nile and by the coasts, hence these areas, which consist of only around 5% of the land, are fairly densely populated and almost 95% of the population live on them. The capital, which is Cairo, is the largest Arabic capital, the second largest in Africa and number 17 globally population-wise. It has over 20 million people in its Metropolitan area (urban and suburbs). Egypt’s second largest city is Alexandria, with a population around 5 million people. The Egyptians are the largest ethnic group in Egypt, consisting of about 91% of the population. The formal language of the country is Arabic, the most spoken language is Egyptian Arabic, and foreign languages taught at schools are English, French, German and Italian2–5.

Politically the country has been stable for the past five years; after the post-revolution instability in 2011, economically the government started implementing a bold and transformational reform programme in 2014 and it was a bit of a bumpy road, especially after the flotation of the Egyptian pound in 2016. However, the country is now on the rise economically as the investment law updated to welcome foreign investments and all systems being digitalised and fastened6,7. The Healthcare System The healthcare system in Egypt consists of both public and private sectors; the public sector consists of the Ministry of Health and Populations (MOHP), which is the largest provider of health services in the country offering primary, preventive, and curative care in Egypt, with around 5000 health facilities and more than 80,000 beds in approximately 1048 inpatient facilities spread across the urban and rural areas of the country. There are also other ministries that operate their own medical facilities, including 14 medical schools affiliated with the major universities operated under the authority of the Ministry of Higher Education, including 36 university hospitals (secondary and tertiary care facilities, which are more advanced in terms of technology and medical expertise in comparison with MOHP facilities). Cairo University is considered the largest and most sophisticated hospital in this group. Additionally, there is the parastatal sector, which is under the government umbrella although a separate body by itself and includes the health insurance organisation with its hospitals, clinics covering those who work in any governmental or public sector and the General Organization of Teaching Hospitals and Institutes (18 hospitals and institutes). As for the private sector, it has 2024 inpatient facilities, with an approximate

total of 22,647 beds. This accounts for approximately 16% of the total inpatient bed capacity in Egypt. Hence for those who work in the private sector, they are either insured by their companies through private insurance companies, whether local or global, or they pay out of pocket for their care. Although the country is working hard to improve the quality of care given in the public hospitals as well as increasing the physicians’ pay, as it is considered very low2–8, most of the population would rather be seen by private doctors provided they can afford them as they consider the quality of care provided in government hospital to be of lower quality.

Conducting Clinical Trials in Egypt: Regulatory Processes – the Past, the Present and the Future Egypt is currently on the verge of issuing the first law regulating the conduct of clinical trials in the country. This programme has been given special attention by the president “Abd El-Fattah -” to ensure the inclusion of all parties in formulating the law, and ensuring its alignment with the global and regional regulations addressing all good clinical practice pillars are included, without complicating the process. The clinical trials community, including physicians, regulators, sponsors and clinical research organisations in Egypt, all feel very optimistic about the law and are waiting for its approval and issuance, which is expected before the end of 2019 as stated by the minister of Health and Population9,10. At this time, the last updated guidelines for conducting clinical trials in Egypt were issued in October 2016 by the MOHP; the same year, the MOHP also issued a guideline for licensing clinical research centres in Egypt, and research ethics committees (RECs). Up to the issuance of this guideline, all interventional clinical trials could only be conducted in governmental institutions, while observational trials could be conducted anywhere, including private clinics. Currently it is not mandatory to perform clinical trials in licensed clinical research centres as long as they are governmental; however, in the future only MOHP-approved centres will be allowed to conduct clinical trials11–13. The approval process is sequential: local ethics committees’ approvals for all sites must be obtained before submission to the National Research Ethics Committee at the Ministry of Health. However, if the institution does not have an ethics committee and falls under the Ministry of Health authority, submission to the National Research Ethics Committee at the Ministry of Health can be done directly11. Similarly to interventional studies, observational studies, submission and approval of the Ministry of Health is needed prior to initiation of the study11. Currently, interventional studies requiring exportation of biological samples to a central laboratory outside of the country must obtain the approval of the National Security Agency for biological sample exportations. It must be noted that in the case of a study approved Journal for Clinical Studies 25

Market Report by the REC and MOH but rejected by the National Security Agency, the approval letter granted will be issued with a statement that biological samples cannot leave the country and must be analysed locally, in Egypt11. For the importation of investigational medicinal product, an import licence has to be applied for and obtained from the Central Administration of Pharmaceutical Affairs after the Ministry of Health’s approval. This approval must be obtained for each investigational medicinal product shipment11. Algeria With its large area and wide sea coast, Algeria is the largest North African country, bordering the Mediterranean Sea between Morocco and Tunisia, giving it a very close relationship with both countries, but also with Europe, which is only a few hours’ flight away. Similarly to all the Maghreb countries, Algeria's population is mainly Arab-Berber ethnically, while indigenous Berbers as well as Phoenicians, Romans, Byzantines, Greeks, Arabs, Turks, various sub-Saharan Africans and French have contributed to the history of Algeria. Descendants of Andalusian refugees are also present in the population of Algiers and other cities. Healthcare in Algeria Since the 1970s, the Algerian authorities have made huge progresses in the country’s healthcare system. They have introduced the national free healthcare system, covering all medication, hospitalisations and exams in public hospitals. This remains the case to date in 2019. The country has quickly decided to emphasise the prevention of diseases by initiating several immunisation programmes and opening many health centres across the country, resulting in very positive outcomes such as the increase in life expectancy, decrease of infant mortality, and considerable decline of malaria and poliomyelitis, both at that period formerly endemic14,15. Today, Algeria is officially malariafree. Algeria continues to invest in healthcare, counting 586 public institutions, including 16 university hospitals (CHU & EHU), 83 specialised institutions (EHS), 207 public health institutions (EPH), and 273 public institutions of health of proximity (EPSP), covering the four corners of the country. These facilities are overall well equipped with major technologies and the latest equipment for ICU departments, imaging, radiotherapies, etc.16. In 2016 the life expectancy was 75 years for men and 77 for women. The life expectancy rate has increased from 52.6 in 1960 to 72.7 in 2016. Neonatal mortality rate has decreased from 70.7 deaths per 1000 live births in 1969 to 14.9 deaths per 1000 live births in 201717. Conducting Clinical Trials in Algeria: Regulatory Processes – the Past, the Present and the Future The first regulatory texts related to clinical research were developed in 1990, but were not published officially until 1995, with the Order of October 22, 1995, the first order setting the rules of Good Clinical Practices in Algeria. Then followed the creation of a committee by Order No. 67 of 6 December, 1998 establishing a Clinical Trials Unit, especially to review clinical research dossiers15. The field was not well explored until 2006, after the publication of the decrees no 387 and 388 of July 31, 2006 that sets the framework for the conduct of clinical trials, very close to international regulation as ICH, which has framed all of clinical studies conducted in Algeria to date. Moreover, the MOH is also working on the ethical aspect, highlighting the importance of the active ethics committees in the ethical assessment of submitted protocols. 26 Journal for Clinical Studies

The Ministry of Health, after publication of the new health law no 18 of July 29, 2018, set up a new committee dedicated to the review of clinical research projects in Algeria. Composed of highly qualified and motivated members, their primary goal is to promote and expand research in Algeria while opening up to research and development conducted in other countries. Tunisia Tunisia is the smallest country in North Africa, bordered by Algeria to the west, Libya in the southeast and the Mediterranean Sea to the north and east. The country is divided into 24 governorates with its capital Tunis. The Tunisian population is around 11,400,000 people (2016), with a literacy rate reaching 81.1 % (2015)18,19. Berbers are the native inhabitants of the country, but major historical settlements from Phoenicians to the French protectorate had an impact on the genetic diversity of the current population. The latter drives its origins from Phoenicians, Romans, Africans, Arab, Turks and Europeans. The official language in Tunisia is Standard Arabic but the Tunisian Arabic dialect (Darija) is used for everyday communications. In addition to the Arabic language, the majority of the population speak French, which is taught as a second language from primary school and used in all institutions. English is now introduced at the elementary school as the second foreign language. Healthcare Coverage Compared to the country’s size, the healthcare coverage is relatively important. Based on the statistics department of the Ministry of Health, there are 27 public institutions, some of which specialise in oncology, ophthalmology, neurology, paediatrics etc., 32 regional hospitals, 108 district hospitals, 91 private clinics, 152 hemodialysis centres and 445 biology laboratories. Additionally, Tunisia has specialised centres such as the Central Unit of Blood Transfusion and the Blood Bank, the National Bone Morrow Transplant Center and the Center for Magnetic Resonance Imaging17. Following the initiative of some key opinion leaders, specialist departments dedicated to the treatment of rare diseases have been created, such as the Department of Pediatrics and Metabolic Hereditary Diseases, the Center of Hemophiliacs, a Department of Nephrology for Pediatrics, and a Center of Alzheimer Disease and Multiple Sclerosis Center. Over the last 50 years, Tunisia’s progresses in increasing life expectancy and decreasing neonatal mortalities rates are remarkable. In 2016, the life expectancy was 74 years for men and 78 for women which is almost the same as Algeria (75 for men and 77 for women) and Egypt (68 for men and 73 for women). The life expectancy rate has increased from 47.8 in 1967 to 75.7 in 2016. Neonatal mortality rate has decreased from 50.2 deaths per 1000 live births in 1968 to 7.5 deaths per 1000 live births in 201720. Figure 2 shows the progress Tunisia made to reduce the gap between its life expectancy and neonatal mortality rates as a developing country, and those of the western developed countries. In its report published on October 2016, the Tunisian Association for the Defense of the Right to Health reported that 82% of the deaths in Tunisia are caused by non-communicable diseases and that Tunisia has about 2 million hypertensives, 1 million diabetics, 15,000 new cases of cancer a year, 10,000 cases of chronic renal failure. Ischemic heart diseases are the leading causes of death in Tunisia21,22. Volume 11 Issue 5

Market Report

Figure 2. Life expectancy and neonatal mortality rates in Tunisia and the western world.

Conducting Clinical Trials in Tunisia: Regulatory Processes – the Past, the Present and the Future The regulations laying down the modalities for the medical or scientific experimentation of medicinal products intended for human medicine have been established in Tunisia since 1990. Thereafter, regulatory laws and procedures for interventional clinical trials continued to evolve. On 13 January 2015, the Ministry of Health published a new law on the creation of the Committees of Protection of Persons (CPP) which replaced the local ethics committees. Before this law, submission of the clinical trial protocol had to be done to all the institutional ethics committees related to every site participating in the trial. The submission to the Ministry of Health (MOH) being feasible only after all committees granted approval. To reduce timelines and efforts, three CPPs have replaced the ECs and submission will be performed to only one CPP. A single CPP authorisation allows to conduct the trial over the full Tunisian territory and it is valid for all the sites participating in the trial. On 1 June 2015, the updated specifications detailing the modalities for trials of medicinal products and the responsibilities of different parties involved in the trial has been published23. In addition to the Ministry of Health, other public or governmental bodies are involved in the regulatory process, namely the Regional Committees of Protection of Persons from whom the trial should be approved before submission to the Department of Pharmacology and Medicine (MOH’s responsible department of clinical trials), the National Center of Pharmacovigilance, and the National Institute of Protection of Persons, which is an organization attached to the Ministry of Justice that guarantees the protection of personal data of any citizen or resident on the Tunisian territory. In Tunisia, all studies can be conducted from Phase I to IV, including PK and genetic studies. Legal barriers to enrol into clinical trials do exist in Tunisia and texts prohibit experimentations on some categories, mainly pregnant women and patients suffering from mental diseases. Regarding experimentation on children, special derogation should be addressed with the clinical trial application and if there is a proven substantial benefit, the approval is guaranteed. The Ministry of Health is currently working on new guidelines for clinical trials involving all the responsible parties and regulatory authorities to improve the regulatory procedures and approval timelines. After the brief overview provided above for these three countries, this article will summarise and finish with why North Africa is an important region that can no longer be ignored for the conduct of clinical trials. We will discuss some of the pros and cons for the region.

North Africa: A Strategic Choice for Rare Patients Consanguineous marriages are widely practiced in several global populations, with some of the highest rates observed in the Arab World, including North Africa. Research among Arabs and worldwide has indicated that consanguinity could have an effect on some reproductive health parameters such as postnatal mortality and rates of congenital malformations. The main impact of consanguinity, however, is an increase in the rate of homozygotes for autosomal recessive genetic disorders. Worldwide, known dominant disorders are more numerous than known recessive disorders. However, data on genetic disorders in Arab populations as extracted from the Catalogue of Transmission Genetics in Arabs (CTGA) database indicate a relative abundance of recessive disorders in the region that is clearly associated with the practice of consanguinity. Consanguineous marriage refers to unions contracted between biologically-related individuals. In clinical genetics, a consanguineous marriage means union between couples who are related as second cousins or closer2,3. Among Arabs, this would include double first cousins, first cousins, first cousins once removed, and second cousins. Generally, the highest rates of marriages to close relatives are consistently reported in the more traditional rural areas and among the poorest and least educated in society24. Reports from some Arab countries have shown that consanguinity rates are lower in urban, compared to rural, settings. Urban to rural first cousin rates in Algeria were 10% and 15%25 and in Egypt, 8.3% and 17.2%26, respectively. Social, religious, cultural, political and economic factors still play roles in favouring consanguineous marriages among the new generations just as strongly as they did among the older generations, particularly in rural areas. However, the frequency of consanguineous marriage is decreasing; amongst these factors are the increasing higher female education levels, the declining fertility resulting in lower numbers of suitable relatives to marry, more mobility from rural to urban settings, and the improving economic status of families. Trends of lower consanguinity rates among educated women, but not educated men, were noticed in Tunisia27. Within the region, and particularly the rural parts, due to lack of diagnostic resources especially for genetic diseases, most of the diseases are diagnosed clinically. Genetic confirmation may take a while or may never be achieved, and patients may be treated based on the clinical features of their disease28. Similarly to global trends, an increased awareness and focus on rare disorders is seen within the region. Egypt is part of the Global Rare Diseases Day Community with multiple events throughout the year and the country with a lot of patient support groups and medical communities. As well as medical units for orphan and rare diseases including blood disease such as thalassemia (around 9–10.2% of the general Egyptian population are carriers29), renal diseases, genetic, neuromuscular and many others especially looking to support children27. In Algeria, the last two years have seen the emergence of new associations and patient advocacy groups for rare diseases, the establishment of The Association and Algerian Alliance Against Rare diseases. These associations take part in organising the National Day for Rare Diseases on the 28 February to celebrate the International Rare Diseases Day. This event sees the attendance of investigators and doctors presenting and discussing cases of rare and ultra-rare disorders identified within their centres and how they are managed locally. Patients and their families are usually in attendance and invited to share their concerns, with an additional stakeholder; local pharmaceutical companies that often sponsor these events. Journal for Clinical Studies 27

Market Report As an example, Tunisia consanguinity rates range from 20.1% to 39.33%, which leads to high frequency of rare diseases29. More than 400 genetic disorders were assessed in Tunisia and over 60% of them are autosomal recessive, 23% are autosomal dominant disorders and 5.4% are X-linked and founder mutations have been identified for at least 73 disorder29, leading to a geographic distribution map of Tunisian specific founder mutations published in 2012 and based on a systematic review study of all available data of scientific literature29. Haemoglobinopathies are frequent in Tunisia and many disorders have been reported, such as ß-thalassemia with a frequency rate about 2.21% and sickle cell disease with an average frequency of 1.9%30. G6PD is reported as the most prevalent enzyme deficiency with an incidence rate of 4%30. Fanconi anemia occurs also at high frequency and a Fanconi Anemia registry TFAR has been created in 2009. A special Department for Metabolic Hereditary Disorders was instituted in 1987 at “La Rabta Hospital” in Tunis, the capital of the country. The department reports a high frequency of metabolic disorders such as primary hyperoxaluria type 1 (PH1), Gaucher disease, maple syrup urine disease (MSUD) and mucopolysaccharidoses. Hereditary rare neurological disorders are also frequent in Tunisia and many studies reported families with Freidrich ataxia, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, Charcot-MarieTooth disease, etc.31–36. Sadly, compared to other western countries, some of these diseases are not so rare in North African countries, as is the case for some haemolytic, neuromuscular and hereditary metabolic disorders36. These numbers are also confirmed by feasibility studies conducted in some of these pathologies, where the number of patients identified in these three countries ends up higher than in Europe and/or the rest of the world. Some of the doctors seeing these patients in paediatrics departments and focusing on specific rare disorders become by default reference centres. Such centres already exist in the region for tyrosinemia, Fabry disease, phenylketonuria and myasthenia syndromes etc., with some well known and established key opinion leaders. Oddly, the number of rare diseases clinical trials including North Africa remains very limited or non-existent locally. Various factors may affect this discrepancy: 1. Most of the biotechnology companies working in this field of disorders and developing new therapeutics are based in North America and have very limited knowledge of this part of the world, thus remain mainly in the North America region and Western Europe for the conduct of their studies. 2. The feeling that the region is unsafe, a subjective notion based on headlines on old news. Tunisia, Algeria and Egypt are stable countries with growing economies and thriving tourism, e.g. Tunisia. Although some unsafe touristic rural areas exist, they are not usually areas with clinical sites, as most of these are in the large cities which are very safe. 3. The limited number of large CROs established in the region. With the recent model focused on preferred large vendors, the inclusion of smaller, local or regional players is even more limited. Most of the CROs in these three countries are local small ones and very few global CROs have a footprint there. 4. The limited amount of real data readily available in these countries; very few patient registries are in place, leading unfortunately to a restricted amount of peerreviewed publications. 5. Finally, the underestimation of the market size, as these pathologies are usually under-diagnosed and underreported. Additional Assets for North Africa Diseases with high prevalence In 2017, the current leading causes of death are non-communicable 28 Journal for Clinical Studies

Figure 3. Egypt disease burden based on WHO data

diseases such as cardiovascular diseases, diabetes, chronic respiratory diseases and cancer in Egypt, Algeria and Tunisia37,38. The countries have also several specialised departments and institutions with internationally-awarded and qualified physicians interested in treating Alzheimer’s disease, multiple sclerosis, and other afflictions. Oncology studies are of special interest to the ministries of health in these countries with the availability of many qualified sites. Qualified and Motivated Staff Clinical trials often being the only path to access new innovative therapies for local patients, physicians, nurses and lab staff are all highly motivated to conduct and grow clinical research in their respective countries. Their interest is the same as any of the newer regions in the world conducting clinical research, including Eastern Europe and Asia. High Recruitment Potential Egypt and Algeria, with their respective large populations and extensive medical infrastructures, have access to a large potential patient pool no matter the indications, rare disorders, cancers and similarly to the western world, non-transmittable disorders and diseases associated with recent changes in lifestyle (diabetes, hypertension etc.). Tunisia also provides the advantage of an extensive history in the conduct of clinical trials and collaborations with international hospitals. For Algeria, Public Health Facilities offers 76533 beds to Algerian patients, and as the population has a high demand, the numbers tended to increase to reach 150,000 beds in 201939. Whether in paediatrics, neurology or oncology, the number of drug-naïve patients which can be recruited for clinical studies is very important and usually exceeds those of Europe and USA for similar pathologies investigated in clinical trials. Complex Protocols at Lower Cost The costs applied (direct and indirect) in the region remains much lower than those applied in Europe and the USA or even their neighbouring countries in the Middle East, reducing greatly the budgets allocated to clinical trial projects and the cost per patient. This is mainly due to currency differences and the lower cost of living which are taken into account when the MOHs review patient grants, as these must consider investigators’ overall salaries and cost of living within these countries. Volume 11 Issue 5

Market Report

Challenges of Conducting Clinical Trials in North Africa Despite the many advantages and assets stated above, the region continues to work on its limitations. One of the most important challenges is the lack of epidemiological data, especially prevalence and incidence of disorders. There are only a few patients’ registries for a few diseases and most of them are local registries either conducted recently by pharmaceutical companies for commercial purposes for the most part, or by doctors for their personal research and doctorates, and mainly those published as part of scientific research projects or in collaboration with international research centres.

suggested for clinical trials is private imaging centres and biology laboratories that can adequately support these tests and collaborate with local study teams.

Another big challenge is the limited or inadequate medical care and treatment locally available, particularly for rare and expensive courses of treatments, leading in some instances to absence of medicines. It is important to consider concomitant treatments required by a protocol and/or registration of a new medicine within the country, as these may not be readily available and/or approved locally and should be provided by the sponsor.

Conclusion North Africa is a unique region of the world whose inhabitants share a common cultural and linguistic identity. Since their independence, these countries have been working on improving their healthcare systems and regulatory environments in order to attract the pharmaceutical industry, and develop their own research and development, and independence when it comes to drug manufacturing and market access.

Additionally, managing study-specific procedures such as biology analyses and some imaging can be challenging within local public hospitals where patients are first seen, which is linked to the large workload within these centres. A strong alternative often

Finally, staff are usually available in the identified sites but may require additional training in good clinical practice, while some sites may have the patient pool researched but have limited clinical trials experience as the region is not part of the top tiers of countries selected at this time in clinical trials. However, their keen interest in participating makes up for their deficiencies and they have willingness to quickly fill the gaps and blanks in their knowledge.

Despite these recent changes and the presence of this large pharmaceutical community in the region, North Africa remains mainly a neglected region when it comes to clinical trials with a Journal for Clinical Studies 29

Market Report limited number of local CROs, even lesser international ones, and has had restricted participation in international studies as shown on Although the region may be nascent in the world of clinical research, it provides the same advantages as many of the preceding other regions: good medical infrastructure, keen investigators and a large pool of patients – all the necessary ingredients to be considered when planning global clinical trials for rare and/or any challenging indications. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8.

Patrick Burton, Pharma Boardroom 12 Mars 2019 Egypt Population clock MOHP, Egypt Service provision Assessment (ESPA) Survey, Overview of the health system in Egypt 2006 9. 10. html 11. 12. 13. 14. pdf 15. LA_REGLEMENTATION_DU_MEDICAMENT_EN_ALGERIE 16. 17. 18. 19. world data atlas: 20. Anwar, W.A., Khyatti, M. & Hemminki, K. (2014). Consanguinity and genetic diseases in North Africa and immigrants to Europe. European Journal of Public Health, 24 (Suppl. 1), 57–63. https://d eurpub/cku104 21. 22. Tunisian Association for the Defense of the Right to Health rapport: http:// 23. 24. Detlef Schwefel, MOHP, Health financing in Egypt. Lessons for Syria? 2006 25. 26. 27. 28. Shawky, R. & El-Awady, M. Consanguineous matings among Egyptian population, Egyptian Journal of Medical Human Genetics, Volume 12, Issue 2, November 2011, Pages 157-163 29. 30. Romdhane, L., Kefi, R., Azaiez, H., Ben Halim, N., Dellagi, K. & Abdelhak, S. (2012). Founder mutations in Tunisia: Implications for diagnosis in North Africa and Middle East. Orphanet Journal of Rare Diseases, 7, 52. https:// 31. Anwar, W.A., Khyatti, M. & Hemminki, K. (2014). Consanguinity and genetic diseases in North Africa and immigrants to Europe. European Journal of Public Health, 24(Suppl. 1), 57–63. https://d eurpub/cku104 32. Guellouz, N., Ben Mansour, I., Ouederni, M., Jabnoun, S., Kacem, S., Mokrani, C. & Khrouf, N. (2010). Neonatal screening of G6PD deficiency in 30 Journal for Clinical Studies

Tunisia. Archives de l’Institut Pasteur de Tunis, 87, 69 33. Ben Hamida, M. & Marrakchi, D. (1980). [Duchenne muscular dystrophy in Tunisia: 31 cases in 13 families with autosomal recessive inheritance]. Journal de Genetique Humaine, 28(1), 1–9. Article in French. 34. Ben Hamida, C., Doerflinger, N., Belal, S., Linder, C., Reutenauer, L., Dib, C. & Koenig, M. (1993). Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Natu 35. Hentati, A., Bejaoui, K., Pericak-Vance, M.A., Hentati, F., Speer, M.C., Hung, W.Y. & Siddique, T. (1994). Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nature Genetics, 7(3), 425–428. https:// 36. Barhoumi, C., Amouri, R., Ben Hamida, C., Ben Hamida, M., Machghoul, S., Gueddiche, M. & Hentati, F. (2001). Linkage of a new locus for autosomal recessive axonal form of Charcot-Marie-Tooth disease to chromosome 8q21.3. Neuromuscular Disorders, 11(1), 27–34. S0960-8966(00)00162-0 37. 38. World Health Organization (WHO), Egypt health profile ( gho/en/) 39. item/41188-algerie-90-000-lits-supplementaires-a-l-horizon-2019-arees. htmlTo vit, tant. Go hortus verei sente inate es Cupic re horit, nihilisse, se

Mariem Melliti Smaali Mariem Melliti Smaali, a Lead Clinical Research Associate, covering Tunisia for ARIANNE and based in Tunis. Mariem has a master’s degree in pathological genetics from the Medical School of Sousse (Tunisia). Prior to becoming a CRA, she had different toles including Study Investigator for a hemophiliac patient registry. Her therapeutic experience includes Hematology, Neurology, Pneumology and Oncology.

Marina Melek Marina Melek is a Senior Regional Clinical Research Associate at ARIANNE responsible for Egypt, Gulf and Levant and based in Cairo, Egypt. Marina has worked previously in different pharmaceutical companies including Sanofi and Novo Nordisk and managed different clinical trials in various therapeutic fields. She has a BSc in Pharmacy and Biotechnology from the German University in Cairo and holds a Project Management Certificate from the American University in Cairo.

Sabrina Mesbah Sabrina Mesbah, PharmD, is the Clinical Operations Manager at Arianne Clinical Research Algeria. In this role, Sabrina is responsible for all clinical operations activities in Algeria and neighboring countries. Soon after obtaining Pharmacy Doctorate and license degree in translation, she assumed the role of pharmacist assistant in charge of regulatory affairs and drugs registration, then integrated clinical research by multiplying experiences as CRA, Lead CRA and Project Manager. She has an extensive expertise in various therapeutic indications.

Volume 11 Issue 5

Corporate Profile Ramus Corporate Group

is a union between Ramus Medical and Medical Diagnostic Laboratory Ramus. Ramus Medical is a full service contract research organisation based in Sofia, Bulgaria. Medical Diagnostic Laboratory Ramus is the biggest private laboratory in Bulgaria. Since 2018, the new member in the group has been the Medical Centre Ramus. Since 2010, Ramus Medical has built a strong portfolio as the Ramus team has successfully completed more than 45 clinical trials. These include BE/BA studies and NIS on drugs from the following groups: antibiotics, corticosteroids, non-steroid anti-inflammatories and medical products with different formulations, as well as clinical investigations on medical devices. The medicinal products being investigated by Ramus Medical have MA granted in the EU. , fast, correc t! Safe


to Cito



The Ramus corporate group also includes the Medical Centre Ramus, which includes a Clinical Pharmacology unit for Phase I BA/ BE studies. Ramus Medical have an experienced in-house team with strong project management skills and a keen understanding of regulatory requirements in each jurisdiction, for both study execution and commercialisation.

These can include clinical data capture, data management and statistical analysis, as well as readability user testing, hazardous waste management, and logistics services. Ramus Medical is closely related to the Medical Diagnostic Laboratory Ramus Ltd, founded in 2001. The laboratory is the largest private clinical laboratory in Bulgaria, with 17 laboratories operating in big cities in Bulgaria. The laboratories are fully equipped and work with analysers, consumables and reagents of the highest quality. The lab participates regularly in all national external systems for quality control, as well as in many international ones. Over the years the laboratory has provided services such as safety, and a central laboratory for more than 350 clinical trials for Bulgarian, EU and US sponsors. The Bio-Analytical Department of Laboratory Ramus is the only one in Bulgaria with ISO/IEC 17025:2006 accreditation.   The CRO and laboratories have well-designed quality systems and procedures which are capable of meeting the relevant regulatory requirements. They are certified in compliance with the requirements of the International Standard for Quality Management System. Ramus Medical and Medical Diagnostic Laboratory Ramus are regularly audited by sponsors. Ramus Medical were audited by Navigant Consulting in October 2016, and inspected by the Bulgarian Drug Agency in November 2017.

We carry out clinical projects as a results-oriented team, monitoring the external situation to achieve our mission of complying with the comprehensive global and governmental regulatory processes. Ramus Medical is building partnerships with key opinion leaders, such as principal investigators and dedicated research teams with good reputations. PIs working for Ramus Medical have a valuable role in designing protocols, having a significant positive impact on timely ethical and governance approvals, answering medical questions, interacting with key investors to confirm commitment to the trial, benefiting patient recruitment and providing quality, scientifically meaningful data. The ability to meet recruitment targets is facilitated by having access to the actual patient pool available. As stakeholder in the whole value chain of the drug development process, Ramus Medical contributes to managing time, costs and performance to guarantee the achievement of project objectives within the desired parameters and quality level. Usually Ramus Medical carries out the entire study, utilising years of experience in clinical development and commercialisation – from planning and medical writing to the final report preparation. Depending on the requirements, the sponsor can also make use of individual modules of our services in clinical development, launching a product or managing a portfolio across the development and product life-cycle.

Medical Diagnostic Laboratory Ramus Ltd

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

Ramus Medical Ltd

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

Dimitar Mihaylov Marketing Director

Journal for Clinical Studies 31

Market Report

Collaboration is Essential for Successful Clinical Trial Outsourcing By 2020, close to three-quarters of clinical trials may be performed by professional contract research organisations (CROs). The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), a 2015 Swiss NGO of pharmaceutical companies among others, defined a CRO as a person or organisation contracted by the sponsor to perform one or more of its trial duties and functions. CROs have already proven successful for pharmaceutical companies carrying out clinical trials, but could freelance scientists add to their expertise as the clinical trial service market grows? Dublin-based Research and Markets predicts that the global clinical trial service market will surpass $64 billion by 2020, up from $38.4 billion at present. This represents a compound annual growth rate (CAGR) of nine per cent between 2015 and 2020. On top of this, there is also a general agreement that clinical trials have become increasingly complicated.

This wider skillset is appealing to pharmaceutical companies, which has led to more opportunity for scientists and science, technology, engineering and maths (STEM) specialists who are willing to step away from education and pursue a freelance career. Scientific organisations in particular see the advantage of using freelancers to fill critical project requirements, and scientists are adapting to the change in career that freelancing offers and many more are continuing to enter this line of work. Science is becoming increasingly interdisciplinary, with researchers often needing to borrow skills from other disciplines. Hiring freelancers makes this process much easier for pharmaceutical companies, as they are able to source individuals with the exact skills that they require. These freelancers can then collaborate with the laboratory’s own staff, cascading their knowledge and picking up new skills themselves.

The current global environment is also forcing drug companies to come up with better drugs that are developed at lower cost and, as a result, a new model of virtually integrated drug development has evolved.

Also, smaller companies rarely have access to generous funding, so may miss out on hiring specialists whose expertise they need only on a project-by-project basis. Opting to use the services of a freelance scientist gives these businesses access to overseas contract workers without the cost associated with hiring a permanent worker. A skilled freelancer can even perform some tasks, such as data analysis or report writing, remotely reducing the geographic limitations on accessing skills.

At present, the developed countries still dominate the global clinical trial market. Today, major CROs in the developed countries that have sufficiently large facilities, global capacity, networked investigators, patient databases and effective recruiting tools, are being more frequently approached by drug companies for partnership collaboration.

“The skills required in a laboratory can vary throughout the year,” explains Leah Shifra Price, a freelance biostatistician for Kolabtree. “For example, a clinical researcher might need the help of an expert statistician to verify the results of a clinical trial. In another project, a bioinformatician might reach out to a data analyst for help understanding DNA sequencing.

The global clinical trial service market is also split between the developed countries and the emerging markets. Among the emerging countries, Asia has become a prominent location for clinical trials.

“On other occasions, they may need help meeting various regulatory requirements when working on the development of a new drug or medical device. Consulting an experienced freelance specialist when putting together a proposal for FDA or MHRA approval can help improve the scientist’s chances of successfully bringing their product to market. Luckily, there are a number of PhDs, postdocs, researchers and experts in these fields that are available for freelance work.

This geographic spread poses specific recruitment challenges for CROs and pharmaceutical companies alike, as qualified staff need to be sourced from a wider geographical area than before. This challenge is added to by the variety of skillsets present among scientists. Businesses may find it difficult to find someone with the expertise they require, sometimes due to geographical barriers and budget constraints. In a niche field, there may be no one in the local area with the required skill set for the task at hand and if the project is short, the company will be unable to hire someone to fulfil the requirements. Collaborating with Freelancers in Clinical Trials Whereas a CRO is usually an independent company that offers an objective assessment of a new drug in the clinical setting, freelancers can enter the research process at pretty much any stage. Because these specialists partnering with many companies throughout their career, they will typically offer broad experience and an impressive skillset. 32 Journal for Clinical Studies

“One of the key assets that freelancers offer is that they are usually fully conversant with the standards required by Good Clinical Practice (GCP), Good Laboratory Practice (GLP), and Good Manufacturing Practice (GMP), because of their vast experience,” concluded Shifra Price. Good Clinical Practice Prospective freelancers should have a first degree or higher, or have relevant experience; for example, several years in a clinical setting. They should also be familiar with Good Clinical Practice (GCP), an international quality standard for conducting clinical trials by ICH, an international body that defines a set of standards, which governments can then draft into regulations for clinical trials involving human subjects. Volume 11 Issue 5

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Journal for Clinical Studies 33

Market Report

GCP enforces tight guidelines on ethical aspects of a clinical study. High standards are required in terms of comprehensive documentation for the clinical protocol, record keeping, training, and facilities, including computers and software. Quality assurance and inspections ensure that these standards are achieved. GCP aims to ensure that the studies are scientifically authentic and that the clinical properties of the investigational product are properly documented. It’s fair to say that these tight guidelines can pose a real challenge to the clinical research process, particularly if certain organisations are unclear about specific regulations. GCP guidelines include standards on how clinical trials should be conducted, define the roles and responsibilities of institutional review boards, clinical research investigators, clinical trial sponsors, and monitors. In the pharmaceutical industry, monitors are often called clinical research associates (CRAs). Even if compliance with these guidelines can slow down clinical trials, this is not a reason to abandon the research process. If you recruit a freelance specialist to consult with on your trials, 34 Journal for Clinical Studies

they can rise to this challenge and ensure that your research is fully compliant. Good Laboratory Practice Good Laboratory Practice (GLP) is a set of principles intended to assure the quality and integrity of non-clinical laboratory studies that are intended to support research or marketing permits for products regulated by government agencies. The term GLP is most commonly associated with the pharmaceutical industry and the required non-clinical animal testing that must be performed prior to approval of new drug products. However, GLP applies to many other nonpharmaceutical agents such as colour additives, food additives, food contamination limits, food packaging, and medical devices. This is a vital stage of the process; however, it can also be a challenge to collaborate with the various trial partners that are involved in the research. The actual regulations in the United States can be found in 21CFR58 and for the European Union via the Organization for Volume 11 Issue 5

Market Report Economic Co-operation and Development (OECD). However, too often the GLP regulations are applied when they should not be used, creating confusion, extra work, and additional costs. GLP is a quality management system, not a scientific management system. Or, in other words, GLP defines a set of quality standards for study conduct, data collection, and results reporting. GLP does not define scientific standards. Freelancers will not only be familiar with GLP and what it takes to ensure the integrity of your trials, but they can also offer the necessary insight to solve any collaboration issues. They may already be working with different trial partners, for example as part of universities and other research areas and will offer a fresh perspective that can help overcome this challenge to your research. Good Manufacturing Practice Good Manufacturing Practice (GMP) describes the minimum standard that a medicine manufacturer must meet in its production processes. GMP consists of the practices required in order to conform to the guidelines recommended by agencies that control the authorisation and licensing of the manufacture and sale of food and beverages, cosmetics, pharmaceutical products, dietary supplements, and medical devices. These guidelines provide minimum requirements that a manufacturer must meet to ensure that its products are consistently high in quality, from batch to batch, for their intended use. The rules that govern each industry may differ significantly; however, the main purpose of GMP is always to prevent harm from occurring to the end user. Additional tenets include ensuring the end product is free from contamination, that it is consistent in its manufacture, that its manufacture has been well documented, that personnel are well trained, and the product has been checked for quality more than just at the end phase. GMP is typically ensured through the effective use of a quality management system (QMS). The US Food and Drug Administration (FDA) regulates the quality of pharmaceuticals very carefully. The main regulatory standard for ensuring pharmaceutical quality is the Current Good Manufacturing Practice (CGMPs) regulation for human pharmaceuticals. Consumers expect that each batch of medicines they take will meet quality standards so that they will be safe and effective. Most people, however, are not aware of CGMPs, or how the FDA assures that drug manufacturing processes meet these basic objectives. The FDA has announced a number of regulatory actions taken against drug manufacturers based on the lack of CGMPs. Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. It is important to note that CGMPs are minimum requirements. Many pharmaceutical manufacturers are already implementing comprehensive, modern quality systems and risk management approaches that exceed these minimum standards. A consumer usually cannot detect through smell, touch, or sight, that a drug product is safe or if it will work. While CGMPs require testing, testing alone is not adequate to ensure quality. In most instances testing is done on a small sample of a batch (for example, a drug manufacturer may test 100 tablets from a batch

that contains 2 million tablets), so that most of the batch can be used for patients rather than destroyed by testing. Therefore, it is important that drugs are manufactured under conditions and practices required by the CGMP regulations to assure that quality is built into the design and manufacturing process at every step. Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully trained, and processes that are reliable and reproducible, are a few examples of how CGMP requirements help to assure the safety and efficacy of drug products. Managing Freelancers The benefits of hiring freelancers are clear, but there are a few things that pharmaceutical companies should bear in mind when following this business model. A freelancer may not always be available as per the suggested timeline. To avoid any delays caused by only having access to a handful of known freelancers, laboratory managers should build a pool of talent that can be accessed when needed. As long as laboratory managers have the means of reaching freelancers, the process of hiring them is often much quicker than hiring a full-time member of staff. The interview process is much more streamlined, often consisting of a quick call or meeting to ensure that they are suitable for the position. Freelancers don’t have notice periods, so are often available to start sooner. However, pharmaceutical companies need to be aware that, despite having extensive experience, freelancers still require training. If they’re working on-site, it’s important to familiarise them with the relevant safety procedures and working conditions. For example, if certain areas are hazardous and therefore out of bounds. There are many ways to keep in touch with freelancers when they aren’t on site, including Skype. When they are on-site, it’s important to help freelancers feel integrated into the team. Providing them with the relevant training is the first step to achieving this and placing them alongside permanent members of staff will also help them pick up good habits. With CROs expected to perform almost 72 per cent of clinical trials by 2020, more businesses are understanding the benefits of outsourcing research, including unifying clinical systems and streamlining trial processes. Meanwhile, companies are also turning to freelance scientists and STEM specialists because of their broad skillset and understanding of guidelines including GCP and GMP. It’s essential that companies collaborate with different trial partners, particularly when it comes to complying with GLP, and this is again something that freelancers can help with.

Ramya Sriram Ramya Sriram is a UK-based content marketer, with a keen interest in all things science and tech. She manages communications at Kolabtree, a London-based platform that helps businesses hire freelance scientists online. She has a decade of experience spanning academic publishing, advertising and digital content creation.

Journal for Clinical Studies 35


Alzheimer’s in Clinical Trials – Is There a Way Out of Ongoing Failures? Abstract The attempt to develop a causal treatment against the progression of Alzheimer’s disease is an unparalleled series of nearly two decades of failures in drug development, with hundreds of molecules being assessed and multiple billions of dollars burnt, while Alzheimer’s disease may be seen as the biggest still-to-address medical need. At least this series of failures also allowed much better insights into the disease pathology, study methodologies and – as a consequence – in the design of future development programmes for anti-Alzheimer medications. These insights, in combination with advances in all types of biomarkers (blood, imaging and digital), are to be used to end the series of failures with novel targets and molecules. Introduction No new drugs have been approved for the treatment of Alzheimer’s Disease (AD) in the past 15 years (Fig. 1) despite US National Institutes of Health (NIH) alone investing more than a billion dollars per year in dementia research [Richard Harris, 10 Years After Alzheimer's Report: Any Progress?, Forbes, 25 March 2019].

Even worse, AD drug development costs substantially exceed development costs in most other therapeutic areas. It is estimated that total costs of an AD drug development programme are at $5.6 billion [T.J. Scott, A.C. O'Connor, A.N. Link, T.J. Beaulieu. Economic analysis of opportunities to accelerate Alzheimer's disease research and development. Ann N Y Acad Sci, 1313 (2014), pp. 17–34]. Even though the expected return on any such investment would justify these enormous costs, only a few and financially highly potent pharmaceutical companies can afford such risks going forward. Not least due to a failure in AD drug development, Pfizer pulled out of neuroscience research in 2018. Most ongoing Phase III programmes are sponsored by multiple companies in a research consortium, minimising the individual company’s risk. Aside from these financial considerations, an estimated 50 million AD patients worldwide and their families urge researchers to push on. And the industry is taking on the challenge: A recent report on the status of the AD drug development pipeline identified 112 agents: 26 in Phase III studies, 75 in Phase II studies, and 23 in Phase I studies [J. Cummings, G. Lee, A. Ritter, K. Zhong. Alzheimer’s disease drug development pipeline: 2018. Alzheimers Dement (N Y) 2018;4:195-214]. And the industry is learning: Whereas most of the negative studies in recent years targeted brain A-beta, current studies are targeting a broader repertoire of mechanisms [J. Cummings et al., for the EU/US/ CTAD Task Force, J Prev Alz Dis 2019;3(6):157-163]. It thus is still too early to be nihilistic, but future drug development needs to change historic concepts to have a realistic chance for a causal treatment reaching the market, at least in the next decade. Also, the competent authorities are willing to change gears. The FDA published in 2018, “Early Alzheimer’s Disease: Developing Drugs for Treatment Guidance for Industry” in the attempt to facilitate future successes.

Figure 1: The last approved drug reaches back to 2003 – for a molecule known since many years before. Since then, a constant stream of assessed molecules led to failures until today, with a peak of 14 drugs failing in 2009, alone [modified from: PhRMA analysis of ADIS R&D insight database, 17 June 2015].

These numerous negative projects include a wide variety of mechanisms of action: • • • •

Inhibition of amyloid-beta aggregation and amyloid-beta (A-beta) antibodies Inhibition and modulation of gamma-secretase Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibition Inhibition of tau-pathology

The fact all these programmes did not reveal even a minimal effect on disease progression may create quite a pessimistic outlook. 36 Journal for Clinical Studies

Why Did Historic Programmes Fail? The first question to ask is: What could have caused the historic failures? Three major reasons can be made accountable: 1. The wrong patient population was observed, e.g., therapy started too late in the progression of the disease, when damage is irreparable, or effects are only happening in still-to-identify sub-populations, e.g. those with an ApoE4 allele. 2. The therapeutic effects were not large enough to reach statistical significance, either because of too-low doses or because the endpoints (ratings scales such as ADAS-Cog) were not sensitive enough to reflect a relevant effect. 3. A-beta is the wrong target, meaning the formation of A-beta does not drive the pathophysiology of AD but instead is only a result of underlying disease progression. Volume 11 Issue 5

Therapeutics Item 1 is still under investigation: Roche has a study ongoing in otherwise healthy people being genetically predisposed to Alzheimer’s, and Lilly runs a similar study in otherwise healthy elderly people who only yet showed a higher than normal level of amyloid plaques in brain PET scans. NIH is sponsoring two more such studies. These projects will be the final “defence” lines to justify the amyloid hypothesis. Reason 2 could be discussed from a statistics viewpoint, but drug effects too small to be detected in studies with several thousand patients – even if the assessment tools are not ideal – would hardly justify a year-long use in otherwise healthy people. Furthermore, the failed Phase III study with Merck’s verubecestat revealed the stunning result that people with prodromal AD who took the inhibitor scored worse on cognitive tests than those on placebo [verbal communication at the 11th Clinical Trials on Alzheimer’s Disease conference, held October 24–27 in Barcelona, Spain]. That means the outcome measures used are sufficiently sensitive to detect a clinically relevant change – in that case unfortunately in the wrong direction. Some further reasons for failure can be found in the pre-clinical stages of development. 1. Scientists still do not fully understand the underlying causes and mechanisms of the disease, particularly when trying to separate potential causes from effects of the disease. Major investments in basic CNS research such as The Human Brain Project (HBP), which is the largest scientific project ever funded by the European Union, employing some 500 scientists at more than 100 universities, teaching hospitals and research centres across Europe, may provide the currently missing insights in the next years. Until then, only more upfront investment in small but sufficiently long-lasting Phase Ib studies in the target population would help to de-risk the subsequent investment in large Phase II and III studies. 2. Poor methodology of animal studies and use of models that do not accurately reflect human pathogenesis. This is due to the fact that the human brain is the most complex structure we know in the universe – much more complicated than any animal brain. A further confounding factor may be that neutral or non-significant animal studies are less likely to be published. This would further flatten the learning curve. Attempts are made to use artificial intelligence and machine learning to simulate the human brain, replacing animal models [Magali Haas et al., on behalf of the Brain Health Modeling Initiative (BHMI), Big data to smart data in Alzheimer’s disease: Real-world examples of advanced modeling and simulation, Alzheimer’s & Dementia 12 (2016) 1022–1030], but these concepts are also years away from being useful. 3. The absence of validated non-invasive biomarkers of disease activity and progression. For A-beta, a number of such markers got developed in the recent past. The most recent advancement is the characterisation of the ratio of A-beta 42 and A-beta 40 in blood being 94% accurate in diagnosing brain amyloidosis [Megan Brooks, New Alzheimer's Blood Test 94% Accurate, Medscape Medical News, August 02, 2019]. This would make the early identification of people “at risk” for Alzheimer’s much easier and cheaper. Even though A-beta may actually be the wrong target, making use of new targets and modes of action is not a sufficient change to avoid ongoing failures.

What Are the “Lessons Learned”? Any coming project should also apply the below lesson learned from the past: A. Marker for early detection of drug effects: In case novel targets such as tau will get selected, these will also require novel imaging agents and biomarkers, a deeper understanding of tau biology and the dynamic interaction of tau and A-beta protein. In the past years, such markers were developed in parallel to ongoing clinical development programmes. When de-risking novel target developments, markers should get developed prior to entering large clinical trials. Markers are anyway a “must” based on the revised Research Criteria for AD [C.R. Jack et al., NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease, Alzheimers Dement. 2018, 14(4): 535–562]. The diagnosis of AD is confirmed for clinical research by the biomarkers amyloid (A), tau (T) plus neurodegeneration (N), observed in imaging techniques. In this ATN classification, the diagnosis is no longer based on the clinical consequences of the disease (i.e., symptoms/ signs), but it shifts the definition of AD in living people from a syndromal to a biological construct. This should also help with any future development programme. B. Even earlier start of therapy: This, however, not only requires a sufficiently cheap and easy to apply test to identify people “at risk” as described above, but also a drug which is cheap and easy to adhere to, justifying its use over many years before the disease shows its first symptoms. C. Less complex and more naturalistic outcomes. In the past decade, the complexity of AD studies has constantly increased. The clinical trials leading to the approval of the first AD treatment Tacrin [Farlow et al., JAMA (1992) 268(18) 25232529 / Davis et al., NEJM (1992) 327 (18) 1253-1259] recruited 20.3 patients and 31.6 patients respectively per site. That was made possible because these studies had no requirements for amyloid or tau-PET, no MRI, no CSF sampling, no PK sampling and no genotyping – all of which are more or less standard in today’s studies. The number of patients fulfilling all the complex selection criteria shrank by half (see Fig 2), with a subsequent consequence on the number of sites required. This leads to a vicious circle as detailed in Figure 3 [from: P. Schueler, M.W. Weiner and J.W. Ashford, Can IT Help with the Screening for Alzheimer’s Disease Trials? J Prev Alz Dis 2017;4(4):288–289].

Figure 2: The change in key study performance parameters in recent years, 2012 to 2017, compared to the years 2000 to 2005: The number of patients per site was cut nearly by half. As a consequence, the number of sites nearly tripled, also because the number of enrolled patients per study doubled.

D. Clinically highly relevant outcomes such as “death” or “requiring home care” would convince payers, but also lower the development costs because these endpoints are more easy and cheap to measure. These will, however, require long observational periods of five to ten years. As another alternative, digital technology may offer alternative solutions. Journal for Clinical Studies 37


modes of action – often only defined years after the drug got approved. The better we started to understand the brain, the more we attempted to develop highly specific therapies. It may well be we do not yet understand our brain sufficiently well to successfully develop targeted anti-AD drugs.

Figure 3: The higher study complexity leads to the need for more sites, which increases the variability of rating-scale-dependent endpoint data. Consequently, the increased data variability requires a larger sample size.

Smartphones are widely available and have an array of inbuilt technology including accelerometers, gyroscopes, magnetometers, global positioning systems (GPSs), proximity sensors, ambient light sensors, microphones, cameras, and touch-screen sensors. These sensors facilitate the capture of a multitude of data, including activity, gait cadence, falls, speech, and location. Such assessments have the potential to make results more reliable and can offer a means of continuous longitudinal monitoring. Even changes in language and voice are being evaluated as predicators of disease progression [M. McCarthy and P. Schueler, Can Digital Technology Advance the Development of Treatments for Alzheimer’s Disease? J Prev Alz Dis, Published online 2019]. E. Last but not least: Less targeted treatments or combination therapies. In other complex and not yet fully understood CNS disease, such as depression and schizophrenia, the initial and still most effective treatments were “dirty” drugs with multiple 38 Journal for Clinical Studies

Conclusion Even though we still lack a profound understanding of our brain’s function, how we create “memory” and what pathologic mechanisms may disrupt these pathways in Alzheimer’s disease, we have learned a lot about the disease progression and the ability to measure that progression with biomarkers. We also learned that Alzheimer’s patients are not a homogenous population. Together with a refined development methodology, it should help us to find new therapies. Unfortunately, in case the still ongoing Phase III studies in presymptomatic populations also fail, it will take another decade for such alternative therapies to reach the first patients as an approved treatment.

Peter Schueler Peter Schueler, MD, is board certified in Neurology and in Pharmaceutical Medicine (Swiss Medical Association). After his medical education he worked in the pharmaceutical industry and since 2000 in the CRO world, being with ICON since 2007. He issued over 40 publications as first author on drug development and drug safety. In 2015 his book “Re-engineering clinical trials” was published by Elsevier. He continues to lecture in Pharmaceutical Medicine at the University of Duisburg-Essen and at the European Center Pharmaceutical Medicine (ECPM), Basel, Switzerland.

Volume 11 Issue 5

19-21 November 2019 CCIB Barcelona, Spain


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Journal for Clinical Studies 39


Giving Diseases a Gut Punch: Microbiome Applications in Clinical Trials The community of microbiota (microorganisms such as bacteria, yeast, fungi, and viruses) in our body (the microbiome) is an important part of human health. It affects immunity, organ system interactions, and the metabolism of nutrients and substances foreign to the body, such as drugs. In addition to a general understanding of how the environment and our diet affect the microbiome, we now also know that an imbalance in our body’s microbiota (dysbiosis) influences our health – from infection susceptibility to inflammation. Although individual differences in the composition of the microbiome and its dynamic nature complicate our understanding of the microbiome, it is these very features that provide an important and relatively unexplored avenue of research that aims at improving personalised medicine and drug development. Clinical researchers are now looking into how altering the microbiome of patients with certain diseases may offer new treatment options beyond traditional therapies or prevent the disease entirely, and the number of studies incorporating microbiome components in clinical trials has increased.1 A deeper knowledge of the biology of the microbiome may ultimately help us better understand the mechanisms underlying nutrition and disease and use the microbiome effectively in clinical trials in a way that will impact health outcomes overall. Drug, Nutrition, and Systems Interactions The study of the microbiome in pharmaceutical drug interactions is known as pharmacomicrobiomics, covering efficacy, toxicity, pharmacokinetics, and pharmacodynamics.2 Within this relatively new field, the concepts of pharmacometabolomics and pharmacometabonics describe the application of metabolomic technology and the analysis of metabolite interactions with drugs, respectively. A lot of research has focused on microbiome-gene-drug interactions, revealing important information about the impact of the gut microbiome on drug response. Armed with the knowledge that gut microbiota can be altered through diet and pharmaceuticals, this science can help develop better therapeutics. One of the key areas of interest in microbiome research is the gut-brain axis, or the cross-talk that occurs between an individual’s microbiome and the brain.3 This example of organ system interaction is implicated in gut disorders that are often co-indicated with major depressive disorders. Neurochemicals that mediate behaviour, such as GABA and norepinephrine, are created by gut microbiota from nutrient intake and play a role in central nervous system health. For example, high anxiety and depression levels were linked to gut permeability (referred to as “leaky gut”), a condition where the small intestine walls (or gut barrier) become damaged and permeable, resulting in inflammation. Understanding organ systems interactions such as these can inform therapy development for probiotics and antipsychotic medications. In addition to the microbiome’s interactions with drugs, nutrition is an important factor to consider because it can interact 40 Journal for Clinical Studies

with the absorption or metabolism of a drug, impacting clinical research results.4 These include macromolecule interactions, such as the link between gut dysbiosis, high-fat diets, and obesity. Smaller compounds such as flavonoids and polyphenols can upregulate genes involved in preserving the gut barrier and prevent “leaky gut” issues.5 Two examples of nutritionmicrobiome-drug interactions are iron and grapefruit. Vitamins and minerals such as iron are an important dietary need, and supplementation through nutraceutical products (i.e., fortified food products or supplements) is often recommended to certain populations and individuals. However, in some populations, iron supplementation has been linked to a microbial imbalance in the gut and has shown interactions with antibiotics.6 As an example of a direct drug-food interaction, grapefruit juice is a common contraindication for many drugs, as it suppresses the enzyme that successfully metabolises and eliminates the drug. Alongside a more whole understanding of nutrition, drug, and microbiome effects, the microbiota present new targets that impact a drug’s pharmacokinetics (absorption, distribution, metabolism, and excretion), and lead to better health outcomes. Microbiota’s Impact on the Life of a Drug Understanding the co-metabolic effects of gut microbiota with different drugs can help formulate effective drugs and, in some cases, lower the toxic profile of compounds. In addition to beneficial effects, microbiota can inactivate drugs, causing harmful toxicity.7 Much like the gastrointestinal (GI) tract’s role in breaking down food enables absorption of nutrients, the GI tract processes pharmaceuticals through a variety of enzyme-facilitated reactions. Any of these reactions affect the pharmacokinetics of a drug. As an example, gut microbiota can increase the absorption of a drug indicated for arrythmia, a heart condition. In tandem, certain microbiota can decrease absorption of drugs, leading to quicker elimination. Pharmaceuticals and gut microbiota interact in a variety of ways. This includes the proteins that cause resistance, particularly multi-drug-resistant bacteria and breast cancer-resistant proteins.8 In addition to metabolising drugs, microbiota can also impact drug response, causing conditions such as diarrhoea in patients. Another example occurs with the anti-diabetic drug metformin.9 When metabolised in the gut, metformin increases the presence of specific gut microbiota, which in turn increase glucose metabolism. Cancer therapies can alter the composition of intestinal microbiota, allowing good bacteria to pass through to other organs, where they can cause damage. In addition to this, enzymes along the GI tract can alter the composition of a drug. All of this emphasises the need to incorporate microbiome knowledge in the formulation process. An understanding of the microbiome’s impact on pharmacokinetics can lead to improved therapies. By incorporating microbiome studies in clinical trials, there is a potential to achieve higher clinical effectiveness and better therapeutic outcomes. This begets the need for studying the microbiome in terms of how therapies can be developed that target specific microbiota, Volume 11 Issue 5

Therapeutics and what kinds of technologies enable the development of said therapies. Developing Microbes With the ability to change an organism’s genetic material, the CRISPR-Cas9 technology has opened the door to a whole new world of therapies. By modifying and targeting the genome of organisms in the microbiome, such as bacteria, yeast, and phages, this technology holds promise for developing new treatments for diseases that affect the microbiome.10 Since CRISPR-Cas9 technologies can be used in a variety of ways, the effect on the microbiota is also variable – leading to three different therapeutic types, described in Table 1.

Table 1. Definitions of therapeutic types.

Additive Therapies Additive therapies involve enriching the host microbiome environment, through either genetically engineered bacteria or natural strains deemed beneficial. For example, certain bacteria can be engineered to secrete molecules to combat digestive disorders such as inflammatory bowel disease. Subtractive Therapies Subtractive therapies use engineered strains of bacteria or other microorganisms to eliminate detrimental strains of bacteria, such as bacteriophages, without harming the host microbiome. An example of an application for this would be eliminating bacteria with the mutations that cause antibiotic resistance. Modulatory Therapies Modulatory therapies or altering the composition of existing host microbiota are administered similarly to additive therapies but complement the activity of existing microbiota rather than functioning to secrete new molecules to aid in combatting disease. An example of this is probiotic supplements, or faecal microbiota transplants for patients with recurrent Clostridium difficile infections. These three therapies show avenues for the use of CRISPRCas9 technologies to edit organisms like yeast, bacteriophages, and bacteria strains. With the option to modify the genetic material of organisms, CRISPR-Cas9 can help us better understand the microbiome, and how to derive and manipulate therapies to best serve human health. Applying New Technologies CRISPR-Cas9 for Editing Microbes CRISPR stands for “clustered regularly interspace short palindromic repeats” and allows for the targeted splicing and editing of DNA strands to perform specific functions. CRISPR-Cas9 differs from previous gene editing technologies, in that it streamlines the editing process to be able to do simple changes. For example, CRISPRCas9 allows us to change the genetic make-up microorganisms in relatively few, simple steps so that they perform specific functions within the microbiome. Nanomedicines for In Vivo Sampling Nanotechnologies are emerging in healthcare as well, and the so-called “lab-on-a-pill” devices show promise in our ability to sample and study microbiota.11 Previously, clinical studies of the gut microbiome required collecting and analysing faecal samples

via standard laboratory methods, including mouse models. For example, the biology of the gastrointestinal tract varies based on location within the tract. The microbiota of the stomach differs from the microbiota in the small intestine, and fecal samples don’t capture this difference well. Through in vivo sampling, a more accurate analysis of the gut microbiome across the GI tract can be captured. Using advanced technologies in microbiome-focused clinical research can better inform therapeutic development, develop a clearer map of the gut ecosystem, and potentially reduce logistical barriers in microbiome trials. Challenges in Clinical Research While incorporating microbiome studies into clinical research is a new and important gateway to achieving higher clinical effectiveness, there are many challenges in studying this new scientific area. One such barrier is the heterogeneity of the microbiome. Put simply, everybody is different. Inter-individual variation between environments, diets, and host microbiome leads to many differences in drug response. The variability also poses additional difficulty in defining what exactly a healthy versus an imbalanced microbiome looks like. Since this is different for everyone, targeting the microbiome offers many opportunities in the area of personalised medicines. From a clinical trial planning angle, the dynamic nature of the microbiome complicates the ability to define dose-response levels, relevant study endpoints, and disease state progression. It is also difficult to select study populations and capture appropriate data. Evaluating a potential therapy based on biomarkers or clinical outcomes is dependent on disease state definition, so the need to develop novel methods for microbiome trials arises. In addition to endpoints and study populations, trial enrolment and preventing loss to follow-up is critical to a successful microbiome trial. Especially with chronic diseases, the ability to sample the microbiome over time is important to the trial. Novel technologies and methods can alleviate some of these complications. Clinical trials that incorporate the microbiome also present unique difficulties in terms of confounding variables and proper statistical analysis. Environmental, diet, and lifestyle differences, for example, affect important pieces of the trial, including statistical power and whether the study can be replicated. With the likelihood of heterogenous study populations, the path to initiating microbiome trials will require appropriate patient sub-group identification, and tailored risk-benefit assessments for each group. This also points to the unique approach needed in defining adverse events and serious adverse events for safety and monitoring during the trial. As with most areas of new therapeutic development, regulatory issues also arise. While adverse events related to faecal transplants are minor, the lack of long-term follow-up and safety data posits regulatory reluctance to approve these new therapies. Because of the instability of microbial therapies, there is understandable concern about the safety of these therapies. What are considered harmless bacteria can change within the body and cause immune reactions. Understanding this piece of the puzzle helps eliminate certain patient populations, such as immunocompromised individuals, from receiving therapies that may not be beneficial. Microbiome applications in clinical trials present new opportunities and challenges for developing new therapies and improving pharmaceutical products. New technologies like CRISPR-Cas9 and “lab-on-a-pill” devices are changing the breadth of clinical trials, our understanding of the microbiome, and how we can manipulate it for better health. Many challenges from clinical Journal for Clinical Studies 41


development, trial planning, and regulatory perspectives exist. However, our growing knowledge of the microbiome and scientific advancements within this field hold promise for overcoming these challenges and creating new pathways to treating diseases. REFERENCES 1. 2.





7., visited Aug 2019. Anukriti Sharma, Mary M. Buschmann, Jack A. Gilbert. Pharmacomicrobiomics: The Holy Grail to Variability in Drug Response? https:// (2019) Stephanie A. Flowers, Vicki L. Ellingrod. The Microbiome in Mental Health: Potential Contribution of Gut Microbiota in Disease and Pharmacotherapy Management. https://accpjournals.onlinelibrary.wiley. com/doi/10.1002/phar.1640. (2015) Aedín Cassidy, Anne-Marie Minihane, The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids, The American Journal of Clinical Nutrition, Volume 105, Issue 1, January 2017, Pages 10–22, . (2016) Julia K Bird, Daniel Raederstorff, Peter Weber, Robert E Steinert, Cardiovascular and Antiobesity Effects of Resveratrol Mediated through the Gut Microbiota, Advances in Nutrition, Volume 8, Issue 6, November 2017, Pages 839–849, (2017) Adnaan Ghanchi, Philip T James, Carla Cerami, Guts, Germs, and Iron: A Systematic Review on Iron Supplementation, Iron Fortification, and Diarrhea in Children Aged 4–59 Months, Current Developments in Nutrition, Volume 3, Issue 3, March 2019, nzz005, https://doi. org/10.1093/cdn/nzz005. (2019) Ian D. Wilson, Jeremy K. Nicholson. Gut Microbiome Interactions with Drug Metabolism, Efficacy and Toxicity. pmc/articles/PMC5718288/. (2016)

42 Journal for Clinical Studies



10. 11.

Edit Mikó, Tünde Kovács, Éva Sebő, Judit Tóth, Tamás Csonka, Gyula Ujlaki, Adrienn Sipos, Judit Szabó, Gábor Méhes and Péter Bai. Microbiome – Microbial Metabolome – Cancer Cell Interactions in Breast Cancer – Familiar, but Unexplored. (2019) Yevheniia Kyriachenko, Tetyana Falalyeyeva, Oleksandr Korotkyi, Nataliia Molochek, and Nazarii Kobyliak. Crosstalk between gut microbiota and antidiabetic drug action. pmc/articles/PMC6422856/. (2019) Gayetri Ramachandran and David Bikard. Editing the microbiome the CRISPR way. (2019) Hojatollah Rezaei Nejad, Bruno C. M. Oliveira, Aydin Sadeqi, Amin Dehkharghani, Ivanela Kondova, Jan A. M. Langermans, Jeffrey S. Guasto, Saul Tzipori, Giovanni Widmer, Sameer R. Sonkusale. Ingestible Osmotic Pill for In Vivo Sampling of Gut Microbiomes. https://onlinelibrary.wiley. com/doi/full/10.1002/aisy.201900053. (2019)

Kinari Shah Kinari Shah, MSPH, is currently a Research Fellow at DIA. Previously, she attended Johns Hopkins Bloomberg School of Public Health and earned an MS in public health focusing on global disease epidemiology and control, with courses in pharmacoepidemiology and clinical trials. She is particularly interested in the intersection of nutrition, microbiome, and drug development. Email:

Volume 11 Issue 5


Optimise Your eTMF Strategy An electronic trial master file (eTMF) sits at the centre of a complex structure of people, process and technology. Processes include many stakeholders ranging from internal departments (clinical operations, regulatory, data management) to external partners (CROs, committees, ethics boards and labs) to regulators. Activities are controlled by a quality management system and require evidence that defined processes were followed. Operating the eTMF requires significant resources, and needs grow each year as the number and size of an organisation’s trials increase. Given the critical role that the TMF plays in ensuring data integrity and the safety of human subjects, the serious impact of negative inspection findings, and the challenges with maintaining a cost-effective solution, an optimised eTMF strategy is an excellent investment. A successful strategy will encompass regulatory compliance, quality, and cost-effectiveness. That strategy can then be mapped to a set of tactics that enable the strategy to meet its objectives. The need for an eTMF strategy is not limited to those organisations implementing eTMF for the first time. It should be part of an overall continuous process improvement philosophy even for mature organisations with extensive eTMF experience. Regulatory Compliance – Designing with the End in Mind Regulatory compliance can be defined as an organisation's adherence to laws, regulations, guidelines and specifications relevant to its business processes. Compliance is measured by the health authority inspector – the ultimate customer of the eTMF. TMF-related issues account for a significant portion of inspection findings. Every decision made in an eTMF strategy should include a consideration of how it would be viewed by a TMF inspector. The following are examples only, meant to illustrate how a tactical decision can support or undermine the overall eTMF strategy.

Can you ensure that a scanned copy is a complete and accurate representation of a paper original? This is a prerequisite to destroying paper originals.

Table 1 shows how health authority requirements such as these can be traced into an eTMF strategy and then into tactics. Health Authority Requirement



Inspections should be completed within the stated timeframes, without inspectors having to return because required documents could not be located.

Ensure that the eTMF can be easily navigated and searched, and that document names clearly and accurately represent the content.

Require document submitters to provide succinct but descriptive document names. Train them on both the importance of doing so and the best practices in document naming.

How are records organised and named? While it’s more work to create accurate document names, MHRA inspection findings have been given based on “the same name for many different documents” and “documents being named incorrectly”.1 Inspectors need to locate documents quickly without having to open a series of documents that can’t be differentiated without looking at the content.

There should be a clear understanding of which records are located in the primary TMF and which are located elsewhere, and the ability to quickly retrieve all records, sometimes with guided access.

Determine the proper location of each record, considering the need to handle dynamic files such as Excel or SAS.

What records are in the primary eTMF, and what are stored elsewhere? How can those files be located? Health authorities state that there should be a primary TMF system for holding essential documents, and a suitable overall index or table of contents to enable the location of essential documents in the TMF to be traced.2

Develop a TMF index that describes where each record is held and how it is made available for inspection. Ensure that records are created in the assigned systems, and verify that they are created, finalised and accessible as part of eTMF completeness checks.

Paper originals should only be destroyed when required certified copies have been created.

Determine which copies need to be certified and define a certified copy process.

Develop, validate, train on and execute a certified copy process.

Table 1 Tracing health authority requirements into associated strategy and tactics Journal for Clinical Studies 43

Technology Studying published inspection findings, listening to conference presentations on agency inspections, and surveying the organisation’s collective experience of inspections will help to determine what strategies and tactics are needed. The TMF Reference Model has created an inspection readiness RACI, presentation and FAQ list that incorporates the experience of a cross-section of industry.3 Quality – A Risk-based Approach ICH Q9 defines quality as “the degree to which a set of inherent properties of a product, system or process fulfills requirements.”4 Therefore quality and regulatory compliance are not synonymous. An effective eTMF strategy is built on quality by design (QbD). ICH Q8 defines QbD as “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management”. An important associated concept also defined by ICH is the critical quality attribute (CQA): “A property or characteristic that when controlled within a defined limit, range, or distribution ensures the desired product quality”.5 Translating these concepts into the eTMF involves identifying the sources of eTMF risk and the CQAs that can be used to measure them. Usually, eTMFs are measured by their completeness, their contemporaneousness (timeliness of filing), and the quality of documents. Depending on how the TMF is used, other CQAs might be relevant; for example, whether monitoring visit reports are filed before the next visit, whether safety reports are promptly distributed to sites, or whether regulatory package documents are properly filed and finalised before drug shipment to sites. eTMF strategy will identify CQAs specific to the organisation and the tactics that will allow them to be measured and monitor, resulting in corrective and preventative actions as needed. Both strategy and tactics will evolve over time as an organisation matures and gains experience in identifying sources of risk. Cost-effectiveness – An Opportunity for Reward Cost-effectiveness is the relationship between monetary inputs and the desired outcome. In the most recent survey by the TMF Reference Model, 30% of respondents felt their TMF was somewhat or very costefficient, with another 31% reporting a neutral perception.6 Although there is little published data concerning eTMF costs, it’s safe to conclude that the majority of costs are attributable to labour rather than technology. The largest cost component at most organisations is related to eTMF quality control (whether done inhouse or outsourced), with cost spikes occurring if any sort of eTMF remediation is needed. Therefore, to increase cost-effectiveness, ask the questions: • • •

Are tasks being performed that are not necessary, as they do not strongly support compliance or quality? Are users performing tasks efficiently? Are users performing tasks that could be automated?

Identifying Non-value-added Activities In examining tasks to determine if they actually contribute to compliance and quality, keep in mind what is being done to meet health authority guidance and regulations, and what is being done due to sponsor or CRO regulations. Internally required activities should be reviewed as part of the eTMF strategy to re-focus on what truly adds value. 44 Journal for Clinical Studies

Translations. Are translations being done that are not required by regulations or by ethics boards? If they are not truly necessary, they are adding to the burden of both clinical operations and eTMF.

Handling of paper. Sources of eTMF inefficiency in this area include scanning of documents that can be obtained as electronic originals, requiring wet ink signatures, and collecting paper originals that can be left with sites. Not only does scanning documents add time and increase the QC burden, but destroying original paper then requires a certification process.2 Collecting wet ink signatures often does not add value, as this necessitates the circulation of paper for signature even though research shows that health authorities only require signatures for about five document types in TMF.7

100% QC. EMA states “The sponsor… should implement risk-based quality checks (QC) or review processes.”2 MHRA GCP recommends “a formal process… for regular checks of documents in the eTMF, usually on a sampling basis, including escalation procedures where issues arise.”8 Thus there is ample evidence that health authorities will accept less than 100% QC provided there is a risk-based framework in place. Hecht et al. have published a methodology for a risk-based approach for quality assessments of TMFs.9

Repeated Activities. Usually, document submitters are responsible for ensuring that their documents are “TMF ready”. Depending on document details, they may need to check for scanning quality, completeness of forms, presence of required signatures, page numbering, etc. Consider whether it’s worthwhile for QC associates to repeat these checks.

Promoting Task Efficiency Several factors contribute to efficient execution of tasks. Of course, an eTMF with a well-designed user interface promotes efficiency, but is not necessarily sufficient. Some other factors that may promote efficiency include: •

Ensuring that a user has all the information needed to make quick and accurate decisions. For example, if the user has a question on document metadata for a specific type of document, how much time is needed to find the answer? If the user has to log into a portal, locate a document and search for the document type to find the information, efficiency is decreased.

Removing low-value metadata. If users are spending significant time entering metadata, re-examine the value of that metadata. Volume 11 Issue 5

Technology • •

Minimising rework. Monitoring quality control failures and instituting preventative actions can drive down rework, making QC faster as well as avoiding the time needed to address issues. Organising work. A variety of studies have shown that repetition decreases the time to complete a task and increases accuracy. Organising tasks so that QC associates specialise in sets of document types will increase QC efficiency.

Often, an informal time and motion study focusing on document upload and QC will uncover many ideas for increasing efficiency. Submitters and QC associates no doubt will have ideas on how their work can be streamlined as well. Implementing Task Automation The volume of work needed to maintain a compliant, high-quality eTMF is daunting. Ultimately, automation, artificial intelligence and machine learning will replace much of the need for filing and quality checks currently done by humans. An eTMF strategy should address how automation will be increased in the near future, and how the organisation will prepare for more sophisticated solutions several years from now. In the short term, options for increasing automation may be limited. An opportunity may exist for organisations using commercial eTMF software: taking advantage of software features that aren’t currently being used. Many companies implement a software solution without using all the available features. That is often a sound decision. Today’s eTMF systems can support an extensive set of processes, but some of them need significant requirements definition, process redesign, change management or training. The best approach is to focus on getting the core processes implemented in an efficient and compliant way, then to consider implementing more advanced features such as site portals, study startup and IP Greenlight functionality, or site document reconciliation. For organisations running a steady-state, healthy eTMF, it may be time to revisit features that weren’t enabled in the original implementation or to explore new features the vendor has added. Forming a cross-functional working group to examine the possibilities is a small investment that can yield significant improvements in compliance, quality and cost. Machine learning and AI offer great promise for automating document classification and metadata assignment, quality control, and translation. However, solutions that would be trusted by industry aren’t available commercially today. It’s reasonable to expect that will change in the next several years. So, a focus on preparing for automation is another sound investment.

the organisation for successful inspections, assists in controlling operating costs, and decreases the probability of expensive and time-consuming remediations due to unforeseen risk. REFERENCES 1.

Medicines & Healthcare products Regulatory Agency (MHRA) (11 May 2018). GCP INSPECTIONS METRICS REPORT METRICS PERIOD: 1st April 2016 to 31st March 2017. government/uploads/system/uploads/attachment_data/file/706356/ GCP_INSPECTIONS_METRICS_2016-2017__final_11-05-18_.pdf, visited on 29 July 2019. 2. European Medicines Agency (06 December 2018). Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic). scientific-guideline/guideline-content-management-archiving-clinicaltrial-master-file-paper/electronic_en.pdf, visited on 29 July 2019. 3. Various resources on, visited on 29 July 2019. 4. International Conference on Harmonisation (9 November 2005). ICH HARMONISED TRIPARTITE GUIDELINE QUALITY RISK MANAGEMENT Q9. ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf, visited on 29 July 2019. 5. International Conference on Harmonisation (August 2009). ICH HARMONISED TRIPARTITE GUIDELINE PHARMACEUTICAL DEVELOPMENT Q8(R2). Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_ Guideline.pdf, visited on 29 July 2019. 6. TMF Reference Model Survey (September 2015). https://tmfrefmodel. com/wp-content/uploads/2016/10/2015-tmf-survey-overview.pdf, visited on 29 July 2019. 7. Kathie Clark (November2014). Signature Practices and Technologies for TMF: An Industry Overview. signature-practices-and-technologies-for-tmf/, visited 26-Jul-2019. 8. Medicines & Healthcare products Regulatory Agency (MHRA) (24 Sep 2012). Good Clinical Practices Guide. 9. Hecht, A., Busch-Heidger, B., Gertzen, H., Pfister, H., Ruhfus, B., Sanden, P. H., & Schmidt, G. B. (2015). Quality expectations and tolerance limits of trial master files (TMF) - Developing a risk-based approach for quality assessments of TMFs. German medical science : GMS e-journal, 13, Doc23. doi:10.3205/000227. PMC4677593/pdf/GMS-13-23.pdf, visited on 29 July 2019.

For example: •

In order to prepare for auto-classification and metadata extraction, work to standardise and increase use of document templates that promote the ability to recognise a document and extract its metadata. Research how documents should be structured to enable machine translation.

Conclusion The eTMF is a critical component of executing clinical trials whose safety and efficacy results will be accepted by health authorities. Developing and executing an eTMF strategy based on risks, goals and constraints specific to an organisation positions

Chet Shemanski Chet Shemanski a proven business and information technology professional with extensive experience serving the healthcare and global life sciences industries. He has specific expertise in software product commercialization including product management, product marketing, solution strategy and alliance management. Chet is a subject matter expert in eClinical and eRegulatory technologies, the author of industry journal articles and a speaker at industry conferences.

Journal for Clinical Studies 45


LIMS in Clinical Trials Sample Management

Imagine, if you will, that you have been fortunate enough in your working life that you are able to afford a 2019 Lamborghini Huracan Peformante Spyder, in which you enjoy making the round trip to your local supermarket at a cool 200mph – no need to put that ice cream in the freezer bag as it won’t melt in the 15 seconds it takes you to get home. Of course, that kind of performance comes at a cost. Tags, taxes, and title will set you back a dizzying $308,000. Now imagine that you took the car to a major sporting event and parked it among 50,000 cars and forgot where you parked it. As panic sets in, you realise you may well have lost $308,000. Most of us will never see a Lamborghini Huracan, much less buy one, but many companies in the biotech field pay $300,000 for a few vials of tailor-made mRNA. Now and then, a few mRNA containers fall through the racks in a deep freezer and frost over, causing lab management to have some sleepless nights before deciding to invest in a system to track such items. Of course, tracking expensive materials is a small fraction of the total usefulness LIMSs have in the clinical trial world. The Evolving LIMS, and What It Means In the 1980s, during the nascent era of laboratory information management systems (LIMSs), major analytical instrument manufacturers figured that producing software to help acquire information from those devices while managing lab samples might leverage sales of those high-margin instruments. Since that time, many so-called “Pure Play” LIMS vendors have emerged. These are vendors who never sold instrumentation, and developed LIMS as standalone products. No matter the history of LIMS vendors, many coveted the cash-rich pharmaceutical and biotechnology accounts seeking to achieve competitive advantages through increasing productivity. Let’s step back a moment. In the world of LIMS, we have always had a naming problem. “LIMS” still triggers a result for library information management systems if you go deep enough into an online search. So, LIMS has different meanings to different people. Specialised LIMS tailored to addressing the needs of clinical environments with the aforementioned specimens and accessioning requirements, along with a need for containing and sometimes obscuring patient-specific information, were often called clinical laboratory information systems, or clinical LIMS, or even just LIS1,4. Many clinical LIMS owed their origins to having been developed for hospital environments or small clinics. As the market for clinical trials specimen management burgeoned, vendors of these systems began to expand their product functionality to appeal to testing labs with increasing needs in terms of specimen volume and functional complexity. Coming from the other end of the spectrum, conventional LIMS vendors recognised the potential of the clinical trials market. They began to offer specialised modules for this purpose, if not standalone applications. 46 Journal for Clinical Studies

Returning to the small hospital-based application vendors, if trying to grow from handling a few dozen patient results to hundreds of thousands of specimens wasn’t challenging enough, layer onto those requirements the need to support clinical trials that require data collation, analytics, and statistical analysis to support new drug applications (NDAs), which are the blue whales of the regulatory world, in that they may require hundreds of thousands of pages of data. Flash forward to the clinical trials industry that has all the requirements of meticulous sample tracking, but also must meet the challenges attendant to a field accelerating in growth at a staggering pace. Follow Regulatory Compliance with LIMS Clinical trials of course are programmes that help move new drugs or therapies from “Imagineering” through Phases 0, I, II, III and IV. This brief description falls significantly short of explaining an astonishingly complex process that is not only expensive, but has a very high failure rate. The terminology for LIMS is a bit different in the clinical trials universe. We refer to specimens rather than samples, sample logging becomes specimen accessioning, and sample sources become subjects. LIMSs used in clinical trials work also have additional functionality not required in a conventional LIMS while meeting regulatory requirements over and above those systems. Clinical laboratory improvement amendments (CLIA) are regulations that establish certain quality standards for laboratory testing of specimens from humans. A LIMS can help researchers meet these requirements, but “CLIA Certified” is somewhat of a misnomer, if not disingenuous. While LIMSs can be used in labs meeting all other CLIA requirements, it does not mean the LIMS itself is certified by CLIA1. The Health Insurance Portability and Accountability Act (HIPAA) demands certain standards be met for protecting subject data. One tool used in clinical trials testing is anonymisation, sometimes referred to as de-identification. While clinicians must record subject information, in the research world, there must be a method to disassociate patient information from the data sets developed at specimen collection from the data sets consumed by researchers. Thus, anonymisation is a key feature in the Clinical LIMS universe [Fig 1].

Figure 1: A clinical LIMS enables masking of sensitive health information to ensure the privacy of patients

The Code of Federal Regulations (CFR) is a massive, overarching directive issued by the federal government of which one section, 21 CFR Part 11, controls certain aspects of electronic data, most critically data audit trails and electronic signatures (ESIG). Not Volume 11 Issue 5

Technology many years ago, some clinical LIMS vendors who organically grew from small hospital or clinical test tracking systems believed that digitised images of hard-copy signatures were “electronic signatures”. No, they aren’t, and knowledgeable suppliers of these systems realise that electronic signatures uniquely identified who is responsible for the data entries in a LIMS. Many LIMS allow the attachment of electronic verification that is tied to a single user logged into the LIMS. When required, users who attest that their ESIG represents data they have just entered or worked with, that record is permanently and indelibly associated with the entry. The other side of the ESIG coin is the concept of audit trails. When and where enabled, audit trails capture changes to data, the time it was changed, and the person changing the entry. Electronic audit trails are not only significantly more sophisticated and reliable than those methods of years past, but also allow the LIMS to quickly generate a history of data changes when prompted by curious auditors [Fig-2]. Think of this moment. If an auditor is alerted to an improper data change in a hard-copy notebook, he/she may ask for many more notebooks to examine. Think of the time required to pore over dozens of notebooks to flag and examine data changes. In the world of clinical LIMS, this query could be executed in seconds with the collateral benefit of not exposing unrelated data to auditors. In Europe, the General Data Protection Regulation (GDPR) rules over data protection and privacy for citizens of the European Union. In general terms, many of those requirements addressed by HIPAA and 21 CFR 11 are analogous to GDPR requirements. However, it is the end user who is ultimately responsible for compliance, and a clinical LIMS can only provide the platform and tools to be compliant. Sample Management Challenges in Clinical Trials That’s just for starters. While some clinical trials are conducted by large biotechnology or pharmaceutical firms, many studies are executed by specialised enterprises called contract research organisations (CRO). CROs face specimen management challenges unknown to mainstream pharmaceutical manufacturers. Top CROs may need to organise the receipt of tens of thousands of specimens each day from distant clinics who may be collecting blood and urine, among other types of biological materials. Reception of such volumes of specimens is bad enough, but many of these specimens still arrive with handwritten labels along with hard-copy test orders. To add one more layer of complexity, CROs also may utilise specialised subcontracted labs for testing. Why is this significant? Because in today’s world of cloud computing, Software as a Service (SaaS), and super-fast reliable networks, the brick and mortar laboratory becomes a concept in virtualisation as specimens rain down on the CRO and are re-distributed to subcontracting labs, or may be routed directly to subcontractors who in turn send results back to the CRO. To understand the utility of LIMS in clinical trials, consider the logistics involved in tracing the life of a specimen. Whomever is collecting specimens for a trial must first issue specimen kits. If, for example, a study involves the collection of multiple blood and tissue specimens, the vials of a kit must be labelled with certain information about the specimens, and the analysis panel (tests) is specified in an accompanying document. The vials are placed in a larger kit box, and multiple kit boxes are placed in still larger boxes and are sent, usually under temperature-controlled conditions, to the testing facilities2,5. Once at the facility, the large boxes are opened, the testing instructions are removed, the kit boxes are removed, and the vials are organised by test type, all after the

temperature conditions of the specimens have been documented. The clinics where the specimens were drawn invariably transpose specimens, commit transcription errors on the orders, or perhaps forget to include them. Testing organisations literally have dedicated groups who are responsible for resolving these issues – usually by phone since there is a sense of urgency attendant to these specimens. These specimens must be sorted and distributed to the testing groups, perhaps serology, haematology, virology, etc. Here is a very critical point – the lab groups who will conduct the testing were made aware that they have specimens to test when the samples arrive at the lab group. This is what is referred to as a productivity killer called a “wait state”. This will become important in a moment. Bear in mind we have not actually tested the specimens at this point. How would this look in a LIMS-enabled clinical trials world? Let’s start by kit building. In the LIMS world, the vials of a kit are barcoded, as are the kit boxes [Fig-2]. In this example, a subject walks into a clinic where a few blood and saliva specimens are taken in this fictional trial. The clinician scans the vial, and then scans the kit barcode, thus linking the vials in the kit to the kit itself. The tests for the specimens are linked to the test panel in a LIMS specimen entry screen that was accessed by the clinic via an icon linked to the URL of the LIMS. At this stage, we now have an electronic linkage between the specimens, the kit box they are in, and the test panel. Now, multiple kit boxes are placed in a larger box of kits, and another barcode is scanned and placed on the parent box, along with a downloadable temperature monitor that accompanies the specimens and records the temperature of the container while en route to the testing site3.

Figure 2: A clinical LIMS enables sample management, kit creation and barcode labels design for kits

Remember the testing facility where the large boxes were opened and the kits and test panel orders were removed? In a clinical trial testing world, the test orders have already been logged into the LIMS. When we identified the wait state earlier, it is important to know that one significant benefit of a LIMS is the elimination of wait states. Because the test orders were logged in when the specimens were drawn, and the tests indicated can be targeted towards specific laboratory work groups such as haematology, the specimens can appear on the testing backlog for the haematology lab. By giving the lab advanced notice of incoming work, the lab can acquire reagents, prepare instruments, and otherwise perform work during slack periods that they would not have known about until the specimens were physically delivered to the laboratory. In the LIMS-enabled clinical trials world, the moment the boxes containing multiple kits are scanned, the electronic linkages we created earlier identify all the kits and the vials contained therein. Messages can now be sent to specimen handlers to deliver the specimens to their target labs. Once the boxes are opened, the temperature sensors that were placed in the box earlier are now linked to the conditions of all the specimens in that box. If there was an excursion over the temperature tolerances for those specimens, that fact would be linked to all of their specimen records as an out of specification warning, and the specimens could be targeted for disposal. Journal for Clinical Studies 47


When the laboratory results are generated, they are entered into the LIMS either manually or via instrument interfaces. At this point, specifications associated with the tests are enforced against the data entered, and out of specification results are flagged for further action. Recall that all of these actions have taken place either at the clinics where specimens have been drawn, or in the testing laboratories. We have just now gotten to the point where data is to be consumed by researchers. Recall that the various stages of clinical trials require data to be incorporated into decisions to move forward. Phase 0 requires an initial evaluation in non-humans of the safety, efficacy, and toxicology of the test material. While animal toxicology requires a special set of LIMS functionality, it is at Phase I when initial testing requires feedback from a LIMS over a very small patient population. Testing from these project-oriented stages helps fuel the decision as to whether it makes sense to move to Phase II. Phase II data evaluates side-effects and the overall efficacy of the drug on a subject population of 100-300 individuals. This is a critical go/no-go stage, where perhaps 70% of drugs fail. Moving a drug to Phase III from Phase II is a very big deal as the number of subjects in Phase III may reach into the thousands. Phase IV is post-release, and studies long-term effects on the population at large. In Conclusion... Finally, let’s not forget that there is a marriage of clinical and conventional LIMS in clinical trials. Those drugs being tested are not evaluated for quality and purity in a clinical LIMS; that responsibility lies in the domain of a conventional LIMS, whose main purpose is to guarantee that the drug being manufactured is produced consistently and with the highest possible tolerances for quality. A LIMS serves to accelerate the pace and quality of research from inception through production, and is no longer optional for companies seeking to stay competitive. 48 Journal for Clinical Studies

REFERENCES 1. (2016). Varied Needs for Biological Sample Management. [online] Available at: http://www. [Accessed 20 Aug. 2019]. 2. Finken, G. (2019). The Biggest Challenges for Biospecimen Management in Clinical Trials. [online] Available at: https://www. [Accessed 22 Aug. 2019]. 3. (2019). Keeping on top of data samples with LIMS. [online] Available at: https://www.manufacturingchemist. com/news/article_page/Keeping_on_top_of_data_samples_with_ LIMS/100149 [Accessed 22 Aug. 2019]. 4. Lab Manager. (2019). Improving Clinical Specimen Management | Lab Manager. [online] Available at: insights/2016/09/improving-clinical-specimen-management-#. XVvRmOgzbIU [Accessed 20 Aug. 2019]. 5. Ashu, A. (2017). Clinical data management: An overview. Journal of Clinical Research & Bioethics, 08(04).

Shonali Paul Shonali Paul has a rich experience of working in diverse industries including IT, heavy engineering and retail. In a career spanning over seventeen years, she has built a long and impressive track record of success in hightechnology software sales, marketing and professional services, developing operational strategies and directing new business initiatives. She is the chair of the Member Relations Committee at ISBER. Email:

Volume 11 Issue 5

Logistics & Supply Chain Management

The Role of the Clinical Supplies Manager in Averting Unplanned Costs and Delays Patient recruitment and protocol design receive much attention when planning a clinical trial; however, it is all too easy to neglect another factor critical to a trial’s success: the availability of clinical supplies. The importance of ensuring the right materials will be available in the right place and at the right time cannot be underestimated. In fact, if the planning process for shipping and logistics is not started in good time, there is the potential that the desired start date for the clinical trial is missed because sufficient investigational drug, the comparator, or both, are not available. The forward planning process for a clinical trial can have a significant impact on its budget and timelines. Ideally, an early conversation between the sponsor, contract research organisation (CRO), and clinical supplies manager (CSM) will set out a plan and timeframe for the study with all concerns fully addressed well in advance of the start of the patient recruitment process. Frequently however, the planning process is less than ideal, with clinical supply planning left until the last minute. While a quotation for the supplies might have been requested and received in good time, if it is not acted upon in a timely fashion, then the order may well require expediting later on. The additional cost of such delay can be significant, and the desired first-patient in (FPI) date even missed. Clinical Supplies Management Clinical supplies management is perhaps the most important part of the supply chain. If undertaken correctly, it will drive the success of every other step in the process, including adherence to budgets and achieving desired timelines. Yet the different parties involved in a trial’s planning and operation – sponsor and CRO – often fail to fully define who should take control of clinical supplies, with each incorrectly assuming the other is taking responsibility. Some responsibilities may be covered by the sponsor, some by the CRO, and some by the clinical supplies vendor. But who takes ownership of the entire supply chain, and where does the CSM reside? And who will fulfil the role of unblinded study manager using an interactive response technology (IRT) to manage the blinded trial supplies? Many of the tasks a CSM can take responsibility for are listed in Table 1. In assigning responsibilities, it is not merely a case of ‘who does what’, but more about making both the CRO and sponsor aware of everything that needs to be done, their own responsibilities, and whether a task is better outsourced to a third party such as the clinical supplies manager. Some of the savings that can be made by assigning a CSM are purely financial. In particular, a CSM can utilise forecasting skills that ensure overages of investigational medicinal product (IMP) are

minimised, and the optimal quantity of potentially very expensive comparator supplies is sourced appropriately. As the trial progresses, the CSM can use IRT data to revise these projections to prevent the occurrence of either shortages or overages. There are, however, many other advantages in using a CSM. A CSM can support set-up and user acceptance testing of IRT, support IMP packaging to ensure planned trial start dates are met, and set up the necessary logistics and depots for distribution of clinical supplies. Additionally, a CSM can manage the preparation of the pharmacy manual, co-ordinate temperature management strategies, and, at the end of the trial, oversee the reconciliation and destruction of remaining IMPs. Such oversight of the supplies process greatly assists in ensuring that the trial runs smoothly and meets its projected timelines and budget. Comparator Products One of the most challenging parts of the clinical supplies management process is often the sourcing of comparator and concomitant drug products. When a trial requires a commercial product as well as the investigational drug, it is likely to have a significant impact on the study’s budget as its sourcing can be extremely expensive. Additionally, sourcing can be difficult, with the product’s shelflife and expiry dates further restricting sourcing options, and it is important to note that manufacturing documentation may be required for a drug’s importation into certain jurisdictions which adds complexity to sourcing. A CSM should be well placed to work with commercial drug sourcing experts to source the product at the best possible unit price, and balance that against the best available shelf-life to reduce packaging costs. By working with manufacturers and wholesalers, a CSM should be able to improve lead times, and work to ensure adherence to study timelines. A CSM will routinely obtain the necessary documentation to facilitate import and export regulatory compliance, as well as ensure that both packaging and shipment timelines are met. A CSM works with the sponsor, CRO and the IRT system to look at the recruitment rates that are predicted for the study. Simulation software is used to predict in which countries patient recruitment rates are likely to be higher or lower, which facilitates stocking the sites appropriately. Striking a balance between ensuring that sufficient supplies are available, while keeping overages to a minimum, is an important consideration, as buying too much – particularly in the case of expensive comparator products – has a major adverse impact on the budget. Striking a balance between the cost and lead times is another important consideration. For example, it might be preferable to buy a product at a slightly higher price and longer lead time provided it has a longer shelf-life, as this could allow for more efficient packaging Journal for Clinical Studies 49

Logistics & Supply Chain Management Patient-friendly packaging options may be a little more expensive, but can be important for ensuring, or increasing, compliance. Local regulations may demand child-resistant packaging, but considerations need to be made to ensure it is also patient-friendly. For example, for a study into a rheumatoid arthritis drug or one where the predominant patient population is elderly, packaging that is easy to open should be used. A CSM works with the packaging operations teams responsible for the blinding and packaging of the IMP and any comparators, ensuring that the release happens on schedule, as well as ensuring that the patient kit complies with regulations, maintains the blind and is patient-friendly.

runs to be made. Working directly with the manufacturer can prove advantageous, as attempting to purchase materials on the open market or from wholesalers can prove challenging when purchasing large quantities. The manufacturer may be willing to make a full new batch specifically for the trial, rather than supplying product off-the-shelf; and clearly, the lead time is going to be longer if this is the case. A compromise would be to put in an order with the manufacturer, but also to buy a smaller “seeding� quantity from a wholesaler to get the study underway. This strategy allows an initial packaging run to be undertaken. As such, supplies can be delivered to clinical sites with patients screened and randomised while the bulk amount is being made to supply the remainder of the studies. Determining the optimal strategy is a choice between cost and availability of product. Accordingly, consultation with a CSM may avoid an adverse impact on both the budget and time to clinic. Documentation must not be neglected. Some countries, such as Russia and Ukraine, require certificates of analysis to accompany imported clinical trial supplies. Disadvantageously, product sourced in countries such as the US will not automatically come with such paperwork, so partnering with a supplier that can find solutions to address this challenge can save considerable time and inconvenience later. Packaging Needs When considering packaging, several requirements must be taken into account. What will the primary packaging be, and what are the secondary packaging requirements? For example, while a blister pack in a carton may suffice for many IMPs, some need to be packaged under special conditions to meet temperature, humidity or light requirements. Additionally, if the drug is cytotoxic, highly potent or a controlled substance, then additional precautions are needed for handling to avoid deviations and to protect those handling the IMP.

Substantial problems can occur if the packaging runs are not undertaken early enough, and it is easy to underestimate the length of time it can take to get the product out to the clinical sites. Early collaboration with a CSM and the packaging operations teams allows one to plan timelines appropriately. A CSM can take into account all the variables that affect packaging timelines and work to ensure the packaging activities and qualified person release happen in time to allow shipment of drug products to clinical sites ahead of FPI. Advanced Packaging Considerations An automated packaging line may prove advantageous for a large Phase III study where, for example, thousands of vials, syringes or blisters need to be labelled. For a first-in-human study in just a few subjects, manual packaging is almost certainly going to be more costeffective and faster. Drug product is not the only lead time that must be considered: bespoke packaging components can take time to be designed and procured as well. This is not just the case for more unusual packaging options; booklet labels that allow the same product to be used in different jurisdictions and by native speakers of different languages cannot be manufactured until all the label text has been approved. The entire process from design to manufacture can take several months, greatly adding to the manufacturing time: if it is going on a complex product it could take up to five months in total before the product is ready to ship to the trial site. One potential solution to this delay would be to carry out an initial, smaller packaging run using country-specific single-panel labels so that the first clinical sites can begin while the multi-country booklet labels are being designed and printed. Whichever strategy is chosen, planning with a CSM needs to be carried out well in advance of FPI. Expiry date labelling also needs to be carefully planned and managed. If the commercial drug is in short supply and can only

If the study is blinded, how will the blind be maintained? Will it be sufficient to blind just at the kit level, or does it need to be blinded right down to the dose level? If it is a large Phase III study with subjects dosing themselves at home, the latter is likely to be necessary; otherwise, attendance at a clinic for administration by an unblinded physician is required. Although full blinding down to dose level is costlier, reducing the number of clinic visits may improve compliance and, therefore, reduce the overall cost and study dropout rate. 50 Journal for Clinical Studies

Volume 11 Issue 5

Logistics & Supply Chain Management be purchased in small quantities, multiple packaging runs become inevitable. The IMP could still be undergoing stability testing, so at the outset perhaps only six months of data will be available, and the expiry date set accordingly; when longer-term data become available, an expiry extension may well be applicable. This change will, of course, add to the cost, as well as the timelines. On occasion, the same drug product may be required for multiple protocols. If it is particularly costly to make, ideally only the required amount will be sent for each protocol. However, in some instances, it may be possible to pool the supplies across multiple protocols using a demand-led approach. Under a demand-led approach, product is held in inventory and not allocated to a specific protocol in advance. Instead, the necessary product is pulled from inventory and packaged into a protocol-specific kit once a patient has been identified for that study. By only allocating what is required for each protocol, overage and wastage will be minimised, and wasting of expensive drug products can be avoided. Right Place, Right Time Once packaged, drugs need to be distributed to the study sites. If drugs are going directly to the clinical research unit, the process is relatively straightforward; in some cases, a dedicated depot will need to be set up, which complicates the situation slightly. In this case, a CSM works with the depot team to ensure the correct import licences and paperwork are available. While on paper a product may have been packaged and released by the qualified person, if insufficient time for shipping and customs release are allowed, then it may not be available on site in time for the first patient to be dosed on schedule. Any processing by customs officials is out of the control of couriers and can introduce significant delays. A CSM can prove invaluable in planning the logistics, particularly when multiple countries are involved. Table 2 shows a list of some of the many factors that need to be considered. In some jurisdictions, an in-country depot and an import licence will be required; in others, it may be possible to ship directly to the clinical site. An important question that is often overlooked is the identity of the named importer into a country, otherwise known as the importer of record (IoR). If this is not agreed in advance of shipping, drug product may arrive and be held in customs with no-one to sign for it, only to be then shipped back to the country of origin. The length of any customs delay is unpredictable, and sufficient time must be built into the schedule to allow for the worst-case scenario. The choice of courier is also important. Notably, a general, nonpremium courier may prove less expensive and, in some cases, sufficient if only same-country or regional distribution is required. However, if the shipment is being sent internationally and there is potential for customs hold-ups, a specialist courier is likely to be the better option. One solution is to adopt a hybrid system, where the courier is chosen depending on what is the best option for each study. This involves using a premium courier to supply a more robust and reliable shipper to protect the IMP, which can then be transported using a non-premium courier for a regional supply not likely to be delayed at customs. If a depot is required, then clearly this needs to be established before anything can be shipped to it, which may require several weeks’ notice. A CSM can facilitate depot set-up to ensure the depot is able to receive inventory so that shipments can be made to sites ahead of FPI.

In summary, assigning a CSM to a study early in the process can prove essential for success, and may be invaluable in ensuring compliance to both timelines and budgets. It is never too early to start discussions, but leaving it too late can, for example, lead to being reliant on expensive expedited packaging and shipping services. An experienced CSM will support both the sponsor and CRO in getting a trial up and running in time and, hopefully, completed on time and on budget. However, the process must be started in good time: months, and for some highly complex, large studies even a year or more, in advance of the planned trial start date, if the process is to run smoothly. It is never too early. Study design & CSM costing Determining subject drug requirements Simulation, forecasting & supply planning IRT set-up (URS) IRT testing (UAT) Comparator procurement strategy Inventory management Revised projections / simulations Reports GCP liaison & issue resolution Temperature management coordination GCP final reconciliation Destruction facilitation at clinical site Table 1: CSM responsibilities

What countries do I need to supply? Which counties, regions and countries will require a depot? How long will it take to set up a distribution depot? What are the import/export requirements? What documentation will be needed for import? Who will be the importer of record? What are the timescales for customs clearance? What are the expected transit times? Should a standard courier service or a premium courier service be used? What are the estimated courier fees for the destination countries? Table 2: Logistics considerations

Iain Webb Iain Webb is an Account Executive for Catalent’s Clinical Supply Services business and in his role, supports CRO customers and their sponsors. He has over 10 years of industry experience, having previously worked within Catalent’s global Client Services team working with a range of CROs and sponsors, from small and virtual companies to large multinational corporations. He holds a bachelor’s degree in biology from Manchester Metropolitan University, Manchester, UK.

Journal for Clinical Studies 51

Logistics & Supply Chain Management

Effective Optimisation and Cost Management in Clinical Trial Logistics Historically, clinical trial distribution was focused on product protection and patient safety at any cost. More recently, just as their counterparts in commercial distribution are facing significant pressure to reduce the cost of cold chain distribution, increasingly over the past several years there has been a significant shift within the clinical trial sector which is adopting more cost-effective processes and operating more and more like commercial colleagues. Within clinical trials, we’ve seen a tightening down and expectation of reducing costs in cold chain distribution. The sector as a whole seems to be looking much more closely at optimisation and cost management versus the past, when it was based on whatever measures were necessary to get the job done. When focusing on cost reduction, it is important to look at the total picture. Most in the industry will agree that secondary packaging comprises approximately 20% of total logistics cost, while the actual transportation makes up the other 80%. So, one must look at not only the cost of the temperature-controlled packaging, but the overall cost of transportation, packaging and other services combined. More recent technological advancements in temperaturecontrolled packaging introduced to the market has seen the utilisation of more innovative technology, such as improved insulation incorporating vacuum insulated panels (VIPs) reducing the thickness (dimension) of the insulation required and driving greater performance. In addition, traditional, more antiquated water-based systems are rapidly being replaced with systems using a variety of phase change materials (PCMs) that are capable of solidifying and melting (storing large amounts of energy) at specific temperature points to support the ideal temperature range required. The latest advancements mean shipper systems using VIPs and PCMs are far more reliable, a critical requirement for clinical trial companies, while providing more stability within the packaging at the desired temperature and using less overall material. As opposed to more traditional water- and foam-based thermal packaging, more innovative thermal packaging that leverages advanced insulation technologies such as VIPs and PCMs for cooling can provide not only better performance and protection, but can do it in a more volumetrically efficient manner. The result is that while the initial purchase price of the box may be more, the total cost of a shipment may come out to be more cost-effective if you consider all costs involved, especially transportation. Thermal performance and protection are often more critical in the clinical space, thus driving them to seek out better performance packaging. Usually the superior performance resides in higher-end packaging such as the more innovative packaging with VIPs and PCMs. These advanced technology containers can often require a larger upfront investment. As mentioned earlier, however, it is not just the cost of the packaging that should be considered but the overall cost of ownership and use, which includes all the inbound transportation, the outbound logistics, potential return logistics. So, the consideration of all the logistics factors is critical, but the consideration that can be a gamechanger is centred around product protection and ultimately patient safety. 52 Journal for Clinical Studies

Given the potential cost advantages of more advanced technology, one is then able to take advantage of the likely enhanced performance. Optimisation and cost management should be looking closely at the value associated with eliminating product temperature excursions and the significant costs associated with product loss, quality investigation of an excursion (estimated by many to be in the $4K–$6K range per incident for a parcel shipment) and, most importantly, the potential delay of a trial due to reduced efficacy of a treatment. There are significant costs associated with any temperature excursion, especially in the clinical world, and the associated repercussions. This includes the cost of potentially replacing product, in addition to the cost of the quality investigation that needs to happen to understand the root cause of the excursion. Also, there are the potential delays in time to market from a trial standpoint. These associated costs around temperature excursions, product protection, and patient safety can be significant. Another critical consideration is to ensure the packaging being deployed is easy to use. If packaging is difficult to use or to pack out, that complexity can also lead to an excursion. There are some products on the market which are difficult and complex to pack out because things have to be done in a certain order for different temperature requirements and at different times of the year. There are many other considerations that can be optimised as well, which have to do with the human element and expertise, such as conditioning and preparation of the coolants. Clinical sites may not have as much experience of working with the conditioning requirements of advanced PCMs, as an example. It might be decided that they want to outsource that capability to their packaging or service provider, as there are some costs associated with having some

Volume 11 Issue 5

Logistics & Supply Chain Management

conditioning equipment and knowing how to use it correctly within their own facility. So, from an excursion and product protection standpoint, ease of use and pack out, as well as other operational support requirements, are an essential element to take into account so you potentially eliminate human error, which can often account for up to 50% of the excursions that occur. As technological advancements within higher performing, pioneering packaging alongside more simplified pack-out processes continue to assist with optimisation and cost management considerations within the clinical sector, technology also plays a pivotal part when it comes to monitoring payload which are often time- and temperature-sensitive. Increasingly, advanced information technology is available to clinical groups, which can be utilised to track the packaging deployed in real time or capture data once the shipment reaches its destination. Real-time monitoring could be used to know quickly if a shipment has, or may have, a temperature excursion, or will be delayed from reaching the patient; therefore allowing a new shipment to be sent out quickly to the patient, with the original being reclaimed or disposed of, depending on its status. IoT solutions, GPS tracking and temperature monitoring are increasingly providing vital assistance in global clinical trials transportation, enhancing the protection offered by advanced temperature controlled packaging solutions. In the case of reusable technologies, in a bid to help in the recovery of these assets, companies are also increasingly utilising advanced asset management software systems to ensure time- and temperature-sensitive payloads are shipped to the right location, at the right time and critically, that they arrive in the right condition, and are returned as planned. Reuse is probably more accepted and common in the clinical space. The reason is that one of the big values in reuse is it drives down the cost per use, but what it really does is give access to much better technology. Clinical trials organisations can afford much better technology because the packaging cost is driven down (on a per-use basis) based on the reusability. We are seeing more and more situations where companies don’t necessarily need to own the actual assets. They are increasingly attracted to a model where they can just pay for the use of a box and the packaging vendor maintains ownership, whether that’s via a lease programme, rental, or pay per use. That’s become a very attractive model whereby there is no real value in owning the asset. So, the packing provider can own the asset and provide services surrounding that asset, while the clinical trial company pays a single monthly bill based on the overall use required. It is critically important for a clinical company to partner with a packaging provider that has an established global network and infrastructure in place to support this reuse. If clinical organisations are going to access the better packaging technology that they need, they are going to leverage the advanced technology to keep the cost under control and in order to be successful, they need a packaging partner who can not only assist in ensuring recovery of the packaging assets, but also provide support with the infrastructure to service any reusable containers deployed,

i.e., to inspect, clean, repair if needed, and even provide conditioning services and support on a global basis as required. While many in the clinical world will rely on the speciality couriers in the early Stage 1 and Stage 2 trials, they often will modify their transportation or logistics approach to keep closer control and transparency when their pharmaceutical under clinical trial progresses to the higher volume stages associated with Stage 3 trials and beyond. As the clinical trial organisations anticipate with the added complexity in getting cold chain logistics done right, they look to bring activities ‘in-house’. However, they will look to leverage partners that can provide not only the advanced packaging solutions, but many if not all of the associated services involved in a complete offering, such as warehousing, conditioning of coolants, refurbishment and repair in the case of reusable technology, and even transportation services if applicable. The goal is to drive quality and to simplify where possible. Accessing optimised shipper solutions, which are high performing and advanced technically, not only helps mitigate the risk of excursions, but they are by design also going to be lighter and take up less space in general than heavier, traditional systems, while offering cost savings during transportation. So it is a case of considering not just the cost of the packaging but looking at the overall cost of ownership, which includes all the inbound transportation, the outbound logistics and return logistics and all the logistics factors associated with that, and the one that can be a gamechanger is centred around product protection and patient safety. Whatever future developments transpire within the industry, alongside more complex transportation challenges, the temperaturecontrolled packaging industry will continue to respond with increasingly innovative shipper solutions, asset management, and monitoring systems to better protect the precious payloads designed to save, heal and enhance lives. Temperature-controlled packaging providers continue to produce innovative products that are increasingly advanced, and deploying high-performance, protective packaging in clinical trial transportation is critical to the clinical trial market.

Kevin Lawler Pelican BioThermal Vice President of Sales Kevin Lawler has over 25 years of sales leadership experience predominantly in early stage, growth oriented companies. He has a strong history in building and leading sales organizations capable of producing strong and predictable growth. Prior to joining Minnesota Thermal Science (now known as Pelican BioThermal) in 2009, he was a leader in the growth of Computech Resources into a $35M technology and consulting services company, positioning it to be acquired by Logicalis, Inc. a global, $1B technology organization. Kevin earned an MBA from the University of Montana. Email:

Journal for Clinical Studies 53

Logistics & Supply Chain Management

What is Artificial Intelligence, and how is it Beneficial for the Healthcare Industry Artificial intelligence (AI) is the branch of computer sciences that emphasises the development of intelligent machines, thinking and working like humans, for example in speech recognition, problem-solving, learning and planning. Today, artificial intelligence is a very popular subject that is widely discussed in technology and business circles. Many experts and industry analysts say that AI or machine learning is the future – but if we look around, we are convinced that it’s not the future – it is the present. With the advancement in technology, we are already connected to AI in one way or the other – whether it is by Siri, Watson or Alexa. However, when we look at AI’s role in healthcare, it is still a relatively new technology, where adoption remains in its infancy. From hospital care to clinical research, drug development and insurance, AI applications are revolutionising how the health sector works to reduce spending and improve patient outcomes. Artificial Intelligence in Healthcare The healthcare industry is ripe for some major changes. From chronic diseases and cancer to radiology and risk assessment, there are nearly infinite opportunities to leverage technology to deploy more precise, efficient, and impactful interventions at the right moment in a patient’s care. Population growth, ageing societies, and changing disease patterns are expected to drive greater demand for well-trained health workers in the next 15 years. The global economy is projected to create around 40 million new health sector jobs by 2030, mostly in middle- and high-income countries. But despite the anticipated growth, there will be a projected shortage of 18 million health workers needed to achieve the UN Sustainable Development Goals (SDGs) in low- and lower-middle-income countries, fuelled in part by labour mobility, both within and between nations.1 As payment structures evolve, patients demand more from their providers, and the volume of available data continues to increase at a staggering rate, artificial intelligence is poised to be the engine that drives improvements across the care continuum.

The use of AI in the healthcare market is growing due to the continued demand for wearable technology, digital medicine, and the industry's overall transformation into the modern, digital age. 54 Journal for Clinical Studies

Hospitals and healthcare professionals are seeing the benefits of using AI in technology and storing patients' data on private clouds, like the Google Cloud Platform. AI allows doctors and patients to more easily access health records and assess a patient's health data that is recorded over a period of time via AI-infused technology. Here are some of the areas where AI is already starting to transform healthcare, and others where experts expect it to revolutionise the sector in coming years.

Applying artificial intelligence has three basic dimensions: productivity aspects or transforming care delivery by optimising workflows and enlarging precision medicine by decreasing unwarranted variations and developing diagnostic accuracy. There are several ways artificial intelligence will revolutionise the delivery and science of healthcare. Combining Mind and Machine through Brain-computer Interfaces Computers in today’s day and age are used as a medium for communication, however using this medium to create a direct interface between the human mind and technology without the monitor and keyboard is a cutting-edge area of research that has significant applications for some patients. Neurological diseases and trauma to the nervous system can take away some patients’ abilities to speak, move, and interact meaningfully with people and their environments. Brain-computer interfaces (BCIs) backed by artificial intelligence could restore those fundamental experiences to those who feared them lost forever.3 Developing the Next Generation of Radiology Tools For non-invasive visibility into the inner workings of the human body, radiological images obtained by MRI machines, CT scanners, and x-rays work. However, for many diagnostic processes, physical tissue samples are still obtained through biopsies, which carry risks with the potential for infection. For this, artificial intelligence will enable the next generation of radiology tools that are accurate and detailed to replace this need for tissue samples in some cases. Artificial intelligence is helping to enable “virtual biopsies” and advance the innovative field of radiomics, which focuses on harnessing image-based algorithms to characterise the phenotypes and genetic properties of tumours. Volume 11 Issue 5

Logistics & Supply Chain Management Expanding Access to Care in Underserved or Developing Regions Shortages of trained healthcare providers, including ultrasound technicians and radiologists, can significantly limit access to life-saving care in developing nations around the world – currently 154 nations. Because of artificial intelligence, several tasks can be taken over that are typically allocated to humans. For example, AI imaging tools can screen chest x-rays for signs of tuberculosis, often achieving a level of accuracy comparable to humans. This capability could be deployed through an application available to providers in low-resource areas, reducing the need for a trained diagnostic radiologist on site. Reducing the Burdens of Electronic Health Record Use Electronic health records have played an instrumental role in the healthcare industry’s journey towards digitalisation, but the switch has brought numerous problems associated with cognitive overload, endless paperwork, and user burnout. Electronic health records developers are now using artificial intelligence to create more natural interfaces and automate some of the routine processes that consume so much of a user’s time. Voice recognition and dictation are helping to improve the clinical documentation process. Artificial intelligence can also help to process routine requests from the inbox, like medication refills and result notifications. Bringing Intelligence to Medical Devices and Machines Smart devices are taking over the consumer environment. In the medical environment, smart devices are crucial for observing patients in the ICU and elsewhere. Using artificial intelligence to improve the ability to identify deterioration or understand the development of complications can significantly improve outcomes and can also possibly reduce costs that will be related to hospitalacquired conditions.

with its size, creates a strong potential for the country to become an AI leader in the region by attracting the right investment. The country’s existing research and development infrastructure is combined with ease of doing business. And with the overall readiness of consumers to adopt AI, this allows it to attract considerable investment in AI-based technologies. The resulting push towards AI the government is able to attract implies that the short-term gains from AI are potentially larger in the UAE as compared to the rest of the region. In 2019, the UAE Cabinet officially approved an ambitious strategy that aims to help place the country at the forefront of global efforts to develop artificial intelligence. The plan is comprised of eight objectives, including reaffirming the UAE's position as a global artificial intelligence (AI) hub, employing AI in customer services and recruiting and training people to work in fields which will be driven by the technology for years to come. This strategy is the first of its kind in the world and covers the development and application of advanced technologies in nine sectors including transport, health, space, renewable energy, water, technology, education, environment, and traffic. The UAE healthcare market is expected to grow 12.7%, to nearly US$20BN (AED 71.56BN) by 2020. The UAE leads the top 20 countries in the world with US$1200 per capita spend on healthcare (AED 4400), which is indicative of residents’ trust in local medical establishments.4 In the healthcare sector, new technologies are being slowly introduced to test its effectiveness. For example, the Government of UAE is currently testing and introducing the following new innovations into healthcare: • The body of health analysis pods to be rolled out in government buildings to assist the staff to monitor health and detect early any signs of illnesses. • An application by Babylon, which uses AI to provide 24/7 video consultancy to patients from all around the world will be soon available in UAE. • Health Care and Innovative New Technology (HINT) neuro band helps detect strokes; and • The flow cell sensors by Admetsys to alert doctors to sudden drops in the vitals of ICU patients.5 With all these advancements across UAE and around the world, these are some of the great things that AI can do. But it is not limited to that. As innovation pushes the boundaries of healthcare, better solutions to save time, money, and inefficiency will be possible. REFERENCES

Examining Health through Wearables and Personal Devices From smartphones with step trackers to wearables that can track a heartbeat around the clock, a growing proportion of health-related data is generated on the go. Collecting and analysing this data – and supplementing it with patient-provided information through apps and other home monitoring devices – can offer a unique perspective into individual and population health. Artificial intelligence will play a significant role in extracting actionable insights from this large and varied treasure of data. Artificial Intelligence for Healthcare in UAE AI will have a significant impact on the economy of UAE as it continues to show indications of audacious shifts in the rule of law to make innovation and investment in artificial intelligence. Given the rate at which AI technology is growing and the region’s overwhelmingly young and tech-savvy population, it is certain that the significant economic benefits that will be reaped from AI will far outweigh any societal concerns. The emerging government focus on AI, combined

1. 2. 3. 4. 5. Artificial+Intelligence+In+Healthcare+Sector+In+UAE

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

Journal for Clinical Studies 55

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