Page 1

Volume 11 Issue 4


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets


An Insight into Conducting Clinical Trials in Lithuania and Latvia Improving Medicines for Children with Advancements in Paediatric Clinical Research eConsent: Tearing Down Barriers to Oncology Trials Exploring the Complexities of Importer of Record to Develop Effective Global Distribution Strategies


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.








Your Resource for Multisite Studies & Emerging Markets


U CLINICAL STUDIES MANAGING DIRECTOR Martin Wright PUBLISHER Mark A. Barker EDITORIAL MANAGER Freya Gavaghan 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


WATCH PAGES FDA Expands Eligibility for Cancer Trials in Five Guidance Documents

To broaden patient participation in cancer clinical trials, the US Food and Drug Administration (FDA) in March released four draft guidance documents on cancer clinical trial eligibility criteria, and one final guidance document on including adolescents in adult oncology trials. Bronwyn Mixter, Clarivate, identifies how these guidance documents provide recommendations on how sponsors can safely and effectively broaden clinical trial criteria to include certain patient populations. 8

Successful Studies Start at Feasibility

Study failure is every sponsor’s biggest nightmare, and there are multiple reasons why it could happen. These may include a failure to properly recruit the correct study patients, missing study-critical data, or the drug not demonstrating the anticipated efficacy. Although there are few solutions when the drug does not exhibit its predicted efficacy, other risks to failure can be minimised or avoided by carefully identifying the study’s potential pitfalls when planning it. Katrien Timmermans of SGS details how studies can be planned to minimise the risk of failure. 10 The Power of Mobile Technology to Optimise Patient Engagement and Study Success In post-industrial countries, the average person spends five hours a day on their smartphone – and cancer patients are no exception. As such, it is a powerful tool that can be used to tear down barriers to participation and optimise patient engagement throughout the lifespan of a clinical trial – from enrolment to treatment and completion. Neetu Pundir of Signant Health explores how mobile technology holds a window to a future of clinical trials built on partnership between study organisers and participants. 12 The Changing Face of Site Feasibility: Why a New Clinical Trial Landscape Demands Greater Collaboration and Flexibility Travis Caudill of Worldwide writes that clinical research professionals have witnessed a shift in the industry’s approach to clinical trials over the past decade. Large-scale, global trials that encompass hundreds of sites and many thousands of patients continue to give way to more narrowly defined studies focused on rare diseases, orphan indications, and the promise of genetic-level advances. This shift not only puts patient access at a premium but also forces us to reconsider our site selection values.

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 4 July 2019 PHARMA PUBLICATIONS

REGULATORY 14 Improving Medicines for Children with Advancements in Paediatric Clinical Research Much progress has been made in paediatric medication development since the implementation of paediatric legislation in the US and EU. Marketing authorisation for new medicines, as well as applications for modification of existing registrations under patent, must include paediatric assessments as described in a paediatric study plan, unless it is exempt due to deferral or waiver, or the medicine does not fall under the scope of the paediatric regulations. Dr Martine DehlingerKremer of Synteract asks: how are regulatory authorities working to improve paediatric drug development? Journal for Clinical Studies 1

Contents 18 Regulatory Convergence and Harmonisation Activities in Latin America

40 The Increasing Importance of Clinical Education in the Rare and Orphan Disease Sector

As demonstrated by numerous initiatives globally, cooperation and convergence activities among national regulatory authorities (NRAs) accelerate the drug development process, improve access to medicines and contribute greatly to public health. Regulatory convergence and harmonisation activities – and the common guidance documents they often produce – are particularly important in emerging regions, where many NRAs often lack the requisite infrastructure and resources needed to regulate medicines efficiently and effectively. Adam Istas, DIA, examines this in relation to Latin America specifically.

Diagnosing and treating rare and orphan diseases remains one of the life science sector’s great challenges. This is compounded by small patient populations, which are difficult to access and lead to significant challenges for the healthcare industry in rare disease management and support of these patient populations. Nagore Fernandez, Ashfield, identifies how rare disease patients require a more personalised approach than those with common conditions, and often these patients extensively self-educate about their condition.



22 An Insight into Conducting Clinical Trials in Lithuania and Latvia

42 eConsent: Tearing Down Barriers to Oncology Trials

Christene Leiper of Onorach examines clinical trials in Latvia and Lithuania, which have been conducted since the early 1990s. The number of studies has increased every year, reaching a peak in 2008 when 105 new clinical trials authorisations were issued in Lithuania, and 88 in Latvia. Despite a decline in the authorisation of new clinical trials due to the global economic crisis, the new clinical trial application dynamics can now be considered as stable, with 244 ongoing studies in Lithuania and 196 in Latvia.

Despite more people surviving cancer than ever before, a staggering 9.6 million people worldwide died from cancer in 20181, making the need for new drugs a global priority. With the search for new treatments stepping up, patient technology and systems that can improve recruitment and retention while contributing to the collection of cleaner, more compliant data are in demand. Bill Byrom et al. of Signant Health discuss how eConsent, when implemented well, has the potential to help companies rise to the challenge by removing some of the common barriers to clinical development.

26 Designing Clinical Trials to Support Pharmaceutical Reimbursement

46 Utilising Large Data Sets and Extended Trial Observations to Close the Alzheimer’s Evidence Gap

The use of health technology assessments (HTAs) to determine whether a healthcare technology should be paid for and at what price is well established in most countries. The evidence requirements of HTA authorities go beyond those of regulatory authorities. Maximilian Lebmeier of Athena Market Access Solutions and Keith Tolley of Tolley Health Economics discuss how, whilst methods for HTAs vary across jurisdictions, assessments of comparative effectiveness of the new technology vs. the standard of care are common and utilise data from clinical trials that are being used for regulatory submissions.

One of the most widely recognised limitations of traditional randomised clinical trials (RCTs) is that the observation period and treatment courses reflect only a fraction of the natural history/ progression of the disease being investigated on an often miniscule and idiosyncratic subset of patients. Henry J. Riordan et al. of Worldwide explore how to close the evidence gap between the data evaluated by regulators for approval, which is by definition derived from idiosyncratic RCTs, and the real-world data used by healthcare providers, payers and consumers to inform clinical practice.

30 Haemovigilance System in the EU and Japan: An Overview Sridhar S et al. of JSS College of Pharmacy consider the haemovigilance system, which must include all appropriate stakeholders and coordinate between blood transfusion service, clinical hospital staff and transfusion labs, hospital transfusion committees, national regulatory agency and national health authorities. The resulting changes in transfusion policies, standards and guidelines, as well as improvements in blood services processes and hospital transfusion practices, result in improved patient safety.

LOGISTICS & SUPPLY CHAIN MANAGEMENT 52 Exploring the Complexities of Importer of Record to Develop Effective Global Distribution Strategies The pharmaceutical sector’s fundamental purpose of advancing human health and its ambition to deliver drugs to market as rapidly, safely and cost-effectively as possible has had a transformative impact on clinical trials management over the last decade. Sharon Courtney of Almac Group explores how this has given rise to globalisation, with the average Phase III trial now spanning 34 countries, with in excess of 1000 patients.

THERAPEUTICS 36 Combination Approaches in Immuno-oncology Trials: New Horizons for Multiple Tumour Indications With an ever-increasing amount of clinical trials reporting significant benefits in long-term overall survival of patients with specific cancers following mono-immunotherapy, the goal has shifted to attaining higher response rates in broader patient populations by employing immuno-oncology (IO) combination approaches. Oana Draghiciu et al. of SMS-oncology present research aimed to shed light on the discovery of effective IO combinations and specific tumour indications in which they can attain durable and long-lasting anti-tumour immune responses, by anticipating new developments in the IO field and identifying trends. 2 Journal for Clinical Studies

Volume 11 Issue 4

Clinical Study Documents

The Medical CRO

Medical Writing Services

Phase I-IV Study Protocols, Synopsis, Amendments

Clinical Development Plan

Investigator’s Brochures, SOPs

Safety Narratives


Regulatory Documents •

Phase I-IV CSR

Aggregate and Safety Reports

Risk Management Plan (RMP)

Product Monograph, Label & SmPC

Common Technical Document (CTD)

documentation requirements

Global Clinical Trial Applications

and marketing activities.

Marketing Applications

Europital offers a wide range of medical writing services to




needs, clinical research project

Europital Medical Writers have a wide breadth of knowledge

Medical Communication & Publications

and experience drawn from

Manuscripts, Posters, Abstracts


Promotional & Educational Materials: Print, PPT, Animation, Video and more...

Medical Marketing Reviews & Reports

Medical & Scientific Literature Reviews

White Papers



clinical research organizations and academia. Our













medical experts. All developed documents undergo thorough scientific




in-house Europital Physicians.

For more information about Europital and available medical services, visit:

Foreword With our fourth edition of the year, we have chosen to focus on Latvia and Lithuania for our country-specific market report, with the national flower of Lithuania being featured on our front cover. Christene Leiper of Onorach has contributed an interesting summary of these regions, titled ‘An Insight Into Conducting Clinical Trials in Lithuania and Latvia’. Despite the small population of these two countries, she regards them as compelling areas for clinical trials, with clinical research having been conducted there since the early 1990s. This number has increased every year – despite a fall during the global economic crisis – however, now the number of ongoing trials is continuing to grow. After joining the European Union, both countries implemented EU GCP Guidelines into their national legislation, with central ethics committees (CECs) overseeing the ethical reviews of clinical trials in each country. The majority of clinical studies in both countries are Phase III, and historically, most clinical research is within oncology. Leiper also touches on clinical research in Russia, describing the market as having compelling potential with a large population, as well as many medical centres with qualified doctors and appropriate research equipment. She looks at the regulatory analysis in Russia, federal laws, government decrees, orders, study designed protocols and logistics. In our Regulatory section, we have an excellent article by Dr Martine Dehlinger-Kremer of Synteract, titled ‘Improving Medicines for Children with Advancements in Paediatric Clinical Research’. She explores how regulatory authorities are working to improve paediatric drug development, and what still needs to be done in this area. The article examines historical progress in the US and the EU, as well as global collaboration and collaboration between the US and EU. She concludes that progress is still welcomed, and that even with the advancements she details there is plenty of room for improvement. Over half of medicines administered to children have not been tested on children, and further support is needed once a drug enters the market. Dr Dehlinger-Kremer also touches on Brexit, asking if Brexit will go into effect, with the impact it could have on clinical research for both paediatrics and adults still being unknown. Paediatric development is now part of drug development, with global paediatric research being on the rise to ensure more medicines are developed for children in need. For Therapeutics, we have featured a piece on ‘Combination Approaches in Immuno-oncology Trials: New Horizons for Multiple Tumour Indications’. This article, by Oana Draghiciu et al. of SMS-

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

oncology looks at how immuno-oncology (IO) combination approaches can create higher response rates in broader patient populations. They present the results of a quantitative and qualitative analysis on Phase II, II/III and III trials which were commenced at the beginning of January, 2019. The authors detail the study methods used and study results, as well as the top five combination therapies assessed in IO trials. They also look at the tumour indications in IO combination trials, as well as discussing future directions of cancer immunotherapy. Their research revealed that IO combination trials initiated in the last five years yielded certain trends, including an exponential increase in the number of trials, a substantial decrease in biomarker use, and all top five therapies assessed having used ICIs (immune checkpoint inhibitors), mainly targeting PD-1 and PD-L1. Henry J Riordan et al. of Worldwide look at ‘Utilising Large Data Sets and Extended Trial Observations to Close the Alzheimer’s Evidence Gap’, in our Technology section. They have provided an extensive piece which details options, alternatives and enhancements to traditional RCTs and options for covering a greater proportion of the patient journey and increasing data dimensionality. They also provide an example of utilising large integrated data sets to limit loss to follow-up and extend observations in an early AD RCT, as well as an example of possible data sets and their utility in AD trials. The writers conclude with a discussion of how large data sets have renewed interest in using real-world data to supplement RCTS and bridge the evidence gap between research and clinical practice, with the FDA encouraging the development of new approaches to evaluating early AD. Finally, in Logistics & Supply Chain Management, we have a fantastic article by Sharon Courtney of Almac on ‘Exploring the Complexities of Importer of Record to Develop Effective Global Distribution Strategies’. She explains how to understand the role of Importer of Record as well as how to identify the common pitfalls, identify country-specific nuances and embrace Importer of Record best practice. She concludes that a competent Importer of Record is a prerequisite to any successful global clinical supply chain and summarises how sponsors can develop better and more efficient global clinical distribution strategies. That rounds off our fourth edition of the year – we hope you enjoy your last month of summer and will be in touch with another edition in autumn!

Freya Gavaghan, Editorial Manager 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

Volume 11 Issue 4

Linguistic Validation & COA Services RWS Life Sciences has deep experience with COA usage in clinical trials, and we specialize in helping our clients navigate COA and eCOA challenges. Our PRO, ClinRO, ObsRO, and PerfO translations are culturally and conceptually equivalent to the source instrument.

Partner with us for Expertise and specialization in eCOAs Experience translating COAs that spans a variety of therapeutic areas. Managing the entire life cycle of your COA translations, saving you time and increasing ROI. COA repository management, copyrights, and licensing management, and more.

Explore Our Industry-Leading Research Patient-reported Outcome Measure Translation: An Overview Usability Testing: Ensuring User–friendly Data Collection in Clinical Trials Translation and Comprehension of Disease Activity An Investigation of Issues in the Translation and Comprehension of the Terms “Self-conscious” and “Embarrassed” in Patient Reported Outcome (PRO) Measures Follow us for early alerts about new research!

Journal for Clinical Studies 5

Watch Pages

FDA Expands Eligibility for Cancer Trials in Five Guidance Documents To broaden patient participation in cancer clinical trials, the US Food and Drug Administration (FDA) in March released four draft guidance documents on cancer clinical trial eligibility criteria and one final guidance document on including adolescents in adult oncology trials. These guidance documents provide recommendations on how sponsors can safely and effectively broaden clinical trial criteria to include certain patient populations—in particular, paediatric patients, patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infections, and patients with brain metastases. “A clinical trial that’s more representative of the patient population can maximise the generalisability of the trial results and the ability to understand the therapy’s benefit-risk profile across the patient population likely to receive the drug in clinical practice,” former FDA Commissioner Scott Gottlieb, MD, said in a March 12 statement. The four draft guidance documents, which were developed by the FDA with input from the American Society of Clinical Oncology and the Friends of Cancer Research, include: • Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients; Draft Guidance for Industry • Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus or Hepatitis C Virus Infections; Draft Guidance for Industry • Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies; Draft Guidance for Industry • Cancer Clinical Trial Eligibility Criteria: Brain Metastases; Draft Guidance for Industry The final guidance, Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials, is the final version of the draft guidance of the same name issued on June 4, 2018. All five of the guidance documents note that sponsors should provide rationale for cases in which it is suitable to exclude patients from a given trial protocol. Minimum Age for Paediatric Patients The draft guidance on paediatric patients discusses the minimum age eligibility criteria in cancer clinical trials and addresses specific situations in which the inclusion of paediatric patients may be appropriate based on disease biology and clinical course, the molecular target of the investigational drug, and/or its molecular mechanism. According to the draft guidance, the eligibility of a specific paediatric population for a cancer clinical trial should be considered 6 Journal for Clinical Studies

when there is clinical evidence or a strong scientific rationale to suggest that paediatric patients with a specific cancer diagnosis, histologic subtype, or tumour associated with the same relevant molecular target may benefit, and when there is compelling nonclinical and/or adequate clinical information to sufficiently justify patient risk. Considerations for Patients with HIV, HBV, or HCV Infections Making cancer trial eligibility more inclusive of patients with HIV, HBV, or HCV infections is justified in many cases and may accelerate the development of effective therapies in cancer patients with these infections, according to the draft guidance on this topic. Eligibility criteria that address requirements regarding concurrent antiviral and other therapies and the degree of immunocompetence in patients with HIV, HBV, or HCV infections should be designed in a manner that is appropriate for a particular type of cancer, investigational drug, and intended use population, the draft guidance says. Considerations for Patients with Organ Dysfunction, or Previous or Concurrent Cancers By excluding patients from cancer clinical trials who have major organ dysfunction or previous or concurrent cancers, trials favour younger patients and may not fully represent the population for whom the drug will be indicated, as noted in the draft guidance on this topic. When it comes to patients with organ dysfunction, the draft guidance says that where pharmacokinetics (PK) and major routes of elimination in humans are not well understood, it is reasonable to only enroll patients with relatively preserved organ function in cancer clinical trials. However, as data on toxicity, PK, and/or pharmacodynamics (PD) become available during drug development, protocols should be revised to include patients with compromised organ function where safe parameters regarding dosage adjustments have been determined, according to the guidance. Patients with prior or concurrent second primary malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug should generally be eligible for enrolment in clinical trials, the draft guidance says. Considerations for Patients with Brain Metastases Clinical trials generally have either excluded all patients with known brain metastases or restricted enrolment to subgroups of those patients (e.g., those with treated and clinically stable brain metastases), the draft guidance on this topic mentions. Excluding patients with brain metastases may result in the assessment of an investigational drug’s efficacy or safety that does not fully represent the patient population that will be prescribed the drug in clinical practice. Volume 11 Issue 4

Watch Pages

According to the draft guidance, patients with brain metastases should be included in clinical trials in a way that contributes to a greater understanding of the efficacy and safety profile of the investigational drug while maintaining patient safety. Patients with cancers that commonly metastasise to the brain should be included in early drug development trials, either in separate cohorts or in cohorts with planned subset analyses to assess preliminary efficacy and toxicity in patients with brain metastases. Inclusion of Adolescents in Adult Oncology Clinical Trials The FDA recommends the inclusion of adolescent patients in diseaseappropriate and target-appropriate adult oncology clinical trials to enable earlier access to investigational and approved drugs for adolescent patients with cancer, according to the draft guidance on this topic. The draft guidance discusses the following topics: •

appropriate criteria for the inclusion of adolescent patients in adult oncology clinical trials at various states of drug development;

• • •

dosing and pharmacokinetic and pharmacodynamic evaluations; safety monitoring; and ethical considerations.

Bronwyn Mixter Bronwyn Mixter is a Medical & Regulatory Writer for the Cortellis Regulatory Intelligence US Module at Clarivate Analytics. Previously, she was a reporter for Bloomberg BNA covering the pharmaceutical industry and the FDA. Her primary assignments at Clarivate include reporting on FDA drug/device advisory committee meetings and drug approvals for Cortellis and the AdComm Bulletin. Email:

Journal for Clinical Studies 7

Watch Pages

Successful Studies Start At Feasibility

Study failure is every sponsor’s biggest nightmare, and there are multiple reasons why it could happen. These may include a failure to properly recruit the correct study patients, missing study-critical data, or the drug not demonstrating the anticipated efficacy. Although there are few solutions when the drug does not exhibit its predicted efficacy, other risks to failure can be minimised or avoided by carefully identifying the study’s potential pitfalls when planning it. This planning must start at the feasibility assessment stage, where the study is reviewed from multiple angles by the different cross-functional stakeholders. This process ensures that the investment made to conduct the study has the best opportunity of producing the reliable and reproducible data required for further development decisions and market registration. Country and Site Choice Feasibility usually starts prior to the study being awarded to the contractor by the sponsor, and typically, significant emphasis is placed on the identification of the region and countries where the study can be best conducted and on the estimation of the recruitment rate. The choice of regions and countries is in part driven by access to the required trial population, which in itself is determined by the prevalence of the indication, and also by the accessibility of medical treatments covered by private insurance or government-subsidised healthcare. Pre-existing treatments for the target indication can create competition for enrolment of patients; thus, the challenge for investigators who strongly believe in a new drug is to inspire their patients to participate in the study, despite the currently available standard of care regimens.

Therefore, benchmarking an upcoming study to similar - ideally identical – studies is an essential exercise in the enrolment rate evaluation. Study Specifications - Recruitment and Retention During this benchmarking exercise, a number of study specifications should be considered that may potentially affect recruitment rates. These may include the inclusion and exclusion criteria, prohibited medications, stipulated (invasive) procedures, the compound’s or device’s mechanism of action, the route of administration, and the burden for sites and patients. Engaging with one or more clinical specialists in the field may also add significant value in this assessment, as will feedback from sites on their experiences in similar studies in setting expectations. This becomes especially important at the final site selection step where each site’s commitment must be considered individually in light of their previous recruitment performance, and how this may translate to the new study. Overall study timelines can be developed from extrapolating the anticipated country/site distribution and recruitment rate analysis. The study’s operational team can subsequently translate the feasibility parameters into a logistics execution plan to ensure targets are met. As for recruitment, four significant barriers are acknowledged and must be adjusted for: • •

subject-related (how the subject’s perspective may impact their desire to enter the study); investigator-related (confidence in and motivation to conduct the study); protocol-related (design aspects which create complications); serendipity (a fourth, miscellaneous category which serves as a catch-all, for example, a delayed or extensive approval timeline).

Additionally, the importance of the availability of wellorganised study sites in chosen regions and countries should not be underestimated, as paradoxically, countries with a high prevalence of the disease, but only with access in the main to poorly-organised sites with limited or no coordination of services, will have challenges recruiting subjects even in seeminglystraightforward studies. Conversely, well-structured sites with dedicated recruitment staff offer the necessary connections with specialists and patient identification methods, even where a lower prevalence of the target population is evidenced.

• •

Countries where trials in the same or similar indications have previously taken place are often well-suited to be shortlisted, as it implies that sites are available in those countries which have the necessary experience in recruiting the required population. However, the impact of potentially competitive studies seeking to recruit from the same patient pools also needs to be factored in, since such studies may substantially reduce the number of available sites that can adequately recruit in a timely manner.

Similarly, the retention of subjects needs to be addressed early in the process and evaluated on an ongoing basis throughout the study until the last patient’s final visit occurs. This is an area frequently overlooked by study teams, as the majority of sponsors place a primary focus on enrolment timelines; however, executing a study successfully goes far beyond merely enrolling the study as expected.

Following on from country and site investigation, recruitment rates are the second critical parameter in the feasibility evaluation. Past experience is a good indicator of what will happen in the future – ‘the best predictor of future performance is past performance’ (Paul Meehl), provided that the context is similar. 8 Journal for Clinical Studies

To identify items in each of the categories along with proactive mitigation measures, stakeholders from the applicable functional areas participate in brainstorming sessions. This core team reconvenes routinely during recruitment to re-evaluate the barriers and approaches against the overall progress.

Achieving High-quality Study Results Requires Meaningful Data Simply completing the enrolment portion is not what ultimately ensures confidence in the data following analysis; it is the quality of the data collected throughout the study for all those enrolled that will eventually drive the merit of the analysis. Efforts that Volume 11 Issue 4

Watch Pages

focus on optimising operational performance are required to deliver high-quality study results. In this, it is imperative to evaluate how the study’s endpoints, and in particular, primary and main secondary endpoints, can be protected. Endpoints may be objective (e.g. plasma viral load); subjective (e.g. quality of life questionnaire); or a combination of both (e.g. lung function spirometry tests where the participant and operator need to be properly trained and be familiar with the process to gain optimal results). Each one has its own critical nature and it is essential to start evaluating and discussing management and mitigations early on in the process with all stakeholders involved, including vendors. A good example is where the feasibility team may suggest the use of an electronic clinical outcome assessment (eCOA) device to capture a specific endpoint. If paper back-ups are requested by the sponsor, this not only implies development, printing and shipment of the paper back-up, but also the need to identify upfront who will be responsible for the data transfer into the database. This may be the study site, eCOA vendor or data management vendor, but each may impact the risks, resources, timelines and cost to the study in a different manner.

Ensuring that a study has the greatest chance of success starts well ahead of the commencement of the clinical trial itself. It begins with meticulous planning and undertaking robust feasibility assessments at an early stage with a multidisciplinary team comprising experienced, knowledgeable and forthcoming stakeholders, who drive the project, and are willing to assess and plan for each potential eventuality.

Katrien Timmermans Katrien Timmermans graduated as a medical doctor from the University of Leuven in 2001. Soon after, she joined SGS’s Clinical Pharmacology Unit in Antwerp as a clinical research physician, before joining an Asian-Pacific CRO. She re-joined SGS in 2012 to launch the feasibility department, which she led for four years. She obtained a Diploma in Pharmaceutical Medicine from the Free University of Brussels in 2018 before moving into her current position of Medical Director, Clinical Operations.

Journal for Clinical Studies 9

Watch Pages

The Power of Mobile Technology to Optimise Patient Engagement and Study Success In post-industrial countries, the average person spends five hours a day on their smartphone – and cancer patients are no exception. The device is within arm’s-reach for over 19 hours a day. It’s checked within moments of waking and viewed more than 500 times in any 24-hour period. In short, a person’s mobile phone is a direct link to them, all day every day.1 As such, it is a powerful tool that can be used to tear down barriers to participation and optimise patient engagement throughout the lifespan of a clinical trial – from enrolment to treatment and completion. With fewer than five per cent of oncology patients2 taking part in clinical trials, and many of those who do sign up dropping out along the way, it’s a tool that should not be left on the shelf. Mobile is Everywhere The use of mobile technology in oncology studies is becoming more and more common, most notably in collecting patientreported outcomes. But despite its ability to improve patient engagement throughout the life of a trial, it isn’t widely utilised in this area. By embracing this potential, companies and sponsors can reap the rewards of engagement while positioning themselves as leaders in this emerging technology. We all know how integral mobile technology has become to our daily lives. For many people, their smartphone is the last thing they look at before they go to sleep and the first thing they see when they wake up in the morning. Utilising mobile technology, then, offers trial organisers more visibility than any other platform. Tapping into this direct line allows sponsors and CROs to seamlessly introduce multimedia protocol instructions and make trial activities part of patients’ everyday lives in trial.

Aside from its ubiquitous nature, the joy of mobile is its adaptability. It can provide information through the use of interactive text, graphics, animation or video to convey information and meaning. Each communication can be tailored to maximise comprehension. Empowered participants who fully understand the study and their role within it, are more invested in its success and less likely to drop out. Mobile can also provide direct connectivity with individuals and services, simplifying and organising activity, and making life easier. Building Clinical Trial Mobile Technology that Works Building mobile solutions that oncology patients want to engage with is about more than technology for technology’s sake. When setting out on a mobile technology journey, it’s important to consider how the applications being designed will be received by the end user – because that is what, ultimately, will build engagement. Is it Easy to Use? In complex, multi-faceted oncology studies, patients have been asked to interact with multiple websites, apps, text messages and emails. This can be overwhelming, and impact negatively on engagement. Fortunately, we are now moving way beyond simply delivering a range of disparate apps. Innovators are designing seamless integrations that bring multiple functions into one digital touchpoint for the study. It means that ePRO and eCOA data capture, eConsent, patient payments, courier and travel services, home health nursing and much more are no longer separate online entities. Study participants can receive visit schedules and alerts regarding their visits and dosage via a single application and feel safe in the knowledge that they can communicate with sites when they need to.

Driving Participation and Engagement Patients value the application of technology in clinical trials because it can reduce the burden studies place them under. This is particularly true in oncology, where protocols, symptoms and treatment-related side-effects are complex and difficult to cope with. According to a study conducted in conjunction with PMG Research,3 31 per cent of people would be more likely to participate in a study knowing that a mobile app would be available. Many study participants are also consumers who are used to conducting much of their lives through their mobile phone. When taking part in a clinical trial, then, they expect a coherent experience that optimises and organises their participation. 10 Journal for Clinical Studies

Volume 11 Issue 4

Watch Pages

Cancer patients have enough to deal with, so it’s up to study organisers to make participating as easy as possible. Combining as many trial activities as they can into a single app is an important step on that journey. Is it Credible? Ensuring technological solutions are designed to be intuitive and clean will help participants understand the importance of the trial as well as give a good impression of its quality. This, in turn, will build personal investment and patient engagement. Is it Creative? Visit reminders, medication compliance alerts and study notifications are the nuts and bolts of mobile clinical trial technology. But it doesn’t have to stop there – and nor should it.

And with growing evidence that patient engagement is synonymous with increased retention and greater per-patient ROI, it is a future the industry cannot afford to miss. REFERENCES 1.



A Decade of Digital Dependency. (2018, August 2). Retrieved from decade-of-digital-dependency The Basics of Clinical Trials. (2016. May 3). Retrieved from https://www. what-you-need-to-know/clinical-trial-basics.html PMG Research Web-based Patient Panel Survey – August 2016 (137 respondents)

Gamification can boost understanding of study outcomes or aid the adoption of the healthy behaviours that are so important for people undertaking a cancer journey. Controlled image capture can assess dermatological side-effects or injection site reactions. Trial instructions can be supported by illustrated or video guides developed by the trial team. Other possibilities include providing access to lay summaries or other relevant data, or images that are culturally appropriate to different participating countries. Trial updates, like patient completion and regulatory submission, as well as simple expressions of gratitude towards patients, can also be shared. All this builds engagement by helping the patient derive value from their participation and understand how much the study appreciates their input. Summary The cancer treatment landscape is advancing all the time, and the future is bright. But continued progress depends on successful clinical trials, and successful clinical trials depend on engaged patients. Innovators are pushing the boundaries of what is possible through mobile technology. The results hold a window to a future of clinical trials built on partnership between study organisers and participants.

Neetu Pundir Neetu Pundir is an experienced product and brand manager with prior professional experiences across the globe in the healthcare and life sciences industry, working for companies such as Johnson & Johnson, BIOTRONIK Medical Devices, Henry Schein, and eResearch Technology. Neetu is currently employed as the Go To Market Director at Signant Health and manages the product strategy for the company’s electronic consent solution TrialConsent®. Neetu has a Master’s in Business Administration with degrees from Northwestern University, USA and the University of New South Wales, Australia.

Journal for Clinical Studies 11

Watch Pages

The Changing Face of Site Feasibility

Why a new clinical trial landscape demands greater collaboration and flexibility Clinical research professionals have witnessed a shift in the industry’s approach to clinical trials over the past decade. Large-scale, global trials that encompass hundreds of sites and many thousands of patients continue to give way to more narrowly defined studies focused on rare diseases, orphan indications, and the promise of genetic-level advances. This shift not only puts patient access at a premium but also forces us to reconsider our site selection values. Today, sponsors and clinical research organisations (CROs) must assess the methodologies used to conduct feasibility studies for site selection. Traditional tactics treated the evaluation of clinical sites much like a competitive battle to see who came out on top. This will no longer suffice for trials in which the global patient pool consists of hundreds of candidates – or even fewer. Instead, we must ask ourselves, “How can we create a coalition that will get the research done?” In a field that has long prioritised attributes such as investigator/ staff experience and equipment and facility resources, sponsors and CROs must place patient access on top of the list of key selection criteria. The onus now is to be sure potential sites are not excluded due to lack of opportunity to participate in clinical trials. A deeper assessment can help foster mutually beneficial relationships between sponsors, potential sites, patients, and advocacy groups. It’s a framework for success that requires a new level of creativity and critical thinking, as well as building strong relationships. Traditional Feasibility Approaches, Proven Methodologies Understanding how the industry needs to evolve begins with appreciating proven feasibility methodologies. There is value in assessing all aspects of feasibility that have traditionally set a study up for success; CROs simply need to consider how and where the application of these approaches fits into smaller-scale initiatives. In the past, best practices dictated assessing the following categories for site suitability: • •

Previous performance history Investigator and staff experience (inclusive of competitive trial activity)

• • •

Access to patients Access to equipment/facilities/logistics Study start-up (inclusive of ethics, regulatory, import/export, etc.)

CROs conducting a feasibility assessment would likely have used a comprehensive questionnaire template that drilled down into hundreds of areas related to these categories. While access to patients has always been an important component, the matrix for establishing suitability would have placed high priority on the previous performance, investigator experience, and equipment/ facilities/logistics categories. Consider Fabry disease, a rare genetic condition that creates complications in key organs such as the kidneys, heart, and skin. Because the population of patients with Fabry disease is small and scattered across global geographies that lack clinical trial experience and resources, this approach would have automatically eliminated many sites that could provide essential patient access. Depending on the depth of the potential candidate pool, the need to re-engineer the selection process may vary. That’s why it’s important to keep proven methodologies at the forefront and weigh each category to establish the right recipe for an effective site selection strategy. Apply Flexibility to Feasibility Best Practices Determining how to balance traditional methodologies with the need for flexibility starts during the proposal process. As CROs conduct epidemiological and other assessments, key information regarding the size of the patient pool, geographies where patients are treated, and the care pathway patients follow, will surface. This data should inform a strategic roadmap that covers tactics for collaborating with patient advocacy groups, partnering with clinical sites, and building strong patient relationships. For example: On the country level, feasibility for a study related to Fabry disease should start with an understanding of the geographical footprint. A quick review would reveal that many of the countries where patients with Fabry disease are located lack clinical sites and investigators with clinical trial experience. As the feasibility assessment progresses, however, the CRO might notice that some of these countries have broader experience in gene

Example: Worldwide Opportunity Matrix 12 Journal for Clinical Studies

Volume 11 Issue 4

Watch Pages therapy trials. Although not directly associated with Fabry disease, such experience could prove advantageous as these studies allowed regulatory authorities to evaluate the complexity of increasingly complex risk/benefit profiles for patients. The CRO would then be able, and arguably obligated, to provide the proper training and support for these research-naïve sites. The key is to develop a ranking matrix to evaluate the country or site opportunity. While “experience” may only rank as “medium” on the country opportunity matrix, high access to patients may ultimately offset the experience score. A CRO would then know where it needs to fill in the gaps. It might want to help

inexperienced partners by providing additional education, best practice recommendations, and oversight, for example. The approach to feasibility on the site level would be similar and would include a review of equipment and logistics. For some indications, ranking low in this area is a deal breaker. With a rare disease, however, CROs might have opportunities to adapt strategy. Take a study protocol that requires access to an MRI machine, for instance. If a site lacks an MRI machine, the CRO may be able to arrange for screenings at another organisation, along with patient transportation resources. Ultimately, it’s important that CROs and sponsors avoid constraining feasibility studies. Consider all data to make the best decisions. Although the methodology empowering traditional feasibility has value, there are very few factors that should be true deal breakers for all studies. We need to embrace flexibility and creativity over efficiency and familiarity as we rise to meet the challenge these new studies present. Setting the Stage for Successful Partnerships The feasibility process is becoming more intimate as the industry works to bring more target trials and rare disease studies to patient populations quicker. Old strategies such as blasting out e-mails to hundreds of sites hoping to identify the ideal sites through volume and then bombarding those sites with a bloated survey of 150 questions will not set the right tone for a long-term partnership. Instead, CROs must invest in providing sites with improved customer service by providing single points of contact for the feasibility and site activation process. Additionally, sites might feel valued if they receive a short questionnaire with an embedded video that explains and showcases the mechanism of action and value proposition to potential patients who lack treatment options. Alternatively, in many situations, forgoing a questionnaire altogether and meeting face-to-face for a hybrid feasibility/prestudy site visit is ideal. Relationships are established through give and take, and strategies should be designed around the unique needs of the sites and the patient story. Investments in technology are needed to improve the experience for all stakeholders. An open mind to innovation sits at the heart of future feasibility success. CROs and sponsors should carefully evaluate where their preconceived assumptions come from and whether they still apply in today’s evolving landscape. Reaffirm effective methods, but throw out those based on older, broad-scope types of trials. With new thinking, the industry can raise the bar and increase the benefits for patients.

Travis Caudill Travis Caudill is the Vice President of Feasibility and Site Activation at Worldwide Clinical Trials, where he is responsible for a spectrum of activities, including early trial planning through the activation of sites. With over 15 years of experience, Mr. Caudill has worked in a number of feasibility and trial optimisation roles at Worldwide as well as at a large CRO since joining the industry in 2005. An expert in data-driven feasibility and enrolment modelling methodologies, Mr. Caudill is passionate about ensuring every study has an achievable enrolment plan, grounded in actionable data and updated throughout the trial life cycle.

Journal for Clinical Studies 13


Improving Medicines for Children with Advancements in Paediatric Clinical Research Much progress has been made in paediatric medication development since the implementation of paediatric legislation in the US and EU. Today, marketing authorisation for new medicines, as well as applications for modification of existing registrations under patent (such as addition of a new indication, new dosage form, new dosing regimen, new route of administration), must include paediatric assessments as described in a paediatric study plan, unless it is exempt due to deferral or waiver, or the medicine does not fall under the scope of the paediatric regulations. How are regulatory authorities working to improve paediatric drug development? And what still needs to be done? Historical Progress In the US Several regulations have governed paediatric clinical trials in the US: •

• •

Paediatric Use Subsection in the Precautions Section of Product Package Inserts (21 CFR 201.57 (f)(9)) (1979), Paediatric Use Labeling Rule (21 CFR 201.57(f)(9)) (1994), Food and Drug Administration Modernization Act (FDAMA) of 1997 – for product labels. Best Pharmaceutical for Children Act (BPCA) (1997/2002) – with incentives for additional marketing exclusivity if the sponsor conducts requested studies in a written request for indication(s) to be studied in paediatrics. The FDA publishes a list of pharmaceutical products needing paediatric studies. Paediatric Research Equity Act (PREA) (2003) – requires sponsors to determine safety and efficacy of new drugs and biological agents in paediatric patients unless a waiver is granted or the product is exempt. An initial Paediatric Study Plan (iPSP) must be submitted for medicines falling under PREA. Food and Drug Administration Safety and Innovation Act (FDASIA), 2012 – makes BPCA and PREA permanent law. FDA Reauthorization Act of 2017 (FDARA) including The Research to Accelerate Cures and Equity (RACE) for Children Act – The RACE for Children Act aims to spur new cancer treatments for children and ends exemption of PREA obligations for cancer drugs with orphan drug designations for molecular targets relevant to children’s cancer.

In August 2018, the FDA published a list of molecular targets (205) substantially relevant to growth and progression of paediatric cancer as well as a list of those not relevant. Congress reauthorised through 2020 the Rare Paediatric Disease Priority Review Voucher programme in the 21st Century Cures Act in 2016. 14 Journal for Clinical Studies

In the EU Though the EU established paediatric rules later than the US, it has leveraged lessons learned from the country. One difference in the EU is that there is only one Paediatric Regulation (Regulations 1901/2006&1902/2006) covering requirements and incentives. Guidance documents are issued to ensure proper implementation of the Regulation. Significant milestones included: •

• •

The Paediatric Regulation of 2006 – to facilitate development of high-quality, appropriate medicines for children without needlessly exposing them to clinical trials or deterring or delaying medicines for adults. In July 2007 – the Paediatric Committee was established, replacing the Paediatric Working Group to determine studies required for children. Progress of the Paediatric Regulation is reported every five years by the EMA and EU Commission. In October 2017, the European Commission report, “10 Years of the EU Paediatric Regulation” revealed that the Regulation’s system of obligations, rewards, and incentives appeared to have had a positive impact overall. • From 2007–2016, over 260 new medicines were authorised for use in children through new marketing authorisations and indications, and, in 2017, there were over 1000 agreed PIPs. • While the Regulation has had an encouraging impact, positive results are not evenly spread among therapeutic areas. Orphan rewards do not seem to be driving paediatric development for rare diseases, for instance. The Commission will further examine challenges, with findings expected to be delivered in 2019. A revised and revoked class waivers list of medicines not required to submit a PIP was put into effect in the EU on July 28, 2018.

Clinical Trials Regulation No 536/2014 (signed April 2014) is set to replace the EU Clinical Trials Directive (EC) No. 2001/20/ EC by earliest end 2020. It will enable drug developers to submit clinical trial applications through one portal for regulatory and ethics committee review, instead of in each country where the trial will be conducted. The Regulation includes conditions to be met to perform trials in minors (information adapted to the age of child, explicit wish of the child to be respected in view of trial participation, etc.). With neonates having the highest unauthorised or offlabel use of medicines across paediatrics, the EMA released a “Concept Paper on the Need for Revision of the Guideline on the Investigation of Medicinal Products in the Term and Preterm Neonate” in September 2018. The paper recommends a review of the Guideline which came into effect in 2010 Volume 11 Issue 4

Regulatory (EMEA/536810/2008), and assessing PIPs covering neonates, research trends, and standards, suggesting existing guidance is not adequately addressing development and investigation of products in term and preterm neonates. It recommends the new draft guidance be available before Q4 2020. Global Collaboration In many cases, authorities are joining forces with stakeholders. In March 2018, the EMA and EU Commission held a workshop with patients, academia, healthcare professionals, industry, and FDA representatives to discuss how to better apply the Paediatric Regulation to boost development of medicines for children. Taking into account the feedback of the stakeholders, the EU Commission and EMA published in October 2018 a plan, with 21 actions in five topic areas: 1) Identifying paediatric medical needs 2) Strengthening cooperation of decision-makers 3) Ensuring timely completion of PIPs 4) Improving handling of PIPs 5) Increasing transparency around paediatric medicines Completion of this plan was initially aimed at within two years. Due to implications of Brexit (EMA relocation and business continuity plan) some deadlines have been extended beyond 2020. With development of the European Network for Paediatric Research at the European Medicines Agency (Enpr-EMA), a network of research networks, investigators, and centres performing paediatric trials, we have seen greater collaboration between stakeholders, networks, industry, regulators and patient/parent organisations. 48 networks are in place (June 2019), including in the US, Canada, Japan, and in therapeutic areas where none existed 10 years ago. The Enpr-EMA networks’ support ranges from advising on PIP or study protocol development to identifying study sites and supporting

patient recruitment. Enpr-EMA suggests companies consider using this support to optimise PIP planning and execution to: • Meet patients’ needs with targeted and evidence-based feasibility • Enhance product development by helping to create a relevant drug development plan • Optimise PIP development focusing on key studies and developing a long-term strategy • Efficiently conduct clinical trials • Save time and money. See Consultation Diagram (Figure 1) More information can be found in the Enpr-EMA Working group on public-private partnership Network consultation recommendation. A pilot phase for the network consultation started early 2019. Collaboration between the US, EU, and globally has increased as well. The guideline ICH E11 (R1) “Clinical Investigation of Medicinal Products in the Paediatric Population” aims to advance paediatric research with clear, compatible guidance specific to global product development of paediatric medicines. The addendum R1 provides clarification and current regulatory perspectives in paediatric drug development with the following added: • Ethical considerations • Age classification and paediatric subgroups, including neonates • Paediatric formulations • Commonality of scientific approaches for paediatric drug development programmes • Paediatric extrapolation and introduction of modelling and simulation • Practicalities in design and execution of paediatric trials, including feasibility, outcome assessments, and long-term clinical aspects. The guideline ICH S11 “Safety Testing in Support of Development of Paediatric Medicines” is expected to reach the final stage, Step 4, in June 2019.

Figure 1: Consultation Diagram Source: European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA); Enpr-EMA Working Group.

Journal for Clinical Studies 15

Regulatory Similarly, in one of the 21 actions following their March 2018 meeting, the European Commission and EMA identified a goal to establish a framework for collaboration with EMA/PDCO and the FDA’s Oncology Center of Excellence to assess relevant molecular targets in paediatric cancers by December 2019.

Hoping to harmonise paediatric clinical trials globally, the ICH has issued new draft guidance urging drug sponsors to consider whether they need to conduct non-clinical safety experiments on drugs before moving to paediatric trials. The guideline, ICH S11, recommends taking an integrated, weight-of-evidence approach to non-clinical trials, considering pharmacology, pharmacokinetic, in vitro, in vivo animal, and clinical safety data to make sure no single factor is considered in isolation. ICH E11 A “Paediatric Extrapolation Guideline” is expected to be available for public comment by November 2020 (Step 2a/2b). A concept Paper was finalised in October 2017. With the expert working group identified, next steps include aligning terminology and evaluating strategies for paediatric extrapolation, study designs, statistical methodologies, and modelling and simulation. Further initiatives include the creation of paediatric networks and advisory groups, such as: •

Institute for Advanced Clinical Trials for Children (I-ACT), established by Critical Path Institute in the US in March 2017 to optimise and accelerate biomedical innovation via child-centred clinical trial networks and collaboration with like-minded institutions, trial sponsors, and others.

The conect4children (c4c) launched in May 2018 in the EU as a collaborative paediatric network facilitating development of drugs and therapies for paediatrics. It is a six-year IMI2 project.

International Children’s Advisory Network (iCAN), consortium of children’s advisory groups, dedicated to giving children and families a voice in health, medicine, research, and innovation by increasing education about the importance of children’s involvement with chapters worldwide, including eYPAGNet in Europe.

The EU Commission and EMA also plan to enhance cluster meetings on topics and therapeutic areas requiring greater exchange of information. These monthly meetings were originally set up by the EMA and FDA in August 2007 as a forum to exchange scientific information. They were shortly after joined by Health Canada, Japan’s Pharmaceuticals and Medical Devices Agency, and Australia’s Therapeutic Goods Administration. Between August 2007 and March 2019, information has been exchanged on 517 products, with 172 discussions on general topics. Frequently discussed product issues include scope of paediatric product development, safety, trial design, endpoints, and study population. The Paediatric Cluster Common Commentary tool was developed to inform sponsors of products discussed at the Paediatric Cluster, with similarities and/or differences in FDA and EMA approach summarised. An approved 1-2 page common commentary document is sent to the sponsor. Comments sent are not binding on either agency. The agencies also set an action item to increase transparency on paediatric cluster discussions to better inform sponsors of them and share information regarding outcomes of non-product-related interactions. Additional collaboration has also included workshops on: • • •

Other advancements include: •

As new trial methodologies, such as extrapolation, modelling, and simulation become more accepted, the FDA and EMA have established Paediatric Extrapolation Guidances that permit extrapolation of adult efficacy data to children through smaller, focused pharmacokinetic and safety trials.

Involvement of children and their families in planning clinical research and medicine development is on the rise. The Paediatric Committee of the EMA (PDCO) has three patient representatives as members, and patients are participating in scientific advice procedures at EMA.

Other signs of EU and US collaboration include the following. While the RACE for Children Act is US law (Title V of the FDA Reauthorization Act to amend the Paediatric Research Equity Act (PREA) (21 US Code 355c) (applicable in August 2020), the FDA and EMA collaborate on the establishment of the list of molecular targets for products to treat cancer that will no longer be exempt from PREA when having orphan drug designation. Representatives from both agencies attended a meeting in April 2018. Under Title V of the FDA Reauthorization Act, sponsors developing a new molecular therapy to treat a rare adult cancer are now required to evaluate new molecular targeted drugs or biologics in paediatrics if the molecular target is substantially relevant to the growth or progression of a paediatric cancer. The FDA has published a list of relevant targets. 16 Journal for Clinical Studies

Gaucher Disease, September 2012 EMA, FDA & HC Paediatric Pulmonary Arterial Hypertension, June 2017 Advancing the Development of Paediatric Therapeutics (ADEPT) • ADEPT 1: Paediatric Bone Health, June 2014 • ADEPT 2: Evaluation of Long-term Neurocognitive Development in Paediatrics, April 2015 • ADEPT 3: Successes and Challenges of Performing Longterm Paediatric Safety Studies, April 2016 • ADEPT 4: on Big Data, September 2017 CERSI University of Maryland – Paediatric Heart Failure, October 2017

Progress Still Welcomed However, even with these noteworthy advances, there is room for further improvement. On average, over 50% of medicines administered to children still have never been tested in this population. Volume 11 Issue 4


PIPs do not always match the disease burden of disabilityadjusted life years – a measure that combines years of life lost due to premature mortality and/or to time lived in a state of less than full health – from the World Health Organization. Mental/behavioural disorders have the highest burden (20%), but the indication is covered in only 3% of PIPs. Conversely, infectious diseases and malignant neoplasms represent a burden of only 5% but are covered in 21% and 13% of PIPs, respectively. Diseases and cancers unique to children are often neglected. With the RACE for Children Act in the US, improvement will certainly be seen here. Other drugs with orphan drug designation will, however, continue to be exempt from PREA. Neonates continue to be overlooked overall, as studies for this group can be challenging given the small market, fragility of patients, and trial operational difficulties such as blood draws, to name a few. Legislation has not yet been as effective at influencing drug development for these younger groups. Legislation is needed that outlines the move from off-label to approved drug use. Both the EU and the US have made significant investments in research on off-patent medicines; despite stimulation in research, it has not yet made a significant difference in licensing. Further support is needed once a drug enters the market. Currently, many reimbursement policies allow reimbursement of the cheapest product for a given indication and do not take into account whether that product has an approved paediatric labelling. Collaboration of all stakeholders, including health technology authorities, is needed. What to Expect in the Future Because legislation currently does not address all needs, it is likely more regulations will be forthcoming in the US and additional requirements or action plans will be put in place in the EU under the Paediatric Regulation, unless the latter is one day reopened.

With the current political situation in Europe, a big question is: Will Brexit go into effect? If it does come to fruition, it could be a hard Brexit with no deal, giving the UK a status of third country. The impact this could have on clinical research for paediatrics, and adults, is unknown. Will a marketing authorisation from the EU be recognised in the UK? Will drug developers need to abide by separate rules for the UK? While it is not optimal that the UK secede from the EU from a clinical research standpoint, could it shorten timelines to make drug development more attractive? We still do not know the answers to these and other questions, and there have not been new regulatory decisions since June 2019. Regardless, one thing is certain. Paediatric development is no longer an add-on, but today, is part of drug development. With collaboration of regulators and stakeholders, global paediatric research is on the rise. The intended result is to make certain more paediatric medicines are developed for children who need them.

Dr Martine Dehlinger-Kremer Dr Martine Dehlinger-Kremer is VP, Paediatric Development at Synteract. She has 30 years of clinical research experience, including 28 in regulatory and medical affairs. She is observer member, Coordinating Group of Enpr-EMA at EMA; member, External Advisory Board of iCAN; chair, Paediatric Working Group by EUCROF; chair, European Forum for GCP Children Medicines Working Party; board member, EFGCP; president, EUCROF. She has contributed to global development of numerous products, including orphan drugs and biosimilars.

Journal for Clinical Studies 17


Regulatory Convergence and Harmonisation Activities in Latin America As demonstrated by numerous initiatives globally, cooperation and convergence activities among national regulatory authorities (NRAs) accelerates the drug development process, improves access to medicines and contributes greatly to public health. From region-specific programmes from organisations such as the Asia-Pacific Economic Cooperation (APEC) and the East African Community (EAC) to seminal initiatives such as the International Council for Harmonisation (ICH), these efforts enable regulators to share information and strategies to better face the challenges of working with an ever-evolving global biopharmaceutical industry. Regulatory convergence and harmonisation activities — and the common guidance documents they often produce — are particularly important in emerging regions, where many NRAs often lack the requisite infrastructure and resources needed to regulate medicines efficiently and effectively. In Latin America, supporting regional cooperation initiatives to strengthen national regulatory capacities is a primary objective of the Pan American Network for Drug Regulatory Harmonization (PANDRH). Established in 1999 by the Pan American Health Organization (PAHO) and multiple NRAs in the region, PANDRH promotes the exchange of knowledge and information required for agencies to conduct essential regulatory functions effectively. In addition to providing a forum and a framework for NRAs to coordinate activities, the network also publishes technical documents to encourage implementation and adoption of common standards among member countries. Based on specific needs of the region, PANDRH has issued numerous technical documents since its inception, covering critical issues such as good laboratory practices, vaccines, counterfeit medicines and bioequivalence testing, among others.1 Although adoption and implementation of standards vary widely across NRAs, the technical documents have nonetheless facilitated capacity-building and have helped to advance the development of regulatory networks within the region.2,3 Applying Common Standards Progress toward improving the regulatory infrastructure in Latin America is evidenced most clearly in Brazil. Already the second largest pharmaceutical market among emerging countries (and seventh overall), pharmaceutical sales in Brazil are projected to reach $39–43 billion by 2023 – up from $31 billion in 2018.4,5 To keep pace with this growth, the Brazilian Health Surveillance Agency (ANVISA) has implemented several programmes that will not only streamline regulatory requirements and improve access to medicines in Brazil but will also influence the manner in which NRAs throughout the region interact with industry sponsors significantly. ANVISA is an active participant in several convergence and harmonisation initiatives and is the only ICH member from South America.6 The ICH membership (achieved in 2016) provides the agency with valuable insight and perspective into global harmonisation efforts and progress toward common standards – 18 Journal for Clinical Studies

knowledge that can then be shared with PANDRH members and other NRAs throughout Latin America to better coordinate their activities. ANVISA has subsequently adopted and implemented the ICH-established Common Technical Document (CTD) for dossier submissions and is working toward implementing the electronic version (eCTD) by 2023. In addition to CTD, ANVISA has also implemented priority review, conditional approval and reliance pathways to help reduce redundancy and speed the development of treatments for neglected, rare, emerging, and re-emerging diseases. A regulation enacted in 2018 established eligibility criteria for the priority pathway and provided a framework for prioritising new drug registration, postauthorisation requests, and clinical research authorisations based on their relevance and import to public health.7 Also in 2018, ANVISA published a technical note regarding interchangeability between reference biologics and biosimilars.8 The note emphasises that although the agency may determine a biosimilar product to be comparable in terms of quality, efficacy and safety, such designation does not imply interchangeability, and further maintains that policy and guidelines on substitution should be determined by the prescribing physicians and the Ministry of Health. Additionally, the directive prohibits multiple exchanges between products due to the difficulties in traceability and monitoring of use and suggests that pharmacovigilance and real-world data may elucidate new findings concerning interchangeability. Although the WHO doesn’t have a formal standard on the interchangeability of biotherapeutics – preferring instead to let national competent authorities define the issues and make determinations on substitution – ANVISA’s procedure effectively delegates this complicated decision to physicians, which may increase the risk for conflicts of interest and potentially jeopardise patient safety.9 In contrast, a position paper from three biopharmaceutical trade associations contends that pharmacy substitution of biotherapeutics should only occur when a product receives a formal interchangeability designation, is approved for all indications, and when physicians retain the option to dispenseas-written.10 Additionally, the associations emphasise the need for relevant clinical evidence to justify switching decisions, as well as a robust pharmacovigilance system to monitor safety. Regulating Advanced Therapies Biosimilars are only one of many types of new medical products presenting challenges for NRAs in Latin America. Cell- and genebased therapies and other advanced therapy medicinal products (ATMPs) require effective regulatory environments and more specialised expertise than is often available to regulators in emerging regions. Recognising the limitations of many Latin American NRAs to regulate and monitor the safety of ATMPs, PANDRH made several recommendations to regulators at its 2018 conference in El Salvador, primarily encouraging NRAs to adopt ATMP-specific guidelines and apply international standards for approving these therapies and regulating the facilities in which they are created.11 Specific recommendations include establishing a manufacturing Volume 11 Issue 4


licensure process to affirm compliance with standard practices (e.g., GMP, CLP and GCP), requiring clinical trial authorisation and monitoring, maintaining an adverse event detection system, and developing a registry of patients who have been treated with an ATMP. To be sure, the amount of resources and technical expertise required to effectively regulate advanced therapies is daunting – even for NRAs in Europe and the United States. For Latin American NRAs, ATMPs present significant challenges yet they also provide an opportunity to adopt, implement and strengthen existing reliance pathways to help facilitate and harmonise regulatory activities in the region.

regulatory authority (SRA) may be a more practical, less burdensome approach than lengthy and costly capacity development. These arrangements can be unilateral or bilateral, and may also be a prelude to more formalised forms of cooperation such as mutual recognition agreements.14 Reliance pathways for some specific regulatory elements are already in use by NRAs in Argentina, Costa Rica, Ecuador, El Salvador and Panama, and more can be reasonably expected as PANDRH’s efforts to encourage adoption and implementation of common, internationally accepted standards envisions a regulatory paradigm based on the concepts of reliance, work-sharing and international collaboration.15,16

Reliance pathways can be particularly useful in emerging regions as they enable resource-constrained NRAs to make use of shared information yet retain their autonomous decision-making responsibilities.12 Recent global examples include reliance on premarketing assessment reports for quality, safety and efficacy, as well as GMP compliance inspections conducted by other authorities.13 For NRAs struggling to address the challenging aspects of ATMPs, reliance upon pre-clinical and clinical data from a stringent

Harmonising Capacities With limited resources and a global biopharmaceutical industry that is increasingly complex, national regulatory authorities in Latin America face significant challenges in their efforts to regulate the safe and effective use of medical products. Internationally accepted guidelines – from ICH, WHO and PANDRH – may help strengthen regulatory capacities and regional cooperation, but consistent application of such standards remains elusive. The CTD,

Journal for Clinical Studies 19

Regulatory 9bb3-324896228c9e. Accessed: April 11, 2019 The IQVIA Institute for Human Data Science (January 2019). The Global Use of Medicine in 2019 and Outlook to 2023. Available at: https://www. Accessed: April 11, 2019 6. Huynh-Ba, K. & Beumer Sassi, A. ANVISA: an introduction to a new regulatory agency with many challenges. AAPS Open. 2018; 4(9). DOI: 10.1186/s41120-018-0029-x 7. Cerqueira, D. Regional and Global Regulatory Priority Updates. Presented at the DIA 2019 Latin America Regulatory Conference; February 2019. 8. Agência Nacional de Vigilância Sanitária (ANVISA), Gerência de Avaliação de Produtos Biológicos (GPBIO) (October 2018). Clarification No. 003/2017/ GPBIO/GGMED/ANVISA – REVISED. Exchange and replacement of registered products by means of development by comparability ("biosimilars") and the biological product comparator. Available at: http:// +003+de+2017+-+Medicamentos+Biol%C3%B3gicos/0774f2d7-5c83-45b7832d-37efdf21790c (in Portuguese). Accessed: April 11, 2019 9. de Assis MR, Pinto V. Strengths and weaknesses of the Brazilian regulation on biosimilars: A critical view of the regulatory requirements for biosimilars in Brazil. Ther Adv Musculoskelet Dis. 2018 Oct 31;10(12):253-259. doi: 10.1177/1759720X18809683. eCollection 2018 Dec. Review. PMID: 30515251. 10. European Biopharmaceutical Enterprises (EBE), European Federation of Pharmaceutical Industries and Associations (EFPIA), International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). (February 2017). Considerations for physicians on switching decisions regarding biosimilars. Available at: wp-content/uploads/2017/04/considerations-for-switching-decisions_ biosimilars-and-rbps-final-branded-1.pdf. Accessed: April 11, 2019 11. Porrás A. Challenges in the regulation of cell therapy products: Regional situation and recommendations endorsed by the IX Pan American Network for Drug Regulatory Harmonisation Conference (CPANDRH). Presented at the DIA 2019 Latin America Regulatory Conference; February 2019. 12. Luigetti, R. Collaboration, not competition: developing new reliance models. WHO Drug Information. 2016;30(4):556-568. Available at: https:// RegCollaboration.pdf Accessed: April 11, 2019 13. World Health Organization (2016). Good regulatory practices: guidelines for national regulatory authorities for medical products. Working document QAS/16.686. Available at: safety/quality_assurance/GoodRegulatory_PracticesPublicConsult.pdf. Accessed: April 11, 2019 14. Liberti. Globally Applicable Facilitated Regulatory Pathways to Improve Equitable Access to Medicines (2017). ISBN 978-94-6182-806-4. Available at: Accessed: April 11, 2019. 15. European Federation of Pharmaceutical Industries and Associations (2017). White paper on reliance and expedited registration pathways in emerging markets. 23/11/2017. Available at: white-paper-on-reliance-and-expedited-registration-pathways-inemerging-markets.docx. Accessed: April 11, 2019 16. Brady, P. Regulatory Cooperation and Reliance. Presented at the DIA 2019 Latin America Regulatory Conference; February 2019 17. Aprea, P. ANMAT Regulatory Initiatives and Priorities for 2019. Presented at the DIA 2019 Latin America Regulatory Conference; February 2019 5.

for example, is only partially accepted in Latin America with only Brazil and Mexico having fully adopted and implemented their use. Argentina’s regulatory authority, ANMAT, recently announced plans to implement the CTD as one of its priority initiatives for 2019, but no other NRAs in the region have established CTD implementation plans.17 Greater harmonisation of requirements in Latin America may be achieved in the coming years, however, as more NRAs participate in global convergence activities. ICH Observers from the region now include Mexico (COFEPRIS, since 2016), Colombia (INVIMA, since 2017) and Cuba (CECMED, since 2017), and it is hoped that these NRAs will influence regulatory coordination by adopting and implementing common global standards. In addition, PANDRH recognises that a shortage of human capital with appropriate competencies limits the effectiveness of many NRAs, and has consequently developed a curriculum for regulatory professionals in the region that incorporates recommendations from WHO and other government leaders in regulatory science. Cooperative regulatory efforts will ultimately be fruitful over time, but harmonisation and convergence initiatives must also include the strengthening of national regulatory capacities to allow for the incorporation and deployment of common standards throughout the region. In doing so, NRAs can potentially decrease the time-to-market for new therapies, reduce uncertainty for biopharmaceutical sponsors, and increase patient access to muchneeded medical treatments. REFERENCES 1.




Pan-American Health Organization (April 2014). Strategic Development Plan 2014–2020 of the Pan American Network for Drug Regulatory Harmonisation (PANDRH). Available at: hq/dmdocuments/2015/drug-harmonisation-Strategic-PlanPANDRH-04-20-2015.pdf. Accessed: April 11, 2019 Pombo ML, Porrás A, Saidon PC, Cascio SM. Regulatory convergence and harmonization: barriers to effective use and adoption of common standards. Rev Panam Salud Publica. 2016 May;39(5):217-225. PubMed PMID: 27706409 Forum on Drug Discovery, Development, and Translation; Board on Health Sciences Policy; Institute of Medicine (IOM); Weisfeld V, Lustig TA, editors. Washington (DC): National Academies Press (US); 2013 Oct 24. Barbosa da Silva, J. Regulatory Advances in Drug Regulation Accelerated Pathways of Approval. Presented at the DIA 2018 Global Annual Meeting. Available at: A+JB+DIA+2018+Annual+Meeting+INGL%C3%8AS/4bea5429-ef3c-4b6a-

20 Journal for Clinical Studies

Adam Istas Adam Istas is a science writer with the Drug Information Association (DIA) in Washington, DC. A long-time advisor and contributor to the DIA, he has 20 years of experience in healthcare communications. Previous roles include directing thought leadership initiatives at Quintiles (now IQVIA) and managing a disease-specific clinical trials registry and educational website at Washington University School of Medicine in St Louis. Email:

Volume 11 Issue 4

Lab experts at your side

Specialised laboratory group within SYNLAB Experience of more than 3,000 preclinical projects and clinical studies Experts to support the entire life cycle of a pharmaceutical product Unique range of laboratory services always working in accordance with the highest quality standards DIN/EN/ISO/IEC, GMP, GLP, GCLP or GCP Worldwide sample logistics solutions

Journal for Clinical Studies 21

Market Report

An Insight into Conducting Clinical Trials in Lithuania and Latvia Latvia and Lithuania are compelling countries in which to conduct clinical trials, despite being relatively small – with a total population of about 4.7 million (1.9 million in Latvia and 2.8 million in Lithuania).1,2 Clinical trials of medicinal products have been conducted since the early 1990s in Latvia and Lithuania. The number of studies has increased every year, reaching a peak in 2008 when 105 new clinical trials authorisations were issued in Lithuania, and 88 in Latvia. Due to the global economic crisis in the subsequent years, there was a decline in the authorisation of new clinical trials, but the new clinical trial application dynamics can now be considered as stable. An average of 73 new clinical trial applications per country per year were authorised; however, today there are 244 ongoing studies in Lithuania and 196 in Latvia.3,4

Figure 1. Approved studies in Latvia and Lithuania, 2008–2018

Regulatory Analysis After joining the European Union in 2004, Latvia and Lithuania have implemented EU GCP Guidelines, Directives 2001/20 and 2005/28 into national legislation. Conducting clinical trials in each country is governed by the following legislation: •

Order of the Ministry of Health of Lithuania No V-435 of May 31 2006 “Regarding confirmation of the description of the order on approval to conduct clinical trial of medicinal product, issuance of certificates and permissions to conduct clinical trial of medicinal product, order of performance and control of trials”.5 Law of the Republic of Lithuania No VIII-1679 of May 11 2000 “On Ethics of Biomedical Research”.

• Cabinet Regulation No 289 of Latvia of 23 March 2010 “Regulations on Conducting Clinical Trials and Non-interventional 22 Journal for Clinical Studies

studies and Labelling of Investigational Medicinal Products, and Procedure for Conducting Inspections on Compliance with the Requirements of Good Clinical Practice”.2 Clinical trials are governed by the State Medicines Control Agency in Lithuania and the State Agency of Medicines in Latvia. In both countries, the ethical reviews of clinical trials are done by central ethics committees (CECs). The Lithuanian Bioethics Committee (LBEC) is the main institution responsible for ethical evaluation of clinical research in Lithuania. In addition to the LBEC, there are two regional ethics committees for biomedical research: one in the Kaunas region (founded at the Lithuanian University of Health Science) and one in the Vilnius region (founded at the Medical Faculty of the Vilnius University). These Regional Committees have the right to review applications for clinical trials, which are planned only at research sites within the committees’ areas of activity. Therefore, the applications for multicentre trials covering both regions are submitted for review by the LBEC, which has the power to issue a single opinion for the whole country. Both the LBEC and regional committees review applications within a deadline of up to 60 days. In Lithuania, additional to approval from an ethics committee and competent authority, an approval from the State Data Protection Inspectorate (SDPI) must also be obtained. There are five independent ethics committees in Latvia, and an opinion from only one ethics committee is required. Applicants are free to decide to which CEC they will submit. According to regulations, ethics committees shall provide a written opinion within 30 days after the registration of the clinical trial application. Applications may be submitted in parallel to all authorities. It is worth noting that the competent authority approval will be issued only after receipt of a positive opinion from an ethics committee. Permission from the Lithuanian SDIP to conduct a clinical trial will be issued once the opinions of the competent authority and the ethics committee have been received. On average it takes about 60 days to get all the necessary permissions. Latvia and Lithuania also accept applications submitted through the international harmonisation procedure. Study Designed Protocols The majority of clinical studies conducted in Latvia and Lithuania are Phase III studies. In 2017, 35 approvals of Phase III trials were issued in Latvia and 37 approvals of Phase III trials in Lithuania, which together accounted for nearly 67% of all applications submitted in both countries. The second largest segment is Phase II Volume 11 Issue 4

Market Report studies. In 2017, 12 approvals were issued in Latvia and 17 approvals issued in Lithuania – which accounted for 27% of all the applications submitted. Phase IV studies in 2017 only accounted for about 3% of the total number of applications (one study in Lithuania and two in Latvia). In the same year, four approvals for Phase I studies were issued (one in Latvia and three in Lithuania), representing almost 4% of all applications submitted.7,8 Historically, across both Latvia and Lithuania, most clinical trials are performed in oncology. In 2017 there were eight new studies in Latvia and seven in Lithuania. Gastroenterology research studies are equally as common, with eight new projects in Lithuania and seven in Latvia. The graph below shows the top 10 research areas in Latvia and Lithuania in 2017. It is noteworthy that, according to the data available on the State Medicines Control Agency of Lithuania website, gastroenterology and oncology are also the most prevalent areas for studies in 2018.

Most investigators are trained in Good Clinical Practice. In Latvia there are no strict requirements for GCP re-training, but now investigators and research staff follow sponsor requirements and perform GCP training at least once every five years. The GCP training in Lithuania is regulated by the Law on Good Clinical Practice Training, (No. 1A-91, January 18, 2007). This law requires investigators to attend an eight-hour GCP training course and refresh their knowledge with a half-day course every five years.9 Patients According to the World Health Organization (WHO), the incidence of oncological and cardiovascular disease in Lithuania and Latvia is higher than the global average. Lithuania and Latvia also have one of the highest cardiovascular mortality rates in the European Union.10 There are a significant number of previously untreated patients in Lithuania and Latvia. One of the main factors in the successful recruitment of subjects into a clinical trial is the doctor's encouragement to participate, and in both countries there is a high level of patient trust and confidence in the doctor’s recommendation. Logistics There are no import / export licence requirements within the European Union for materials related to clinical trials – investigational medicinal products (IMPs), laboratory kits, medical devices, etc. In addition, the export of biological samples to other EU countries does not require any licences.

Figure 2. Top 10 research areas in Latvia and Lithuania on 2017 approved studies.

Investigators, Sites and Training There are around 200 hospitals in Latvia and Lithuania and more than 5000 outpatient clinics (GP’s practices and doctor’s private practices). Multifunctional hospitals are concentrated in the larger cities – Riga, Liepaja, Daugavpils, Valmiera in Latvia, and Vilnius, Kaunas and Klaipeda in Lithuania. These hospitals are well equipped and can perform all necessary examinations – CT, MRI, etc. Currently, research covers the whole of Latvia with clinical trials also being conducted in GP’s practices. In 2017, clinical trials were conducted in 93 research centres. The most popular of them were P. Stradins Clinical University Hospital, Riga Eastern Clinical University Hospital (clinic “Gailezers”, Latvian Oncology Center, clinic “Bikernieki”), Daugavpils Regional Hospital, Vidzeme Hospital, Children's Clinical University Hospital, Health Center 4, Liepaja Regional Hospital, and Piejuras Hospital in Liepaja. Across both countries, there are many laboratories that offer high-quality tests staffed by physicians who are highly-skilled/qualified professionals. Additionally, physicians see clinical trials as an opportunity to improve their knowledge, skills and qualifications, as well as providing patients with free modern treatment and diagnostics.

Clinical Trials in Russia11,12 The clinical trial industry in Russia developed in the late 1990s and reached its peak in the early 2000s. The clinical research market in Russia has great potential – the total population is 144.5 million (according to statistical data from 2017) and there are good numbers of large medical centres with qualified doctors and the necessary research equipment to service the population.

The new clinical trial application dynamics can be considered as stable, despite the fact that the total number of permits issued has decreased slightly compared to previous years. In 2018, 653 approvals were issued, which is 7% less than in 2017 (when 700 approvals were issued). As for today, there are 1210 ongoing studies in Russia. The graph below shows information about studies approved in Russia since 2008. (Abbreviation: IMCT = International multicentre clinical trial.)

Article 3. Approved studies in Russia, 2008–2018 Journal for Clinical Studies 23

Market Report Regulatory Analysis Clinical trials conducted in Russia are supervised by the Ministry of Health of the Russian Federation and are governed by the following legislation: Federal Laws • •

Federal Law “On Circulation of Medicines” 61-FZ, 12 April 2010 FEDERAL LAW On Public Health Protection in the Russian Federation, No. 323-FZ, 21 November 2011

Government Decrees • •

Government Decree No. 714 “Approval of rules for compulsory insurance of the life and health of patient” Government Decree No. 673 of 3 September 2010 “Approval of Rules for Import and Export of Biological Materials Obtained in Clinical Trials of a medicinal product for medical use into and from the Russian Federation” Government Decree No. 683 of 3 September 2010 “Approval of Rules for Accreditation of Medical Institutions for the Right to Conduct Clinical Trials of Pharmaceutical Drugs for Medical Application” Government Order No. 771 of 29 September 2010 “On Procedure of Import of medicines for medical use into the Russian Federation”

The share of applications for which no requests or comments were received, according to a survey in 2018, was only 38.8%. Moreover, a significant part of the comments were made by the ethics council. The ethics council made comments or refused to hold IMCTs in 43.9% of cases. Study Designed Protocols The majority of clinical studies conducted in Russia are Phase III studies (see Article 4). In 2018, 192 approvals of Phase III trials were issued (67% of all applications submitted). Phase II studies also well represented (63 approvals (22%)). Whereas Phase IV studies in 2018 accounted for only 5% of the total number of applications. Oncology traditionally is the most prevalent area of study, with a total 77 approvals for new studies in 2018. Together with oncohaematology, oncological studies accounted for 97 authorisations for new studies. That represents one-third of all new permits (33.8%). The second most popular area is gastroenterology, with 37 permits followed by cardiology / cardiovascular diseases with 21 approvals for new studies.

Orders • •

Order No. 200n dated 1 April 2016 of the Ministry of Health of the Russian Federation On Approval of Rules for Good Clinical Practice Order No.1071 dated 15 February 2017 of the Federal Service for Surveillance in Healthcare Concerning Approval of Pharmacovigilance Procedure

The Ministry of Health of the Russian Federation are responsible (within five working days from the date of the application) for: - -

conducting an inspection; examining of documents for obtaining permission to conduct clinical trials and ethical analysis; - notification of the decision to the applicant; - preparation and submission to the ethics council and the expert institution. The task of conducting the relevant examinations and reporting conclusions by the commission of experts and the ethics council on the approval/rejection of clinical studies and sending these conclusions to the Ministry of Health of the Russian Federation are carried out within a period not exceeding 30 working days from the date of receipt of the application. If the result of both examinations is positive, the Ministry of Health of the Russian Federation decides on issuing a permit for conducting a clinical study and issues an appropriate permit within five working days from the date of receipt of expert opinions. In practice, the average time for issuing authorisations by the Ministry of Health of Russia in 2018 (calendar days): Authorisation to conduct clinical trial – 92 days Authorisation to import drugs for clinical trial – 14 days Authorisation to import / export biosamples – 21 days Authorisation to amend the protocol – 47 days 24 Journal for Clinical Studies

Article 4. Distribution of IMCTs in Russia by phases, 2018

Logistics In Russia, an import licence is required for IMPs and any study material needed by clinical sites. The requirements to obtain an import licence include: Import (export) of biological materials is carried out for their study on the territory of the Russian Federation and (or) outside the territory of the Russian Federation on the basis of a permit issued by the Ministry of Health and Social Development of the Russian Federation. To obtain permission to import (export) biological materials, the applicant organisation shall make a submission to the Ministry of Health and Social Development of the Russian Federation: a) a statement on the import (export) of biological materials; b) justification for calculating the number of units of each type of imported (exported) biological material; c) a copy of the permission to conduct clinical research issued in accordance with the established procedure; d) copies of constituent documents and certificate of state registration of a legal entity, certificate of registration with the tax authority of the applicant organisation. If the applicant organisation is a foreign legal entity in the event of a clinical trial of a medicinal product for medical use in the Russian Federation, documents must be submitted that confirm the Volume 11 Issue 4

Market Report

accreditation of the representative office of a foreign legal entity in the Russian Federation. Within 10 working days from the date of the adoption of the documents, the Ministry of Health and Social Development of the Russian Federation will conduct an inspection and decide on the issue of permits for the import (export) of biological materials or the decision to refuse to issue permits for the import (export) of biological materials. The fee for issuing permits for the import (export) of biological materials is not charged. REFERENCES 1. 2.

Central Statistical Bureau of Latvia, Statistics Department of Lithuania,

3. 4.

State Agency of Medicines of Latvia. State Medicines Control Agency of Lithuania, http://www. 5. State Medicines Control Agency of Lithuania, http://www. 6. State Agency of Medicines of Latvia. 7. 8. 9. State Medicines Control Agency of Lithuania, http://www. 10. World Health Organization, "Environmental Burden of Disease: Country Profiles," ehimpacts/countryprofiles/en/ 11. INFORMATION ANALYTICAL BULLETIN number 18, Results of 2018, Moscow 2019, issued by Association of Clinical Trials Organizations (ACTO), Russia 12. Association of Clinical Trials Organizations (ACTO) - http://

Christene Leiper Professor Christene Leiper attended Sydney University, RMIT Melbourne and Bond University in Australia is where she achieved A Professor of Health Sciences and Medicine. Christene has also undertaken part of her PhD at Edinburgh University, Scotland. Christene’s specialisation has been in Nuclear Medicine and her international experiences encompasses many therapeutic areas of medicine. Christene is the Managing Director and Director of five companies including three CROs and two Software / Medical Applications companies. Email:

Journal for Clinical Studies 25

Market Report

Designing Clinical Trials to Support Pharmaceutical Reimbursement The use of health technology assessments (HTAs) to determine whether a healthcare technology should be paid for and at what price is well established in most countries. The evidence requirements of HTA authorities go beyond those of regulatory authorities. Whilst methods for HTAs vary across jurisdictions, assessments of comparative effectiveness of the new technology vs. the standard of care are common and utilise data from clinical trials that are being used for regulatory submissions. HTA considerations in the design of regulatory clinical trials are gaining importance in companies developing healthcare technologies. However, the application of these considerations varies and if insufficient attention is given to HTA needs, could significantly increase the risk of a technology not getting reimbursed and / or not achieving a desirable return of investment. In this article, we present a framework on what to consider during the design of clinical trials intended for regulatory purposes in order to address the evidence requirements for HTAs. Key Words Reimbursement, clinical trial, HTA, scientific advice Funding Sources This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Introduction Concerns regarding the growing gap between demand for health services and technologies and available resources has long created the need to regulate healthcare expenditure, and governments have increasingly introduced formal systems to assess the value for money of healthcare technologies coming to market. The predominant processes to do so are health technology assessments (HTAs). The introduction of the National Institute for Health and Care Excellence (NICE) in 1999 in England significantly contributed to the globalisation of HTAs. Nearly every country now has an HTA organisation in place to help payers determine the value of new medical interventions. Value assessments conducted by these authorities consist of compiling and analysing the evidence to show the health and economic benefits of a product, compared to the standard of care, are sufficient to justify the price desired beyond the requirements of the regulatory authorities. Delays in reimbursement decision-making can lead to substantial delays in a new product gaining market access. Negative reimbursement decisions by payers hinder market access 26 Journal for Clinical Studies

substantially, and in turn delays or can impact adversely on sales and return on investment Historically, HTAs were performed after regulatory marketing authorisation had been granted. Due to the resulting gap between marketing authorisation and reimbursement, HTAs tend now to start much earlier – often in parallel with regulatory approval processes. Given the central role played by pharmaceutical clinical trials in generating evidence for use in HTAs, those involved in designing clinical trials need to be aware of the methods and procedures required to generate evidence required for HTAs beyond the evidence requirements for regulatory approval. Furthermore, for a company developing a new health technology, e.g. a new medicine, an understanding of the evidence requirements of HTA decision-makers can help in investment decisions, clinical development plan design and commercial strategy development. In this article, we present a framework on what to consider during the design of clinical trials to address the evidence requirements for HTAs. The Role of Clinical Trials in HTAs Whilst there are differences between countries regarding defining the value of a new health technology, certain central requirements are common and can be addressed in clinical trials. HTAs appraise a new health technology or indication in comparing a set of product attributes relating to its efficacy, safety, impact on quality of life (QoL) and functional status and pricing compared to the current standard of care. Evidence used in HTAs for assessing the relative clinical and cost-effectiveness of new pharmaceuticals comes from a variety of sources, such as systematic literature reviews, indirect treatment comparisons and economic modelling. However, clinical trials conducted during the drug development process provide the most important source of treatment effect data for HTAs. When and What to Consider when Designing Clinical Trials The when Traditionally most medicines receive marketing authorisation after completion of large Phase III clinical trials. Increasingly medicines with novel or breakthrough status are receiving regulatory approval based on much smaller Phase II trials and / or non-comparative single-arm trials. Therefore, it is important to consider the specific evidence requirements for HTAs (i.e. initially when designing phase II trials, but certainly when designing phase III trials) much earlier in clinical development programmes, i.e. when designing Phase II trials but also still be considered when designing Phase III trials. Volume 11 Issue 4

1919 - 2019

When you need print in clinical trials • Experts in clinical trials print production and global distribution • over 40 years experience • Working with all the leading CROs, Pharma and Biotechs • Worldwide reputation • Online project managment tool - GreensVista

Think A 100 Years of Greens and 40 years of producing clinical research print.

UK +44 (0)1494 834 900

USA +1 (215) 275-6251 Accreditations: ISO 22301 - ISO 27001 - ISO 14001 - ISO 9001

Journal for Clinical Studies 27

Market Report The what For the ‘what’, we consider five critical areas for pharma companies to consider in designing clinical trials to be HTA ready as well as regulatory ready. Choice of Comparator The first key consideration concerns the choice of comparator. Non-comparative / single-arm trials create issues when HTA decision-makers try to compare the new technology vs. the standard of care. Placebo-controlled trials result in similar issues, if the placebo arm of the trial differs substantially from clinical practice. Both result in the need for extensive indirect treatment comparisons (ITC), which potentially reduces the robustness of the clinical evidence used in HTAs We recommend, wherever possible, to use the standard of care as the comparator. This may be difficult where there is no gold standard and clinical practice across or within countries involved in the trial varies. In such cases we recommend consideration of the use of an active comparator based on physician choice, to enable treatment comparisons relevant to HTA decision-makers in their respective jurisdictions. It is, however, still useful and prudent in some cases, such as when there are many possible comparators to include placebo to increase the capacity for ITC and network meta-analysis to be performed, using placebo as the reference comparator. This, for example, is important in psoriasis where a new biologic entrant would face numerous existing biologic therapy comparators with too many to be able to perform head-to-head clinical trials against. Measurement of Clinical Effectiveness The second key consideration is the measurement of clinical effectiveness (efficacy and safety). HTA requires outcomes to be patient-relevant, and there is a growing interest in the use of patient-reported outcome measures (PROMs) in clinical trials1. In some disease areas, e.g. cancer, it may not be possible to power a trial to capture the treatment effect on hard outcomes, such as mortality / overall survival, and surrogate endpoints are used, such as progression free survival, which is an issue for ensuring the trial results are relevant to patient outcomes. However, surrogate endpoints can be useful when a clear and robust link can be established with patient-relevant outcomes, e.g. as for the link between HbA1c in type 2 diabetes and cardiovascular events. However, this is only when those links have been or can be validated by studies, so that HTA decision-makers can accept them. We recommend, where possible, to select endpoints relevant to patient outcomes, e.g. survival, PROMs (see more below). Where this is not possible, we recommend establishing robust links between surrogate endpoints and patient outcomes and to validate them in separate studies or with external databases. When considering the selection of endpoints for a clinical trial, it is also important to keep in mind how the data will be used in HTAs where the new technology will be compared with other technologies used in clinical practice via an ITC. Therefore, it is important to review which endpoints have been collected in trials of most relevant comparator technologies to enable such treatment comparisons. We recommend reviewing the comparator trials and consider endpoints used in those trials as the endpoints in the trial for the new technology, or to supplement those already planned for use. 28 Journal for Clinical Studies

Qol, PROMS and Cost-Effectiveness The third key consideration concerns quality of life (QoL) and patient-reported outcomes (PROMs). HTA organisations use QoL and functional status data, either for use in cost-effectiveness evaluations or as individual value attributes of additional benefit a new technology offers. A separate economic model needs to be developed (typically in Excel) to utilise input data from the clinical studies and other sources. To support the economic value case for a new pharmaceutical, the instruments used in the trial need to allow the generation of utilities (QALYs). Utility measurement data from generic health status measures, like the EQ-5D, tend to be preferred by HTA organisations. In some cases, it is also possible to use condition specific instruments with a validated mapping function to utilities, such as mapping the EORTC QLQ-C30 questionnaire for cancer patients to the EQ-5D2. Besides their use in cost-effectiveness evaluations, the use of generic and condition specific instruments will generate data to inform HTA decision-maker’s assessments of the additional benefit of the new technology compared to the standard of care as individual value attributes. QoL and functional status data should be collected at baseline and throughout the trial and follow-up period. We recommend collecting QoL and functional status data using generic health status measures which allow the generation of utilities (such as the EQ-5D), as well as including a conditionspecific instrument. In selecting which PROMs to choose, it is important to review the trials of the most relevant comparators to enable better comparison between technologies during HTAs. Resource Use and Cost Data The fourth key consideration concerns the collection of resource use data, such as hospitalisations, outpatient/GP appointments and tests/investigations to inform the cost-effectiveness analysis. There is no universally recognised method for economic data collection in clinical trials and a variety of techniques are used. The methods and instruments used should reflect the health condition the new technology addresses. The researcher planning the trial should again review the trials of the most relevant comparators to identify potential methods and instruments. Resource use data should be collected at baseline and throughout the trial and follow-up period. However, resource use data collection from a multinational clinical trial should be performed with caution due to the concerns over the generalisability of the data for country-specific HTA submissions. Hence, there is a key role for local validation of resource use estimates from a trial and/ or observational data collection. Follow-up Time in Trials, and Data Analysis Plans The fifth key consideration is the follow-up time of the trial. Studies should have an appropriately long enough follow-up time to enable the collection of sufficient and robust data relevant to HTA decision-makers. In addition, a plan detailing how and when individual endpoints will be collected is essential. This should include the frequency, methods, sources and time horizon within which the data is needed. Besides the data collection plan, the researcher planning the trial should also consider the development of a specific health economics / HTA statistical analyses plan (SAP) covering such aspects as to Volume 11 Issue 4

Market Report how PROM and resource use data will be analysed for HTA and use in economic models. This would complement the regular clinical study SAP. HTA Scientific Advice The official procedures NICE in the UK provides HTA scientific advice as a fee-for-service consultation to developers of health technologies advising companies on how to generate evidence relevant for future HTA submissions to NICE and other HTA authorities. Advice can be requested on medicinal products, devices and diagnostics. Also, the EMA and EUNetHTA (EU body responsible for co-ordinating HTA methods and policies in Europe) offer a joint scientific advice programme to companies with up to three HTA organisations involved. All of those processes come with varying requirements for preparation and company input and varying levels of opportunities for engagement with the involved parties. Unofficial Procedures There are several options, including: 1. Advisory board meetings with health economists with clinical trial experience for selected key territories, HTA experts and clinicians to review and input into clinical trials. 2. One-to-one meetings with payer / HTA experts to review and gain input for clinical trial programmes from specific experts for specific regions and / or countries. 3. Working with specialist health economics consultants with clinical trial, HTA scientific advice and HTA experience to review plans and gain input into clinical trials, to develop a whole HTA scientific advice programme tailored to the individual company requirements and to provide wider market access and HTA advice, also supporting and / or conducting individual projects. For all of the above we recommend working with health economics/outcomes experts with clinical trial and HTA experience to review plans and gain input into clinical trials, to develop a whole HTA scientific advice programme tailored to the individual company requirements and to provide wider market access and HTA advice. Also to support and / or conduct individual HTA relevant projects. This can also include the consultants helping the company to navigate the official procedures. Conclusion In summary, we would like to emphasise that for a product to be able to get a positive HTA recommendation leading to reimbursement by payers, companies need to carefully consider the evidence needs of HTA authorities when planning clinical trials for all new medicines these can and will differ from regulatory evidence needs. For each new product this should start early, i.e. when planning Phase II trials, in and throughout the clinical development process, in order to optimise the chances of gaining reimbursement and consequently return of investment. REFERENCES 1. Braithwaite T, Calvert M, Gray A et al. The use of patient-reported outcome research in modern ophthalmology: impact on clinical trials and routine clinical practice. Patient Relat Outcome Meas. 2019 Jan 24;10:9-24 2. Ameri H, Yousefi M, Yaseri M et al. Mapping EORTC-QLQ-C30 and QLQ-CR29 onto EQ-5D-5L in Colorectal Cancer Patients. J Gastrointest Cancer. 2019 [Epub ahead of print]

Maximilian Lebmeier Maximilian is founder and director of Athena Market Access Solutions Ltd., providing pricing, reimbursement and wider market access project work, consulting and support for organisations in the life sciences industry. He has worked on over 150 reimbursement submissions. His experience ranges from very common to very rare diseases in both adults and children. Maximilian is a certified facilitator for the NICE Scientific Advice programme. Maximilian is also co-founder of Aestimo Limited, providing early stage to market release valuation and strategies for health technology development. Email:

Keith Tolley Keith is founder and director of Tolley Health Economics Ltd. providing project services, strategic advice and support on health technology assessments (HTAs) and health economic evidence needs for market access, pricing and reimbursement. He worked in academia, pharmaceutical companies and consulting. Keith is also an economic assessor for the Scottish Medicines Consortium (SMC) and provided expert advice as part of the NICE HTA Scientific Advice programme. Email:

Journal for Clinical Studies 29

Market Report

Haemovigilance System in EU and Japan: An Overview The objective of haemovigilance is to trace and analyse all inappropriate effects of blood transfusion with a view to correcting their cause, preventing reoccurrence and improving the safety of blood transfusion. Long-term encounters with the therapeutic use of blood products are prevalent and expertise in adverse effects occurrence is accessible, but systemic safety surveillance in clinical practice is not in place in several countries. Despite the life-saving effects of blood transfusion, it is not very concrete and is based on surrogate markers to demonstrate effectiveness. There are huge differences in therapeutic protocols and there is still limited knowledge of the best implementation of a product in a particular indication, and the optimal use of blood components. In order to enhance this knowledge, the first objective must be to collect epidemiological data as a basis. Haemovigilance has been an essential part of the principle of blood safety. National haemovigilance systems are now in place or are being developed in European Union Member States. The Japanese Red Cross (JRC) headquarters was established in Japan's haemovigilance system in 1993, with the initial purpose of collecting reports from medical facilities of adverse transfusion reactions. Although the JRC has a voluntary system of reporting, almost all severe adverse reactions caused by blood transfusion are collected in cooperation with medical facilities. Non-haemolytic transfusion reactions account for >90% of all reported events and 5–6% of transfusiontransmitted infections (TTIs). Laboratory analyses conducted at the JRC Central Blood Institute and other laboratories support the JRC haemovigilance system. Key words: Haemovigilance network, Red Cross, Blood transfusion Introduction Haemovigilance is a collection of monitoring procedures covering the entire blood transfusion chain, from donating and processing blood and its components to providing and transfusing it to patients, including their follow-up.1 It includes monitoring, reporting, investigating and analysing adverse events associated with blood donation, processing and transfusion, and taking action to prevent their occurrence or recurrence. Reporting systems play a key role in improving patient safety by learning from failures and then implementing changes to the system to prevent them in the future.1 The haemovigilance system must include all appropriate stakeholders and coordinate between the blood transfusion service, clinical hospital staff and transfusion labs, hospital transfusion committees, national regulatory agency and national health authorities. The resulting changes in transfusion policies, standards and guidelines, as well as improvements in blood services processes and hospital transfusion practices, result in improved patient safety.2 30 Journal for Clinical Studies

A life-saving intervention is the transfusion of blood and blood products. Adverse events associated with blood donation and its components, and the transfusion of blood and blood products to patients, however, are associated with risk. Adverse events also include blood donation and transfusionrelated reactions, incidents, near-misses, errors, deviations from standard operating procedures and accidents. Learning from adverse events and identifying system problems can lead to measures being introduced to improve the quality, safety, efficacy and cost-effectiveness of blood and blood products, and also the processes of donation and transfusion. The main goal of haemovigilance is to improve the transfusion chain's continuous quality through corrective and preventive actions to improve patient safety and outcomes, improve donor safety, and reduce waste. Haemovigilance should also be completely integrated in to the quality systems of all institutions involved in blood and blood products donation and supply, including processing, inventory management, storage and distribution, and clinical transfusion.3 Key Elements in a Haemovigilance System The Ministry of Health (MoH) is ultimately responsible for the quality, safety and adequacy of the supply of blood and blood products for its national blood system. A system of haemovigilance contributes to donation safety, blood products and transfusion.4 It improves risk management, increases confidence, and in nature should be confidential and non-punitive. The MoH should include a national haemovigilance system with effective leadership and governance, such as:5 Leadership and Governance6 1. Haemovigilance as part of the national blood policy and plan, as well as the legislative and regulatory framework 2. Haemovigilance advisory committee(s) 3. Adequate human and financial resources 4. Standards and definitions 5. Confidential and non-punitive system 6. Traceability of donor-to-patient blood and blood products 7. Quality system throughout the transfusion chain 8. Corrective and preventive action Organisation and Coordination7 1. Identification of stakeholders and institutions responsible 2. Organisational arrangements for the haemovigilance system 3. Coordinated links with organisations and institutions involved in the system 4. Defined roles and responsibilities of all stakeholders 5. Haemovigilance education and training for all healthcare staff 6. Monitoring, reporting, investigating and analysing adverse events, with safety and quality improvements recommendations. Volume 11 Issue 4

Market Report Haemovigilance in the Donation and Provision of Blood and Blood Products8 1. Donor haemovigilance: recognition of adverse events associated with donation, clinical management, monitoring, reporting, investigation and analysis 2. Policies, guidelines, protocols and standard operating procedures for all processes 3. Reporting of errors and deviations associated with these processes 4. Post-donation information and look-back 5. Liaison among blood transfusion services and hospital blood banks, clinical services and transfusion committees. Haemovigilance in Clinical Transfusion9 1. Patient haemovigilance: recognition, clinical management, monitoring, reporting, investigation and analysis of adverse events associated with transfusion 2. Clinical guidelines, hospital protocols, standard operating procedures, patient identification and sample labelling 3. Hospital transfusion committees 4. Response to recall and look-back notification 5. Coordination between hospital departments and services, and liaison with blood transfusion services. Local



Define data sets and terms


Document Submit notification

Receive notification

Corrective / Preventive action


Conclude Report and recommendations

Article 14: Traceability 1. MS will take every essential measure in order to ensure that blood or components collected, manufactured, tested or released should be traced either from donor to the recipient or vice versa and should be as per the provisions in Article 29(a). 2. MS will take all the measures to ensure that the framework for the labelling is ensured in all the steps of blood collected, stocked or released and thereby identification has paramount importance. 3. Records should be maintained for at least thirty years.

Haemovigilance in France11 In 1993 by law, in France, haemovigilance turned into a national arrangement of surveillance and alert, from blood collection to the follow-up of the beneficiaries with the intention to prevent untoward effects, and reporting is mandatory, disregarding their seriousness and their transfusion, in contrast to other Member States. The law expresses that ''anybody, professionals, specialists, medical attendant or attendant, [who] detects any unexpected effects probably due to a blood component, should report it without delay to the haemovigilance officer and [the] haemovigilance officer should report it further to French Security Agency" (ANSM). The organisation of haemovigilance is in three dimensions:

Monitor Flow of Haemovigilance Data

Discussion European Union The European Medicines Agency (EMA) is accountable for scientific analysis, supervision and safety monitoring of medicines developed by pharmaceutical companies for use in the EU. Before 2004, it had been known as EMEA. It tries to harmonise (but not replace) the work of existing national medication control bodies roughly parallel to USFDA.10

But No Guidelines are Formulated for Haemovigilance by EMA. Haemovigilance – European Union Countries The four European Blood Directives are the prime legal framework on blood • 2002/98/EC (pertaining to principles involved and organisation) • 2004/33/EC (specifies control over donations, donors and products) • 2005/61/EC (requirements on traceability and notifications – haemovigilance) • 2005/62/EC (specifications on quality management)

Article 15: Notification of serious events to the authority is mandatory and an SOP should be there for each establishment for the timely withdrawal of the product for which any untoward effects have been observed, and should follow official formats for reporting, as specified in Article 29(i).



The extra requirements to those set down in Directive 2001/83/ EC and Regulation (EC) 726/2004 Article fourteen4 of Regulation (EC) No 1394/2007 presented by the Legal Basis Regulation (EC) No 1394/2007 of the European Parliament and of the Council requires monitoring of effectiveness and adverse reactions, and also hazard management after authorisation. Procedures for electronic data exchange with other vigilance systems like haemovigilance is also required under pharmacovigilance system, whenever it is applicable.

1. National 2. Regional 3. Local. A haemovigilance officer (HVO) is there in every establishment (HE) dedicated for transfusion steps (1482 HVO) and at each blood centre site (153 no). Local healthcare establishments are attached to regional blood centres which supply labile blood products. A regional Journal for Clinical Studies 31

Market Report haemovigilance officer is appointed in each region. A regional coordinator (RHC) is delegated in each administrative region.

IGZ (Health Inspectorate) and / or the blood supply organisation, Sanquin, via the TRIP digital reporting system.

Haemovigilance in Germany12 Directive 89/381/EEC has special provisions for products obtained from human blood or plasma. The Paul-Ehrlich-Institute is the responsible authority for the annual surveillance of blood supply in conjunction with sec 21 of the German Transfusion Act. Haemovigilance was started in 2001. Confidential and obligatory coverage is observed.

Similarly, the hospitals are also endowed with haemovigilance officers (staff members officially responsible for reporting to TRIP) supported by haemovigilance assistants who prepare the report to TRIP (visit ward, collect and collate information), as well as providing education and training on blood transfusion.

In Germany, the labile blood products are listed under medications and are controlled by German drug law. In keeping with the national legal provisions covering medicines, untoward effects are reportable to the pharmacovigilance programme. It ought to be mentioned that the recent German Transfusion Law conjointly establishes haemovigilance as a separate entity and assessment of the reports of severe adverse transfusion reactions are consistent to Section 63i AMG (German Medicines Act). Haemovigilance Italy13 In Italy, haemovigilance was activated in 2004 by the National Institute of Health. The Italian system of haemovigilance is considerably in line with the EU Directive, though it lacks the monitoring of adverse or sudden events in donors and registration at a national level of severe incidents associated with collection and handling of blood that may have effects on the standard and safety of the blood component. Haemovigilance Austria14 The business segment of AGES Medicines and Medical Devices is responsible for a wide range of tasks in pharmaceutical licensing, clinical testing of medicines and medical devices, pharmacovigilance and vigilance in medical devices as well as inspection. The main customer and owner is the Austrian Republic, represented by the Federal Ministry of Health and Women's Affairs (BMGF). Around 280 employees employ medicines and medicinal devices. This business segment is ISO 9001 certified and the Official Medicines Control Laboratory (OMCL) testing activities are recognised by Accreditation Austria. The Austrian Federal Office for Healthcare Safety (BASG), an agency subordinated to the BMGF, has been entrusted with the performance of statutory tasks in line with the work of the Medicines & Medicinal Devices segment. Haemovigilance – UK15 In the UK, the Blood Safety and Quality Regulations (2005) controls the blood services (called blood establishments and hospital transfusion laboratories). The competent authority is the Medicines and Healthcare Products Regulatory Agency (MHRA). The data are confidential and individual patient details are not included. The adverse events are reported to SHOT, which is the independent haemovigilance scheme of the UK. Haemovigilance – The Netherlands14 Reporting Procedure The Netherlands provides a digital reporting system referred to as TRIP. Reporting of transfusion-related events by clinicians and patients to TRIP is anonymous. Though voluntary, it is widely practised. After analysis, it provides an annual overview of serious adverse reactions (grade 2 or higher) to the European Commission. In addition, the reporter can directly make a report available to the 32 Journal for Clinical Studies

Japan Haemovigilance is defined as prospective surveillance from donors, blood centres and medical institutions, to recipients of a series of transfusion processes. The method begins with early diagnosis of adverse events (adverse reactions and infectious diseases) and unknown infectious diseases in recipients, followed by causal analysis and assessment. The analysis should also cover relevant blood products and plasma derivatives, as well as the practical transfusion process in medical institutions, testing and manufacturing processes in the medical condition of blood centres and donors. It includes epidemiological study in the population or region to which the donors belong, in addition to evaluating the medical condition and the eligibility of donors, particularly in tracing donors related to infectious diseases. When an adverse event in a blood centre or medical institution was found to be caused by errors, all aspects including the organisation's operating system, procedures, and methods should be reviewed for immediate action.15 Establishment of the Japanese Red Cross (JRC) Haemovigilance System The JRC is Japan's only organisation that deals with the blood business, from collecting, processing, and manufacturing blood to delivering blood components to healthcare providers. In 1993, the JRC set up its own nationwide haemovigilance system to collect reports of blood transfusion-related adverse events. This is a voluntary reporting system, not a compulsory system, where doctors report to JRC blood centres cases of moderate and severe adverse events. Some doctors may not report such events to the JRC; however, reporting to the Ministry of Health, Labor and Welfare (MHLW) of serious cases is compulsory and the MHLW routinely refers such reports to the JRC. History of Transfusion Medicine in Japan In 1918, Japan's first transfusion experience was reported. Most of the blood components from sold blood have since been transfused. In 1964, a law came into force and new JRC statutes were established. At the same time, the Cabinet decided that all blood components should be derived from donations rather than Volume 11 Issue 4

Market Report blood sales, and all blood components have been supplied through donated blood since 1969. In 1972, hepatitis B surface antigen (HBsAg) screening was started. In 1986, the test for HTLV-I Ab was added.16

Scheme of Haemovigilance in Japan

Establishment of the Tracing System In haemovigilance, priority should be given to setting up a tracing system for investigating the causes. Since September 1996, the JRCS tracing system has been characterised by storing all donated blood samples for 10 years. Sampling enables us to trace transfused blood and plasma derivatives related to adverse reactions and infectious diseases, confirm the causal relationship, and shed light on the causes of future potential unknown infectious diseases. Current Risks in Transfusion17 1. Transfusion-transmitted Infectious Diseases (TTI) In recent years, between 80 and 100 suspected TTI cases have been reported annually. For example, the JRC reported 18 hepatitis B (HBV), 28 hepatitis C (HCV), 20 bacterial, seven human cytomegalovirus (CMV), four hepatitis E (HEV), one hepatitis A (HAV) and two human parvovirus B19 suspected TTIs in 2016. Only one HBV, one bacterium and three HEV infections were confirmed as transfused by evaluating the gene sequence identity between donor and patient-derived microorganisms, e.g. HBV, HCV, HIV. 2. Transfusion-associated Circulatory Overload (TACO) Despite the fact that circulatory overload has been a recognised transfusion complication for decades, there is still relatively little attention in the scientific literature paid to what constitutes TACO. Patients develop respiratory distress during or several hours after transfusion and may develop orthopnea, cyanosis, tachycardia, and hypertension. On auscultation, rales can be identified, and some patients may have jugular venous distention, cardiac auscultation S3, or lower extremity edema.

Procedures for dealing with reported adverse reactions and infectious diseases

3. Transfusion-related Acute Lung Injury (TRALI) TRALI is an acute injury to the lungs (ALI) that occurs during or after transfusion. It has emerged as the leading cause of transfusion-related fatality reported to the Food and Drug Administration of the United States. Recently transfused patients show respiratory distress, hypoxemia, auscultation rates, and diffuse bilateral chest radiograph infiltration. Breathing distress may be sufficiently severe to require mechanical ventilation.

Journal for Clinical Studies 33

Market Report there is a need for stricter regulations and guidance for bloodrelated issues. In order to comprehend this progress, the observation of suitable or best possible blood use in a more exhaustive way, e.g. through the assortment of a set of indicators that may be provided simply by most hospital information systems, has to be started. At the same time, assessment methods should be more adapted to measure and analyse critical parameters for optimal blood use. REFERENCES 1.

4. Allergic Reactions Non-haemolytic transfusion reaction symptoms vary and may include one or more of the following: hives, fever, anaphylaxis, anaphylactic shock, hypotension, and / or dyspnoea. Eighty per cent of reported platelet or FFP transfusion non-haemolytic reactions are allergic in nature. Symptom distribution is similar in both platelet and FFP transfusion reactions, which suggests that reactions to both components are caused by similar mechanisms. Summary Haemovigilance plays a vital role in reporting blood-related problems to the authorities. When cases have been increasing day by day, these should be standard guidelines for reporting such issues to the authorities. The European Union has established the European Haemovigilance Network (EHN) where all Member States are requested to post blood-related reports to maintain uniformity for all Member States. In Japan, haemovigilance is carried out by the Japanese Red Cross Society (JRC), established in 1993. There is a well-developed haemovigilance network in Japan and the reporting is divided into TRALI, TACO and TTI for the better evaluation of the bloodrelated reporting and the measures to be taken to overcome the issues under the Red Cross Society. Conclusion Haemovigilance is an indispensable component of quality management in a blood system and is needed for the persistent augmentation of quality and safety of blood products and the transfusion process by monitoring and safeguarding the undesirable events associated with the use of blood products. In comparison to the EU Haemovigilance Network, Japan has well-developed guidance and a better evaluation procedure for blood-related issues. The EHN is in a development process and 34 Journal for Clinical Studies overview_of_existing _hemovigilance_systems 2. 3. 4. Part_of_Pharmacovigilance 5. 6. Haemovigilance_Part_of_Ph armacovigilance 7. tb00157.x 8. WHO | Haemovigilance [Internet]. WHO. [cited 2019 Mar 11]. Available from: 9. System.pdf?ua=1 10. Haemovigilance_Part_of_Pharmacovigilance 11. haemovigilance_The_European_Haemovigilance_Network_EHN 12. Skeate RC, Eastlund T. Distinguishing between transfusion related acute lung injury and transfusion associated circulatory overload: Current Opinion in Hematology. 2007 Nov;14(6):682–7. 13. Satake M. Experience of haemovigilance in Japan. ISBT Science Series. 2018;13(3):298–301.

Sridhar S Sridhar S is pursuing a Masters in Pharmaceutical Regulatory Affairs, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email:

Balamuralidhara V. Balamuralidhara V. is an Assistant Professor in the Department of Pharmaceutics in JSS College of Pharmacy, JSS Academy of Higher Education & Research, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India. Email:

Kaushik Devaraju Kaushik Devaraju is a PhD Research Scholar, Regulatory Affairs, Department of Pharmaceutics JSS College of Pharmacy, Mysuru Email:

Volume 11 Issue 4

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 35 Germany


Combination Approaches in Immuno-oncology Trials: New Horizons for Multiple Tumour Indications Cancer immunotherapy has steadily been gaining momentum over the last decade, due to its proven efficacy as monotherapy in patients with various tumours, including tumours resistant to chemo- or radiotherapy. With an ever-increasing amount of clinical trials reporting significant benefits in long-term overall survival of patients with specific cancers following mono-immunotherapy, the goal has shifted to attaining higher response rates in broader patient populations by employing immuno-oncology (IO) combination approaches. Our research aimed to shed light on the discovery of effective IO combinations and specific tumour indications in which they can attain durable and long-lasting anti-tumour immune responses, by anticipating new developments in the IO field and identifying trends. This paper describes the results of a quantitative and qualitative analysis on Phase II, II/III, and III trials started between 1st of January, 2014, and 17th of January, 2019. Overall, 1096 clinical trials assessing IO combinations were started in the aforementioned period, 97.3% of which are currently ongoing and 80.1% of which are Phase II trials. The majority of IO trials (89.2%) assessed only one combination therapy, and the use of biomarkers in the trials decreased from 41.7% of the trials started in 2014 to 21.4% of the trials started in 2018. The top five IO combinations used in these trials employed immune checkpoint inhibitors (ICIs), together with chemotherapy (19.1%), another ICI (11.9%), radiotherapy (7.5%), targeted therapy (4.9%), or chemoradiotherapy (3.9%). Furthermore, ICIs were predominantly used for the treatment of solid vs haematological tumours (86.2% vs 23.3% of trials, respectively). The most commonly investigated tumour indications were the lung (14.2%), lymphoma (6.7%), melanoma (6.5%), breast (6.0%), multiple myeloma (5.6%), head and neck (5.6%), and leukaemia (5.2%). Despite the limitation imposed by the fact that most analysed trials are not yet completed, our research offers a structured overview of the recent ongoing trials in the IO field, the combinations used and tumour types evaluated. This knowledge is crucial in guiding the design, duration, and development of new clinical trials assessing IO combinations in multiple tumour indications. Introduction Immunotherapy has gained significant attention in the oncology field over the last 10 years, due to its established efficacy as monotherapy. Among the most promising new cancer therapeutics are immune checkpoint inhibitors (ICIs), with monotherapies leading to longlasting responses in 40–50% of patients in selected indications1. The two main modes of action leading to these durable responses are the neutralisation of the immune suppressive machinery and the stimulation of effector mechanisms2. More recently, however, the emphasis has shifted towards combination regimens encompassing various phases of the cancer-immunity cycle, as a means to 36 Journal for Clinical Studies

increase the response rate and to obtain results in broader patient populations. Such combination regimens, consisting of several immunotherapies or associations with standard therapies, enhance the capacity to prevent immune escape by simultaneously targeting multiple tumour immune evasion mechanisms. To this end, the US Food and Drug Administration (FDA) approvals of bevacizumab plus interferon-alpha for the treatment of metastatic renal carcinoma3, 4 and nivolumab plus ipilimumab for the treatment of unresectable/ metastatic melanoma5 are stepping stones in highlighting the potential and revealing the added benefit of immuno-oncology (IO) combination regimens. With almost 200 drugs and more than 15 immunotherapeutic agents currently approved by the FDA for cancer treatment6, the discovery of effective combinations and the specific tumour indications in which these can achieve more durable responses than with monotherapy is a challenging endeavour. Some of the main challenges are triggering of anticancer immunity and a plethora of immune evasion mechanisms, increases in the occurrence of immune-related adverse events due to overlapping toxicities, and enhanced immunotherapy specificity leading to high variations in response rates depending on tumour type7. To elucidate the progress made thus far in the discovery of promising IO combinations, a quantitative and qualitative data analysis was performed at SMSoncology, a clinical research organisation specialising in early-phase oncology trials and drug development strategies. The aim was to anticipate promising developments in IO trials with combination regimens and to identify the most commonly assessed tumour indications in these trials. Methods The competitive intelligence data platform GlobalData Plc was used to gather and analyse the relevant information. The public clinical trial databases and the European Union (EU) Clinical Trials Register were used as validation and back-up databases. All IO Phase II, II/III, and III trials initiated between January 1st, 2014 and January 17th, 2019 and assessing combination regimens were included in the analysis. Sorting of the total registry was performed by classification of immunotherapy modality, the combination treatments used, and the tumour types assessed. Combination therapies lacking immunotherapy were excluded from the analysis. SAS Visual Analytics (SAS VA) was used for data analysis and output visualisation. Results IO Trials Assessing Combination Regimens in 2014–2019 The current field analysis revealed that 1096 clinical trials were initiated between January 1st, 2014 and January 17th, 2019. Compared with 2014, when only 60 IO trials were initiated, in 2018 a total of 374 trials were started, leading to an approximately six-fold increase in the number of IO trials (Figure 1A). Of the total analysed trials over this period, 80.1% are Phase II (Figure 1B) and 97.3% are currently Volume 11 Issue 4

Therapeutics ongoing (Figure 1C). Noteworthy, only a small percentage (2.7%) of trials are completed, while the majority (85.4%) are presently recruiting patients.

Figure 1. IO combination trials initiated from Jan 1st, 2014 to Jan 17th, 2019. Depicted are the number of trials per trial phase and year (A), and the percentages of trials per phase (B) and trial status (C). Data shown is reflective of two separate analyses. IO: immuno-oncology.

Top Five Combination Therapies Assessed in IO Trials Assessment of the number of combinations used in IO trials during the aforementioned period revealed a total of 1237 combinations and 237 unique IO regimens (Figure 2A), thus indicating that most trial designs included several experimental arms and treatments. The majority of trials (89.2%) assessed only one combination therapy (Figure 2B), whereas combinations including ≼3 therapies were evaluated in only 2.5% of the trials. This trend was also observed in the completed trials, where only one of the 29 finalised trials used multiple combinations (data not shown), most likely due to the outweighing of benefits by the frequency and severity of adverse events. Considering that biomarkers are commonly employed for patient inclusion in clinical trials as well as for monitoring response to treatment, the use of biomarkers in the total IO trials included in the analysis was assessed. Noteworthy, biomarker use was recorded in a third of the analysed trials and decreased from 41.7% (25/60) of the trials initiated in 2014 to 21.4% (80/374) of the trials initiated in 2018 (Figure 2C).

An in-depth examination of the types of combination therapies revealed ICIs as the predominant IO therapy used, in combination with ≼1 standard treatment (Figure 3A). Nearly one-fifth (19.1%) of the total landscape of IO trials consisted of the combined therapy of ICIs plus chemotherapy. In 11.9% of the trials, a combination of two different ICIs was used, whereas 7.5% of the trials evaluated ICIs plus radiotherapy combinations. Approaches using ICIs plus targeted therapy (4.9%) or chemoradiation therapy (3.9%) completed the top five combinations assessed in these trials. Together, these top five unique regimens account for 47.3% of the total IO trials. Clearly visible is the domination of ICIs in these trials, as each IO regimen in the top five included an immunomodulatory agent that targets programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1), as well as the cytotoxic T-lymphocyte associated protein 4 (CTLA-4). To further clarify the role of ICIs in cancer immunotherapy, an additional analysis was performed to evaluate whether ICIs are predominantly used in solid or haematological tumours or both. Overall, 780 (72.1%) trials are investigating ICI combinations and 291 (26.9%) trials are investigating non-ICI combinations. Interestingly, the use of ICIs in IO clinical trials proved to be considerably higher in solid versus haematological tumours (86.2% vs 23.3%, respectively; Figure 3B).

Figure 3. Combination therapies investigated in IO trials initiated from Jan 1st, 2014 to Jan 17th, 2019. Depicted are the top five combination therapies, including ICIs (A), and the use of ICIs in solid and haematological tumours (B). ICI: immune checkpoint inhibitor; IO: immuno-oncology.

Tumor Indications Assessed in IO Combination Trials In the current analysis, 34 different cancer types were categorised based on their frequency of assessment in the IO combination trials. The most commonly investigated cancers, altogether covering approximately 50% of the IO landscape, were those of the lung (14.2%), lymphoma (6.7%), melanoma (6.5%), breast (6.0%), multiple myeloma (5.6%), head and neck (5.6%), and leukaemia (5.2%) (Figure 4). The remaining 50% of the trials assessed 26 tumour types, with the five least investigated being those of bone, uterine, germ cell, thyroid, and thymus.

Figure 2. Analysis of IO combination trials initiated from Jan 1st, 2014 to Jan 17th, 2019. Depicted are the numbers of combination therapies and unique IO regimens (A), the percentages of trials per number of combination therapies (B), and the use of biomarkers in combination trials (C). IO: immuno-oncology.

Discussion, Conclusions, and Future Directions With cancer immunotherapy being designated breakthrough of the year in 2013 due to its capacity to treat even advanced and metastatic disease, IO was officially recognised as a separate, stand-alone field in cancer research. Since then, the significant advances obtained with IO monotherapies have led to the initiation and development of a large number of clinical trials assessing various IO treatments, either in combination with the current standard of care or with other novel therapies in the field. In this context, a structured qualitative and quantitative analysis of recent IO combination trials was stringently Journal for Clinical Studies 37

Therapeutics the field. While only 2.7% of these trials are currently completed, finalisation of all trials is expected in the following 3–5 years. The outcomes of these trials are of crucial relevance, as they might potentially help pave the way for immunotherapy combinations to become the standard of care for cancer treatment by 2025.

Figure 4. Overview of tumour indications assessed in IO trials initiated from Jan 1st, 2014 to Jan 17th, 2019 (n=1096). ASR: age-standardised risk; IO: immuno-oncology.

needed to identify existing trends and potentially anticipate favourable developments in the field. SMS-oncology’s secondary desk research involving IO combination trials initiated in the last five years yielded the following trends (possible interpretations are rendered in italics): •

An exponential increase was observed in the number of IO combination trials initiated in the last five years, an expected trend considering the recent preclinical and clinical progress in

38 Journal for Clinical Studies

A substantial decrease in biomarker use was observed in IO trials initiated in 2018. The recent advancements in the field have led to a deeper understanding of the variability in results obtained with biomarker use (e.g. variability in standardisation, measurement, and interpretation of early biomarker assays; heterogeneity in biopsy location/type, primary vs metastatic tumours; dynamics of the tumour microenvironment; resistant tumour cell clones)8, and have possibly introduced more stringent biomarker selection criteria.

All top five combination therapies assessed in IO trials over the last five years involved the use of ICIs, predominantly targeting PD-1 and PD-L1. Using the PD-1/PD-L1 axis blockade as a backbone for an increasing number of IO trials can be explained by its capacity to exert an enhanced efficacy as compared with the associated monotherapy and a relatively more favourable safety profile than that of other checkpoint inhibitors1,9,10. The approval of the anti-PD-1 antibody pembrolizumab as first-line treatment for patients with metastatic/unresectable recurrent head and neck squamous cell carcinoma in combination with platinum and fluorouracil, granted in June 2019, is a recent evocative

Volume 11 Issue 4

Therapeutics example concerning the efficacy of ICIs. The approval was based on the results from the randomised, multicentre KEYNOTE-048 trial, which reported a significant improvement in the median overall survival of patients randomised to pembrolizumab plus chemotherapy versus cetuximab plus chemotherapy at a prespecified interim analysis11. •

Despite recent indications that checkpoint blockade also exhibits beneficial outcomes in patients with haematological tumours 12, 13, our results show a clear trend of ICI use predominantly in IO trials assessing solid tumours. Explanations for this trend might be the reportedly modest effects observed thus far with ICIs in haematological tumours13,14, the specificity of improvements in outcomes to limited tumour types, such as Hodgkin lymphoma15, or the increased haematological complications of ICIs that might compound the disease burden16.

The most commonly investigated cancers were lung, blood, skin, breast, and head and neck cancers, altogether covering approximately 50% of the IO landscape. Noteworthy, the only type of cancer assessed in more than 100 IO combination trials was lung cancer. A reason for this might be the recent progress in the understanding of molecular pathways specifically involved in lung cancer, which led to the development of targeted therapies. Additionally, as the most commonly diagnosed cancer and the leading cause of cancer death worldwide17, lung cancer has a great impact on the world population; this puts forward a stringent requirement for novel, more effective therapies.

Overall, the outcomes of our research offer a general overview of the recent IO combination trials, the top five IO combinations used and the most common tumour types investigated, and they represent a tool to better understand the present status and new advances in the IO field. This deeper understanding is crucial in guiding development of new clinical trials that make use of tailored IO combinations for specific tumour types, as well as selecting and implementing the most suitable changes in trial design and duration. REFERENCES 1. 2. 3.

4. 5.

6. 7. 8.

Cogdill, A.P., Andrews, M.C. & Wargo. J.A. Hallmarks of response to immune checkpoint blockade. Br. J. Cancer. 117, 1–7 (2017). Farkona, S., Diamandis, E.P. & Blasutig, I.M. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 14, 73 (2016). Escudier, B., Pluzanska, A., Koralewski, P., Ravaud, A., Bracarda, S., Szczylik, C., Chevreau, C., Filipek, M., Melichar, B., Bajetta, E., Gorbunova, V., Bay, J.O., Bodrogi, I., Jagiello-Gruszfeld, A. & Moore, N. AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 370, 2103–2111 (2007). Summers, J., Cohen, M.H., Keegan, P. & Pazdur, R. FDA Drug Approval Summary: Bevacizumab plus Interferon for Advanced Renal Cell Carcinoma. Oncologist. 15(1), 104–111 (2010). Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., Ferrucci, P.F., Hill, A., Wagstaff, J., Carlino, M.S., Haanen, J.B., Maio, M., Marquez-Rodas, I., McArthur, G.A., Ascierto, P.A., Long, G.V., Callahan, M.K., Postow, M.A., Grossmann, K., Sznol, M., Dreno, B., Bastholt, L., Yang, A., Rollin, L., Horak, C., Hodi, F.S. & Wolchok, J.D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015). Morrissey, K.M., Yuraszeck, T.M., Li, C.C., Zhang, Y. & Kasichayanula, S. Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities. Clin. Transl. Sci. 9(2), 89–104 (2016). Sambi, M., Bagheri, L. & Szewczuk, M.R. Current Challenges in Cancer Immunotherapy: Multimodal Approaches to Improve Efficacy and Patient Response Rates. J. Oncol, Article ID: 4508794 (2019). Spencer, K.R., Wang, J., Silk, A.W., Ganesan, S., Kaufman, H.L. & Mehnert, J.M. Biomarkers for Immunotherapy: Current Developments and Challenges. DOI: 10.1200/EDBK_160766 American Society of Clinical Oncology Educational Book

36; e493–e503 (October 29, 2018). 9. Baumeister, S.H., Freeman, G.J., Dranoff, G. & Sharpe, A.H. Coinhibitory pathways in immunotherapy for cancer. Annu. Rev. Imunol. 34, 539–573 (2016). 10. Hoos, A. Development of immune-oncology drugs – from CTLA4 to PD1 to the next generations. Nat. Rev. Drug. Discov. 15, 235–247 (2016). 11. FDA Drugs - Resources for Information on Approved Drugs. Available at: https:// Last accessed: June 14, 2019. 12. Jelinek, T., Mihalyova, J., Kascak, M., Duras, J. & Hajek, R. PD-1/PD-L1 inhibitors in hematological malignancies: update 2017. Immunol. 152(3), 357–371 (2017). 13. Costa, F., Das, R., Bailur, J.K., Dhodapkar, K. & Dhodapkar, M.V. Checkpoint Inhibition in Myeloma: Opportunities and Challenges. Front. Immunol. 9, 2204 (2018). 14. Yoon, D.H., Osborn, M.J., Jakub Tolar, J. & Kim, C.J. Incorporation of Immune Checkpoint Blockade into Chimeric Antigen Receptor T Cells (CAR-Ts): Combination or Built-In CAR-T. Int. J. Mol. Sci. 19(2), 340 (2018). 15. Pianko, M.J., Liu, Y., Bagchi, S. & Leshokhin, A.M. Immune checkpoint blockade for hematologic malignancies: a review. Stem Cell Investig. 19(4), 32 (2017). 16. Davis, E.J., Salem, J.E., Young, A., Green, J.R., Ferrell, P.B., Ancell, K.K., LebrunVignes, B., Moslehi, J.J. & Johnson, D.B. Hematologic complications of immune checkpoint inhibitors. The Oncologist. 24(5), 584–588 (2019). 17. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R.L., Torre, L.A. & Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 68(6), 394–424 (2018).

Oana Draghiciu Oana Draghiciu, MSc, PhD, is a medical writer at SMS-oncology and is responsible for developing clinical trial-related documentation in the oncology and immuno-oncology fields. Oana has over four years of experience in publication planning, publication development, and medical writing in oncology, immuno-oncology and haematology, and a background in pharmaceutical sciences. Email:

Roy Feenstra Roy Feenstra is a graduate intern at SMSoncology, investigating immunotherapy combinations in clinical oncology trials. This summer he earns his research master’s degree in biomedical sciences, for which he obtained considerable expertise in immunology and cancer, including an additional focus on forming a bridge between science and business.

Inka Pawlitzky Inka Pawlitzky, PhD, is director of oncology drug development affairs at SMS-oncology. Inka obtained her PhD in immunology at Tufts Medical School in Boston and conducted two postdoctoral fellowships at the MaxPlanck Institute for Immunobiology and Epigenetics (Freiburg) and the Netherlands Cancer Institute (NKI, Amsterdam). Moving to industry, she was a senior scientist at Leica Biosystems within oncology diagnostics. Inka joined SMS-oncology in 2017 as a consultant, where she provides expert advice on the design, setup and implementation of oncology trials. Email:

Journal for Clinical Studies 39


The Increasing Importance of Clinical Education in the Rare and Orphan Disease Sector Diagnosing and treating rare and orphan diseases remains one of the life science sector’s great challenges – there are effective therapies for less than five per cent of 7000 known rare diseases and it often takes over five years to reach a diagnosis. These problems are compounded by small patient populations, which are difficult to access and lead to significant challenges for the healthcare industry in rare disease management and support of these patient populations. Rare disease patients require a more personalised approach than those with common conditions, and often these patients extensively self-educate about their condition. This is making patient support even more challenging as those with a rare condition are often very knowledgeable and have set ideas and perceptions before they come into contact with health professionals. To respond adequately, the industry must not just support patients but extensively educate health professionals and other key stakeholders, such as patient HUB service providers and payor groups, that are involved in the ecosystem of care around a patient. Education ultimately empowers everyone to better understand the disease, make more informed and better choices and improve patient outcomes. Tailored clinical education is a vital tool in the care for those with a rare disease. Here Nagore Fernandez, Head of Patient Solutions, Ashfield Europe and Canada (EUCAN) discusses its increasing importance and positive effect on care in the rare and orphan disease sector. Recognition Estimates vary, but the number of rare diseases the medical community has identified could exceed 7000. A rare disease is defined as affecting fewer than 1 in 2000 people in Europe and fewer than 200,000 Americans at any given time. Rare diseases have a devastating impact on families. Of the approximately 7000 rare diseases, only a small proportion have an approved treatment and about 50% of rare disease patients are children. Tragically, rare diseases are responsible for 35% of deaths in the first year of life and 30% of children with rare diseases won’t live past their fifth birthday. Unfortunately, it is common that primary care physicians either do not recognise specific symptoms or don’t make the link between common symptoms and a rare disease. As a result, the patient journey to an accurate diagnosis can be long and difficult. For people living with a rare disease, their quality of life is typically greatly affected by the chronic, progressive and frequently lifethreatening nature of the disease. Investing in clinical education raises awareness and encourages the healthcare industry and decision-makers to understand the needs of those living with rare diseases. 40 Journal for Clinical Studies

Treatment Whilst there is generally no cure for a rare disease, there have been huge advances in treatment options. The goal for first-generation treatments was survival, but second-generation treatments are now helping patients live a more ‘normal’ life and enjoy a better quality of living. Just last year we saw landmark breakthroughs in advanced genetic therapies, such as viral mediated gene transfer and CAR-T therapies. Today, thankfully, adults and children with rare diseases can often live much longer and continue to enjoy the milestones of life through childhood, adolescence and adulthood. Clearly treatment can be life-saving and life-changing. However, the lack of awareness around rare diseases, and the diagnosis challenge, still remains. And, as patients live longer, this creates whole new challenges to make sure they receive the level of care they need. Diagnosis and Detection Diagnosis is not always an easy journey – sometimes primary care physicians do not link the initial signs and symptoms to a rare disease because often the symptoms suffered by the individual mimic other more common diseases – this can result in patients being misdiagnosed. 40% of rare disease patients are misdiagnosed at least once, making it a very difficult journey for the individual. It is astonishing to learn that it takes 4.8 years on average to get an accurate diagnosis – and this can be even longer depending on the disease. Because of this, investing in and supporting the identification of patients with rare diseases is very important. We know that early detection of genetic disorders is key for the survival of rare disease patients, even more so when dealing with children. For example, in lysosomal storage diseases like Fabry, a young patient can suddenly suffer from stroke or develop terminal kidney injury without early detection. Genetic testing is available, but awareness of the disease and genetic testing amongst physicians in contact with these patients is key. Advocacy Advocacy, including patient-driven advocacy is becoming increasingly important in driving research into and awareness of rare diseases. Working with advocacy groups and raising awareness amongst the healthcare professional community via targeted campaigns in their practice or through social media is an important part of industry activity and now, thanks to advocacy, learnings and treatments derived from research are evolving. Working Together It is important to offer personalised support to patients with rare diseases and their families. This can be delivered in many different forms, including; informative campaigns for patients or their carers or education around the administration of the often very Volume 11 Issue 4


complex therapies that may have been prescribed by specialist centres. Partnering with pharmaceutical companies to deliver patient support programmes to the patients affected as well as their families and carers is also an effective way of garnering positive outcomes when considering support options. Medical information is often complex, but it can be broken down to make it relevant and easier to understand, both in the content, style and language and the format it is delivered in. Dedicated writers, who are experts in both the therapy area and writing for people without medical training or expertise, are essential to this. The industry needs to talk to patients to understand their experiences and challenges, continuing to get their feedback along their journey, and understand that their needs will change as they transition from early childhood, through to adolescence and adulthood. This helps with understanding how a difficult journey to the right care increases stress for the patient and family and that disease-specific, multichannel awareness campaigns are key to addressing this challenge. The objectives of these campaigns are to: •

Raise awareness of the symptoms with patients/families and encourage them to visit their primary care doctor and ask the right questions.

Educate the primary care doctors.

Hands-on Intensive Support Highly-trained, specialised clinical educators can make a huge difference to a patient’s experience and their outcomes of treatment by providing: • •

Supplemental training on treatment administration Support materials on managing side-effects

• •

Support using health psychology techniques shown to help patients cope Someone at the end of the phone to answer questions and talk through concerns.

Conclusion The industry is quickly recognising that the challenges a rare disease patient meets throughout their journey should be met with a different skill set than those treated for common illness. Clearly, treatment can be life-changing, however the lack of awareness around rare diseases, and the original diagnosis challenge, needs to be addressed. Post diagnosis, and in receipt of a medical prescription, patients, families and carers will still need support to find specialist care and navigate the maze of diagnosis problems. Listening to these patients and their care givers and advocates and finding ways to identify with their unique concerns and struggles will ultimately benefit all.

Nagore Fernandez Nagore Fernandez, Head of Patient Solutions, Ashfield Europe and Canada (EUCAN). With more than 15 years’ experience in the pharmaceutical and health industry, Nagore Fernandez, is responsible for building and executing the strategy for Patient Solutions division in Ashfield for Europe and Canada. Nagore’s background includes 15 years of experience gained from working across the pharmaceutical industry and providers of healthcare services. She is a highly experienced leader in the area of patient services and engagement with 10+ years’ experience in international programme management, clinical operations and quality and compliance in regulated environments. Nagore completed her master’s degree in Pharmacy at the University of the Basque Country and her clinical postgraduate diploma at the De Montfort University in the United Kingdom. She also holds a master’s degree in Clinical Research by Cardiff University. As well as Spanish and English, she is fluent in Italian and French.

Journal for Clinical Studies 41


eConsent: Tearing Down Barriers to Oncology Trials Benefits for Patients

With huge leaps in the understanding of cancer resulting in an ever-expanding set of treatment targets, it’s an exciting, yet fiercely competitive, time to be working in oncology.

Greater convenience

The consenting process can be started, and in some cases completed, from the comfort of the patient’s own home.

Despite more people surviving the disease than ever before, a staggering 9.6 million people worldwide died from cancer in 20181, making the need for new drugs a global priority.

Greater consideration

The patient is in control of the process and can stop and start as they see fit. This puts them under less pressure to sign straight away. It also means they can speak to friends and family, resulting in a more considered decision.

With the search for new treatments stepping up, patient technology and systems that can improve recruitment and retention while contributing to the collection of cleaner, more compliant data are in demand.

More informed

eConsent allows for information to be presented in a variety of ways, including graphics, videos and infographics. It can also include links to further information and can incorporate approaches to test understanding.

Greater engagement

eConsent allows for two-way interaction i.e. participants can ask questions and sites can provide the answers. This ensures the patient-site interaction can cover all the areas patients have highlighted so they feel comfortable and confident before making the decision to participate.

eConsent, when implemented well, has the potential to help companies rise to the challenge by removing some of the common barriers to clinical development.

Benefits for Sponsors/CROs/Investigators/IRBs

What is eConsent? Traditionally, the patient consent process has been done in-clinic, on paper. Electronic informed consent, or eConsent, allows the processes to be carried out via an intuitive, interactive, collaborative online platform – both in-clinic and at home.

Increased enrolment

Greater convenience and understanding of the study’s requirements can increase enrolment rates. The consent document is the first main touchpoint for the study and providing this in an engaging format can aid enrolment.

Increased comprehension

It uses a multimedia approach, incorporating pictures, videos and graphics, to convey study information to the patient in an accessible way. It then obtains and documents informed consent to participate in the trial.

By verifying that participants comprehend consent information, eConsent supports better information review with structured content, interactive assessments, rich media and support for interactive communication with study staff.

Increased retention

Why eConsent? Failure in the clinical trial consent process can negatively impact regulatory compliance and data integrity, enrolment and retention, participant protection and costs.

Increased comprehension reduces the risk of patient non-compliance to the protocol or early withdrawal from the study. In fact, industry research suggests that simply by using eConsent, clinical trials may enrol 25% fewer patients to achieve the same completion goals as those using paper consent.2

Decreased regulatory compliance risk

Documenting the consent process electronically helps ensure compliance through tools such as automated version control, date and time stamping, and an activity audit trail.

Streamlined development

eConsent can accelerate study timelines through the use of template libraries, reducing the time and cost of consent design and implementation for a faster study start-up process.

Enhanced collaboration

eConsent makes it easy for sponsors, sites, and IRBs/IECs to work together efficiently through online collaborative tools that facilitate form creation and deployment.

Increased geographical reach

Being able to consent patients remotely means sites can reach a wider participant base with ease.

Centralised remote monitoring

eConsent offers real-time monitoring dashboards that can result in cost savings on site and study monitoring – with instant insight into ongoing enrolment metrics.

We all know that informed consent is about more than securing a signature. It’s about ensuring that patients fully understand what they are signing up for. And when they do, it’s a win/win for trial sites and study participants alike.

Why e-Consent in Oncology? One-fifth of oncology clinical trials fall at the first hurdle because they do not recruit enough patients3. In fact, just three per cent of people with cancer take part in research4. Of those who do, many drop out before their data can be utilised. Oncology trials in the 21st century are complex, with complicated protocols and dosing regimens. Fortunately, eConsent can help. 42 Journal for Clinical Studies

Volume 11 Issue 4


Patient Understanding Patients may simply decline to take part when faced with what they perceive to be an overwhelming level of information. Alternatively, they may sign up without understanding specifically what is expected of them, and this can impact drop-out rates if they find the protocol surprising and not to their liking. With eConsent, information is presented in an accessible way and digested at the participant’s own pace. Because they have the time and support to internalise the aim of the study and its requirements, they are prepared and ready for what is to come – leading to realistic expectations, higher satisfaction and lower dropout rates. Consent Reliability As any cancer researcher knows, oncology trials are typically adminheavy. There are multiple arms and consent doesn’t stop at the front door — additional permissions are needed for investigations such as biopsies, tissue samples and more. Oncology studies tend to include multiple consent documents on these additional patient consenting requirements. In paper consent processes, this leads to a complex process of managing their creation (including country and site variants, and associated languages) and implementation at sites. We know that sites sometimes use sticky notes to help manage the multiple forms and define the right set of forms per patient – even today, in 2019. By removing inefficiencies and the opportunity for human error, eConsent systems make this process easy and trustworthy while enabling full transparency and visibility of any additional consenting requirements. Amendments and Re-consent Management Oncology studies also tend to have frequent protocol amendments and updates. Because eConsent automatically provides the appropriate version of every document the moment it is updated, it ensures patients sign the current and correct consent form at all times. This unprecedented level of control which paper can never offer eliminates mistakes in the collection of patient consent, which

otherwise result in regulatory compliance issues or data being rendered useless. This is why the paper-based informed consent process is one of the most cited causes of regulatory deficiencies. It results in data integrity issues, spoiled reputation, delays, litigation and even trial failure. With eConsent, teams running oncology studies always have a clear process path and audit trail to ensure they can make the most of all patient data captured. How to Implement e-Consent Continually increasing sponsor, CRO and site adoption suggests the value and benefits of eConsent are well understood. Most of the world’s largest pharma companies now have an eConsent strategy in place, ranging in scope from small pilot studies to enterprise-wide global platforms at the world’s largest pharmaceutical companies. One of the most overlooked advantages of eConsent is its ability to transform internal consent creation processes. Contrary to what some believe, eConsent is not about digitising paper consent forms. To the contrary, it unlocks potential for quality and efficiency and therefore deserves and requires careful planning to have maximum impact, not just on patients but on study teams and bottom-line ROI. To this end, there are several key considerations for stakeholders preparing to implement eConsent technologies: Data Security Data security is of the utmost importance, not least because it is a regulatory requirement. When choosing a system, it needs to protect patients’ private health information and comply with all national and regional privacy laws. Business Processes eConsent needs to be part of, not overlay, current business processes. Before embarking on eConsent, stakeholders should map out how it will impact on all other business processes. For example, sites should think about how they currently schedule patients and perform the consent process, and how eConsent may impact on factors such as workflows or how teams work with ethics committees. Journal for Clinical Studies 43

Technology More than 40% of studies do not meet enrolment goals, and even when recruitment succeeds, 85% of trials fail to retain enough patients.5 This leaves sponsors and sites struggling to conduct trials effectively. eConsent represents a major advancement in clinical research programmes. It improves the presentation and flow of information, allowing for better patient support, comprehension, and experience. When participants are fully informed and updated easily, study teams can yield better quality data while ensuring they meet regulatory requirements. Recent medical advances have placed the medical community closer than ever to achieving the goal of beating cancer, but there is still work to be done. Tearing down the barriers to drug development, including those presented by the informed consent procedure, has never been so important. REFERENCES 1.

World Health Organisation (2018) Cancer: Key Facts. Retrieved from http:// 2. Moeckel and Brady, 2003 Centerwatch Study 3. Bennette, C. S., Ramsey, S. D., McDermott, C. L., Carlson, J. J., Basu, A. & Veenstra, D. L. (2016). Predicting low accrual in the National Cancer Institute’s cooperative group clinical trials. JNCI: Journal of the National Cancer Institute, 108(2). 4. English, R., Lebovitz, Y. & Giffin, R. B. (2010). Transforming clinical research in the United States: challenges and opportunities. In Workshop Summary. 5. Considerations For Improving Patient Recruitment Into Clinical Trials (2012). Retrieved from considerations-for-improving-patient-0001

Documentation Different systems offer widely variable functionality. Some will document patient questions or allow sites to store document notes. Others will not. Sponsors and vendors must assist sites in an outline of what will be automated by the eConsent system, and which steps staff will need to document manually. It will change depending on the study protocol, so both general and trial-by-trial advice is advised. This will avoid confusion and ensure compliance. Training To avoid delays in use or unexpected issues, sponsor and site teams should start preparing for system training early on. It’s important to consider how training will be completed and documented, as well as how new users will be supported. Note that in some cases, the sponsor or eConsent vendor will offer to train site personnel. Inspection Readiness eConsent can mitigate the risk of regulatory deficiencies by providing a clear audit trail of digital timestamps, version control, real-time remote monitoring, and ongoing consent tracking. Consideration should be given to how direct access to this information can be provided if regulatory authorities request it during an inspection. Summary eConsent can help overcome many of the known barriers to effective clinical trials. The poor recruitment and retention of study participants, especially in oncology trials, has long been an issue facing researchers, resulting in longer study durations and delayed completion, not to mention higher costs. 44 Journal for Clinical Studies

Bill Byrom Bill Byrom, PhD. VP, Product Strategy and Innovation, Signant Health. Bill has worked in the Pharmaceutical Industry for over 25 years, in clinical development and as an eClinical thought-leader and strategist. He has helped to develop and launch a range of innovative technology solutions and services across the industry, and has a rich, first-hand knowledge of clinical trial operation. Academically, Bill also has a strong track-record of contribution to the scientific advancement of the electronic clinical outcome assessments (eCOA) and the wearable technology disciplines.

Neetu Pundir Neetu Pundir, Go To Market Director, Signant Health. Neetu Pundir is an experienced product and brand manager with prior professional experiences across the globe in the healthcare and life sciences industry, working for companies such as Johnson & Johnson, BIOTRONIK Medical Devices, Henry Schein, and eResearch Technology. As the Go To Market Director at Signant Health, Neetu manages the product strategy for the company’s electronic consent solution TrialConsent®. Neetu has a Master’s in Business Administration with degrees from Northwestern University, USA and the University of New South Wales, Australia.

Volume 11 Issue 4

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 45


Utilising Large Data Sets and Extended Trial Observations To Close the Alzheimer’s Evidence Gap One of the most widely recognized limitations of traditional randomized clinical trials (RCT)s is that the observation period and treatment courses reflect only a fraction of the natural history/progression of the disease being investigated on an often miniscule and idiosyncratic subset of patients. Investigators and patient phenotypes frequently do not map into the post-approval setting as they are chosen to enhance assay sensitivity, and the visit structure including restrictions on concomitant medications, patient management procedures, and study duration constrain the range of outcomes which can be measured.1 This is not surprising as RCTs are designed for statistical rigor and specifically to ensure adequate internal validity based on a distinctive set of highly selected enrollment constraints and treatment delivery conditions which are designed to reduce or eliminate both bias and confounding factors. In fact, RCTs, are considered the hallmark of evidence-based medicine which forms the basis for translating research into practice, and as such must possess internal validity to ensure that the differences observed between treatment groups are related to the intervention(s) tested in the trial. However, to also ensure some degree of generalizability and clinical utility once market authorization has been achieved, the results must be relevant to a definable group of patients in a clinical setting; and it is this lack of external validity that is the most frequently cited criticism of RCTs by clinicians and systematic reviews. This may provide one possible explanation for the poor adoption of recommended guidelines stemming from RCTs resulting in an ever-widening evidence gap between research and clinical practice. External validity can be enhanced in RCTs through the use of eligibility criteria that are as broad as possible when randomizing patients, and in a postmarketing setting through a construct called “pragmatic trials”.2 Once randomized, patients in longitudinal studies often drop out differentially and not at random, and often do not adhere to assigned treatments, or may even receive post randomization supplementary treatments. Importantly, both attrition and selection bias are the two major sources of bias that represent major threats to internal validity and when these occur the benefits of randomization often dissipate3. Additionally, the high complexity and costs of conducting RCTs restrict the use of very large numbers of patients and that in itself introduces selection bias. This partiality can be due to patient factors related to geography, trial access, health insurance, the availability of past medical records, and the economic resources that would permit and support participation in RCTs. In RCTs of Alzheimer’s disease (AD) studies examining the rates of patient eligibility have suggested that as little as 10–27% of potential AD patients are trial eligible4,5. Regrettably, only a small portion of AD patients are even marginally aware of research opportunities and many are unable or unwilling to participate. Many older adults live alone and may not have access to a caregiver who can accompany them to study visits and aid with various procedures. Indeed, AD trials require not 46 Journal for Clinical Studies

one but two participants – the patient and a study partner – and enrolment of this dyad is imperative in ensuring clinical trial success. Of interest substantive differences have been noted between enrolled AD samples and the general AD population which primarily reflect the idiosyncratic subject entry/eligibility criteria specific to any given AD study. More often than not the diagnosis of AD in clinical practice as opposed to research setting is based on an individual clinician’s distinctive diagnostic approach rather than any specific research criteria. The greatest challenge for most investigators is how to properly select the right patients for a particular AD study and appropriately translate that patient’s medical data and history into protocol-specific entry criteria. This becomes even more important in oligosymptomatic disease presentation in early AD where the patient’s spontaneous reports of cognitive impairment are very often rare, inconsistent, and may not have not been taken seriously. Even for those patients who are willing and able to enter RCTs actual enrolment into the trial faces many other obstacles including proscribed medical comorbidities, extensive use of prescription and over the counter medications, and behavioural complications of AD which may all be exclusionary. In practice the use of such strict enrolment criteria and enrichment designs may paradoxically end up excluding the exact cohort of patients most likely to actually use or possibly even benefit from the drug, and essentially exclude those patients who are most likely to provide the richest data sets (e.g., those most likely to utilize healthcare services) of interest to payers and clinicians. During clinical development and long before observational studies begin, an effort should be made to include a broader, more representative cross-section of the population that is ultimately likely to receive the drug therapy. Additionally, some AD patients are anxious about biomarker related procedures such as lumbar puncture for cerebrospinal fluid examinations or MRI/PET imaging procedures, whereas other subjects might have difficulties with extensive and numerous psychometric tests that often require three to six hours to complete and can result in frustration and emotional anguish upon confrontation of deficits. In the end RCTs in AD are designed to test verum in a very specific patient cohort utilizing very strict eligibility criteria. So, even after a large positive registration trial, the number of patients that the results of an RCT may apply to could be relatively small6. Arguably it is important to make painstaking efforts to include as many of those patients with the most frequent comorbid illness and those taking the most common comorbid medications as possible, as these patients are also the ones most likely driving utilization costs and are therefore are ultimately the most informative. Enrolling “super” AD subjects who are exceptionally healthy except for their AD does not tell us much about the typical patients who will eventually be taking the drug once it is approved, let alone those in the “deeper end of the pool” who have “messy” multiple and severe comorbid illnesses that ultimately drive utilization costs. Volume 11 Issue 4

Technology Linking Real-World Evidence with Large Multidimensional Data Sets There are several broad approaches to help enrich data sets to include information on more typical patients who more greatly resemble those who will ultimately receive the drug. These include Real-World Evidence (RWE) studies, pragmatic trials (conducted post-approval), platform trials and extended observations that go beyond the constraints of a randomized investigation. Table 1 presents the methodologies that have garnered a renewed interest in recent years thanks largely to payer and regulatory concerns regarding the deficiency of practical and valuable data on drugs already approved.

Table 1. Options, Alternatives and Enhancements to Traditional RCTs

Simply put, RWE is the capture and analysis of the actual experience of medical practice. Most often based upon electronic medical record (EMR) data and drug and/or treatment-centric data, RWE provides a retrospective view of exactly how drugs are used “in the wild� without the constraints of rigorous RCTs and the associated monitoring processes. Many drug developers are looking to the rapidly evolving field of real-world evidence (RWE) to serve as the critical bridge between these disparate domains. Assuming that clinical trial research has covered a significant proportion of the total timeline of the disease progression, as shown in Figure 1A, the next opportunity is to increase the dimensionality of data as shown above in Figure 1B. A single study rarely samples sufficiently long outcomes – even an entire program would not likely cover the full transitions in clinical care that might take place.

Here, there are many options but, in general, the goal is to bridge the data and methodology gap between drug development and clinical care. Techniques include the use of same/similar measures over extended time frames or the use of new measures over similar time frames (see figure 1.) While these two can often appear similar, they are in fact quite distinct with differences in data collection platforms, staff training, monitoring conventions, methods of data aggregation and analysis, and regulatory requirements to enable the trials. In a post marketing environment, physicians are limited by practice apology and by payers to the types and frequency of diagnostic tests they can perform. In RCTs, costs are also important but can be secondary to concerns that extraneous data collection can confound clinical trial data interpretation and results7. A Path Forward The art and science of RWE is rapidly evolving as many hope RWE will fill the data divide between medical practice and biomedical product development for topics ranging from drug safety endpoint development to the regulatory review of generic drugs8,9. That said, it is also clear that RWE alone is also inadequate as the only basis of drug review and approval due to its retrospective and fragmented nature but, when linked with large data sets, RWE can serve as a solid basis of medical evidence. Recent regulatory guidance on the topic provides a mosaic of opportunities both in terms of facilitating approval, but particularly in describing the impact of novel therapy on systems of care. The key lies in exactly how to link and pull these complex stories together to gain a comprehensive view over time and across a fragmented health system, of a single patient journey as well as the aggregate experiences of larger populations. This can be done and has been recently demonstrated in a recent study in combining RWE and large genomic databases to provide an in-depth view and guide for a single cancer patient9. By linking RWE, large scale genomics databases, data from independent labs and specialty genomics sequencing companies, these researchers were able to recreate the entire longitudinal patient journey for a single cancer patient despite the complex, fragmented and nonstandardized nature of all the data sources. Notably, one methodology that involves simply extending observations outside the scope of a traditional RCT has shown great promise in gathering data sets important to payers and regulators in economically efficient and practical manner and will be discussed in more detail. Extended Observations and Patient Reported Data As previously noted, RCTs have a highly selective focus and short

Figure 1. Options for Covering a Greater Proportion of Patient Journey (A) and increasing Data Dimensionality (B)

Journal for Clinical Studies 47

Technology duration which limits understanding of disease history, progression or trajectory. Most importantly, traditional strategies to optimize the timing of interventions using nomenclature which would resonate with providers as opposed to investigators are limited to coarse and subjective labels such as early or late AD. Overcoming these limitations to provide a comprehensive and enhanced perspective on disease course, symptom progression and treatment efficacy over the full-time course of disease progression could be transformational for patients and progress is being made in that endeavor. For example, recent work using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) has shown that highly fragmented data can be linked and modeled algorithmically to demonstrate a comprehensive view of AD progression over 20 years or more10. While retrospective investigation of large data sets has inherent limitations, these challenges may be greatly reduced when coupled with prospective data collection especially when key variables missing from a retrospective study are prioritized within the prospective study11. There are many options, both novel and long-standing, for capturing and studying a greater percentage of the AD disease journey as summarized in Figure 1. Starting with the more established methods, it has long been known that patient and caregiver diaries were suitable and valuable as research collection tools despite being seldom used12. Methodologies that exploit the concept of patient-reported data (PRD) continue to mature and are now highly digitized and used across a wide swath of healthcare from complex chronic diseases, such as cystic fibrosis and cancer, to complex underserved populations and even dentistry and other healthcare disciplines13,14. Although these tools have matured greatly over the years, their usage remains traditional and restricted, and they are most often primarily limited to utilization within RCTs. While there are many reasons for this, economics and liability top the list. RCTs in AD are sponsored and all incurred costs are reimbursed by the sponsor in research for neurodegeneration and it is unclear if medical payers would reimburse PRD activity as an essential part of the course of care. It is also unclear who is ultimately responsible for following up on interesting or odd data or who would follow up if something important is missed. One set of models that appears effective are those implemented by patient advocacy organizations and registries. These groups are capable of self-funding extended data collection and have become pivotal in the research and development continuum15. Having available tools and business models obviously aids the cause but most researchers remain uncertain as to how best to implement these. As previously discussed, one creative and novel approach would be to simply extend a study database by offering an alternative observational PRD-based protocol to patients that are screened out of traditional RCTs. Regulatory agencies have more recently requested better characterization of potential patients who screen fail and followup with longer-term outcomes offers an attractive model to pursue. Another potential benefit of this would be to gather information on natural history and disease course that could be used to design and power future studies, especially when disease trajectory is not linear, and the nature of assessments that would be most sensitive clinically is not uniform across the disease trajectory. An alternative might be to offer a voluntary observational protocol for all patients that complete or drop out of trials regardless of whether they responded or even dropped out of the clinical trial; and this alternative could also be extended to those patients who are screen failures reflecting the most common and salient reasons for screen failure such as use of a concomitant medication or past medical history or those who fail for some reason idiosyncratic to the study such as past exposure to the study drug. All of these groups and subgroups are potential cohorts for future prospective or retrospective study but only if they are engaged and tracked. Prior studies already cited have shown that patients can and will stay engaged for decades or until their demise. Further, these studies 48 Journal for Clinical Studies

need not be limited solely to patient-reported measures. Under proper informed consent procedures, these observational studies can be built to enable future data collection of almost all types including electronic medical records, imaging, surveys and even data types that are not yet foreseen16. Practically speaking the following schema in Figure 2 could be followed whenever possible for all patients who screen fail or drop out early with the ultimate goal of gathering important PRD and reducing loss to follow up to zero.

Figure 2. A Schema for Optimizing Patient Data Throughout an RCT

An Example of Utilizing Large Integrated Data Sets to Limit Loss to follow up and Extend Observations in an Early AD RCT Patients in early AD RCTs are typically younger than their mild to moderate AD counterparts, have characteristic pathophysiologic changes of AD and subtle detectable abnormalities on sensitive neuropsychological measures, but no functional impairment, and as such may continue to be employed and socially active. The diagnostic criteria for Early AD, sometimes referred to as Prodromal and/or Mild Cognitive Impairment (MCI) due to AD, have recently been developed and include evidence of amyloid burden and/or neurodegeneration. Although amyloid PET scanning or CSF amyloid measurement is integral for identifying subjects who are more likely to develop AD the expense and relative limited availability of PET scanners uniformly throughout various geographic regions, and the regional variations in obtaining lumbar punctures limits their widespread application for many AD trials. Screening for amyloid positivity is now a routine part of enrolment criteria in clinical trials. However, this one criteria may effectively eliminate approximately 1 out of 3 patients with MCI17. Additional screening criteria regarding cognitive function, concomitant medications and illnessxes has routinely resulted in extremely high screen failure rate (approximating 75–85%) driving up costs and timelines of early AD RCTs. And unless this same type of rigor (confirmed by imaging or CSF) is utilized by general practitioners to diagnose patients who will ultimately receive these AD drugs it is very likely that once approved these medications will be utilized in a population with nominally the same diagnosis that nevertheless is markedly different from the one that led to the drug’s approval. One suggestion to help remedy this problem of poor generalizability is simply to follow those patients who screen failed for various reasons (lack of biomarker, concomitant medication, concomitant illness, lack of a reliable caregiver etc.) minimally for the length of the trial period in order to better understand the natural history of the disease but also for an extended period of time after the conclusion of that trial. Following these patients outside the confines of the RCT through the use of large related data sets may help limit the cost of the study, will be virtually unobtrusive to patients, and help extend generalizability. These patients could serve as a “control arm” in support of a current study in terms of healthcare utilization (especially if it is a rare disorder); help plan post marketing studies; Volume 11 Issue 4

Technology help characterize a pool of potential patients for future clinical trials diagnostic lab, the record might correspond to BB0001. When this data is transferred to the sponsor, however, both tokens will be decrypted which may have a much more liberal set of eligibility criteria; and and re-encrypted such that each record will be identified with the token importantly help establish the burden of disease against which to model CC0001. In the sponsor’s environment, all CC0001 tokens correspond drug effects. Obviously, patients who met criteria and enter the trial to the same de-identified individual (in this case, John Smith). could also be followed in this manner whether they drop out early or complete the study. To enhance a traditional RCT, a sponsor might begin by tokenizing As noted patients in early AD trials may still be active socially the clinical data that is collected during the clinical trial. By then using and may even still be employed. Many of these patients have health the same method to tokenize the various real-world data sources that insurance and even supplemental health insurance in addition to Medicare. By chance it might be expected that approximately the sponsor will leverage as part of the enhanced clinical trial, the sponsor can link the traditional clinical trial data to other real-world 10–20% of subjects in any given large RCT for early AD conducted in the data which are routinely collected outside of RCT setting may be useful United States would be covered by a single health care insurer provider depending on geography. This estimate can be greatly increased by in tracking clinical state and many of those suggested below have been shown to be closely related to patients’ overall level of cognition and simply changing geography to match a single payer market penetration function. These include the following examples in Table 2, but the or by including data from more than one payer, or even by obtaining suggested outcomes are only limited by the types of data available and provider data from patients who may belong to specific organizations the creativity of the researcher: such as the American Association of Retired Persons (AARP). Data from payers tends to be broad but not very deep, meaning that there is data on many patients, but the quantity and quality of that data may be limited to top diagnostic codes and procedures that are paid for by the provider. Routinely collected data from managed care companies on procedures can be used to infer if the drug continued to show overall benefits on an individual patient level. Less compellingly would be differences between dose groups or the Table 2. Example of Possible Data Sets and Their Utility in AD trials active comparator versus standard of care Discussion which continue to exist. Patients who are enrolled in early AD RCTs are typically assigned to one of two to three medication dose groups or placebo (as This type of payer data can also be supplemented by other large monotherapy or added therapy to an underlying drug like a data sets that can be integrated with payer data and includes data cholinesterase inhibitor or memantine). In an early AD RCT of a related to social media, activity, driving, etc. Of course, there must be disease modifying agent, or even for a drug that would prevent the a way to integrate these disparate databases as data silos have greatly onset of dementing symptoms in a population of patients likely limited the realization of health data benefits. One such solution is to develop these, trial durations are often long and typically the to use a “token” that can be applied to individual patients to enhance duration is 18–24 months. Therefore, attrition of upward of one third trial datasets, enabling researchers to connect trial data sets to other of the sample would be expected. This attrition is problematic in large and diverse health care, marketing and social data sets or any dethe trials as there is always a chance to see non-random differences identified datasets pooled from multiple real-world sources in a passive in drop-out rates and missing data, as well as poor adherence to observational study without compromising patient privacy, enabling treatment over long treatment durations. It is therefore important to new avenues for researchers and a better understanding of the patient attempt to track these patients over time to what would have been journey. their pre-established endpoints by using traditional RCT endpoints whenever possible, and when not possible by using integrated data Disparate datasets often need to be de-identified in order to be sets that are available to the researcher. The availability of large exchanged. In the process of de-identification, it is possible to leverage integrated data sets has resulted in a renewed interest in the use of the underlying identifying information to generate anonymous such real-word data to supplement RCTS and bridge the widening identifiers or “tokens” that can be used to link corresponding patient evidence gap between research and clinical practice. records across datasets. These tokens are essentially hashed and encrypted combinations of those identifying elements. Hashing the Additionally, even for those early AD patients who complete the underlying identifying elements ensures that a bad actor cannot RCT much can be learned by following them for an extended period reverse the token to identify the patient. Encryption is a second layer of time past the traditional 18–24 month treatment period of the of security that results in tokens which are specific to a given site (so RCT. Specifically, data garnered from this extended period of time that a breach anywhere in the network of tokenized data does not put can help assess if the drug has disease modifying effects that persist anyone else’s data at risk). While it is not possible to reverse the hash, long after the cessation of study drug. Compared to patients on site-specific tokens can be decrypted and re-encrypted so that records approved symptomatic treatments which do not alter the underlying can be linked across sites. course of the disease, a drug which is a true disease modifier will To take a simple example, imagine that a man named John Smith, continue to show benefit even after the drug is discontinued and who was born on January `1, 1950 exists in both an EHR dataset and long after the trial is formally over supporting a claim for disease a diagnostic lab dataset. If all of John Smith’s identifying information modification. This clinical benefit could be evidenced across was removed from both datasets, there would be no way to link his varied sets of medical and social media data that track clinical state records. However, by creating tokens from first name (“John”), last dependent upon the type of data that the researcher has access to, name (“Smith”), gender (“M”) and birth date (“January 1, 1950”), it is and reasonably could even be accompanied by evidence of a delay possible to create two hashed and encrypted tokens for John Smith. At the EHR data source, the record might correspond to AA0001. At the in the progression of brain neurodegeneration as seen by imaging

Journal for Clinical Studies 49

Technology or CSF biomarker if available. Extended observations may also help differentiate dose groups that were very similar in terms of efficacy and safety upon conclusion of the RCT and help to determine which dose(s) will ultimately be used for marketing purposes or provide better evidence for add on versus monotherapy. Of course, it is helpful if there is an existing literature to support a link of various types of data to cognition or function; that the data have some level of face validity; or be related to some clinically meaningful outcome accepted by healthcare practitioners or regulators. For example, the FDA has become much more interested in real-world outcomes and have recently encouraged the development of novel approaches to the integrated evaluation of subtle early AD functional deficits/impact that arise from early cognitive impairment such as facility with financial transactions, and adequacy of social conversation18. These can be tracked by formal outcome measures during a RCT or even outside of the trial using data from large data sets without steadfast requirements as to the exact type of data nor linkage to disease. In fact, by relating this type of data back to clinical trial outcomes and patient characteristics it is possible to discover data relationships that support or predict longer term outcomes that are as yet unknown. All of this should be done in an effort to close the evidence gap between the data evaluated by regulators for approval which is by definition derived from idiosyncratic RCTs, and the real-world data used by health care providers, payers and consumers to inform clinical practice. REFERENCES 1

O’Sullivan AK, Thompson D, Drummond MF. Collection of healtheconomic data alongside clinical trials: is there a future for piggyback evaluations? Value Health. 2005;8:67-79. 2 Zuidgeest MGP, Goetz I, Groenwold RHH, Irving E, van Thiel GJMW, Grobbee DE; GetReal Work Package 3. Series: Pragmatic trials and real world evidence: Paper 1. Introduction. J Clin Epidemiol. 2017 Aug;88:7-13 3 Rothwell PM. Factors that can affect the external validity of randomized controlled trials. PLoS Clin Trials. 2006 May;1(1). 4 Schneider LS, Olin JT, Lyness SA, et al. Eligibility of Alzheimer's disease clinic patients for clinical trials. Journal of the American Geriatrics Society. 1997; 45(8):923–928. 5 Treves TA, Verchovsky R, Klimovitsky S, et al. Recruitment rate to drug trials for dementia of the Alzheimer type. Alzheimer disease and associated disorders. 2000; 14(4):209–211. 6 Mayo CS, Matuszak MM, Schipper MJ, Jolly S, Hayman JA, Ten Haken RK. Big Data in Designing Clinical Trials: Opportunities and Challenges. Front Oncol. 2017 Aug 31;7:187 7 Sedgewick P. Randomised controlled trials: understanding confounding. BMJ. 2015 ;351:h5119 8 Costanzo A et al. Effectiveness End Points in Real-World Studies on Biological Therapies in Psoriasis: Systematic Review with Focus on Drug Survival. Dermatology. 2018. DOI: 10.1159/000488586 9 Argawala V et al. Real-World Evidence In Support Of Precision Medicine: Clinico-Genomic Cancer Data As A Case Study. Health Affairs. 2018. 37, NO. 5 (2018): 765–772 10 Ishida T. et al. A Novel Method to Estimate Long-Term Chronological Changes From Fragmented Observations in Disease Progression. Clinical Pharmacology and Therapeutics. 2018. Epub ahead of print. 11 CohortStudies/EP713_CohortStudies2.html 12 Välimäki T1, Vehviläinen-Julkunen K, Pietilä AM. Diaries as research data in a study on family caregivers of people with Alzheimer’s Disease: methodological issues. J Adv Nurs. 2007. Jul;59(1):68-76 13 Stuart J et al. Eliciting the Impact of Digital Consulting for Young People Living With Long-Term Conditions (LYNC Study): Cognitive Interviews to Assess the Face and Content Validity of Two Patient-Reported Outcome Measures. JMIR. 2018 Oct 11;20(10):e268. doi: 10.2196/ jmir.9786 50 Journal for Clinical Studies

14 Joda T, Ferrarri M, Bragger U, Zitmann NU. Patient Reported Outcome Measures (PROMs) of posterior single-implant crowns using digital workflows: A randomized controlled trial with three-year follow up. Clin Oral Implants Res. 2018 Sep;29(9):954 961. doi: 10.1111/clr.13360. Epub 2018 Aug 24 15 Bartek RJ. Foundation-industry relationships—a new business model joint venture philanthropy in therapy development. Curr Top Med Chem. 2014;14(3):313-8 16 Grady C et al. Informed Consent. NEJM. N Engl J Med. 2017 Mar 2;376(9):856-867 17 Landau SM et al. Amyloid negativity in patients with clinically diagnosed Alzheimer’s disease and MCI. Neurology 2016: 86: 1377-1385. 18 Early Alzheimer’s Disease: Developing Drugs for Treatment. Guidance for Industry. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER)/ Center for Biologics Evaluation and Research (CBER). February 2018. Clinical/Medical Revision 1.

Henry J. Riordan Henry J. Riordan, Ph.D. is Executive Vice President of Scientific Solutions at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various neuroscience drugs and disorders in both industry and academia for the past 20 years with a special emphasis in Alzheimer’s disease. He has over 100 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology. Email:

Eric D Perakslis Eric D Perakslis, Ph.D. is the Rubenstein Fellow at Duke University where his mission to modernize Duke Med School and Health System via data and technology transformation. Dr. Perakslis is also a faculty member of Harvard Medical School. Dr. Perakslis is a widely recognized research, informatics, and technology leader with more than 20 years’ experience in healthcare, biotechnology and pharmaceutical discovery/development, in addition to serving at the FDA and HMS where he was the CIO and Chief Scientist (Informatics) and the Exec Dir at the Center for Biomedical Informatics.

Sam Roosz Sam Roosz, MBA is the Cofounder and Head of Life Sciences at Datavant, Inc. where his mission is to enable disparate deidentified healthcare datasets to be linked together in a fashion that protects patient privacy. Mr. Roosz also has experience in bringing healthcare products to market in his roles working as a strategy consultant to the biopharmaceutical industry and a product and portfolio manager with a clinical genomics company focused on oncology, reproductive health, and transplant.

Michael Murphy Michael Murphy, M.D., Ph.D. is the CMO/CSO or Worldwide Clinical Trials. As a psychiatrist and pharmacologist who specializes in translational medicine and phase IV services Dr. Murphy has extensive experience in AD and neurogenerative disorders. He serves as Research & Development Editor for American Health & Drug Benefits™, and faculty member within the Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences and Technology.

Volume 11 Issue 4

Volume 9 Issue 1 - Spring - 2017

Volume 9 Issue 1

Peer Reviewed

International Pharmaceutical Industry

Supporting the industry through communication

IPI – International Pharmaceutical Industry


MALDI Mass Spectrometry in Drug Discovery Gaining A Deeper Understanding

Three Ways to Mitigate the Risk of

Late-Stage Failure in CNS Drug Development


The Foundation of Clinical Trials

Temperature Management Keep Your Cool



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


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

Volume 4 Issue 1 Volume 4 - Issue 1 Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed


Applying Game Theory to One Health Modelling Veterinary Healthcare Delivery International Animal Health Journal - Supporting the Development of Veterinary Drugs, Veterinary Devices & Animal Feed

Mastitis due to Mycoplasma bovis Insights Pet Obesity Prevention is Better than Cure Leadership Skills of Extraordinarily Successful Executives

Official Supporting Associations -

Sponsor Companies - 11_IAHJ_February2017.indd 1

25/02/2017 13:37:17


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


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

Journal for Clinical Studies 51

Logistics & Supply Chain Management

Exploring the Complexities of Importer of Record to Develop Effective Global Distribution Strategies The pharmaceutical sector’s fundamental purpose of advancing human health and its ambition to deliver drugs to market as rapidly, safely and cost-effectively as possible has had a transformative impact on clinical trials management over the last decade. This has given rise to globalisation. The average Phase III trial now spans 34 countries, with in excess of 1000 patients. Indeed, the number of countries serving as clinical study locations outside of the United States has more than doubled in the space of 10 years.1 Not only has this been driven by cost reduction, with estimates suggesting that a clinical site in India can be up to 10 times cheaper than a US-based facility,2 greater geographical reach equals more potential for study participants. This leads to faster and more effective patient enrolment,3 which enables quicker, more cost-effective development and approval of investigational products. Accompanying the rise in globalisation, and in part an achievement of it, is the development of biologics, which are predicted to replace 70% of small molecule drugs over the next two decades.4 Unlike chemically synthesised drugs, biologics are incredibly expensive. Biologics also need to be processed and stored in controlled conditions, usually in refrigerated or frozen temperature ranges, and have limited stability data to withstand excursions. When both trends combine, complexity manifests, risk increases and the margin for error shrinks drastically. A key element of the globalised clinical supply chain that poses a significant risk to a trial’s timeline, patients and commercial viability is importer of record processes. Understanding the specific risks associated with the role of importer of record should be a core consideration at the onset of any clinical trial involving sites in multiple countries, especially those involving temperature-controlled products. Avoiding the pitfalls that lead to costly and chaotic customs experiences means developing effective distribution strategies that promote drug integrity and compliance. Understanding the Role of Importer of Record Obtaining a sound understanding of the role of importer of record is essential before effective clinical distribution plans can be designed.

From an import perspective, the importer of record is also legally responsible – and financially liable – for accurate valuation, tariff classification, country of origin assurance, payment of import duties and taxes and effective record-keeping. The rules on who can act as importer of record varies from country to country. Some countries dictate that only trial sponsors can fulfil the role, whereas others allow a third party to serve on a sponsor’s behalf. If sponsors choose or are required to operate as importer of record, a local office or associate can provide the ‘boots on the ground’. If these options are unavailable or without an appropriate trading license, the sponsor will need to engage and grant power of attorney (or provide a letter of delegation) to a third party. Examining the specific requirements of each country involved in a clinical trial will help sponsors to better determine their options. Identifying the Common Pitfalls Once the role, and how it relates to specific countries, is thoroughly understood, sponsors must familiarise themselves with some of the more common areas of risk. These typically relate to product classification, product valuation and the drug’s country of origin. When it comes to product/tariff classification, often referred to as a harmonised tariff code, it’s important to remember that descriptions and values differ between product types and between active IMP and placebo. Placebos are often classified as a food component and are typically applicable to duty, which is usually between 6% and 12% of the product’s value. Incorrect classification can lead to delays in customs clearance and mis-payment of duties. Contrastingly, active IMP is typically duty-free. Of equal risk is the methodology used to determine a shipment’s value. If customs are dissatisfied with the value declared on the shipment invoice, they will re-value consignments independently. This impacts the duty and taxes applicable to a shipment and can negatively impact trial budgets and timelines. It is no longer enough to apply a nominal value without appropriate methodology. Value evidence statement requests, to clarify how

Introduced as part of the Customs Modernization Act of 1993, the importer of record is responsible for ensuring imported goods comply with local law and regulations, and for payment of import duties, tariffs and fees. The first point of contact should auditors require more information, regulatory responsibilities of the importer of record include evidencing that products have been manufactured and labelled according to country-specific requirements, are correctly branded and meet Good Manufacturing Practice (GMP) standards. 52 Journal for Clinical Studies

Volume 11 Issue 4

Following a successful comeback to Europe last year, we are delighted to present stimulating discussions and presentations devised to tackle recent regulatory challenges and explore innovations within packaging and labelling within the pharma and device industry. Experts from all over Europe will gather in one room across two days for close knit networking, open debates and interviews.

Analysing the EU MDR and its implications for Labelling and Artwork E-Labelling: accessing digital information from a packaging barcode using a standardised approach Minimizing the confusion and clarifying the future of FMD for packaging and label design Improving artwork change implementation across supply chain, tools and stakeholders and interactions across functions Regulation on MDR & IVDR: Deadlines approaching, are you complaint to the regulation?

Journal for Clinical Studies 53

Logistics & Supply Chain Management product value has been determined, is becoming status quo for most customs authorities around the world – creating additional hoops for sponsors to jump through. The same is true when it comes to clearly and correctly declaring a shipment’s country of origin. Failure to provide the required substantiation in relation to tariff classifications, value methodologies and country of origin risks shipments being placed on hold by customs officials, while debates take place and the clock ticks on temperature-sensitive shipments. Equally, failure to appropriately manage processes and paperwork will cause delays that can compromise the integrity of temperature-sensitive consignments, introduce cost and negatively impact patients. Another point to note is that repeated non-compliances in these three core areas can result in more regular customs audits or financial penalties. A World of Difference: Identifying Country-specific Nuances Once the role is understood and core risk hot spots identified, it is necessary to drill down into the precise nuances in import/export criteria for each country involved in the global trial in question. Although there may be similarities, no two countries’ import/ export criteria are the same. There is huge variation in import/export requirements. For example, the Ukraine sits at the more straightforward end of the spectrum. Newly introduced regulations remove the need for an import licence for both new and existing studies, along with a quick customs clearance timeframe of two to three days. Countries in South America have more complex requirements. Some countries require an umbrella import licence that is valid for the duration of the study, but also require a shipment-specific

import permit that needs to be obtained prior to shipping. This can take up to 50 days to receive, and customs clearance can take up to 30 days. Customs in Argentina require an import license that forms part of the annex to the clinical trial authorisation (CTA) submission. This can take 90 days to obtain. An import permit per shipment is also required and takes approximately four days to obtain. Customs clearance timeframes take 12 days on average. China is also incredibly challenging to import clinical material into; involving highly regulated processes that require a local importer of record. Chinese customs authorities dictate that shipments are packed in advance, to obtain the weights and pieces information, which must be transferred onto the shipment invoice and physically verified by Chinese customs. Pack lists must also state the contents, number of boxes and both the nett and gross weight of the shipment. Meanwhile the type of import permit needed will depend on the product classification code recorded with Chinese customs. This can take between three and five days for a ‘Q’ permit and 30 days for an ‘L’ permit. Adding further complexity, Chinese customs also demand a certificate of origin for all shipments, along with a chain of custody document that must contain the same batch number as the one shown on the shipment invoice. Shipments of IMP require transportation/movement documentation to evidence full transit from manufacturer to importer of record. A photograph of the drug label is also required, as is the sponsor’s business licence and a guarantee letter to the BFDA confirming clinical trial approval. If sponsors plan to import their IP to China, they should ensure products have at least 12 months’ expiry remaining, or risk nonadmittance. Equally, if trials involve temperature-controlled shipments, sponsors should expect consignments to be removed from temperature-controlled storage during customs inspection, which typically last between 24 and 48 hours. Managing the risk of excursions will need to be a key priority. Understanding the variations of import requirements for each country included within a clinical trial will help form the foundation of an effective global distribution strategy, minimise delays, keep distribution ‘on budget’, and lessen the risk of negative impact to patient kits. Embracing Importer of Record Best Practice By exploring the variations in country-specific customs import/ export requirements, it’s clear just how complex developing a robust distribution strategy for a globalised clinical trial can be. The ability to centralise all data pertaining to the lead times, documentation requirements and airport facilities of each country involved in the trial will help manage this complexity and reduce risk. Yet achieving holistic visibility of up-to-date import/export criteria, typical clearance times, customs facilities, duty and VAT liabilities and the recommended incoterms, which help establish where an importer of record’s liability begins and ends, for 80+ countries, is a monumental task for sponsors to manage alone. Furthermore, understanding the country-specific nuances of import/export criterial is only part of the battle. An importer of record will also need to build strong relationships with third parties in the global clinical supply chain. Courier partners, for example, must have the skills and expertise to manage high-value, high-risk, time-critical shipments to countries

54 Journal for Clinical Studies

Volume 11 Issue 4

Logistics & Supply Chain Management

with complex import criteria. Partnering with an international logistics company with a global network and demonstrable knowledge and experience of import/export requirements within the pharmaceutical sector is a key responsibility for the importer of record. To form an effective link in the supply chain, selection criteria should assess a prospective courier partner’s processes and standard operating procedures. It should also look at what controls exist within IT systems, the training of staff, drivers, and the security of vehicles. Customs brokers also need to be selected by the importer of record, who will need to cultivate a global network of professional agents that can accurately prepare and submit documents for compliantly and cost-effectively clearing pharmaceutical shipments through customs. The customs broker must be licensed, have demonstrable relationships with custom authorities and be well versed in the nuances of pharmaceutical shipments; from laws and regulation to classifications, documentation and duties. Despite multiple third-party involvement, the importer of record must maintain continuous oversight of drug shipments from the moment they depart a facility, until proof of delivery has been received from clinical sites. A final branch of responsibility is meticulous record-keeping. During customs audits, officials will expect to review a complete record-keeping pack. An importer of record should have a sound understanding of what documentation must be contained within these packs. Customs will also expect importers of record to perform audits on their imports on a regular basis to identify errors in entry and allow for amendments to be submitted. For this to work, it is essential that trained, knowledgeable personnel are utilised to promote self-governance and compliance best practice. Right Drug, Right Patient, Right Time, Right Temperature A competent importer of record is a prerequisite to any successful global clinical supply chain. The role is vast and the remit wide, covering everything from liaison with third parties, troubleshooting delays, ensuring the correct tariffs and duties are paid, that all paperwork is present and correct and that drugs are released on time, to nurturing and co-ordinating global networks of couriers and brokers, contingency planning and compliance management. While there is no one-size-fits-all approach, by understanding the key elements of the role, the risks, the country-specific nuances and what general best practice looks like, sponsors will be better equipped to develop effective global clinical distribution strategies.

Whether sponsors choose to manage the importer of record process themselves or outsource to specialists, by harnessing this knowledge and combining it with early, in-depth planning, the importer of record can play an essential role in delivering the right drug, to the right patient, at the right time and under the right temperature conditions. In doing so, sponsors can embrace the benefits of global clinical trials and concentrate efforts on developing therapeutic breakthroughs that transform the lives of patients faster, and more effectively, than ever before. REFERENCES 1. 2. 3. 4.

International Journal of Clinical Trials da Silva RE et al. Int J Clin Trials. 2016 Feb;3(1):1-8 International Journal of Clinical Trials da Silva RE et al. Int J Clin Trials. 2016 Feb;3(1):1-8 International Journal of Clinical Trials da Silva RE et al. Int J Clin Trials. 2016 Feb;3(1):1-8 “Global biosimilars market could be worth US$55bn by 2020, says new report,� Manufacturing Chemist, July 2015.

Sharon Courtney Sharon is an International Logistics Specialist having worked for 18 years in Clinical Supply Chain. She has expert knowledge in a number of key areas within the end to end supply chain process including management and control of temperature sensitive shipments; risk mitigation (identifying and managing risk); developing and managing robust relationships with transport partners; chain of custody responsibilities; active and passive shipping solutions and import/export country knowledge. Sharon has consistently delivered reliable and validated logistics solutions for customers based on her experience of establishing numerous international logistics models over the years. Sharon is passionate about providing excellent customer service in the area of logistics and this is demonstrated in her understanding of every role within the end to end supply chain process. She has first-hand knowledge of working with customers, external organizations and the appropriate departments within Almac to deliver well established logistics solutions in the Pharma industry. Sharon has travelled widely with her work and has been instrumental in the development of the logistics service provided by Almac.

Journal for Clinical Studies 55

Ad Index

Page 3 Europital

Page 27 Greens Ltd

BC Medical Research Network Ltd

Page 35

MLM Medical Labs GmbH



Page 53

Pharma Packaging & Labelling Europe 2019

Page 51

Pharma Publications

Page 45 Ramus

Page 5 RWS


Page 21

Synlab International GmbH

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

JCS is also now active on social media. Follow us on:

Subscribe today at or email

56 Journal for Clinical Studies

Volume 11 Issue 4



Patients are at the core of what we do. Bringing clinical study visits to the patient not only reduces burden on patients and their caregivers but it also allows those who live far from the clinical site an opportunity to participate.

Increase enrollment, retention and geographic reach with the experts! UK Tel: +44 (0)1908 261 153 | | US Tel: +1 (847) 779 7857