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Volume 6 - Issue 2


U CLINICAL STUDIES Your Resource for Multisite Studies & Emerging Markets PEER REVIEWED

New FDA Guidance Clarifies the DDT Qualification Process Patient-derived Xenograft (PDX) Model An Evolution in Oncology Drug Study The Role of Mobile Technology In Reshaping the Pharmaceutical Industry How Changes in Practice are Changing Bleeding End Points In Coronary Interventional Trials.


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08 New FDA Guidance Clarifies the DDT Qualification Process Meg Egan Auderset of Thomson Reuters explains the Final FDA guidance released in January 2014, which outlines the formal qualification process for drug development tools (DDTs), and offers a guide for interactions between entities proposing DDTs for qualification and the Center for Drug Evaluation and Research (CDER). 10 The Role of the Artery in Chronic Kidney Disease It is well-established that patients with chronic kidney disease (CKD) have a significantly higher cardiovascular risk than those with normal renal function. In fact, the majority of patients with stages 3 to 4 CKD are more likely to die of CV causes than they are to progress to renal failure. Bobby Stutz and Dr Winter of Atcor Medical, Inc. address the fact that an increased prevalence of major CV risk factors in this population (including hypertension, diabetes, and dislipidemia) does not explain the discrepancy.

PUBLISHED BY Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 0207 237 2036 Fax: +0014802475316 Email: Journal for Clinical Studies – ISSN 1758-5678 is published bi-monthly by PHARMAPUBS.

The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. Volume 6 Issue 2 March 2014 PHARMA PUBLICATIONS

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Contents 12 Logistics in Emerging Markets Column China makes up 19% of the world’s population, and is expected to overtake the US as the world’s largest market by 2020, putting it right at the top of the list of target countries for clinical research. With 4648 trials currently taking place, Sue Lee of World Courier clarifies the logistics of conducting clinical studies in China, and describes how systematic processes lead to success, a minimum of delays, and ultimately access into this vast marketplace.

research than those in North America and Western Europe, the conventional wisdom is that study teams need to apply more rigorous on-site monitoring, as the level of compliance and quality is expected to be problematic. Stephen Young, Kyle Given, and Laurie Falkin of Medidata Solutions ask whether sites in emerging regions are indeed showing signs of lower quality that warrant more intensive scrutiny in a riskbased monitoring paradigm.

14 Egypt Regulations for Clinical Research With a vast patient pool, feasible timelines for approval, and written procedures for submission to ethics committees and regulatory authorities, there is wide scope for conducting clinical research in Egypt. Adhiti Sharad Kumar of the Association of Clinical Research Professionals (ACRP) examines the potential study sites and regulations for running clinical trials in this country.

30 Risk-sharing: Supplementing Clinical Trials for Payer and HTA Success As the benefits of real-world data become more apparent, so too, do issues around its appropriate collection methodology and reliability. Olivier Ethgen of SERFAN Innovation & EMIR (University of Liege) explores the creation of risk-sharing agreements and how to use these to mitigate the potential weaknesses of clinical trial data.



16 Prospects of Conducting Bioavailability/ Bioequivalence (BA/BE) Studies and Outsourcing in Semi-regulated Countries Given the rapid progress of the global generics drug market, organisations must critically manage and assess bioequivalence studies that are mandatory when bringing new generic drugs to the market. Most pharmaceutical companies outsource these pivotal bioequivalence studies to CROs in order to expedite the generic drug registration, and the majority outsource facets of these studies to less-regulated regions. Parasiya Sachinkumar, V. Balamuralidhara, and T. M. Pramod Kumar of the JSS College of Pharmacy consider the critical factors associated with outsourcing any clinical or BE study to semi-regulated or emerging markets.

32 Establishing Fundamental Fair-market Value Practices in the Middle East The primary challenge facing country-level managers in the Middle East is the lack of healthcare providers (HCP) compensation data for the region. Furthermore, little to no guidance exists to instruct companies how they should approach HCP compensation in this region. Elio Evangelista of Cutting Edge Information explores the development of FMV fee schedules and compliance processes that reflect the Middle East region’s unique cultural, political and socioeconomic dynamics.

20 Regulatory Framework for Developing Clinical Trials in Romania The measure of Romania’s success as a clinical trials destination lies in the rapid evolution of the regulatory framework, which was promptly transposed from EU rules and regulation into national legislation. It has been observed that this regulatory environment was one of the principal reasons why the number of completed and active studies in Romania increased from 75 in 1994 to 214 in 2004, and to 1484 in February 2014 (Fig.2)(4). Mirela Vita and Adina Pirvu of the National Agency for Medicines and Medical Devices, and Cristina Florescu Moraid of Synevo explicate the regulatory framework in Romania, and suggest why the country is becoming such a desirable destination for conducting clinical trials. 26 Is Risk-based Monitoring an Appropriate Methodology for Clinical Trials in Emerging Regions? When it comes to emerging regions - where sites and monitors generally have less experience in clinical 2 Journal for Clinical Studies

Volume 6 Issue 2

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Contents 36 Conducting Clinical Studies in Lebanon Since the 1990s, Lebanon - a pioneer of clinical research in the Middle East Region, has been selected for participation in multiple international multicenter clinical studies sponsored by top ranked pharmaceutical, biotechnology and medical device companies. Alexa Younes of MCT-CRO describes the growing number of Contract Research Organizations conducting activities in Lebanon, and the increase in the number of clinical studies taking place, which attest the promising future of clinical research in the country and region.

their smartphones. This increasing demand for medical information has been accompanied by the development of a wide variety of mobile medical apps that are changing the way people think and perform their professional duties. In the pharmaceutical industry, mobile apps are also making a significant contribution by assisting companies improve customer outreach. Morten Kjaer of BaseCon explains why mobile technology can be regarded by pharmaceutical companies as a significant stepping stone to becoming friendly entities, and how it can help them to survive in a highly-competitive environment.

THERAPEUTICS 40 Patient-derived Xenograft (PDX) Model: An Evolution in Oncology Drug Study In order to address shortcomings at the discovery stage in oncology studies, PDX has recently emerged as the upcoming technique. Through the PDX model, original tumour characteristics of humans are simulated in immunodeficient rodents, which eventually offer better predictive insights into the clinical outcome when evaluating the efficacy of novel cancer therapies. Siddhartha Shaurabh of Beroe Inc. explores the adoption of this method across industry participants over different geographies. 44 New Standards in Alzheimer’s Disease Trial Design Over the last decade, the only new treatment for Alzheimer’s to make it to market is memantine (Namenda™). The number of failed drug programs in that span provides a roadmap of scientific approaches that initially appear promising, but flame out in latestage development. Most recently, two encouraging drugs, bapineuzimab (Pfizer/Janssen) and solanezumab (Lilly), completed large Phase III programs, only failed to meet the designated endpoints necessary for approval. Thomas E. Zoda of INC Research asks: is there a better way? 46 CNS Clinical Trials in Russia In Russia, most CNS clinical studies have been conducted in MS, epilepsy, AD, stroke, depression and schizophrenia. A number of leading Russian biopharmaceutical companies and life science institutional investors are engaged in the development of new disease-modifying therapies in these areas and are actively seeking regional in-licensing and partnering opportunities with foreign drug developers - especially in biologics. Ekaterina Mochalova of Global Clinical Trials (GCT) explores the huge potential of the region to contribute to international clinical research. IT & LOGISTICS 48 The Role of Mobile Technology in Reshaping the Pharmaceutical Industry With the growth of mobile devices, healthcare professionals (HCPs) and the general public are accessing and collecting medical information via 4 Journal for Clinical Studies

52 Import of Investigational Medicinal Products into Israel Israel has a robust and growing pharmaceutical industry, particularly for biopharmaceuticals and advanced therapeutic medicinal products (ATMP). It is home to one of the largest generic drug companies in the world, which invests in Israeli drug development companies supporting the growth and development of new medicines. Because of its close links with Europe and the US, many of the new products being developed in Israel undergo clinical trials in Europe and the USA. Rachel Griffiths of Biotec Services International explores the legislation that has been passed to make the transfer of medicinal products between countries easier. SPECIAL FEATURES 54 How Changes in Practice are Changing Bleeding End Points in Coronary Interventional Trials Cardiac catheterisation and coronary intervention both require catheters to be placed into arteries engendering risk. In their paper, L. Allen Kindman, Joshua Betcher and Philip Galtry of Quintiles illustrate how the bleeding risk during cardiac catheterisation and percutaneous coronary intervention (particularly for acute myocardial infarction) has been largely mitigated since the original TIMI Group studies (Thrombolysis In acute Myocardial Infarction) were performed in the 1980s. 58 Orphan Drugs: R&D Challenges with Updates from Turkey and Middle East Countries Rare diseases (RDs) are an important public-health issue and a challenge for the medical community. They are called ‘health orphans’, as a result of being neglected for many years due to research and development challenges. Dr Duygu Kuyuncu Irmak of MEK Consulting, Hilal Ilbars of the Ministry of Health - Turkish Medicines and Medical Devices Agency Clinical Trials Department, and Professor Hamdi Akan of Ankara University School of Medicine, review the social and scientific need for the R&D of orphan drugs, discuss the management of challenges, and propose considerations for the future to better meet the medical needs of this area, with status updates from Turkey and the Middle East (ME).

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The March issue of JCS provides critical insights into drug development - a long, strenuous and expensive process that demands close interaction between academia, industry and regulators. In recent years, the FDA has placed a strong focus on drug development tools (DDTs), designed to expedite the process and allow products to reach patients more safely, quickly and cheaply. Meg Egan Auderset of Thomson Reuters breaks down the extensive Final FDA guidance released in January 2014, which frames the qualification process for developing and validating DDTs. Drug development in oncology has seen major innovations over the years, and new drugs are being developed to specifically target the molecular changes identified in malignant tumours. However, the so-called ‘war on cancer’ is far from over: there is a crucial need for more effective therapeutic approaches and research in this area, which has been held back lately by a lack of significant preclinical models able to reliably predict clinical activity of novel compounds. Siddhartha Shaurabh of Beroe Inc. looks into Patient-derived Xenograft (PDX) models - the cutting edge of new cancer drug development, considered highly relevant for studies of cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy, and preclinical drug efficacy testing. The socio-economic impact of Alzheimer’s disease - the most widespread degenerative neurological disorder in the world - is enormous, and drug development entails remarkable investment in time and money. Thomas E. Zoda of INC Research discusses the importance of setting up trials correctly the first time through proper patient selection, appropriate endpoints and study design. By all accounts, there is only one new treatment for Alzheimer’s that has hit the market over the last decade, and more recently, two promising drugs completed large Phase III programs but failed to meet the designated endpoints necessary for approval. Despite the hurdles, the orphan drug landscape seems to be finally changing for the better. In the field of rare diseases, considerable progress is constantly being made and the development of orphan drugs is becoming increasingly attractive to pharmaceutical companies. Dr Duygu Kuyuncu Irmak of MEK Consulting, Hilal Ilbars of the Ministry of Health - Turkish Medicines and Medical Devices Agency - Clinical Trials Department, and Professor Hamdi Akan of Ankara University School of Medicine explore the unique clinical, regulatory, and commercial challenges associated with the development of therapies for rare diseases in Turkey and the Middle East. Thousands of clinical trials take place everyday around the world and are instrumental in finding answers to medicine’s essential questions. But clinical trials cost 60% more today than they did just five years ago, and trial sponsors and CROs are increasingly turning to risk-based monitoring to more effectively target and prioritize resources around identifiable risks that might compromise the quality and integrity of clinical trial data. As monitoring activities can account for up to 30% of the cost of a clinical trial, any increase in efficiency can provide important savings. Find out what Stephen Young, Kyle Given and Laurie Falkin of Medidata Solutions have discovered in their analysis of clinical site performance across global geographic regions. Also, don’t miss the first article of JCS’ new series on the opportunities and challenges involved in delivering health-related interventions through mobile technology. Despite the ever-growing availability of health apps on the market, the research on the development and evaluation of such tools is arguably in its early stages. Yet, there is enough promising evidence to suggest that mHealth can be used to provide better quality health care services to individuals and communities, whilst giving new energy to health systems. In his paper, Morten Kjaer of BaseCon examines the impact of app use on the interactions between clinicians and patients, and the role of mobile technology in reshaping the pharmaceutical industry. Cecilia Stroe Editor Editorial Advisory Board Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc.

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet Development Group

Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP

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

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

Nermeen Varawala, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation

Bakhyt Sarymsakova - Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

Georg Mathis, Founder and Managing Director, Appletree AG

Caroline Brooks - Associate Director, Logistics, ICON Central Laboratories

Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

Rabinder Buttar – President & Chief Executive Officer of ClinTec International

Hermann Schulz, MD, CEO, INTERLAB central lab services – worldwide GmbH

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

Catherine Lund, Vice Chairman, OnQ Consulting Cellia K. Habita, President & CEO, Arianne Corporation

Janet Jones, Senior Director, ICON Clinical Research Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global

Jerry Boxall, Managing Director, ACM Global Central Laboratory

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

Jeffrey Litwin, MD, F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

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

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

Elizabeth Moench, President and CEO of MediciGlobal

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Eileen Harvey, Senior VP/General Partner, PRA International

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA - Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences

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LEADING THE WAY IN GLOBAL CLINICAL TRIAL TESTING SERVICES Announcing our NEW locations in Singapore and Shanghai ACM Global Central Laboratory is proud to announce our expanded global capabilities with new wholly-owned and operated central lab facilities in Singapore and Shanghai, China. Along with our US lab, our newly enhanced facility in the UK and our facility in India – the new locations further strengthen our global footprint. These additions will allow us to deliver increased operational and financial efficiencies to clients conducting clinical studies in the Asia-Pacific region.

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New FDA Guidance Clarifies the DDT Qualification Process Final FDA guidance released in January 2014 outlines the formal qualification process for drug development tools (DDTs), offering a guide for interactions between entities proposing DDTs for qualification and the Center for Drug Evaluation and Research (CDER). Guidance for Industry and FDA Staff: Qualification Process for Drug Development Tools defines DDTs as “methods, materials, or measures” intended to assist drug development. While sponsors are not required to use qualified DDTs, qualification spares CDER the need to reevaluate the tool, helping to speed the development process. The guidance describes qualification as a “conclusion”: a decision that a DDT has been shown to be reliable within a particular context of use for a specific interpretation and application in drug development and regulatory review. CDER has created qualification programmes for three specific types of DDTs: biomarkers, clinical outcome assessments (COAs), and animal models. Biomarkers are indicators of biologic or pathologic processes, or of biological responses to a therapeutic intervention, which can be measured and evaluated objectively. Biomarkers can help to characterise a baseline state, disease process, or treatment response. According to the guidance, CDER would consider qualification for diagnostic, prognostic, predictive, and pharmacodynamic biomarkers. Composite biomarkers could be considered as well.

The guidance outlines qualification process:






Stage 1: Initiation. The first stage begins with an applicant’s request for a “DDT tracking number.” The applicant must also submit a concise “DDT letter of intent” describing the DDT concept, its proposed context of use, and reasons qualification should be granted. The applicant moves to stage 2 only if the assigned CDER “qualification review team” decides that 1) the proposed DDT has scientific merit and 2) CDER has resources to perform the review. Stage 2: Consultation and Advice. The applicant must prepare an initial briefing package. According to the guidance, the qualification review team provides “ongoing advice” about the data required. After the briefing is submitted, face-to-face meetings may occur to resolve outstanding issues. Meetings and correspondence should focus on the rationale for the proposed DDT and its context of use, on new data, gaps in the existing information requiring additional data, and methods for acquiring it.

Clinical outcome assessments (COAs) are used to assess a patient’s symptoms, overall mental state, or the effects of a disease on functioning; they can provide evidence (direct or indirect) of treatment effect. As described in the guidance, a COA consists of a measure that produces a score (with defined instructions for administration and assessment), a standard format for data collection, and documented methods for scoring, analysing, and interpreting results. The guidance refers specifically to patient-reported outcome (PRO), clinicianreported outcome (ClinRO), and observer-reported outcome (ObsRO) measures. In circumstances when it would be neither ethical nor feasible to conduct clinical research in humans, researchers rely on data from animal studies. The guidance defines an animal model as a “specific combination”: a particular animal species, challenge agent, and route of exposure. The disease process or condition studied must correspond “in multiple important aspects” to the human experience. CDER’s qualification program is intended for animal models used to support the efficacy of drugs developed under the FDA’s “Animal Rule” regulations (found at 21 CFR 314.600, subpart I, for new drugs; at 21 CFR 601.90, subpart H, for biologics). 8 Journal for Clinical Studies

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Watch Pages Stage 3: Review of the Full Qualification Package. At the conclusion of the consultation and advice stage, applicants submit a full qualification package of evidence supporting the proposed DDT for its intended context of use. The full qualification package should detail completed studies and analyses; CDER typically expects primary data from studies, according to the guidance. CDER notifies the applicant when the data are considered complete and the submission enters the review stage. The review process involves internal meetings of the qualification review team to analyse the full qualification package; applicants may be contacted to clarify or provide additional data. The review team also has the option of holding public meetings if a DDT development programme is particularly complicated or controversial. Members of the team prepare reviews from the perspective of their individual disciplines, and a combined executive summary is written as well. Various FDA offices then receive the discipline reviews for additional discussion. If CDER recommends the qualification of a DDT, a statement summarising the recommendation is posted on the FDA Guidance webpage, beginning a public comment period. CDER may revise its recommendations after the comment period closes. Following any revisions, CDER issues the final qualification recommendation.

A DDT qualified within a stated context of use becomes publicly available for future drug development programmes so long as three conditions are met: • The study follows all procedures and protocols described in the context of use. • The DDT is being used for the qualified purpose. • No new information has arisen that conflicts with the basis for qualification.

Meg Egan Auderset is a writer and editor of 20 years who has worked in a variety of settings in both the US and Western Europe. Currently a Medical/Regulatory Writer for Thomson Reuters, her assignments include reporting on FDA advisory committee meetings and drug approvals for Cortellis Regulatory Intelligence AdComm Bulletin. Email:

Prove outcomes,

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The ‘how to’ of real world data

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The Role of the Artery in Chronic Kidney Disease It is well established that patients with chronic kidney disease (CKD) have a significantly higher cardiovascular risk than those with normal renal function. In fact, the majority of patients with stages 3 to 4 CKD are more likely to die of CV causes than they are to progress to renal failure 1. An increased prevalence of major CV risk factors in this population, including hypertension, diabetes, and dislipidemia, does not explain this discrepancy. Aortic stiffness and central aortic blood pressure measurements have been shown to be predictive of cardiovascular (CV) outcomes independent of traditional risk factors in a number of populations, including those with CKD. Studies on patients with end-stage renal disease were among the first to show the predictive value of these measurements 2,3. More recent studies showed that arterial stiffness and central aortic blood pressure measurements are predictive of a wide range of cardiovascular diseases 4,5. A newly published metaanalysis showed that inclusion of arterial stiffness into traditional CV risk models resulted in correctly reclassifying from 10% to 27% of subjects 6. Aortic stiffness is most commonly measured as the speed at which a pressure wave travels through the aorta – the aortic pulse wave velocity (aPWV). A stiffer aorta results in a higher aPWV and increased CV risk. Recently determined reference values for aPWV show that it increases with age and is strongly dependent on blood pressure 7. Measurement of the central aortic blood pressure provides an additional independent parameter for CV risk assessment. Brachial systolic pressure is higher than central systolic (a result known as pressure amplification – PA), and is due to the effect of pressure wave reflections which occur throughout the conduit arteries. Systolic PA varies between individuals with a difference in systolic pressures between the aorta and brachial artery from just a few millimetres of mercury to as much as 30mmHg or more. In addition, measurement of the central aortic blood pressure often includes measurement of the entire central aortic blood pressure waveform. Analysis of this waveform provides information about wave reflections and arterial stiffness which is independent of brachial systolic and diastolic pressure. These wave reflections are quantified by parameters such as the augmentation pressure (the additional pressure during systole due to the reflected wave) and the augmentation index (the percentage of the pulse pressure due to wave reflection) 8. Briet et al., in a recent literature review, showed that patients with CKD stages 2-5 have elevated levels 10 Journal for Clinical Studies

of aPWV compared to normotensive and hypertensive controls 9. Townsend et al. examined the relationship between aPWV and kidney function in the Chronic Renal Insufficiency Cohort (CRIC), a multiethnic observational study including over 2500 non-dialysed participants with impaired kidney function. Their results showed that a decrement in estimated glomerular filtration rate (eGFR) was associated with a rise in central pulse pressure (CPP) and that in each declining eGFR category there were an increasing percentage of participants with a CPP > 50 mmHg (Figure 1) 10. A CPP above 50 mmHg is known to be a significant and independent predictor of CVD 4.

Figure 1: Top left panel plots CPP in 10 mm Hg increments among those with eGFR <30 mL/min per 1.73 m2. Top right plots those with eGFR 30.0 to 44.9; bottom left plots those with eGFR of 45.0 to 59.9; and the bottom right panel depicts those with an eGFR >60.0. Arrow onset marks CPP of 50 mm Hg, and percentage indicates the portion of participants within that eGFR range with a CPP >50 mm Hg.

Aortic stiffness and central BP measurements have also been shown to be associated with incident CKD, as well as be predictive of renal function decline, CV events, and allcause and CV mortality. The Health ABC study followed 2129 adults over an average of 8.9 years and found that baseline values of aPWV were associated with incident CKD 10 suggesting that aortic stiffness is a risk factor for the development of kidney disease. In a cohort of ESRD subjects, Guerin et al. found that failure to demonstrate a reduction in pulse wave velocity during a mean follow-up of 51 months was an independent predictor of mortality. Seventy-four per cent of patients who had a decrease in aPWV during follow-up survived, while 70% of patients whose aPWV did not decrease died (Figure 2) 2. This further demonstrates the prognostic utility of aPWV in this high-risk population and suggests that treatments aimed at reducing aortic stiffness may improve their outcomes.

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Watch Pages these parameters is important in understanding the increased CV risk burden that comes along with CKD and the efficacy of therapies aimed at treating this disease.   References

Figure 2: Changes of MBP (solid circle) and aortic PWV (open circle) from inclusion to end of follow-up for survivors and nonsurvivors. Values are mean±SEM. Guerin et al. note that mean blood pressure is roughly the same extent in survivors and nonsurvivors, whereas aPWV differentiates between the two groups.

Finally, in another examination of 180 ESRD subjects who were monitored for an average of 52 months, an increase in wave reflections, as measured by AIx, was found to be a significant and independent predictor of all-cause and cardiovascular mortality (Figure 3) 11. These findings have since been expanded by Weber et al. to include stage 3 and 4 CKD patients to demonstrate that increased wave reflections significantly predicted a decline in renal function and cardiovascular events 12.


Schiffrin E et al. (2007). Chronic kidney disease: effects on the cardiovascular system. Circulation, 116 (1), 85-97.


Guerin et al. (2001). Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation, 103 (7), 987-92.


London GM et al. (2001). Arterial wave reflections and survival in end-stage renal failure. Hypertension, 38(3), 434-8.


Roman M et al. (2009). High central pulse pressure is independently associated with adverse cardiovascular outcome the strong heart study. J Am Coll Cardiol, 54 (18), 1730-4.


Wang KL et al. (2010). Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities. Hypertension, 55, 700-805.


Ben-Shlomo Y et al. (2013). Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant metaanalysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol , on-line 13 Nov, 2013.


Reference Values for Arterial Stiffness’ Collaboration (2010, Oct). Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J, 31(19), 2338-2350.


Nelson Noninvasive (2010). Measurement of Central vascular pressures with arterial tonometry: clinical revival of the pulse pressure waveform. Mayo Clin Proc. 85(5), 460-472.


Briet et al. (2012, Aug). Arterial stiffness and pulse pressure in CKD and ESRD. Kidney Int, 82 (4), 388-400.

10. Townsend et al. (2010). Central pulse pressure in chronic kidney disease: a chronic renal insufficiency cohort ancillary study. Hypertension, 56 (3), 518-524. 11. Madero et al. (2013, Mar). Association of arterial rigidity with incident kidney disease and kidney function decline: the Health ABC study. Clin J Am Soc Nephrol, 8 (3), 424-433. 12. Weber et al. (2011, Jul). Association of increased arterial wave reflections with decline in renal function in chronic kidney disease stages 3 and 4. Am J Hypertens, 24 (7), 762-769.

Bobby Stutz is currently the Senior Research Engineer for AtCor Medical, Inc. He has spent the last seven years in the medical device industry and prior to that earned his Masters and undergraduate degrees in biomedical engineering at The Catholic University of America in Washington, D.C. Email:

Figure 3: Probability of CV and overall survival of the study population according to the level of AIX divided into quartiles. London et al.

In summary, arterial stiffness and central blood pressure, including analysis of the central pressure waveform and wave reflections, are closely tied to the development, progression, and ultimate outcomes of renal disease. Studies have demonstrated that evaluating

Dr. Winter is currently Vice-President of Scientific and Clinical Affairs for AtCor Medical, Inc. Prior to joining AtCor, he was Director of Bioengineering at Southwest Research Institute, where he developed the first commercial blood pressure monitor based on arterial tonometry. He is an internationally recognized expert in physiological fluid mechanics, biomechanics and medical device development. Email:

Journal for Clinical Studies 11

Watch Pages Logistics in Emerging Markets - The People’s Republic of China China is a land of superlatives: the world’s second largest country by land area, with the largest population at 1.35 billion and growing. It is incredibly diverse, with 56 recognised distinct ethnic groups. Mountain ranges form a natural border to the West, the Gobi and Taklamakan deserts are in the North, and there are subtropical forests in the South. It has the Yangtze and Yellow Rivers, the third- and sixth-longest in the world. More importantly for our purposes it has the world’s second-largest economy by both nominal total GDP and purchasing power parity. It is the world’s largest exporter and importer of goods. China spent approx 66.8 billion US dollars in 2011 1 just on pharmaceuticals. China is not alone in requiring that any drug sold must have been tested in a clinical trial conducted in China. Pharmaceutical companies have little choice if they wish to market their drug once it is approved. Given that China makes up 19% of the world’s population, and is expected to overtake the US as the world’s largest market by 2020 2 , there is no wonder that it is right at the top of the list of target countries. Currently 4648 trials are taking place there. 3 There used to be a perception that it could take a couple of years to get approval to run a trial, but timelines have reduced dramatically. China is working towards a 90-day process, and typically it takes between three and six months. China benefits from a centralised healthcare system, and with such a huge population and regional centres of excellence there is a large patient pool accessible very quickly for many diseases in China. Recruitment can be swiftly completed. When shipping takes place, probably the most important single document is the import permit issued by the BFDA (Beijing Food & Drug Administration). There are a lot of documents to be brought together in advance, which must be supplied to the BFDA for this to be issued. Once the permit is in place, arrangements should be made to import through Beijing rather than another port, in order to comply with all their requirements. The documents required include a customs invoice, a copy of the draft airline paperwork (the MAWB), packing list, certificate of analysis, clinical trial approval which comes from the consignee, together with a copy of their business licence, and a first leg document showing the batch / lot number as indicated on the invoice. The customs invoice is very detailed, including the shipper’s and consignee’s name and address, what the contents are, shipment commodity description, country of origin, expiry date, batch number, manufacturer company name, and shipper company name, all of which need to be confirmed with the importer of record, and every single one of which must match the details on the inner packaging label on the packages. Any discrepancies lead to delays at customs and China Inspection and Quarantine. Every shipment has to be sent with a packing list and this is another place where attention to detail is imperative, otherwise things could go terribly wrong. The packing list needs some really specific information, 12 Journal for Clinical Studies

including specifics on the content and the number of pieces, net weight and gross weight. Once the packaging has been decided on then it’s very difficult to make changes. Customs are expecting these exact details, and if anything is different when it arrives then they won’t let the shipment go through without further inspection. This may lead to a new import permit needing to be issued, during which time the clock is ticking, the shipment is waiting at the airport, and there is the potential for it to be moved into storage at the wrong temperature, or even damaged! In Beijing it takes around two days to clear customs, or longer if the shipment is selected for inspection. Storage facilities at the airport need to be booked in advance, and documentation provided for the need for temperaturecontrolled storage. Temperature-controlled shipments selected for customs inspection will be taken out of the temperature-controlled area into an uncontrolled ambient area until inspection, which takes 24-48 hours. Packing the shipment carefully so that it can withstand this temperature challenge, which could be several days after leaving the origination point, will almost certainly need a box using PCMs to control temperature. The consignee also needs to provide letters of instruction for customs purposes and quarantine purposes, their 10-digit registration code for both customs and CIQ, and an authorisation letter for the transport company to collect from the airline. It is clear that China can be challenging, but systematic processes lead to success, a minimum of delays, and ultimately access into this vast marketplace. “The spirited horse, which will try to win the race of its own accord, will run even faster if encouraged,” wrote Ovid, the Roman poet, and in this the Chinese year of the horse we should all be encouraged to embrace China and include it in our global plans. References 1. International Federation of Pharmaceutical Manufacturers & Associations 2. IMS Health, 2011 3. h t t p : / / w w w . c l i n i c a l t r i a l s . g o v / c t 2 / s e a r c h / m a p / click?map.x=607&map.y=187

Sue Lee, Technical Portfolio Manager, World Courier Management has worked for World Courier for 25 years. During this time she has experienced a variety of customer service and operational functions, including the setting up of numerous, multi-national, clinical sites for the transportation of biological samples. She has orchestrated the shipping of thousands of shipments with very specific temperature requirements to a host of challenging locations, and each presenting their own obstacles and dilemmas. Email: Volume 6 Issue 2


Clinical Services Data Management Clinical Trial Management Drug Safety Biostatistics

has a global reach on 5 continents in over 25 countries, including: USA, Canada, Mexico South Africa, North Africa, Middle East Asia, East and Central Europe

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Egypt Regulations for Clinical Research Potential reasons for conducting clinical research in Egypt:• Written procedures for submission to ethics committee and regulatory authority • Feasible timelines for approval • Vast patient pool Facts about Egypt Population: 80.72 million (2012) 1 Location: Northern Africa, bordering the Mediterranean Sea, between Libya and the Gaza Strip, and the Red Sea north of Sudan, and includes the Asian Sinai Peninsula.

Introduction The process of submission in Egypt is: first of all the necessary documents are submitted to the local ethics committee, and then following approval they are submitted to the regulatory authority, the Ministry of Health, for final approval before the study can be started. Potential Sites for Conduct of Clinical Research in Egypt 1. Ain Shams University 3 At the Faculty of Medicine, Ain Shams University, the Research Ethics Committee was established in October 2007, under the authority of the Head of the Ain Shams University and the Dean of the Faculty of Medicine. There are a total of 15 members, comprising of one non-Egypt-affiliated non14 Journal for Clinical Studies

medical member, a Muslim religious man, one non-affiliated medical member, and a Christian religious female. Research ethics committees (RECs) should provide an independent, competent and timely review of the ethics of proposed studies. RECs should establish written SOPs to ensure: • Transparency, • Consistency, and • Efficiency in their operations. Other functions of the REC include:• Review of changes in the approved research proposal. • Review adverse events that occur during the research. • Suspend or terminate approval. • Review research procedures during the conduct of the research, including the informed consent process. • Ensure that research is in compliance with the laws and regulations of the community, especially in relation to the protection of human subjects. • Conduct educational exercises so as to inform researchers of their role, function and requirements.

2. Faculty of Medicine- Alexandria University Alexandria Clinical Research Center (Alex CRC) is the cornerstone for human research within the University of Alexandria. It is the first well-established centre for clinical trials in Egypt. The Ethics Committee started operating on 19 July 2005. All clinical trials at Alexandria Faculty of Medicine, Clinical Research Center, are conducted according to good clinical practice (GCP) guidelines developed by the International Conference on Harmonization (ICH) and the principles contained in the World Medical Association Declaration of Helsinki on the ”Ethical Principles for Medical Research Involving Human Subjects” (2004). The Research Ethics Committee of the Alexandria School of Medicine has to approve all clinical researches carried out in the faculty prior to its conduct. Alexandria CRC was constructed with the assistance of University of Maryland under the twinning agreement between Alexandria and Baltimore cities. The Center provides a full range of resources and services directly or in coordination with the institutional resources of Alexandria University Hospital: Volume 6 Issue 2

Watch Pages

• • • • •

Research patient care Trained research personnel Lab facilities Statistical consultation Computer and data management support.

3. Theodor Bilharz Research Institute 4 Theodor Bilharz Research Institute – Institutional Review Board (TBRI-IRB) was created in May 2006 to contribute to safeguarding the dignity, rights, safety and welfare of all actual or potential research participants. TBRI-IRB was approved by the Office for Human Research Protections (OHRP), USA and got Federal Wide Assurance (FWA). •

• •

TBRI-IRB advises investigators how to design research projects in a manner that minimises potential harm to human subjects, reviews all planned research involving human subjects prior to initiation of the research, and approves research that meets established criteria for protection of human subjects. The IRB is not only entrusted with the initial review of the proposed research protocols, but also has a continuing responsibility of regular monitoring for compliance with the ethics of the approved programmes till they are completed. TBRI-IRB provides independent, competent, and timely review of the ethics of proposed studies. TBRI-IRB has independence from political, institutional, professional and market influences. We try to demonstrate competence and efficiency in our work. Meetings are scheduled to be held on the 2nd Wednesday of every month, excluding July and August. The General Secretary is responsible for organising the meetings, maintaining the records and communicating with all concerned. She will prepare the minutes of the meetings and communicate to the researchers. She has all these steps approved by the Chairperson. The date of the meeting will be intimated to the principal investigator, who will come, present his protocol in front of the IRB members and give clarifications, in addition to the primary and secondary reviewers from the TBRIIRB members. TBRI-IRB may call upon subject experts as independent consultants who may provide special review of selected research protocols, if needed. These experts may be specialists in specific diseases or methodologies, or statisticians. They are required to give their specialised views but do not take part in the decision-making process, which will be done by the members of the IRB.

Regulatory Authority The regulatory authority in Egypt remains the Ministry of Health, who will approve the studies once approved by the local ethics committee where the study will be taking place. The Ethics Committee at the Ministry of Health acts as a central EC that regulates the performance of local RECs and issues the final approval for national studies. The process of submission in Egypt is that the researchers (companies, government department, university, CRO, etc) will prepare

the submission package and fill in the application form for protocol submission. Start

Applying for Needed Documents & Regulations Submission of researches for RHD Revising of Researches – documents & calling of RCC members REC Meeting for Scientific & Ethical Revision Notification of Researchers by





Approved Preparing Decision Notification of decisions 3 Months Follow up


Closing of the study



Continuing of research & annual renewal SAE or Study Amendment Requires

Continuing of research till the end & results publication


Timelines for Approvals Site Ain Shams University Faculty of Medicine-Alexandria University Theodor Bilharz Research Institute Ministry of Health

Timeline 30-45 days 30-45 days 30-45 days 30 days

Conclusion Clinical research has a wide scope to be conducted in Egypt because of the huge patient pool and specified timelines for the local ethics committee and regulatory authority. References 1. World Bank 2. Central Intelligence Agency 3. Ain Shams University 4. Theodor Bilharz Research Institute

Adhiti Sharad Kumar, is working for a clinical research organization for four years, and is responsible for the regulatory, training and marketing activities. Currently, she is also the Coordinator for the Gulf Chapter of the Association of Clinical Research Professionals – ACRP. Email:

Journal for Clinical Studies 15

Regulatory Prospects of Conducting Bioavailability/Bioequivalence (BA/ BE) Studies and Outsourcing in Semi-Regulated Countries Abstract The global generics drug market has grown substantially in recent years and is expected to see even more growth in the coming years. Given the rapid progress of the sector, organisations must critically manage and assess bioequivalence studies (BE) that are mandatory when bringing new generic drugs to market. Most pharma companies outsource these pivotal bioequivalence studies to clinical research organisations (CROs) in order to expedite the generic drug registration, as these studies constitute a major part of the generic dossier. Nevertheless these clinical organisations have already expertised the bioequivalence studies which form a part of clinical studies, which will benefit the sponsors in terms of quality, cost and time. The majority of generic companies queried outsourcing facets of their bioequivalence studies to less-regulated regions such as India, China, Russia and Eastern Europe, with India being the preferred outsourcing destination, For prospects for conducting BA/BE studies compared with regulated markets like the US. India is a hotspot for clinical and bioequivalence studies for various reasons, such as easy availability of study subjects, well qualified investigators and other staff, less stringent regulations, and lower costs compared to regulated countries. The main objective of this study is to guide generic manufacturers to consider the associated critical factors while outsourcing any clinical or BE study to semiregulated or emerging markets. In conclusion, the selection of CROs in emerging markets considering regulations in the relevant market remains a crucial factor for any manufacturer who intends to outsource bioequivalence/clinical studies. Keywords: BE studies, CROs, clinical trials, less-regulated regions, generic drugs. Introduction Bioavailability (BA) and bioequivalence (BE) studies play a major role in the drug development phase for both new drug products and their generic equivalents, and thus attract considerable attention globally. BE is a strategy to introduce generic equivalents of brand-name drugs (innovator drugs) to lower the cost of medication through proper assessment as directed by the international regulatory authorities. The generics drug market has grown substantially over the last several years and this expansion is expected to continue. Generic companies are increasing the level of abbreviated new drug application (ANDA) filings and in support, adopting a business model that increasingly relies on outsourcing to optimise efficiencies and contain costs. Pharmaceutical and biotechnology companies face the challenge of managing the operation and costs associated with bringing a drug to market. Outsourcing bioequivalence has its challenges, particularly regarding all matters concerning FDA quality assurance requirements and regulatory issues. Quality assurance, which is a critical step in the bioequivalence study process, is seldom outsourced.

16 Journal for Clinical Studies

Definitions:1 Bioavailability (BA): The rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. Bioequivalence (BE): The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. Why do BA/BE studies? Because of the importance of generic drugs in healthcare, it is imperative that the pharmaceutical quality, safety, and efficacy of generics should be reliably compared with the corresponding innovator drugs (brand-name drugs). The FDA’s designation of “therapeutic equivalence” indicates that the generic formulation is (among other things) bioequivalent to the innovator formulation, and signifies the FDA’s expectation that the formulations are likely “to have equivalent clinical effect and no difference in their potential for adverse effects”2. The assessment of “interchangeability” between the innovator and generic products is carried out by a study of “in vivo equivalence” or “bioequivalence”3. The steps involved in the development of a potential generic product are briefly described in Figure 1.

Characterisation of reference product

Bioequivalence Bioavailability

Design of the generic product and process

Pharmaceutical equivalent

Bio-batch Pharmaceutical alternative

Bioequivalence study


Pharmaceutical equivalent products

Reference product

Test product

Possible differences: Excipients, drug particle size, manufacturing site, equipment, batch size and so no (Generally same dissolution specifications)

Documented bioequivalence = Therapeutic equivalence

Figure 1: Pathway for the development of a generic drug product. Volume 6 Issue 2

Regulatory Objective • Cost and time are the major factors in the competitive generic industry. A generic drug has to be compared to the innovator drug in order to prove that its bioavailability is in line with the already approved innovator product. • This study illustrates the benefit to generic manufacturers of outsourcing the BE studies to emerging countries. • The main objective of this study is to guide generic manufacturers to consider the critical factors associated with outsourcing any clinical or BE study to semi-regulated or emerging markets, such as evaluation of potential of CROs, cost-benefit analysis etc. to yield a quality study in the stipulated time. Discussion The concepts of BA and BE have gained considerable importance during the last three decades and have become the cornerstones for the approval of brand-name and generic drugs globally. Consequently, regulatory authorities have also started developing and formulating regulatory requirements for approval of generic drug products. It is encouraging to know that efforts by regulatory authorities and the scientific community at national as well as international levels are continuing, in order to understand and develop more efficient and scientifically valid approaches to assessing BE of various dosage forms, including some of the complex special dosage forms. Using the BE as the basis for approving generic drugs was established by the Drug Price Competition and Patent Restoration Act of 1984 (HatchWaxman Act). Subsequently various criteria and approaches for conducting and reporting have been introduced. Regulatory Authorities, Regulatory Aspects, and International Efforts to Harmonise Approaches to Bioequivalence Assessment Due to significant recognition of the BA/BE concept all over the world, tremendous advancements have been made by the FDA, as well as by various national, international, and supra-national regulatory authorities. In parallel, the pharmaceutical industry and academia are also contributing exclusively in the area of assessment of BE. Currently available approaches to determine BE of generic products are largely standardised due to discussion and consensus reached among various stakeholders at numerous national and international meetings, conferences, and workshops (e.g. American Association of Pharmaceutical Scientists, Federation International Pharmaceutique). Thus the currently available excellent scientific and regulatory guidance documents are due to the combined efforts of industry, academia, and regulatory scientists. Every country now has its own individual regulatory authority as well as regulatory guidance for BA/BE studies, and the magnitude of assessment of BE of drug product is influenced by the regulatory environment of the respective country of marketing. The regulatory authorities of various semi-regulated countries and international organisations are listed in Table 1.

Country Regulatory authority




Central Drugs Standard Control Organization (CDSCO)


China Food and Drug Administration




US Food and Drug Administration


International Conference on Harmonisation


World Health Organization

Table 1: Regulatory authorities of various countries and international organisations General Regulatory Considerations for BA/BE Studies: The processes of study design and workflow of BA/BE studies are presented in brief in Figures 2 and 3, respectively. The general considerations for the advancement of conducting BA/ BE studies are: • Study design and protocol. • Bio analysis. • Selection of appropriate analytes. • BE metrics and data treatment. • Statistical approaches and analysis. Literature survey from different sources: RLD information; regulatory specification; physic-chemical properties; pharmacodynamics and pharmacokinetics data; information about previous/pilot studies; safety and efficacy information; other relevant information of the drugs etc. Sample size

Regulatory & SOPs compliance

Requirements for the clinical operations

Statistical approaches & analysis

Selection of appr. analyte and bioanalytical method feasibilities

Fresh study design and protocol

Establishment of BE criteria Documentation, review & reporting procedure etc.

BE metrics, data handling and transformation

Denied approval

Study design & protocol & ICF preparation Fresh study design and protocol

Revision of study design & protocol IEC/IRB review Minor suggestions/ modifications

Regulatory authority review, if required

Approval Denied approval


Commencement of the study

Submission of approved protocol and ICF

Figure 2: Brief process of bioequivalence study design and protocol approval.

Abbreviations: BE, bioequivalence; ICF, informed consent form; IEC, independent ethics committee; IRB, institutional review board; RLD, reference listed drug.

Journal for Clinical Studies 17


Screening Volunteer consent Check-in Dosing

Clinical operation

Clinical Report

Blood sampling Safety assessment Post study laboratory investigations

Storage of sample



Method development

Transfer of blood sample

Method validation

Bioanalysis of sample

Bioanalytical operations

Bioanalytical report

Chromatography and generation of conc. vs time date

PK operation

Drug conc. data transfer

Generation of PK parameters Statistical operation

Handling PK data

ANDA approval

Regulatory authority review

Marketing generic drug product

Handling of drug conc. data

PK report

Pharmacokinetic analysis Statistical analysis

Stats. report

Clinical study report & submission of ANDA Generic product is bioequivalent to brand drug

Figure 3: Brief representation of work flow of bioavailability/bioequivalence study.

regulatory authorities, pharma industry researchers and academic researchers, and indeed on the efforts of the ICH, WHO, and various international conferences. However, a lot remains to be done, especially to promote global harmonisation of BA/BE approaches, which should focus on uniformity, standardisation of nomenclature, agreement on general concepts, alternative approaches for locally acting drug products, choice of test procedures, outlier challenge, consideration of BE criteria and objectives, all of which reflect regulatory decision-making standards, as well as ensuring product quality over time for both innovator and generic drugs. To achieve these objectives, efforts should continue from international health organisations, pharmaceutical industries, researchers and regulatory authorities, to understand and to develop more efficient and scientifically valid approaches to assess BE, and develop generic drugs in a cost-effective manner. BE Outsourcing:4-8 Pharmaceutical and biotechnology companies face the challenge of managing the operation and costs associated with bringing a drug to market. The return on investment (ROI) must be greater than the huge amounts of money spent during years of research and development. The right choice for clinical trial outsourcing can facilitate trial execution and reduce the timeline to completion, thus reducing costs and increasing ROI. Central and Eastern European and emerging markets are increasingly being incorporated in clinical trials from planning to trial execution. Outsourcing and vendor selection choices have broadened to include emerging markets, which have demonstrated clinical trial success by tapping patient populations, increasing enrolment rates, and achieving early completion.

Abbreviations: ANDA, abbreviated new drug application; PK, pharmacokinetics. Acceptance Criteria for Bioequivalence: An equivalence approach is generally recommended, which usually relies on i. a criterion to allow the comparison; ii. a confidence interval for the criterion; and iii. a BE limit. Log transformation of exposure measures (Cmax and AUC) is generally recommended by various regulatory authorities. To compare measures in these studies, data are generally analysed by using an average BE criterion, with some considerations allowed for special category drugs. The general BE profile of generic vs brand product is shown in Figure 4. Future Prospects: The adaptation of the BA/BE concept worldwide for over 20 years has enabled the production and approval of quality generic products through profound scientific, technical, and regulatory advances (especially through replicate designs, application of BCS, scaled average BE) by various approaches to assessing BE for various complex and special groups of drugs. This continuing success story of BA/BE is based on the contribution to efficacy, safety, and quality by international 18 Journal for Clinical Studies

Figure 4: General Bioequivalence profile of generic vs. brand products. Outsourcing bioequivalence has its challenges, particularly regarding all matters concerning FDA quality assurance requirements and regulatory issues. Despite these challenges, outsourcing is pervasive: commonly outsourced activities include clinical and sample analysis, results reporting, and data and statistical analysis. The most frequently outsourced bioequivalence function is clinical activity, according to the Best Practices Report (Figure 5). Outsourcing activities also commonly include working with CROs, investigators and clinical Volume 6 Issue 2

Regulatory sites, which may or may not be in a contract relationship with the CROs. The selection of a CRO is based on a best-practice selection process involving bids from more than one CRO, and framed so that outsourced activities are generally contractually delineated with deliverables on a set timeframe and the ability to terminate the outsourcing relationship. Quality assurance, which is a critical step in the bioequivalence study process, is seldom outsourced. Most generic companies house a dedicated and centralised clinical quality assurance (CQA) function – and for good reason. The CQA function plays a key role in pre-study assessment of clinical sites and the CROs, and is viewed as an essential component in improving bioequivalence study quality, reducing deficiency letters, accelerating the review process, and improving the relationship with the FDA.

developed and strictly regulated countries such as the US, the EU, Japan and Australia. In these developed nations, regulations are stringent, which may lead to delays in study approval, and the cost to conduct studies is too high, leading to study sponsors looking for less stringent developing nations such as India and African countries. Cost, time and quality are the most important parameters in BE studies, which have to be balanced properly in order to be the first generic maker in the market. References 1.

Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations. US Department of Health and Human Services, Food and Drug Administration Center for Drug Evaluation and Research (CDER), March 2003. Accessed December, 2013. lianceRegulatoryInformation/Guidances/ucm070124.pdf.


US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Accessed December, 2013. cder/ob/default.cfm.


Midha KK, McKay G. Bioequivalence: its history, practice and future. AAPS. 2009; 11:664-670.


Genovesi L. Outsourcing Key to Generics Business Model., Jun






articles/2013/1306_outsourcing_excellence.html 5.

Accelerating Generic Approvals: 5 Keys to Being First to Market. PharmaCompare, January 17, 2012. Accessed December, 2013.


Managing Bioequivalence Studies to Optimize Cost, Quality, and Outsourcing of Generics Manufacturing. PR Newswire, Feb. 10, 2013, Accessed December, 2013 http://www.


Brennan Z. Preclinical CRO Pushes into India to Reduce Human Bioequivalence Studies. April 10, 2013. Accessed December, 2013


Figure 5: Extent of outsourcing for bioequivalence testing functions Maintaining a regulatory department is a critical element of the study process and, similar to QA, is seldom outsourced. The regulatory department plays a key role in ensuring that documentation is complete and up-to-date to ensure necessary repeat analysis of clinical, medical and analytical studies; internal regulatory compliance for acceptance of bioequivalence data in support of ANDA; and to promote regulatory transparency. To ensure excellence, as well as cost containment and efficiencies, while managing the risk, partner selection is a critical process and the key to bioequivalence outsourcing excellence. Efficient organisations have in place best-practice procedures for monitoring the outsourcing partner and the progress of the bioequivalence studies underway. Vigilance, due diligence and communication create an atmosphere of success and will always support the effective management of these relationships. Generic companies also need to carefully select their outsourcing partner, holding both core competencies and cost containment as key components. Following selection, instituting best practices to successfully manage the outsourcing relationship is a key factor for outsourcing excellence. Conclusion The CRO has to be properly evaluated by generic manufacturers or sponsors in order achieve the objective. This can be achieved by inspecting the CRO site before signing the agreement. The contract between CRO and sponsor should be objective-oriented, indicating the roles and responsibilities of the CRO. Many pharma companies are outsourcing BE studies to countries other than

Opportunities and challenges for Indian CROs: End of a dream run…, Modern Pharma, August 20, 2012. Accessed December, 2013

Parasiya Sachinkumar R. is currently a Post Graduate student at JSS College of Pharmacy, Mysore. He is graduated (B. Pharma) from Rajiv Gandhi University of Health Science, Bangalore. He has published an article titled Need for Drug Price Control in India & A Paradigm Shift in Drug Regulations in Taiwan in a reputed journal. Email: Balamuralidhara V. is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has teaching experience of 10 years. He has authored 16 International and 11 National publications in reputed journals and a Book. He has attended various conferences and currently he is working on Biosimilars. Email:

T. M. Pramod Kumar is Professor and Head in the Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has teaching experience of 20 years. He has guided 5 Ph. D candidates. He has authored 70 International and 50 National publications and has chaired scientific sessions nationally & internationally. Email: Journal for Clinical Studies 19


Regulatory Framework for Developing Clinical Trials in Romania Romania is a country located between Central Europe and Southeastern Europe, bordering the Black Sea. Romania shares a border with Hungary and Serbia to the west, Ukraine and Moldova to the northeast and east, and Bulgaria to the south. At 238,391 square kilometres (92,043 sq mi), Romania is the eighth largest country in the European Union by area, and has the seventh largest population of the European Union with 20,121,641 inhabitants (20 October 2011). Its capital and largest city is Bucharest – the sixtieth largest city in the EU.

audits and inspections conducted by sponsor, regulatory or third parties. All of the above make Romania an attractive destination for big pharmaceutical companies. It is worth mentioning that almost all European guidelines and rules governing medicinal products in EU have been transposed into national legislation in Romania. Three main European directives are in place in Romania as follows: •

Fig.1 Map of Romania

Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use – transposed by Minister of Health Order (MHO) No. 904/2006 Commission Directive 2003/94/EC of 8 October 2003 laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use – transposed by MHO No. 905/2006 Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice in regard to investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such products – transposed by MHO No. 903/2006

The country attractiveness index for clinical trials (as ranked by the top 12 pharmaceutical companies)1 has taken into consideration advantages such as:

The relevant Eudralex Vol 10 guidelines were also translated and transposed into national legislation (NAMMD Scientific Council Decisions, MHO).

• • • • •

Here is a comprehensive list of European guidelines2 which have been transposed into national legislation, useful for any submission of documents by a sponsor requesting permission to open their trial in our country.

Patient availability, Cost-efficiency, Relevant expertise, Regulatory conditions, National infrastructure and environment.

• Besides being a large country, Romania has other attractive prospects for pharmaceutical companies which deserve to be taken into consideration when pursuing a clinical study in this part of the world. To mention a few: the size of the Romanian population among CEE and EU countries, with a high number of eligible and participating compliant patients and high enrolment rates; the epidemiological profile; the low level of healthcare expenditure and consumption per capita with a high percentage of treatment-naïve patients; regulatory and legislative reforms following EU accession; trial start-up times and requirements which are comparable with other EU countries; competitive costs per patient; high standards of medical education; highly concentrated and specialised healthcare services; experienced personnel (including eCRF and IVRS solutions); supportive infrastructure; good regulatory and protocol compliance with good-quality data, certified by 20 Journal for Clinical Studies

CT1: Detailed guidance on application for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial – transposed by NMA SCD No. 22/2010 CT2: Detailed guidance on the application format and documentation to be submitted in an application for an ethics committee opinion on the clinical trial on medicinal products for human use – transposed by NMA SCD No. 50/2006 Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’) – transposed by NMA SCD No. 27/2011 ICH guideline E2F - Note for guidance on development safety update reports September 2010 (not transposed, applicable as such) Volume 6 Issue 2

Regulatory •

• • •

Good Manufacturing Practice for Medicinal Products Annex 13: Investigational Medicinal Products - transposed by NMA SCD 5/2012 Guideline on the requirements to the chemical and pharmaceutical Quality documentation concerning investigational medicinal products in clinical trials – transposed by NMA SCD 15/2008 Guidance on investigational medicinal products (IMPs) and ‘non-investigational medicinal products’ (NIMPs) transposed by NMA SCD 20/2011 ICH E6: Good Clinical Practice: Consolidated guideline, CPMP/ICH/135/95 – transposed by NMA Scientific Council Decision (SCD) No. 39/2006 Detailed guidelines on good clinical practice specific to advanced therapy medicinal products (not transposed, applicable as such) Clinical investigation of medicinal products in the paediatric population– transposed by NMA SCD 41/2006 Ethical considerations for clinical trials on medicinal products with the paediatric population Recommendation on the content of the trial master file and archiving – transposed by NMA SCD No. 51/2006

There are also specific national regulations for conducting clinical trials in Romania: • NAMMD SCD no. 29/2011 on approval of the Regulations concerning authorisation by the National Agency for Medicines and Medical Devices of clinical trials/notification to the National Agency for Medicines and Medical Devices of non-interventional clinical trials conducted with medicinal products for human use in Romania - provides procedure steps for assessment and approval of an Application for a Clinical Trial. • MHO no. 912/2006 on approval of the Regulations for the authorisation of medical units for conducting clinical trials on medicinal products for human use - provides rules and standards for authorisation of clinical trials sites (medical units and investigators) The regulatory framework in Romania is very well-structured, where all international or European rules of conducting clinical trials find their place. Immediately after the 1989 December Revolution, Romania first set up the Bioethical Committee in 1992, followed in 1997 by the approval of the first Ministry of Health Order to make ICH-GCP compliance mandatory. In 1998, the National Ethics Committee for clinical trials was established, and 1999 saw approval of the first Medicine Law and assignment of the National Medicines Agency as Competent Authority for Clinical Trials. In the years since 2000, Romania has begun the translation and adoption of new European legislation in clinical trials as seen above3. The measure of Romania’s success lies in the rapid evolution of the regulatory framework, which was promptly transposed from EU rules and regulation into national legislation. It has been observed that this regulatory environment was one of the principal reasons why the number of completed and active studies in Romania increased from 75 in 1994 to 214 in 2004, and to 1484 in February 2014 (Fig.2)4.

22 Journal for Clinical Studies

Fig.2 Distribution of clinical trials across Europe, Feb 2014 As a result of the activity report by the National Agency for Medicines and Medical Devices (NAMMD) for 2011, the number of requests for authorisation of developing clinical trials is registering a small decrease in comparison with the number of requests received annually in previous years (i.e. 246 for 2011 against 266 for 2010, 253 for 2008 and 275 in 2008). Phase III studies have the greatest percentage, which means that the respective experimental drugs are in an advanced phase of development, and close to receiving market approval. They are followed by Phase II studies. As for Phase I studies, NAMMD has received a limited number of requests as there are few Phase I units located in Romania. Bioequivalence clinical trials were also conducted in Romania in 20115. The principles of conducting clinical trials are driven by the Declaration of Helsinki of the World Medical Association: entities involved in running clinical trials and GCP inspections. If we talk about the role of entities involved in running a study in Romania, we have to underline the investigator’s role in Romania. As study teams are usually well-structured, Romania has experienced investigators (Fig.3)6, a competitive speed of recruitment7, one of the lowest costs per patient (Fig.4)8, and supportive infrastructure (Fig.5)9. Regarding GCP inspections, there are national inspections programmes in place - NAMMD having its own standard operating procedures made in accordance with the guidelines for inspection, vol 10 Eudralex - Clinical Trials - Chapter 4 – Inspection. The purpose of any inspection is the verification of protection of the rights and comfort of the study subjects, compliance with GCP, and data quality. The National Inspections Programme contains routine inspections for ongoing clinical trials at the sponsor/CRO investigation centres, and triggered inspections. The Romanian inspectors have also conducted GCP inspections in the context of the centralised procedure of the European Medicines Agency (EMA).

Volume 6 Issue 2

Regulatory access to the latest medication, and sometimes gain a cure for their disease. In regard to therapeutic study areas and medical conditions, the leading place is taken by oncology studies, but psychotic disorders, neurology, respiratory, haematology, diabetes, endocrinology, cardiology, and viral and bacterial infections are also studied in Romania (Fig.7)5,13.

Fig.3 Experienced investigators by country

Data extracted from NAMMD shows that in the period 2008‐2011, the total number of GCP  inspections (10) was 96 (both announced and unannounced) with the distribution per year  shown below (Fig.6), indicating a low number of critical findings. An analysis of findings  observed during 2010‐2011 GCP inspections shows a percentage of 22.98% in the source  documents (11); findings related to other areas of clinical trials conduct are below 10%.  Fig.5 Supportive infrastructure in Europe  

Fig.4 Cost per patient Data extracted from NAMMD shows that in the period 2008-2011, the total number of GCP inspections10 was 96 (both announced and unannounced) with the distribution per year shown below (Fig.6), indicating a low number of critical findings. An analysis of findings observed during 2010-2011 GCP inspections shows a percentage of 22.98% in the source documents11; findings related to other areas of clinical trials conduct are below 10%. From a financial perspective, clinical trials relieve part of the social burden on the national healthcare system, and ensure treatment with active medication for therapeutic areas which the national healthcare system cannot support. Clinical trials represent an alternative12 (sometimes the only) option for patients to have access to innovative, new-generation molecules. There is truth in the fact that the Romanian pharma market is small and usually endures several years of delays in registering and ensuring commercially available new molecules, and that national treatment programmes/reimbursement plans are generally not 100% able to meet the needs of the population. But that is why the running of clinical studies in this country is an option for patients registered on “waiting lists”: to gain


Fig.6 GCP inspections in Romania

Some of the identified findings were distributed as per the chart Fig.6 GCP inspections in Romania  below: Some of the identified findings were distributed as per the chart below:  DEFICIENCY CATEGORY 


Source documents 


Facilities and equipment 




Supply storage/retrieving/destruction of IMP 


Training of staff/qualifications 


Journal for Clinical Studies 23

Regulatory Management, April 2013, Bucharest 11. Adina Pirvu, “The principles of conducting clinical research” pdf., slides 100-102, Postgraduate Course in Clinical Trials Management, April 2013, Bucharest 12. Camelia Ghitan, “Clinical Trials in Romania” ppt, Postgraduate Course in Clinical Trials Management, June 2012, Bucharest 13. Cristina Florescu Moraid, “Clinical Research in Romania” ppt, slide 59, Postgraduate Course in Clinical Trials Management, May 2013, Bucharest

Fig.7 CT conditions distribution in Romania

From a public and media perspective, there is still room for improvement in developing clinical trials in our country. The public is rather unaware of the existence of clinical research, and lacks knowledge with regard to the legal framework, guidelines and rules involved, which may lead to some negative views over using humans as ‘’laboratory animals’’, etc. So, why do Romanian patients participate in clinical trials? Because they offer access to innovative medication; sometimes they are the only option for treatment; patients hope that partaking in the trial will improve their quality of life; the laboratory tests are performed in accredited laboratories (located abroad or in Romania); patients can get more attention from medical site staff; and last but not least, many patients hope that their involvement will help others with the same disease in the near future. In conclusion, the development of clinical trials in Romania is very promising, and the country’s existing legislative framework and organisation is inviting to any pharmaceutical company wishing to conduct studies on its patients/subjects. This development is a positive step for both the medical profession, and for patients whose access to treatment has thus advanced. References 1. A. T. Kerney, “Make your move: Taking clinical trials to the best location”, March 2006, http://www.pharmafocusasia. com/knowledge_bank/white papers/clinicaltrials_ bestlocation.htm, visited on 20 Feb 2014 2. Mirela Vita “Clinical trials regulatory framework” ppt., slides 12-17, Postgraduate Course for Clinical Trials Management, Bucharest, 2012-2013 3. “Romania’s Regulatory Milestones”, T & F Informa UK Ltd., September 2005 4., visited on 20 Feb 2014 5. Brosura_ANM_2011.pdf, visited on 24 Feb 2014 6., visited on 30 Oct 2010 7., visited in Jan 2007 8., visited on 30 Oct 2010 9., visited on 30 Oct 2010 10. Adina Pirvu, “The principles of conducting clinical research” pdf., slide 93, Postgraduate Course in Clinical Trials 24 Journal for Clinical Studies

Cristina Florescu Moraid is the Regional Country Director at Synevo Central Lab Romania, Moldova, Serbia and Bulgaria and European Laboratory Medicine Specialist. She graduated Faculty of Medicine Bucharest, Romania in 1998, has been working in laboratory medicine since 2000 and in clinical research since 2005. She was project manager for more than 60 local and international clinical studies of phase I-IV. She is also responsible for developing and extending clinical research business in Romania and surrounding countries for projects with sites from Romania and countries such as Moldova, Hungary, Bulgaria, Serbia; developer of clinical research training programs and for implementing them in Romania for specialists involved in clinical research business (i.e. investigators, clinical research associates, laboratory specialists,study nurses, etc). Email: Adina Pîrvu has a medical background and 10 years of experience as GCP inspector at the Romanian National Agency for Medicines and Medical Devices. She plans, organizes and conducts GCP national inspections. She is European Medicines Agency (EMA) expert in GCP inspection field and she conducts inspections as lead inspector in Centralized and Decentralized Application Procedures GCP inspections. Email: Mirela Vita, MD Graduate from the Bucharest University of Medicine and Pharmacy, the General Medicine Faculty, double specialisation in Internal medicine and Clinical Pharmacology. For 10 years working with the National Agency for Medicine and Medical Devices, firstly involved in assessment of medicinal product information in the SmPC, leaflet, clinical trials and pharmacovigilance bureau and further employed in clinical trials assessment and authorisation, with 4 years experience in the field. As part of her activity, Dr. Vita is involved in the process related to set up of legislation, at the same an active member in working groups related to clinical trials on European level. Email:

Volume 6 Issue 2

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Is Risk-based Monitoring an Appropriate Methodology for Clinical Trials in Emerging Regions? An Analysis of Clinical Site Performance Across Global Geographic Regions The current industry climate demands that sponsors of clinical trials find ways to reduce clinical trial complexity and drug development costs while getting more value from limited research and development budgets. Today, more than 30 per cent of a clinical trial budget is allocated to cover site monitoring costs, and more than 50 per cent of that is spent on source document verification (SDV) activities. 1 While SDV has traditionally been done on 100 per cent of data points collected in a clinical trial, research shows that less than 3 per cent of all case report form (CRF) data is actually changed due to SDV activities (i.e., post-data capture monitoring and data cleaning) 2. Given the high resource demand and cost of the traditional 100 per cent SDV approach, and the mounting evidence that proves it has a minimal impact on data quality, many life science organisations are applying risk-based monitoring methodologies in line with regulatory guidance from the FDA and EMA. Risk-based monitoring allows life sciences companies to more effectively target and prioritise resources around identifiable risks that might compromise the quality and integrity of clinical trial data. Implementing this methodology, often described by activities such as reduced SDV or targeted monitoring, requires a thorough assessment of risks prior to study start as well as their documentation in operational quality management plans (e.g., site monitoring and data management plans). Monitoring strategies should be tailored based on studyspecific risks. While risk categories such as critical data, the type of patient and the investigational product can be easily identified up front, it is often challenging to determine the quality and experience level of investigative sites participating in a study. When it comes to emerging regions—where sites and monitors generally have less experience in clinical research than those in North America and Western Europe— the conventional wisdom is that study teams need to apply more rigorous on-site monitoring, as the level of compliance and quality is expected to be problematic. That assumption prompted us to ask whether sites in emerging regions are indeed showing signs of lower quality that warrant more intensive scrutiny in a riskbased monitoring paradigm. To help answer this question, we analysed several key risk indicators related to site quality and compared them across global regions. We computed an aggregate value for each comprising data from more than 6500 studies contributed from over 120 sponsor organisations. 3 While we expected to see indications of lower site quality and 26 Journal for Clinical Studies

lower patient enrolment, our analysis showed that sites in emerging regions are actually trending more favourably than those in established regions! Methodology and Analysis The metrics we assessed by global region include the following: • • • •

Subject enrolment per site eCRF auto-query rate Subject visit to eCRF entry cycle time Data management query opened-to-answered cycle time.

For each metric above, we computed an aggregate value for each of eight global geographic regions. They include: North America, Western Europe, Eastern Europe, Pacific Asia, South America, Central America, Middle East and Africa. North America and Western Europe, for the purpose of this analysis, are considered “established regions,” while the other six regions are considered “emerging regions.” Figures 1 through 4 present the results for each metric, and what they reveal is quite striking. Starting with subject enrolment (Figure 1), five of the six emerging regions have demonstrably higher per-site enrolment rates than the established regions. And the one emerging market that is not higher—the Middle East—is at least on a par with North America at ~5.3 subjects per site, and not far behind Western Europe (5.8). Enrolment performance is particularly impressive in South and Central America, both with rates of over 8 subjects per site. The excellent per-site enrolment performance in these two regions is especially interesting to note given that previous research has shown that these regions contributed less than three per cent of the total research subjects recruited globally. 4 This may be indicative of longer regulatory approval periods, which often results in rapid enrolment at a few sites later in the enrolment period. eCRF auto-query rate is an important indicator of eCRF data quality. In particular, a higher auto-query rate indicates that a site is making a relatively high number of mistakes when transcribing data from patient source documents into the sponsor-provided eCRF. The reasons for data entry errors are variable, but may include insufficient training of site staff and/or lack of engagement and attention to detail by those staff. Figure 2 presents auto-query rates and reveals that overall there is no significant degradation in eCRF data quality in the emerging regions as compared to the established ones. Volume 6 Issue 2

Regulatory at least as well as the two established ones. And again, as with auto-query rates, sites in Eastern Europe and Pacific Asia are performing significantly better than sites in North America and Western Europe with respect to timely entry of subject visit data. Both of the established regions are averaging over 9 days (9.3 and 9.4), while the two emerging regions are averaging less than 8 days (6.9 and 7.7).

Subject Enrollment Rate (Subjects per Site) 9




1 North America

Western Europe

Eastern Europe

Pacific Asia

South America

Central America

Middle East


Figure 1. Subject Enrolment per Study at Sites in Different Geographic Regions Source: Medidata Insights™ metrics warehouse

In fact, the rates in Eastern Europe and Pacific Asia are significantly lower than in North America and Western Europe. This is particularly impressive given that the sites in these two emerging regions are managing more subjects per study on average than in the two established regions (as shown in Figure 1). One might expect that managing more subjects in a study would present greater opportunity for errors during eCRF data capture; however, this factor may be offset to the extent that sites in established regions are conducting more studies on average than sites in emerging regions. eCRF Auto-Query Rate (Queries per 1,000 Datapoints) 60 50 40

Figure 3. Average Cycle Time from Subject Visit to eCRF Entry at Sites in Different Geographic Regions Source: Medidata Insights™ metrics warehouse Data management query opened-to-answered cycle time is another important measure associated with both eCRF data quality and site responsiveness. As shown in Figure 4, we once again see no particular issues with this cycle time at sites in emerging regions as compared with sites in established regions. Sites in Eastern Europe and Pacific Asia appear to be on a par with sites in North America and Western Europe, while sites in South and Central America are performing significantly better than in the other regions.


Data Mgt. Query Opened-to-Answered Cycle Time (Days)


12 10

10 North America

Western Europe

Eastern Europe

Pacific Asia

South America

Central America

Middle East


Figure 2. Rate of Auto-Queries per Volume of eCRF Data Entered at Sites in Different Geographic Regions Source: Medidata Insights™ metrics warehouse

Subject visit to eCRF entry cycle time is also a critical measure of site quality, indicating not only eCRF data quality but site responsiveness and overall engagement in the study as well. This cycle time is of particular urgency for successful risk-based monitoring, as long delays in receiving subject data and information from sites confounds a study team’s ability to proactively identify areas of emerging risk. The critical importance of timely data entry by sites to support effective centralised and remote monitoring was aptly noted in TransCelerate’s position paper on risk-based monitoring issued in 2013. 5 The results for this cycle time—shown in Figure 3—reveal again that sites in the emerging regions are performing

8 6 4 2 North America

Western Europe

Eastern Europe

Pacific Asia

South America

Central America

Middle East


Figure 4. Average Cycle Time from Data Management Query Opened to Query Answered at Sites in Different Geographic Regions Source: Medidata Insights™ metrics warehouse

Results and Conclusion So what are we to make of these results? While the metrics we selected for this analysis do not cover all aspects of site conduct and quality, these measures do allow us to make the following key observations: Journal for Clinical Studies 27

Regulatory 1. Enrolment: Sites in emerging regions tend to enroll more subjects per study than sites in established regions, but this may be due to the volume of competing studies in North America and Western Europe. 2. Data Quality: Sites in emerging regions tend to have less—and certainly no more—difficulty with reliable eCRF data capture than sites in established regions. 3. Responsiveness: Sites in emerging regions tend to be more timely with data capture and cleaning than sites in established regions. This again may be reflective of the workload burden of site staff in established regions where multiple competing trials exist. The above observations are supported consistently and clearly across all four metrics, and the volume of studies and sites contributing to these metrics across all regions is significant; therefore there is little doubt that the results are meaningful. The outcome may at first appear to be counter-intuitive because many experts have expressed concern that less experienced sites— especially in these emerging regions—will struggle with good clinical practice (GCP) compliance and high-quality conduct of clinical research. While this concern may yet be warranted for some aspects of site conduct, the findings from our analysis suggest that sites in emerging regions are highly motivated to participate in research. They show themselves to be engaged and responsive, at least with respect to subject recruitment and patient data capture and management. The motivation may be driven by the financial opportunity, relative to clinics in Western Europe and North America that often face challenges associated with low financial return on their clinical research efforts (when compared with their nonresearch practices). Whatever the cause, these results actually bode well for moving more confidently toward a risk-based monitoring paradigm across the globe. What is most critical in this paradigm is to conduct an effective risk assessment prior to study start, including site-specific risks. And appropriate levels of scrutiny should be planned across all sites in a global study, with processes in place to remediate emerging site quality issues as they are identified. However, as these results suggest, study teams should not automatically assign higher risk to sites in non-established regions, at least when it comes to the risk-categories measured here. This also means that monitoring plans should not necessarily apply more intensive on-site monitoring—including more frequent visits and higher levels of SDV—to sites simply based on their geography. An exciting implication here is that the resource efficiencies and higher quality promised through riskbased monitoring need not be restricted to studies conducted in North America and Western Europe. It is time to move forward with risk-based monitoring globally! 28 Journal for Clinical Studies

References 1. IOM (Institute of Medicine). 2010. Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Washington, DC: The National Academies Press. 2. Denise Myshko, “Risk-Based Monitoring: A New Way to Ensure Quality Data,” PharmaVOICE (January 2014): 24. 3. Medidata Insights™ metric warehouse, 2014 4. Medidata Solutions, “Oncology Subject Recruitment Trending Down in All Geographies Except North America.” Applied Clincial Trials. Aug 26, 2013. 5. Position Paper: Risk-Based Monitoring Methodology. TransCelerate BioPharma Inc. 2013.

Stephen Young brings more than 20 years of experience to his role as principal engagement consultant at Medidata Solutions. Since joining the company in 2010, he has led the development of Medidata’s insights and site monitoring solution portfolios, providing customers with turnkey metrics and analyticsdriven solutions to improve site monitoring workflows. Previously, he headed eClinical services for J&J Global Clinical Operations. He holds a BS in mathematics from St. Joseph’s University and an MS in mathematics from Villanova University. Email:

Kyle Given is principal of consulting services at Medidata Solutions, focusing on risk-based monitoring. With over 20 years of industry experience, Kyle has spent the last 10+ years holding strategic leadership positions in business operations, where he has helped design and deploy large global clinical development teams and developed skills in technology enablement, resourcing models, process improvements, business analytics and training. He received his BA from Franklin & Marshall College and holds a graduate degree from Susquehanna University. Email:

Laurie Falkin is a director at Medidata Solutions, where she leads initiatives to support the use of risk-based monitoring technologies at clinical development organizations. She has more than 10 years of experience in the healthcare and life science industries. Laurie holds an MBA from New York University Stern School of Business and received her BS in microbiology from The University of Massachusetts—Amherst. Email: Volume 6 Issue 2


Risk-sharing: Supplementing Clinical Trials for Payer and HTA Success As the benefits of real-world data become more apparent so, too, do issues around its appropriate collection methodology and reliability. Olivier Ethgen, Scientific Director at SERFAN Innovation & EMIR (University of Liege), explores the creation of risk-sharing agreements and how to use this to mitigate against the potential weaknesses of clinical trial data. The Understated Requirement for Financial Analysis The optimum design of risk-sharing agreements requires the perfect understanding of the financial risks at stake. This point has unfortunately received very little attention so far - works published on the area are mainly descriptive, describing the different forms of agreements, but lack the required depth. Others have mainly insisted on the administrative burden resulting from this kind of contract. Too few studies have really tackled the challenging question of optimal design or focused on how to construct acceptable agreements from an operational viewpoint while providing financial guarantees to the two parties involved. We see this as an important area of research for the coming years in the field of market access.

investigation. This information is increasingly being considered as less than reliable by payers because its results, based on small patient cohorts, are not always transferable to the larger target population they are to be prescribed to. The manufacturers have the legal obligation to disclose all data and results stemming from their clinical research programme. However, this ex-ante information remains very incomplete. The risk-benefit ratio it carries remains quite unrepresentative of real-life conditions (the ex-post conditions). Faced with such uncertainty, the launch of a new pharmaceutical product induces, among other things, an ex-post financial risk for the payer. This risk actually comprises two parts. First, there is the risk that the actual value of the drug will be lower than claimed, notably in terms of effectiveness. This is a risk of under-performance: the product does not produce the expected benefits within the target population. In this case, the risk is that the payer has to pay the negotiated price but for a product that proves to be less effective in daily practice as compared to the ex-ante performance documented by the clinical research programme and precisely used to set the negotiated price. Second, there is a risk of over-prescription and/or over-consumption. The practical use of the product significantly exceeds the forecasts that were precisely used for the pricing negotiation. In this case, the payer incurs the risk of paying more than anticipated, putting at risk its budget planning (â&#x20AC;&#x153;volumeâ&#x20AC;? effect). This is also where the information between the pharmaceutical manufacturer and the payer is asymmetrical. The payer may have much less information about the market size, potential prescribing behaviours and uptake scenarios as compared to the manufacturer. Market research data are not necessarily disclosed to the payer.

To start exploring the creation of risk-sharing agreements, it is important to recall the two main forms of underlying financial risks that healthcare payers bear. In many European countries, the pricing of medicinal products is not free. The price and the reimbursement level of a new pharmaceutical product generally result from relatively exacting negotiations between the pharmaceutical company and the payer. In addition, the majority of payers attach a great deal of importance to health technology assessment (HTA). Combating the Inherent Weaknesses of Clinical Data During HTA and price negotiations, the decisions have primarily been based on the data generated by clinical 30 Journal for Clinical Studies

The first type of risk leads to the so-called performance or outcome-based risk-sharing contracts. If a treatment is not up to its expectations, the manufacturer has to reimburse the cost of that treatment or to restore a fraction of the price, generally in the form of discount. The second type of risk leads to the so-called financialbased risk-sharing contracts. If the cost of a treatment exceeds the anticipated budget, the manufacturer has to reimburse a proportion of the difference between the planned budget and the observed budget. The budgetary situation of many countries has perceptibly tensed up in the last number of years. Both forms of financial risk (i.e. paying for disappointing outcomes and paying more than planned) are becoming increasingly unbearable for payers. This risk aversion is Volume 6 Issue 2

Regulatory model can estimate the financial implications for both parties. Indeed, in this second step, the objective would be to define the part that the manufacturer would have to return to the payer as per the contract terms and conditions. When contracts are based on the tracking of performance indicators, the extrapolation of the risk-benefit ratio into the real-life long-run can be taken from the cost-effectiveness analysis, which is now quasi-systematically carried out by manufacturers of new products. Note that during this step, the operational implications for clinical staff and administration can also be analysed across multiple scenarios.

probably even further exacerbated as the cost of new pharmaceutical products continues to soar unabated. It is in this context that â&#x20AC;&#x153;risk-sharingâ&#x20AC;? agreements between manufacturers and payers began to gain some momentum and attraction. The major issue of risk-sharing contracts between manufacturers and payers is the understanding of the financial and operational implications of the contract. The collection and processing of the ex-post performance and volume of use of the product also deserve considerable attention. This information has also to be collected and managed impartially and transparently. Modelling can help both parties to address these issues. In effect, a model can provide both the payer and the manufacturer with a series of assessments on the likely financial and operational implications of the contract they are settling. The ultimate objective is of course to design a contract whose terms are suitable to all stakeholders, including patients and clinical staff. Modelling a risk-sharing contract can be broken down into two steps. First, the model should propose several prediction scenarios of the potential volume of use of the new treatment, i.e., the number of patients to be included over time in the risk-sharing contract. This is primarily a forecasting exercise. This step is quite similar to budget impact modelling already widely used in pricing and reimbursement negotiations. The time horizon should be neither too short nor too long and should fairly reflect the dynamics of adoption and diffusion of the new product. This time horizon must also enable the relevant real-life observation and evaluation of performance criteria for those agreements based on performance. Once the dynamics of the target population to be included into the risk-sharing scheme is modelled, the

By combining such projection assumptions, both parties are better able to anticipate the financial implications of the contract they may wish to conclude. In addition, such projections can also help to better understand the informational and operational requirements that will be imposed by the contract. In Conclusion In short, a risk-sharing contract is a form of warranty offered by a seller to a buyer. As such, it is a powerful selling approach and may help to secure the intended visible price of the seller. A risk-sharing strategy has unquestionable financial implications for the manufacturer. It is recommended that risk-sharing is a full part of the market access strategy of costly products. Multiple approaches and scenarios should be thoroughly thought about early in the process and modelling can help in this matter, borrowing analytical tools from the field of finance. Results and analytical frameworks of budget impact and cost-effectiveness models can also be used. As demonstrated, risk-sharing agreements should be considered and implemented as part of a controlled strategy; the last thing for a seller to do is to offer a warranty based on unexpected negative outcomes from negotiations.

Olivier Ethgen has worked in the pharmaceutical industry for 10 years, taking on roles in IMS, BMS and GSK. He is now currently an Associate Professor of Health Economics at the University of Liège in Belgium as well as the founding director of SERFAN innovation. SERFAN innovation provides modelling and analysis to support market access strategies and negotiations of innovative healthcare technologies. He is also heavily involved with eyeforpharma, producing articles, such as this one, and presenting on the area of Real World Data and Risk-sharing at many conferences. Email:

Journal for Clinical Studies 31

Market Report

Establishing Fundamental Fair-market Value Practices in the Middle East The primary challenge facing country-level managers in the Middle East is that they lack enough healthcare provider (HCP) compensation data for the region. Furthermore, little to no guidance exists in the region to instruct companies how they should approach HCP compensation. To date, drug manufacturers operating in the Middle East have developed their fair market value (FMV) processes based largely on directives handed down from corporatelevel compliance committees and guidelines based on limited information about the local markets. With this issue in mind, a research study was completed to provide real-world fair market value metrics for key opinion leader (KOL) compensation in the Middle East. Analysis was also conducted on best practices for developing FMV fee schedules and compliance processes that reflect the region’s unique cultural, political and socioeconomic dynamics. Setting FMV Rates: A Familiar Story In almost every way, the process for developing fair market value (FMV) rates in the Middle East is similar to that of any other country. Interviewed executives agree that the most common method for contracting with a key opinion leader (KOL) in the Middle East is to first categorise the healthcare provider. Most companies establish three tiers of thought leader segmentation with differing criteria. Then, based on those qualifications, teams determine an appropriate payment for the services provided. This is essentially the process that medical affairs and compliance teams go through hundreds of times a day worldwide. Nevertheless, there are some key elements to understanding how working with healthcare providers in the Middle East differs from the process found in other regions. Some of these differences are due to customs and traditions unique to the Middle East, making it logistically more difficult for some country-level teams to work with KOLs across the region. Some of those differences emerge from political and socioeconomic disparities throughout the region. These challenges may force some life science companies to opt to work with international thought leaders instead of with local physicians who could have a larger impact. The rates paid to Middle Eastern thought leaders are typically lower than healthcare providers’ compensation in other regions, which is to be expected given the reduced costs of living across the Middle East compared to other areas, such as Europe. Due to the lower ranges of payments, the differences between the average payments for Tier 1, Tier 2 and Tier 3 KOLs are relatively small. Therefore, compensation for Middle Eastern healthcare providers is a fairly straightforward negotiation process. In many cases, executives at the country level in the Middle East take their compensation directives from the company’s corporate level. Typically, a corporate-level group develops the company’s FMV calculation procedure and then rolls it 32 Journal for Clinical Studies

out to the individual countries to implement. At the country level, executives will try to incorporate any local regulations and considerations when implementing FMV procedures. For example, one multinational pharmaceutical organisation’s corporate group provides its Middle Eastern affiliates with company-wide FMV policies and guidelines. The responsibility then falls to the country-level managers and directors to implement the relevant rates into their individual markets. The corporate team provides the country-level teams with KOL criteria so that each country unit can develop a clear guidance applicable at the local level. The criteria handed down by the corporate team typically include academic level and years of experience. But the country-level teams can modify the criteria to reflect local customs and traditions as well. The team analyses the different healthcare provider criteria necessary to perform the different activities and assigns an approximate compensation range. Different KOLs with varying skill levels will be classified in tiers to which the team assigns different compensation ranges. Often, Company 1 sets the compensation rates based on a full working day of eight hours. For activities that take less time, the country-level team divides the full-day rate into an hourly rate (see Figure 1). Industry Benchmarks vs. Salary Data: The Eternal Debate

Figure 1: Average Hourly Rates by Company Type: Tier 1

One of the long-standing debates over the process for setting FMV rates is whether to determine a payment based on the value of the activity performed or on the healthcare provider’s salary. Both sides of the debate have strong arguments. Salary information would allow companies to at least match the amount that the physician receives at his or her regular job. But that job’s duties may be more or less valuable than the activity required by the company. So the actual payment may need to be different from the doctor’s hourly salary. In the Middle East, however, drug and device companies find it difficult to gather consistent, reliable salary data for healthcare providers. Each Middle Eastern country faces different challenges to collecting salary data. Volume 6 Issue 2

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Market Report Furthermore, the standards of living differ greatly from country to country. As a result, using salary data as a basis to set FMV rates across the entire region is difficult — yet it is a practice that many multinational pharmaceutical companies subscribe to. An interviewed senior medical executive from one drug manufacturer’s Kuwaiti affiliate explained that his organisation has had difficulty gathering physicians’ salary information in the Middle East and integrating that information into FMV standard operating procedures. Manpower is a primary challenge in gathering this data. Affiliate medical organisations in the Middle East are not the large-scale structures seen in more developed markets, such as the United States or at the company’s corporate level. Therefore, gathering salary data and managing the differences between low-income countries, such as Syria, and high-income nations, such as the United Arab Emirates, adds a level of complexity that the country-level medical staff remains unequipped to handle. To address the difficulty in collecting and normalising salary data across the region, the company’s medical group bases its FMV rates on a combination of the healthcare provider’s credentials as an expert and the activity in question. At one time, the company sought to gather healthcare providers’ salary data using the information in its FMV calculations. But at the affiliate level, the small medical team ran into too many complexities in gathering reliable and consistent data. Companies do not have to give up on collecting salary data and incorporating this information into their FMV processes. However, utilising industry benchmarks is one way that drug manufacturers can at least provide competitive HCP compensation rates. Until countrylevel teams in the Middle East – or in any smaller countrylevel affiliate, for that matter – can acquire more resources to dedicate to collecting consistent salary data, gathering industry benchmarks presents a viable solution to better understand how much they should pay healthcare providers for their services. FMV Regulations and Guidelines in the Middle East Another challenge some Middle Eastern country-level teams encounter when determining FMV is that they operate in an environment with few regulations and guidelines. Despite the lack of regulations in many Gulf-area and Levant countries, country-level teams are often required to abide by corporate compliance procedures. These procedures provide some guidance on determining fair-market value. The local governments, however, have little to no requirements for disclosing healthcare provider payments. Yet the physician compensation databases and tracking systems that corporate compliance teams have implemented are also in place in the Middle East. For this reason, Middle Eastern medical affairs teams may be well ahead of other countries. These teams are prepared to meet any future regulations that may require them to disclose physician payment data. Still, few regulations govern the amounts that drug and device companies can pay to healthcare providers throughout the Middle East. In other markets where HCP 34 Journal for Clinical Studies

compensation regulation is scarce, life science companies frequently benchmark their rates against the compensation levels of other companies operating in those countries. The benchmarking process is fairly straightforward and is available to Middle Eastern drug manufacturers. Companies can work through third-party benchmarking firms to gather compensation data, aggregate it and deliver a range of rates for various types of physicians. In our research study, we interviewed an executive at one pharmaceutical organisation who said that her company’s teams pay healthcare providers based on benchmarks derived from data that detail what other multinational companies pay to Middle Eastern KOLs. The company benchmarks the range of rates paid by other companies, establishes the minimums and maximums for those ranges, and then often sets the midpoint of those ranges as its compensation rate. The company’s benchmarking process helps its countrylevel teams in the Middle East region set its fee schedules. Once these rates are in place, the marketing and medical affairs associates at the affiliate level can access the established fee schedules. The ranges, however — including the minimum and maximum rates — are only available to the affiliate-level executives in the marketing and medical affairs teams. These executives would be responsible for any compensation negotiations between the company and an individual healthcare provider. Therefore, by providing highlevel executives access to the full ranges of compensation rates, companies can allow some room for negotiation with KOLs. Conclusion Ultimately, the challenges that Middle Eastern affiliate medical teams face when determining FMV are fairly similar to the challenges that their counterparts in the United States and Europe have faced from time to time. An obstacle that these teams face in the Middle East, however, is obtaining country-specific benchmarks. Middle Eastern affiliates can learn from solutions that their counterparts in more developed markets have already put in place. But affiliates must be careful to implement solutions designed to work in their countries, meeting their local needs.

Elio Evangelista has studied key opinion leader management fair-market value benchmarking since joining Cutting Edge Information in 2002. He has built his expertise around medical affairs, MSL program operations, patient recruitment, publications processes and the effects of regulatory change on medical affairs teams at drug manufacturers. As a leader of Cutting Edge Information’s operations group, he has helped clients develop better performance measurement systems, implement strategic recommendations and create more efficient operations. He has also helped to develop Cutting Edge Information’s Fair-Market Value Benchmarking Service, which provides clients up-to-date FMV rates for more than 100 countries and 27 therapeutic areas. Email: Volume 6 Issue 2

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Conducting Clinical Studies in Lebanon Since the 1990s, Lebanon, a pioneer in the region in the field of clinical research, has been selected for participation in multiple international multicentre clinical studies sponsored by top-ranked pharmaceutical, biotechnology and medical device companies. According to, the number of Phase I, II, III and IV trials with an “open” status in Lebanon as of February 4th, 2014, is 53, exceeding by far other Middle Eastern countries such as Jordan, UAE, Qatar and Kuwait. These figures do not take into account the non-interventional studies that are also very widely spread in Lebanon. Located at the crossroads of the Mediterranean Basin and the Arabian hinterland, Lebanon has a long history of exchanges with Western countries. In the health field, almost all key opinion leaders were educated in the US and Western European countries. In addition, huge investment is being made in Lebanon in the healthcare infrastructure. Most hospitals in Lebanon have a proper and modern set-up and equipment, as per international standards. Lebanon is therefore characterised by a quality of care that is comparable to the one provided in the West. There are 22 university hospitals in Lebanon. Some university hospitals are affiliated to major European and American hospitals such as Clemenceau Medical Center, Beirut, Lebanon, affiliated to Johns Hopkins Medical Center, Baltimore, USA. American University of Beirut – Medical Center was founded 147 years ago. It has a Federal-wide Assurance (FWA) with the Office of Human Research Protection (OHRP), in the Department of Health and Human Services (DHHS), as a domestic institution. Hotel-Dieu de France, also located in Beirut, was established in 1888. Saint George University Hospital started its activities in 1878. Other university hospitals such as Hammoud Hospital in Saida and Ain Wazein Hospital in the Chouf region have flourished during the past 50 years. In line with Lebanese law, it is acceptable to conduct a clinical study at a non-university hospital provided that a special approval is granted by the Ministry of Health. Practice has shown that such approval is usually easy to obtain. Despite the fact that Lebanese hospitals offer a quality of care that is similar to that available in the US and Western European countries, institution and investigator grants remain lower than in the West, which makes Lebanon a country of choice for the conduct of cost-effective and quality-driven clinical studies. Most hospitals in Lebanon have clinical research units, hence adequate monitoring space and staff solely dedicated to the conduct of clinical studies. With a surface area of 10,452 square kilometres and a coastline of 225 kilometres, where most investigational sites are concentrated, the whole Lebanese territory can be covered by a single clinical research associate based anywhere in the country. Lebanon has a Mediterranean mild climate that does not cause interruptions in professional or clinical activities. Even though Arabic is Lebanon’s official language, most investigators and site staff are fluent in English. Patient 36 Journal for Clinical Studies

files are usually not maintained in Arabic. Medical notes and laboratory results are either produced in English or in French. The Ministry of Health and the ethics committees do not require translation into Arabic of the clinical study protocol, protocol synopsis, investigator’s brochure and case report form. However, in compliance with good clinical practice, it is required to translate into Arabic documents provided to the patients (informed consent forms, dosing diary cards, etc.). In case other Arabic-speaking countries participate in the same study, a single translation can be performed and customised to local specifications accordingly. A significant advantage of conducting clinical studies in Lebanon is the shortness of the overall approval timelines, that do not exceed four months. Moreover, these timelines are very much predictable which is well appreciated by sponsors. Short approval timelines and predictability allow sponsors to consider Lebanon more and more as a rescue country for their ongoing clinical studies. The submission process is sequential and starts with the local ethics committee submission. Once the local ethics committee approval is received (review timelines estimated to two months), and if the study involves an investigational medicinal product, an application for an import licence is submitted to the Ministry of Health. The approximate time for the import licence to be granted is also two months. The Ministry of Health does not review the clinical trial protocol and the related trial essential documents. The focus is put on the importation of the investigational medicinal product. Since Lebanon is not an EU member state, an IMPD is not required. It is necessary to note that clinical trials on narcotics are not allowed in Lebanon. Local ethics committees’ requirements vary but usually remain similar to the ones outlined in good clinical practice. All university hospitals and the majority of hospitals in general have their own ethics committees who meet on a regular basis and comply with good clinical practice. There are no central ethics committees in Lebanon, and hence no need to select and appoint a national coordinating investigator. In terms of patient recruitment, it is not rare for Lebanon to be the highest recruiting country worldwide in a clinical study. Also, in many cases, the first patient in was enrolled in Lebanon. Indeed, Lebanese investigators are usually motivated to take part in clinical studies. In some institutions in Lebanon, acting as principal investigator is even a condition for a physician to evolve in his/her career. The key opinion leaders treat approximately 90% of the patients. Collaboration with medical societies can easily be established in order to boost patient recruitment. If needed, referral networks have also been shown to be a quick and effective way of boosting patient recruitment. In 2012, WHO estimated Lebanon’s population to be 4,228,000. With the adoption of Western lifestyle habits, the diseases that dominate the industrialised world have become significantly present in Lebanon. On the other hand, life expectancy has increased. For example, cancer rates in Lebanon are similar Volume 6 Issue 2

Market Report to the ones found in the West. Local smoking habits and low public awareness of cancer risk contribute to the high cancer rates. Neurodegenerative diseases such as multiple sclerosis and Parkinsonâ&#x20AC;&#x2122;s disease, auto-immune diseases such as systemic lupus erythematous and rheumatoid arthritis, endocrinology diseases such as Type II diabetes mellitus and osteoporosis, cardiovascular diseases such as familial hypercholesterolemia and coronary artery diseases are also very much prevalent in Lebanon. Indeed, Lebanon has one of the highest worldwide rates of familial hypercholesterolemia. Also, coronary artery disease is the leading cause of death in the Middle East. Moreover, the high consanguinity rate in Lebanon offers a relatively wide patient population for rare genetic disorders such as Gauchers disease Type II, sickle cell anemia, beta thalassemia, glucose-6-phosphate dehydrogenase deficiency, cystic fibrosis, phenylalanine hydroxylase deficiency and fragile X syndrome. Last but not least, the Middle East region could have the highest incidence of pulmonary infections in the world. It is thought that water-pipe smoking is partially responsible for the high rate of pulmonary diseases and infections in this region.

Since the beginning of its civil war in 1975, Lebanon has suffered tremendously from the image broadcast by the media. But in reality, since the end of the war in the 1990s, Lebanon has offered a safe and pleasant environment. Unfortunately, unrest can still be expected in Lebanon at short notice. However, it is usually restricted to a specific area and for a limited time. Local contract research organisations and clinical research professionals are used to working in such circumstances, and unrest risk mitigation plans are already in place. Storing a paper study master file in offices does not constitute any risk as long as adequate fireproof/waterproof measures are followed. Since protocols usually allow a time window for the patient visits to take place, deviations usually do not occur. If a site monitoring visit exceptionally needs to be postponed, the clinical research associate simply performs as many remote checks as possible in the meantime. Communication with sites through email, phone and fax channels is never affected by unrest. As soon as the risk of airport closure becomes probable, site study teams order additional central laboratory and investigational medicinal product kits in order to ensure that a sufficient stock is available at site. The use of a local depot for the storage of large amounts

Journal for Clinical Studies 37

Market Report content of an informed consent form, and fill in health-related questionnaires and other patient documents. Sponsors should, however, take into consideration the local cultural specificity when conducting a study in Lebanon. For example, during the month of Ramadan, a large part of the Muslim population fast from dawn to sunset. This may have an impact on the administration of the investigational medicinal product or on the related study procedures. Audits at sites in Lebanon usually result in no critical findings. Generally speaking, patient safety is followed up by the investigators in a very timely and rigorous manner. It is common, however, to notice a lack of availability of source documentation corresponding to medical history conditions and to the history of treatments. Electronic patient files have indeed only recently been introduced in Lebanon and are not yet implemented by all hospitals.

of investigational medicinal product is encouraged in Lebanon as it allows decreasing the number of import licences necessary for the whole duration of the study. Local depots in Lebanon receive a licence from the Ministry of Health in order to act as a local depot for pharmaceutical products. However, there is no special authorisation requested in Lebanon for the storage, distribution or transportation of investigational medicinal products. A certificate of good practice is not required by local law. In case of unrest, exportation of frozen lab samples does not constitute any risk as the latter can be stored at site for a longer period of time. Ambient lab samples (hematology, biochemistry and urinalysis) can be analysed locally. In Lebanon, local labs are accredited by the Ministry of Health. In the exceptional situation where clinical research professionals’ access to the contract research organisation offices is jeopardised by unrest, portable modems are commonly used in Lebanon; thus staff can work from home until the situation is back to normal. In summary, the risk of unrest in Lebanon is indeed higher than it is these days in the West. It is, however, worth mentioning that Lebanon was not affected at all by the current wave of protests in the Arab world. With a solid and exhaustive risk mitigation plan and the ability to activate it at any moment, the impact of potential unrest on clinical studies is, objectively speaking, very low. In Lebanon, relationships between patients and physicians are usually built on trust. Therefore, out-patients are usually very compliant with the administration of their treatment and other study-related procedures. Many patients don’t have social security coverage and high quality medical care is not always available for them. Therefore, being part of a clinical trial is viewed very positively by those patients. The young generation is quite motivated to participate in clinical trials. With a literacy rate of 90% (UN data, 2012), Lebanon offers a large pool of patients who are perfectly able to read, understand and sign the 38 Journal for Clinical Studies

As per MCT estimates, and as of December 2013, there were seven contract research organisations based in Lebanon, around 40 clinical research associates with at least one year of monitoring experience, and five pharmaceutical companies based in Lebanon who have their own local clinical teams. These numbers do not take into account the contract research organisations based in the region whose staff visit Lebanon on a regular basis for monitoring purposes. As far as the evolution of the number of clinical trials conducted in Lebanon is concerned, and based on data, 40 trials were attributed to Lebanon in 2007 (“open” and “closed” status). This number increased to 54 the year after. Between 2009 and 2010, it jumped from 68 to 103. The progression has never stopped since then, with 123 trials in 2011, 153 in 2012 and 187 in 2013. The growing number of contract research organisations with activities in Lebanon and the increase in the number of clinical trials conducted in Lebanon testify to the promising future of clinical research in the country and the region. Indeed, sites in Jordan and the Gulf countries can be easily monitored from Lebanon (no language or cultural barrier, short and direct flights, etc.). A few years ago, local regulation was still lacking basic aspects in Lebanon. But in the recent years several laws, decisions, memos and guidelines on the use of investigational medicinal product by university hospitals, exportation of biological specimens and importation of sterile medical equipment were issued. All Lebanese clinical research professionals are now looking forward to the next milestone, which is planned for the end of 2014: the capacity to destroy locally used and unused investigational medicinal product at the end of a clinical trial.

Alexa Younes has 7 years of experience in Clinical Research across a broad range of therapeutic areas and phases of clinical development. She acquired her experience in the Pharmaceutical and Biotech. industry as well as in Contract Research Organizations, both in Switzerland and Lebanon. In her role of Clinical Team Lead, she has simultaneously led several projects with multifunctional teams based in different countries. As she was passionate about Quality, and after 6 years working in Operations, she has made a successful career change to Quality Manager by joining MCT-CRO. She’s based at MCT – Lebanon office. Email: Volume 6 Issue 2

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Patient-derived Xenograft (PDX) Model - An Evolution in Oncology Drug Study Abstract / Business Case Introduction: Cancer is considered to be one of the greatest health burdens impacting people globally. In fact, one in eight deaths worldwide occur due to cancer. Finding a cure for cancer is gaining higher priority as the number of patients suffering from the disease is expected to pass 21 million by 2030, compared to todayâ&#x20AC;&#x2122;s figure of 15 million globally. Difficulty in replicating the disease, lack of appropriate models and technology in cancer studies at early discovery stage create an uphill task for pharma and academia alike. Main: In order to address shortcomings at the discovery stage in oncology studies, PDX has recently emerged as an upcoming technique. Through the PDX model, original tumour characteristics of humans are simulated in immunodeficient rodents, which eventually offer better predictive insights into the clinical outcome when evaluating the efficacy of novel cancer therapies. This white paper further explores the adoption of this method across industry participants over different geographies. Recommendation: PDX holds a lot of promise for improvement in cancer treatment as it offers time reduction in model generation, a higher predictive model, and an avenue for personalised medication. The adoption of these models is spearheaded by not just large pharma, but academia and CROs as well. The research model breeders as well as CROs are entering into partnerships with leading hospitals and universities, wherein the latter provide access to significant pools of patient tissues. Introduction Why is Cancer Drug Development Difficult? The challenges in developing drugs targeting cancer are the sheer number of genes involved within a particular type of cancer and among different types of cancer. Furthermore, diversity of cancer genes leads to resistance to treatment, resulting in remission. Therefore, heterogeneity in tumours makes discovery and development of new drugs complex.

Introduction to PDX Advancement in oncology drug development has been increasingly stalled by a lack of appropriate preclinical models that reliably predict clinical activity of novel compounds during oncology study in cancer patients. In order to address these limitations, there has been a recent preference for the adoption of heterotransplantation of human cancer cell lines into immune-compromised rodents. Hence, several tumour-specific PDX models have been generated which are biologically stable in terms of gene expression and mutation, drug sensitivity, etc. This in vivo model has emerged as the latest approach for oncology-related study by suppliers and the research fraternity. What is PDX? Patient-derived xenograft (PDX), also known as tumour graft models, are based on the transmission of primary tumours directly from the cancer patient into immunodeficient mice like BALB/C nude, SWISS nude and SCID mice. PDX helps transform clinical samples into mouse models to further oncology study. Since PDX are derived from human tumours, it acts as a tool for designing anti-cancer therapies and personalised medicine for patients with cancer. Furthermore, these models help study metastasis and tumour genetic development. Why do we Need PDX? The lack of appropriate animal models at the early discovery stage for oncology study forms a big hurdle as ~5% of cancer treatments entering clinical trials get approved. Major reasons for attrition are efficacy (~30%) and safety (30%). Hence, an appropriate predictive model at preclinical stage contributes to the likeliness of a promising oncology drug development programme. Patient-derived xenograft (PDX) aims to replicate the human situation better, thus being more predictive than through the use of conventional cell-based models. Process Flow: Existing Vs. PDX

This complexity at early stages of cancer drug development has brought forth a novel method in the patient-derived xenograft (PDX) model, through xenotransplantation of human cancers into immunodeficient mice.

The tumours derived from patients are grafted into animal models (immune suppressed), and the tumour is allowed to proliferate for about 1-2 months. Once the tumour grows, the research model is bred to generate multiple offspring that carry the grafts. The research model populations thus obtained are quite similar to humans in clinical trials. The cells of the initial graft can also be propagated as PDX cell lines, which can be cryopreserved and used for generating multiple hosts. 40 Journal for Clinical Studies

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Therapeutics Qualitative Analysis (Traditional versus PDX) The PDX model not only refines the testing method but also significantly helps reduce the valuable timelines. The PDX method stands way ahead of its traditional method counterpart on account of the parameters below:

Traditional Vs. PDX Methods:

The traditional method of preclinical trials utilises conventional research models, as well as genetically modified species, for predicting the efficacy of the investigational drug. However, the efficacy prediction for oncology drugs is relatively low when translated into clinical trials on humans, as these models fail to account for the heterogeneity observed in humans. Therefore, only after Phase II clinical trials can the efficacy of a drug be judiciously determined. Overall, the determination of efficacy of a drug through the above-mentioned conventional methods ranges from 7-9 years.

markets due to the availability of technical sophistication and infrastructure. However, this technology is seeing a rapid shift to emerging nations, mainly China, as witnessed in the recent past. A leading Chinese CRO, WuXi AppTec, entered into a strategic partnership with Mayo Clinic to generate PDX models for oncology using tissue samples from >500 patients. This partnership enables WuXi AppTec to access the extensive tumour collection of the Mayo Clinic. On similar lines, Crown Bioscience acquired PRECOS, a preclinical CRO specialising in oncology drug development and a pioneer in PDX model development. This acquisition makes Crown Bioscience one of the prominent providers in China, the USA and Europe for oncology PDX models. Others venturing into this lucrative market are leading research biology service provider GenScript and genomics giant BGI. Furthermore, suppliers in Western markets are adopting the application of imaging techniques on PDX models to enhance the sensitivity of pharmacology studies. For example: Molecular Imaging, Inc. and Oncotest GmbH have recently collaborated to co-promote their individual expertise, i.e. applying the experience of the former in in vivo pre-clinical imaging to the pioneering PDX capability of Oncotest. These developments indicate a highly competitive market in China in the next 3-5 years for PDX model generation, as well as testing services. Case Study

Conclusion/Summary PDX holds a lot of promise for improvement in cancer treatment, as it offers time reduction in model generation, a higher predictive model, and an avenue for personalised medication. The adoption of these models is spearheaded by not just large pharma, but academia and CROs as well. Research model breeders as well as CROs are entering into partnerships with leading hospitals and universities, wherein the latter provide access to significant pools of patient tissues. The virtual method, on the other hand uses PDX research models, which mimics the heterogeneity encountered in humans within preclinical trials. Therefore, the resultant efficacy data from studies on PDX models is equivalent to Phase II clinical trial data. This in turn reduces the considerable time, capital and manpower associated with development of the drug in comparison to conventional methods.

The past few years have witnessed a great spurt of innovation in the PDX space. Emerging nations like China are witnessing rapid growth, as the heterogeneity of the tissue varies with geographies and lifestyles. Service providers in the PDX space from China, like BGI, WuXi AppTec, Crown Bioscience and GenScript, offer indigenous PDX models developed from tissue from patients in China.

Geographic Outlook (Western Market & China) The PDX model development originated in developed 42 Journal for Clinical Studies

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Industry Speak/Acknowledgement 9. 10. 11. 12. 13. Keywords Used In vivo testing, Oncology Study, PDX References 1. labinvest201392a.html 2. 3. 4. 5. h t t p : / / i n s t i t u t e o f c a n c e r r e s e a r c h . w o r d p r e s s . com/2013/12/24/the-challenges-of-big-data-for-cancerdrug-discovery/ 6. F1.large.jpg 7. MCF_infographic_Bult.pdf 8. aspx?mID=3429&

403244f19325&cKey=ff2919cc-7be3-4d05-8c439073932f3afb&mKey=18fa2242-fd0d-4689-82a0e4d68ac8a74a PDXomics@BGI.pdf lines.html

Siddhartha Shaurabh is a Lead Analyst with Beroe Inc., a global provider of customized procurement services specializing in sourcing, supply chain visibility, financial risk analysis and environmental impact to Fortune 500 organizations. Siddhartha specializes in tracking various early stage areas (pre-clinical) under Pharma R&D. He has worked on multiple projects for many Fortune 500 clients involving categories such as discovery and medicinal chemistry services, animal models procurement services, animal based research services. Siddhartha earned his degree in Industrial & Production engineering from Gogte Institute of Technology, Belgaum and post graduate diploma in business management - Marketing from Bharathidasan Institute of Management, Bangalore. Email: Journal for Clinical Studies 43


New Standards in Alzheimer’s Disease Trial Design It is expected that between 2010 and 2050, the number of patients diagnosed in the US with Alzheimer’s disease will roughly double, from approximately 5 million to 10 million individuals, with a worldwide population approaching 40 million1. The economic and social impact is tremendous, with billions of dollars in lost productivity, increased healthcare cost and increased family burden. Thus the effort to find a viable treatment for the prevention or symptomatic relief of Alzheimer’s continues with great fervour. Over the last decade the only new treatment for Alzheimer’s that has hit the market is memantine (Namenda™). The number of failed drug programmes in that span provides a roadmap of scientific approaches that initially appear promising, but flame out in late stage development. Most recently, two promising drugs, bapineuzimab (Pfizer/Janssen) and solanezumab (Lilly), completed large Phase III programmes, only failing to meet designated endpoints necessary for approval2. This begs the question: Is there a better way? The Profile Drugs developed for treatment of Alzheimer’s disease usually fall into two categories: disease-modifying or symptomatic. Currently, all approved drugs are categorised for symptomatic. These include the acetylcholinesterase inhibitors (AChEI; donepezil, galantamine, rivastigmine) as well as an NMDA antagonist (memantine). Though pursuit of symptomatic agents continues, Alzheimer’s research has shifted focus more upstream and sought to find a disease-modifying drug that either prevents or delays disease progression. Tremendous progress has been made in building a profile of the prospective Alzheimer’s patients, based on use of imaging and other biomarkers4-7. Clifford Jack5,6 provided solid guidance for the potential relationship between β-amyloid plaque deposition in the brain, structural MRI imaging, neurodegeneration as detected by PET scanning, and cerebrospinal fluid (CSF) levels of amyloid-β42 peptide and tau. Others4,7,8 have extended this work to create a representative profile of a pre- or early dementia subject, but for whom likelihood of disease increases. In addition, certain genetic markers, namely ApoE49, have also shown correlation in patients to develop dementia later in life. Finally, vast amounts of research has been derived from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to further define an Alzheimer’s patient profile, both prior to and post disease onset. Thus, researchers now have a more defined way of targeting the best patients to participate in their trials. The Outcomes Both FDA and EMA guidance ask that any efficacy claims for Alzheimer’s be accompanied by data supporting both cognitive and functional improvement. Historically, researchers sought to target a mild to moderate Alzheimer’s population looking for statistically significant changes in a cognitive endpoint (normally the ADAS-cog) and some other functional or global 44 Journal for Clinical Studies

measure, e.g., ADCS-ADL, CGI, CIBIC, etc. Successive failed programmes have been unable to meet the defined endpoint criteria, and have found no significant differences between patients treated with study drug and those with placebo. The reasons are varied and controversial, though population heterogeneity, data variability and error from subjective rating scales are likely culprits. By defining patients through use of biomarkers, it is hoped that such endpoints will become more sensitive. Recently, the FDA issued guidance for developing drugs for treatment of early stage Alzheimer’s, providing direction for use of biomarkers as a way to design a more practical trial, but not for use as primary endpoints themselves. Kozauer and Katz3 state that it remains unclear whether the effect of a drug on one or more such biomarkers can actually predict a meaningful clinical benefit. However, the FDA has provided guidance for use of a single endpoint, the Clinical Dementia Rating- sum of boxes (CDR-sb), as a scale that may be used to combine cognitive and functional measure for better longitudinal sucess10; this also has support within the Alzheimer’s research community11. Between building a solid patient profile, and determining the right endpoints, the final challenge is tactical execution of a successful clinical trial. Conclusions Drug development in Alzheimer’s disease requires significant investment in time and money. Consider that a Phase III programme could take three to four years to complete and cost over $200M. Thus, setting up the trials correctly the first time through proper patient selection, appropriate endpoints and study design is critical. Likewise, realistic expectations for the number of investigative sites, a global approach and regulatory Volume 6 Issue 2

Therapeutics and enrolment timelines should be factored in the planning stages. It is always recommended to stay attuned to the current regulatory guidance and competitive climate to know where one’s study fits and how the research community will respond to it. A careful merging of science, strategy and tactics provide for the best opportunity to address the conundrum plaguing Alzheimer’s research today.

References 1. Brookmeyer, R., Evans, D.A., Hebert, L., Langa, M., Heringa, S.G., Plassman, B.L., & Kukull, W.A. (2011) National estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimer’s & Dementia 7(1), 61-73. 2. Vellas, B., Carrillo, M.C., Sampaio, C., Brashear, H.R., Siemers, E., Hampel, H., Schneider, L.S., Weiner, M., Doody, R., Khachaturian, Z., Cedarbaum, J., Grundman, M., Broich, K., Giacobini, E., Dubois, B., Sperling, R., Wilcock, G.K., Fox, N., Scheltens, P., Touchon, J., Hendrix, S., Andrieu, S., Aisen, P. & the EU/US/CTAD Task Force Members (2013) Designing drug trials for Alzheimer’s disease: What we have learned from the release of the Phase III antibody trials: A report from the EU/US/CTAD Task Force. Alzheimer’s & Dementia, 9(4), 438-444.

3. Kozauer, N. & Katz, R. (2013) Regulatory innovation and drug development for early-stage Alzheimer’s disease. N Engl J Med 368(12), 1169-1171. 4. Dubois, B., Feldman, H.H., Jacova, C., Cummings, J.L., DeKosky, S.T., Barberger-Gateau, P., Delacourte, A., Frisoni, G., Fox, N.C., Galasko, D., Gauthier, S., Hampel, H., Jicha, G.A., Meguro, K., O’Brien, J., Pasquier, F., Robert, P., Rossor, M., Salloway, S., Sarazin, M., de Souza, L.C., Stern, Y., Visser, P.J. & Scheltens, P. (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurology, 9(11), 1118-27. 5. Jack, C.R., Knopman, D.S., Jagust, W.J., Shaw, L.M., Aisen, P.S., Weiner, M.W., Petersen, R.C. & Trojanowski, J.Q.(2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurology, 9(1), 119-128. 6. Jack, C.R., Vemuri, P., Wiste, H.J. et al. (2011) Alzheimer’s Disease Neuroimaging Initiative. Evidence for ordering of Alzheimer’s disease biomarkers. Arch. Neurology, 68(12), 1526-1535. 7. Prestia, A., Caroli, A., van der Flier, W.M., Ossenkoppele, R., Van Berckel, B., Barkhof, F., Teunissen, C.E., Wall, A.E., Carter, S.F., Scholl, M., Choo, I.H., Nordberg, A., Scheltens, P. & Frisoni, G.B. (2013) Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer’s disease. Neurology, 80(11), 1048-1056. 8. Albert, M.S., Blacker, D., Mos, M.B., Tanzi, R. & McArdle, J.J. (2007) Longitudinal change in cognitive performance among individuals with mild cognitive impairment. Neuropsychology, 21(2), 158-69. 9. Corder, E.H., Saunders, A.M., Risch, N.J., Strittmatter, W.J., Schmechel, D.E., Gaskell, P.C., Rimmler, J.B., Locke, P.A., Conneally, P.M., Schmader, K.E. (1994). Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nature Genetics, 7 (2): 180–4. 10. 10. Guidance for Industry. Alzheimer’s disease: developing drugs for the treatment of early stage disease. Washington, DC: Center for Drug Evaluation and Research, February 2013 ( GuidanceComplianceRegulatoryInformation/Guidances/ UCM338287.pdf). 11. 11. Cedarbaum, J.M., Jaros, M., Hernandez, C., Coley, N., Andrieu, S., Grundman, M., Vellas B. & the Alzheimer’s Disease Neuroimaging Initiative (2013) Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer’s disease clinical trials. Alzheimer’s & Dementia 9(1), S45-S55.

Thomas E. Zoda, Ph.D., Senior Vice President, CNS Clinical Development at INC Research, has worked in the pharmaceutical and CRO industry for 20 years. Dr. Zoda has extensive experience designing, managing and overseeing clinical trials for the development of CNS therapeutics. He currently directs multiple programs at INC Research focused on psychiatric and neurologic indications including Alzheimer’s, Parkinson’s, depression, schizophrenia, and epilepsy. Email:

Journal for Clinical Studies 45


CNS Clinical Trials in Russia Neurological and psychiatric diseases are becoming the second most health-threatening burden after cardiovascular disorders, and are among the most popular research and development areas worldwide. In Russia, more than 10% of annual sales refer to neurology and psychiatry medications – ranking in second or third place after GI and endocrinology, cardiovascular drugs and taking the lead in natural volume. More than 40% of these drugs are analgesic. More than three-quarters of drugs are imported and produced by foreign biopharmaceutical companies.1 15% of medicines from the List of Vitally Needed Important Drugs refer to neurology and psychiatry - reflecting the governmental policy on provision of the population with the most essential and affordable drugs. According to the current legislation, to market a drug in Russia, it must have been previously clinically researched at Russian sites as well. This could be, for example, an international Phase II or Phase III programme involving Russian investigators. First-in-man studies of foreign drugs in healthy volunteers are forbidden. To initiate first-in-man clinical trials in psychiatry patients in Russia, the sponsor should provide either a very impressive preclinical package, or some Phase I clinical study results from outside of Russia; however, in general it is recommended to place all Phase I research of foreign investigative products abroad. Nowadays, the population of Russia is around 143.37m. As per current statistics, approximately 40%2 of the population suffer from various types of mental illnesses, and more than 20m need psychological help3. More than 900,000 people have schizophrenia, and 250-300,000 have manic state4. Alcohol addiction affects more than 20m Russian citizens - 60% of which are 24-30 years old5 - causing one-third of deaths among men. In accordance with the Federal Law 61-FZ of 12-Apr-2010 On Medicines, clinical research of psychiatry therapies in psychiatry patients declared legally incapable is allowed only on provision of a written informed consent from legal representatives. The Council on Ethics at the Ministry of Healthcare is very cautious of psychiatry studies, and as per the recent ACTO report6, only half of the protocols in this therapeutic area are approved by the body.

medications and state-of-the-art diagnostics in the Alzheimer’s disease (AD) and multiple sclerosis (MS) areas. Currently 1.8m Russians have dementia8 and 150,000 have MS9. A number of leading Russian biopharmaceutical companies and life science institutional investors are engaged in development of new disease-modifying therapies in these areas and are actively looking for regional in-licensing and partnering opportunities with foreign drug developers - especially in biologics. Taking into consideration that in Russia most care-givers are relatives, the economic burden of such diseases is substantial. AD and MS are the most difficult CNS areas for patient enrolment; however, this does not really concern Russia. A number of late-stage projects sponsored by Abbott, Roche, Eli Lilly, Servier, TauRx, Biogen, Teva, Novartis, GSK, Mitsubishi Tanabe and others (as well as Russian companies) are being conducted in the country now. Clinical research of diseasemodifying agents requires huge sample sizes of patients to recruit into AD studies, as well as longer treatment periods. Symptom treatment trials are considerably smaller and shorter; however, monotherapy placebo-controlled studies require the recruiting of treatment-naïve patient populations, which is still possible in Russia. The incidence of epilepsy is 3.4 per 1000 in Russia10. Ineffective and untimely therapy is the key reason for aggravation and low curability. Substantial prevalence of generics and lack of certain

Annually, more than 480,000 Russians suffer from strokes7, which is one of the key causes of disability and death among the population. In Russia, to approve a clinical study requiring emergency measures, a developer is recommended to include special terms of patients’ enrolment into the study protocol. These terms should allow an investigator to escape obtaining a written informed consent from a subject and his/her legal representatives prior to urgent medical interventions, due to the critical condition of a patient. Such protocols are carefully reviewed by the national and local ethics committees. The Russian market is still looking for new effective 46 Journal for Clinical Studies

Volume 6 Issue 2

Therapeutics drug formulations in the Russian AED market complicate the treatment of patients. Taking into account that epilepsy is one of the four most frequent infant diseases (7 cases per 1000 children) as well as diabetes, bronchial asthma and autism (1 case per 1000 children)11 , clinical development and launch of novel anti-epileptic drugs becomes a crucial task for the Russian government and biopharmaceutical sector. As per infant diseases, the problem of child psychoneurology is a burning issue. 83% of children in Russia have neurological symptoms and signs. In the country, 7-28% of children suffer from attention deficit hyperactivity disorder (ADHD)12. ADHD leads to serious negative social impact if not treated in a timely manner. However, only one international multicentre clinical study and one local clinical trial in this therapeutic area have been conducted in Russia during the last few years. In accordance with the Russian legislation, paediatric clinical trials are permitted only if an investigative product has been previously researched in adults, unless a drug is solely prescribed for infants. A written informed consent form signed by parents and adopters is sine qua non to conduct paediatric clinical research in Russia. Placebo-controlled paediatric studies are limited and account for less than 10% of paediatric studies in the country. Nevertheless, for instance, in pain therapy a placebo effect is variable; hence, the placebo-controlled design is applicable. Today there is an urgent unmet need for marketing more effective treatments of pain in Russia, especially non-invasive drugs for oncology palliative care. For the moment, only four non-invasive opioid analgesics are registered in the country in comparison with many registered in the EU. Aside from general legislation covering clinical research such as the Federal Law On Medicines and others, there are special regulations for psychotropic and narcotic medications in Russia stipulating very strict conditions of circulation (including clinical development) of such drugs (Federal Law 3-FZ of 08-Jan-1998; etc.). According to the recent report of the Association of Oncologists of Russia, the CNS tumour rate is 4.08 per 100,00013; incidence of brain tumours in the country is 3.7 per 100,000 .14 CNS tumours in children rank second place in malignant neoplasms after leukosis, and account for 18%15 of all infant oncological diseases. Clinical research in CNS tumours is important in Russia as the required amount of financial resources to treat a patient is enormous for the average man, but the current governmental support is not sufficient to cover the existing need: more than 50-60% of oncology drugs are paid for by patients and their relatives, despite the fact that these medicines are to be reimbursed by the state16. The quality of clinical research data coming from Russia is comparatively high. One-third of FDA/EMA approved drugs studied within international clinical trials have been placed, in part, in Russia, and that percentage is increasing (29% in 2010, 33% in 2011, and 37% in 201217). Most CNS clinical studies amounting to several hundred - in Russia have been conducted in MS, epilepsy, AD, stroke, depression and schizophrenia; however, the potential of the region in terms of a pool of treatment-naive patients and a number of sites to contribute to

international clinical research is huge. A few trials took place in rather challenging indications such as alcohol addiction, where for the moment, most sponsors are presented by the Russian biopharmaceutical companies. As per SynGR Orange Papers18, 6-11% of the total number of clinical studies approved annually in the country are in neurology and psychiatry. However, we expect this share will increase, and more and more new safe and effective diseasemodifying therapies will be suggested to Russian patients. References 1. Pharmaceutical Market of Russia. Analytical review, July 2013 2. 3. h t t p : / / m e d p o r t a l . r u / m e d n o v o s t i / news/2013/12/11/178psiho/ 4. 5. http://xn--b1adaebrf2aic6aens.xn--p1ai/ 6. 7. 8. bolezn-altsgeimera-nastupaet 9. 10. 11. 12. 0090&action=1&nd=458235721 13. h t t p : / / w w w . o n c o l o g y . r u / s e r v i c e / s t a t i s t i c s / morbidity/2011.pdf 14. 15. h t t p : / / w w w . o n c o l o g y . r u / s e r v i c e / s t a t i s t i c s / morbidity/2011.pdf 16. 17. Orange_Paper_2012Y.pdf 18.

Ekaterina Mochalova studied in St Petersburg State University of Economics and Finance where she obtained Master Degree in Finance, Currency, and Credit. In 2003 Ekaterina joined the leading global CRO PSI taking a financial position for 3 years. In 2007 Ekaterina joined a regional CRO as a Business Development Manager and was responsible for establishing relations with Russian and foreign biopharmaceutical and medtech companies interested in placing clinical research in CEE region, Russian healthcare regulatory bodies, and life science institutional and corporate investors looking for in-licensing and partnering opportunities worldwide. In 2007 Ekaterina successfully defended her thesis on the subject of financial planning in contract research organizations and obtained PhD in Finance. Since 2013 Ekaterina has been working as a Business Development Director for Global Clinical Trials, LLC (GCT), a regional CRO established in 2001 and headquartered in Princeton, US with Phase I-IV clinical operations in Russia and other CEE countries and with solid experience in CNS as wells as other therapeutic areas. Email: Journal for Clinical Studies 47

IT & Logistics

The Role of Mobile Technology in Reshaping the Pharmaceutical Industry In this age of information technology, people from all strata are benefiting from the opportunities provided by mobile devices. One of the most noticeable changes has been the growth in healthcare professionals (HCPs) and the general public accessing and collecting medical information via their smartphones, making full use of the mobiles’ convenience and easy-to-use features. This increasing demand for medical information has been accompanied by the development of a wide variety of mobile medical apps that are changing the way people think and perform their professional duties. In the pharmaceutical industry, mobile apps are also making a significant contribution by assisting companies improve customer outreach. Current Status of Mobile Device Penetration Mobile devices are everywhere and according to a recent report commissioned by the International Telecommunication Union (ITU), there are around 6 billion mobile phone subscribers in the world. Another study by the Pew Research Center in America found that 91% of American adults have a cell phone, and more interestingly, 55% of American adults have a smartphone 1. This phenomenal growth in mobile phone users has also led to the increased use of mobile apps to fulfil a variety of needs. With just a single click, people can download apps on to their smartphones and use them to find new music, track the weather, meet new friends, get directions, and play games. Not only this, but an app can also possess life-saving potential. For instance, an app from Pfizer called Vaxtext sends personalised messages to parents’ smartphones based on the age of the children indicating which vaccine is next in line. The GoMeals app from Sanofi-Aventis works well for health-conscious people which allows users to keep a tally of calories, carbs and fats consumed in a meal. This app possesses a rich database containing the nutritional information of over 40,000 known foods and 20,000 menu items, which can be highly beneficial for patients suffering from serious health conditions like diabetes. Cancer patients enduring chemotherapy can be assisted by an extremely useful app, called iChemoDiary, from Merck & Co. Using this app, the cancer patients can maintain a personal oncology diary, which can help them keep track of their chemo schedules and other treatment procedures. Another app that is worth mentioning here is ‘Daily Carb’ from Maxwell Software. The patient can set the carb budget and track daily nutrition intake of the food, carbs, fibre, fat, etc., and also track quantity of water intake, readings of glucose, HbA1c, blood pressure, heart rate, weight, exercise, medications and insulin. They can share the readings with doctors in CSV, HTML or PDF format by email2. Novartis GIST Calculator allows physicians to calculate a patient’s risk of recurrence for Gastrointestinal Stromal Tumors (GIST) with an iPhone or iPod Touch. Roche’s Nursing ACE can be useful for nurses in getting patient educational information and contacts for nearby clinical coordinators. It is clear that pharmaceutical companies have also started to realise the value 48 Journal for Clinical Studies

of mobile apps; in particular well-designed apps that can help companies reach potential customers and improve organisational efficiency. Use of Mobile Technology in the Pharmaceutical Industry Mobile technology offers promising market potential for pharma companies. This technology gives drug manufacturers the opportunity to access patients directly. This allows the companies to have an improved image as perceived by the patients. In addition to this, the relationship between pharma companies and healthcare professionals is also improving. Companies have started using mobile facilities for influencing healthcare decisions of the consumers and building a connective channel between their products and the patients and doctors. Mobile technology can be regarded as a significant stepping stone with which pharma companies can transform themselves as friendly entities, allowing them to survive in a highly competitive environment. According to a report commissioned by Ernst & Young called ‘Progressions: Building Pharma 3.0’, companies need to shift their focus from selling drugs to offering services that improve overall health outcomes by better management of diseases, coordinated care, and an expansion across different stages of care. Recently, pharmaceutical companies have started investing heavily in building user-friendly mobile apps, aimed at the needs of potential customers or patients and healthcare professionals, as well as the companies themselves. Almost all the major pharma companies, including AstraZeneca, Abbott, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer, Johnson & Johnson, Sanofi-Aventis, Roche, etc., have apps on the market. A well-designed app, be it a disease calculator, a medication tracker, a patient diary, or an educational catalogue, can improve the lives of patients and physicians and thus increase customer collaboration3. Once a drug has been licensed for sale, it is paramount to monitor its adverse effects and notify the pharmaceutical company and regulatory authorities whenever an adverse drug reaction (ADR) is suspected. However, busy schedules mean that healthcare professionals (HCPs) and pharmaceutical sales representatives have difficulty finding the time to report ADRs either to the company or the appropriate authority, resulting in very significant (98%) under-reporting of spontaneous ADRs4. Virtual PV Ltd., a UK-based company specialising in pharmacovigilance (PV), has developed an effective and innovative solution to this problem. They have launched an ‘Adverse Event Reporting App’, suitable for iPhones and iPads and designed to make it easier and more convenient for sales representatives, patients, or healthcare professionals to report an adverse drug reaction to a central location quickly. These reports are transmitted in XML format either over the cell phone network or wireless network using secure network protocols. Dr Stephen Hutson, the Founding Director of Virtual PV Ltd., highlighted the fact that “Reporting adverse event data directly from an app Volume 6 Issue 2

IT & Logistics allows the data to be transmitted straight into a company’s safety database or suitable registry. This not only saves time, by reducing the need to key in the data, but also induces significant cost savings as well. Deploying this app as part of a risk mitigation strategy would also allow access to the data in near real time, enabling companies and regulators to make faster decisions on critical patient safety issues, such as how to market the drug or possible withdrawal of the drug.” Some other mobile apps have also been found to be useful in the pharmaceutical industry. For instance, GlaxoSmithKline introduced an iPhone app with maps of its facilities in order to make life easier for newcomers to its sites. Glaxo employees can use this app for gaining access to the internal maps which show the locations of individual desks, and the best ways to get around an office. Benefits Obtained from Mobile Technology Mobile apps like the ‘Adverse Event Reporting App’ from Virtual PV Limited are capable of bringing immense benefits for a pharmaceutical company. Besides providing an easy and convenient way for HCPs and non-HCPs alike to gather and report adverse events, the app offers the potential for considerable resource savings. For example, consider a pharmaceutical company with ten sales representatives who on average report one adverse event per week. Like all sales representatives, they are trained to report the four basic data elements of patient identifier, reporter (usually HCP) contact details, suspect drug, and adverse reaction. All are required for a case to be valid. The

representatives report adverse events to the PV department via hasty phone calls, often on poor mobile connections, or via an email composed at the end of a long day, and as a result one or more data items (usually the HCP contact details) are often missing or incomplete. If an app like the ‘Adverse Event Reporting App’ is used, its user-friendly design ensures that entering the data is easy and fast and can be transmitted directly into the company safety database in a timely manner, minimising the overall cost involved in this process, allowing a significant amount of effort to be redeployed to more valuable tasks. This is in addition to the benefit of further improving the reliability with which sales representatives report adverse events5. Moreover, pharmaceutical companies can also use mobile technology to replace their traditional sales approaches with state-of-the-art techniques to boost their sales. Mobile tools and applications of different types providing real-time information have enabled companies to adopt strategic approaches to establish direct contacts with customers. This may drive these companies towards gaining sales efficiency and productivity, better customer experience, and maximised cost management initiatives. For instance, “Sales team members also take advantage of built-in mobile specific capabilities such as location services (GPS) to enhance sales planning and decision-making even further. With location-based alerts and customised notifications, representatives will be able to gauge their proximity to various customers, target them more effectively, and provide more relevant product and selling information”6.

Journal for Clinical Studies 49

IT & Logistics Mobile technology can also help pharmaceutical companies minimise their cost by equipping the sales force with relatively cheap mobile devices. Companies can also save a significant amount of time and money previously spent on maintaining and troubleshooting laptops and upgrading different software regularly. Various types of mobile applications can also be used to provide training to new sales representatives, for which pharmaceutical companies currently spend a huge amount of money. Conclusion Pharmaceutical companies today are increasingly investing in a whole range of healthcare initiatives and innovations that aren’t drugs at all, including smartphone apps, social media platforms, educational websites, and other programmes. As smartphones and tablets are becoming more pervasive, pharma companies from all over the world should come forward to enhance their research and development (R & D) initiatives, as well as try to invest more in introducing new, innovative mobile apps that will come out as useful for the patients, doctors, sales representatives and all concerned parties. In order to maintain the competitive advantages, it is crucial for drug-producing companies to take advantage of the mobile technology and come up with novel mobile applications to promote their brands and make a significant contribution in the health sector.

It is always essential for pharmaceutical sales representatives to manage their inventory of drug samples. This involves not only the ability to track the inventory and distribution of the sample material, but also the need to validate the identity of a physician and authorise the accuracy of their signature. Many pharma companies at present have started to utilise mobile solutions capable of capturing an electronic signature, and also providing access to physician validation data, and recording sample inventory information. This may eventually result in the reduction of paperwork and increased accuracy7.

References 1., visited on 12 February 2014. 2., visited on 12 February 2014. 3., visited on 12 February 2014. 4. Hazell, L. and Shakir, S.A. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 29(5), 385-96 (2006). 5. Virtual PV. Adverse Event App for Sales Representatives. White Paper (2013). 6. Accenture. Leveraging Mobility to Maximize Pharmaceutical Sales Force Effectiveness. (2011). 7. Groover, T. and Allen, P. The Value of Wireless Applications in the Pharmaceutical Industry. Clarkston, Durham, North Carolina. Available at mobile_coms_in_pharma.PDF, visited on 13 February 2014. 8., visited on 14 February 2014.

Furthermore, mobile applications provide the opportunity to establish a direct channel of communication between the patient and the manufacturer of a pharmaceutical product. Patients using an application can “tell” when and how they use their medications – the dosage, etc., and are able to give feedback on the drug’s impact and their own satisfaction with the product. These applications provide direct usage information which can assist in understanding the usage habits of patients, helping the pharma companies immensely. In addition to these, companies may use different kinds of mobile apps to improve relationships with the key clients of the pharmaceutical industry, the doctors, due to the opportunity that these apps may provide to communicate with them directly and easily8.

Morten Kjær has nearly 10 years of experience from the pharmaceutical drug safety industry. He is currently the Chief Operating Officer at the Danish based drug safety solution provider BaseCon. He holds a degree in Business Economics from IHM Business School in Gothenburg, as well as diplomas in Pharmacovigilance Processes Management and Software Development. Email:

50 Journal for Clinical Studies

Volume 6 Issue 2

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IT & Logistics

Import of Investigational Medicinal Products into Israel Israel has a robust and growing pharmaceutical industry, particularly for biopharmaceuticals and advanced therapeutic medicinal products (ATMP). It is home to one of the largest generic drug companies in the world, which invests in Israeli drug development companies supporting the growth and development of new medicines. Because of its close links with Europe and the US, many of the new products being developed in Israel undergo clinical trials in Europe and the USA. Therefore, there is a large amount of export of material from Israel: either the API (active pharmaceutical ingredient) which is then manufactured in Europe or the US, or the finished material which is shipped to EU or US companies for packaging and distribution. Legislation has been passed making the transfer of medicinal products between countries easier. Emphasising Israel’s growing links with Europe is the Agreement on Conformity Assessment and Acceptance of Industrial Products (ACAA) between the European Union and Israel which came into effect on 19 January 2013. This is very similar to the mutual recognition agreement (MRA) the EU already has with Switzerland, Canada, Australia, New Zealand and Japan, whereby standards of good manufacturing practice for pharmaceuticals have been assessed as equivalent. For pharmaceuticals, this means that inspections for compliance of manufacturers and importers to EU GMP and equivalent Israeli GMP guidelines and GMP certificates issued by either party will be recognised. This can also apply to inspections carried out outside the parties’ territories. Therefore, audits of facilities within the global supply chain performed by a European qualified person (QP) will be recognised by the Israeli responsible pharmacist (RP) and vice versa. Manufacturing and import authorisations confirming compliance with legislation will be recognised and batch certification confirming conformity to specifications will be recognised. For example, any manufacturing release certification in the EU is a release in Israel and vice versa. In addition to standard MRA benefits discussed above, the ACAA allows Israel to participate in various networks and meetings including EudraGMP, Official Medicines Control Laboratories (OMCL) network, GMP / Good Distribution Practice Inspectors Working Group meetings, EU joint audit programme (JAP) and the European Directorate for the quality of medicines and Healthcare (EDQM) mutual joint audit programme. All of these enable Israel to bring its regulations in line with those of the EU. The ACAA simplifies the release and movement of material with a marketing authorisation in the EU or Israel. However, the following medicinal products were excluded from the ACAA: Medicinal products derived from human blood or human plasma, advanced therapy medicinal products, investigational medicinal products, homoeopathic medicinal products, medicinal gases and veterinary immunological products. These will be considered for inclusion after two years, but currently any materials manufactured within Israel for clinical trial in the EU will have to be released by a QP following inspection 52 Journal for Clinical Studies

of the manufacturing site. In April 2013, the Israeli Institute for Standardisation and Control of Pharmaceuticals published an update to the ‘Manufacture and import of investigational products in the state of Israel’, procedure number EX-012/01. This was brought into effect on 1st July 2013 and covers the provision of regulations for the manufacture and import of IMPs for clinical trials in humans and explains the role of the responsible pharmacist in Israel. These regulations are clearly based upon the current GMP regulations of the European Union Eudralex volume 4, and particularly Annex 13: Manufacture of Investigational Medicinal Products and Annex 16: Certification by a Qualified Person and batch release. Currently, the new regulations only apply to Phase III and Phase IV clinical trials initiated after the 1st of July. In summary, the rules require IMP manufactures in the State of Israel to receive a manufacturer’s authorisation if they are manufacturing product for clinical trials conducted in Israel. This includes a manufacturer’s/importer’s authorisation and GMP certificate, and they will need to employ a responsible pharmacist. The role of the responsible pharmacist is equivalent to that of an EU QP. They are employed by the manufacturer or importer to certify or re-certify materials for use in clinical trials in Israel. This includes verifying the manufacture of the product is in line with GMP requirements, verifying that the product has been manufactured in line with the procedures submitted to the clinical trials authority, the product specification file and labelling requirements. As in the EU, the RP is also responsible for verifying the material has been delivered to its appropriate destination (the trial site) in accordance with its temperature specification. What do these New Rules mean for Imports from the EU to Israel? Although the new rules are clearly aligning Israel’s procedures for IMP with the EU in readiness for future inclusion in the ACAA, the current reality is that they have increased the complexity and paperwork required for setting up imports into Israel. The requirements for import are the following: • All IMPs (and comparators) should be manufactured according to GMP guidelines and released by an authorised person; in the EU this is a QP, while in the other recognised countries this a quality assurance person certifying batches. • All products have to be recertified by the importer’s responsible pharmacist prior to distribution to the sites. • Trial approval from the medical institution’s director has been received. • The IMP has been manufactured in a GMP-certified site and either the site is in a recognised country and is certified by an authorised person or the manufacturing site is in an unrecognised country but certified by an authorised person from a recognised country, or is manufactured in an unrecognised country and certified by the Israeli importer’s RP. • A proforma invoice. • Importer’s authorisation for clinical trials. Volume 6 Issue 2

IT & Logistics Once these requirements are in place, the pharmaceutical administration will issue an IMP import authorisation for the shipment. Although this list appears to be fairly short and simple, the re-certification of the material by the RP is a virtual repeat of the QP release and requires a large amount of paperwork to be in place before it can take place. Assuming the product being imported is final labelled material ready for distribution to a trial site, the following will need to be reviewed by the importer’s RP in order to re-certify the material: • • • • • •

• • •

Proforma invoice Transport conditions (including shipping documents and temperature graphs during transit) Certificate of analysis for the product (this may be difficult to obtain for comparators) Medical institution director’s approval Trial protocol including all amendments Product certification by the authorised person. The certificate should include a declaration stating that the material has been manufactured under GMP conditions in accordance with the protocol, randomisation code and product specification file (PSF). The supply chain of the product should also be stated. Current GMP certificates of the manufacturing sites. Where sites are not issued with a GMP certificate (eg the USA) a GMP certification from the authorised person is required. Unblinding procedures. For material supplied blinded, a document linking the individual batches to kit number is required. For a comparator that does not have a distribution licence in Israel, the authorised person will need to provide a statement declaring the product is registered in an authorised country. If this is not possible the material will need to receive import authorisation from the Israeli Import Department of Pharmaceutical Administration.

Additionally, if there has been a temperature excursion during the shipment to Israel the RP will need to review documentation to support the use of the product. If there has been a major deviation during the manufacture of the material, this should be provided to the RP. If material is being imported to Israel for final manufacture, identification testing is required to be performed. If nude vials are imported for primary labelling they will need to be analysed for identification before they are labelled. Materials that are blinded and randomised at Israeli authorised manufacturers should undergo an identity test upon completion of the procedure. Testing must take place in a GMP-certified laboratory. Where testing is required at import, a copy of the PSF must be available for inspection. For trial material packaged within the EU, all the required information is available as it forms part of the QP certification of the product. However, previously if there was only one trial site in Israel, material would have been shipped directly to site. For Phase III and IV trials, this is no longer possible unless the site has a responsible pharmacist and an import authorisation. Therefore, like the EU, you need to import via a licensed facility, which adds time and cost to the process. Although the import requirements to Israel have increased, the Israeli authorities do allow the RP to recognise the product certification performed by authorised

persons in recognised countries. In the EU we do not currently recognise the RP’s certification of manufacturers or product for IMP and, therefore, need to carry out audits, manufacturer’s certification, full batch release and batch certification for any IMP manufactured in Israel and imported into the EU. It is assumed that the two-year timeframe put in place for review of the products excluded from the ACAA is to allow Israel time to extend the new requirements out from just Phase III and IV trials to all trials, bringing it in line with the EU regulations and so allowing EU QPs to be confident that GMP standards for all phases of IMP manufacture are equivalent in Israel. What are the Timeframes for Importing into Israel? For IMP in Phase I or II trials, or Phase III trials initiated prior to July 2013, the import procedure is relatively quick. A proforma invoice is raised stating the name, quantity, batch number, expiry date, product description, and product value and trial protocol reference. This is sent to the importer who sends it to the pharmaceutical administration for authorisation. In this instance the importer may be an authorised importer, the trial site or the CRO (contract research organisation) responsible for the trial in Israel. Once the authorised permit is received, the import can take place. In our process, we generally raise the proforma invoice at the start of the week, and authorisation is received by Thursday. We then ship the product on a Friday for receipt and customs clearance on the Sunday. Customs hold-ups are very rare but facilities are available at the airport to hold material at the appropriate temperature. As the majority of material we ship is temperature-sensitive, we use specialist couriers who will automatically move shipments to controlled temperature storage if there are any delays. For new Phase III trials, importation needs to be performed via an authorised importer. This requires contracts to be agreed and all the information listed previously to be supplied and reviewed by the importer’s RP. Generally this will take six to eight weeks. There will also be increased costs, as previously shipments may have been made directly to site but now require receipt, storage, release and distribution by the Israeli importer. All these costs will be passed on to the sponsor of the trial. Therefore, over the next few years there is likely to be a reduction in the number of European trials taking place at Israeli trial sites, but if the ACAA is expanded the market will open up significantly as Israeli companies with trial sites in Europe will not have to be audited, and there will be no repeat of batch document review for final EU QP release. Rachel Griffiths is the Associate Director at Biotec Services International. Rachel joined Biotec Services in 2004, during her time at Biotec Services Rachel has been responsible for Operations and now has responsibility for the Technical Team. Part of her role involves overseeing supply routes and innovations in the supply chain for Biotec Services controlled temperature storage and distribution world wide. With a degree in Microbiology and Virology, Rachel has previous experience as a development scientist, a technical support scientist and a product support specialist. Email: Journal for Clinical Studies 53

Special Features

How Changes in Practice are Changing Bleeding Endpoints in Coronary Interventional Trials Cardiac catheterisation and coronary intervention require placing catheters into arteries and this engenders risk. The first coronary arteriogram was performed in 19581, using a brachial artery approach. Arterial access by the brachial approach often required cut downs and surgical repair of the artery. Because early catheters were large, 8 French (2.7mm) or greater, these complications could be devastating, with loss of hand or arm due to acute occlusion of the brachial artery, or injury to the brachial plexus. By the 1980s, as cardiac catheterisation became a routine procedure, the vast majority were being performed accessing the vascular system through the femoral artery. While the femoral approach suffers from similar complications to the brachial approach, femoral complications occur much less frequently. But compared with the brachial approach, two drawbacks of the femoral approach are the even greater bleeding risk, and the necessity of prolonged bed rest to allow hemostasis following removal of the catheters. These complications were at times prohibitive. The original TIMI Group studies (Thrombolysis In acute Myocardial Infarction), were performed in the early 1980s. Bleeding and transfusion rates were 33% and 22% respectively2. These studies involved administration of thrombolytics followed by cardiac catheterisation. To mitigate bleeding and vascular complications, device manufacturers reduced the outer diameters of catheters to 6 and even 5 French (2mm and 1.7mm respectively). The use of smaller catheters with the femoral approach reduced the frequency of both occlusive and bleeding complications but did not eliminate them. And bed rest post-procedure was still necessary, although not as prolonged. But the smaller catheters allowed interventionalists to consider the use of smaller arteries as access sites. In 1989, Campeau reported his experience using a trans-radial approach for vascular access with 5 and 6 French catheters3. In 1997, Kiemeneij et al. reported a randomised comparison of the femoral, brachial, and radial approaches4. These investigators found all three approaches to be largely equivalent in expert hands, but that in contrast to the femoral and brachial approaches, the radial approach had no major vascular complications. The advantages of the radial approach were clear: ambulation times were nil, which patients preferred, and access site complications, particularly bleeding complications, were drastically reduced. Adoption of the radial approach in the US was slow. To reduce complications of the femoral approach, other technologies were developed. Vascular ultrasound was employed to locate the femoral artery (often hidden deep within layers of fat) prior to attempting percutaneous access. A variety of percutaneously delivered arterial closure devices were developed which improved hemostasis and allowed earlier ambulation following catheter removal. Although early devices had significant complications, more recently evolved devices seem to further reduce bleeding and vascular complications when compared with manual compression, the prior standard5.

In 2005, Yang et al. reported that excessive bleeding in patients undergoing cardiac catheterisation and PCI for treatment of an acute myocardial infarction is highly correlated with death6. As a result, US operators and their institutions began migrating to the transradial approach. By 2012 the proportion of procedures performed using the trans-radial approach in the US exceeded 16% overall, and was even higher (24%) in the northeastern US7. Review by these authors of the NCDR CathPCI registry (a comprehensive registry of >90% of all PCI performed in the US) found that of 2,820,874 patients undergoing cardiac catheterisation with PCI, the risk of major bleeding complicationsi was 2.67% for radial access patients versus 6.08% for femoral access patients (P<0.01). Essentially all of the difference in bleeding rate is associated with the access site. Major vascular complications were also reduced (0.16% versus 0.45%, P<0.01). While somewhat ahead of wider clinical practice, the access site of choice for clinical trials, until recently, has also been the femoral artery. In a pooled analysis of the ACUITY, REPLACE-2, and HORIZONS-AMI trials (trials performed in the early and mid 2000s)8, only 7.1% of patients had the procedure performed trans-radially. With the overall TIMI major/minor bleeding rate of 5.3%, only 2.0% of all patients experienced an access site-related bleed, and 3.3% experienced non-access site-related bleeds. Forty-five per cent of all non-access site bleeding (absolute number of 1.5% of all patients studied) could not be further localised. It was detected only by a drop in hematocrit. At least some unlocalised bleeding is due to the procedure itself â&#x20AC;&#x201C; catheter exchanges, removal of fluid to purge air bubbles from the system, etc. This blood loss is unavoidable but with scrupulous technique, can be minimised. Localised, non-access site-related bleeding occurred in 1.6% of all patients. Gastric ulceration due to stress, and traumatic urinary catheter placements, are just two of many potential factors which contribute to this bleeding. Careful management of antithrombotic therapy is most likely to uniformly reduce both localised and nonbleeding, perhaps by as much as 40%8. Reduction in bleeding regardless of location or cause has considerable clinical importance. Verheugt et al. characterised the prognosis associated with the three different types of bleeding: access site-related, localised non-access site-related, and non-access site-related unlocalised bleeding. Access site complications tend to have a somewhat more benign prognosis (hazard ratio for one-year mortality of 1.82 compared with no bleeding) than does bleeding which occurs at other sites. Bleeding at localised, non-access-related sites (predominantly gastrointestinal, genitourinary, and head and neck, and occurring in 1.6% of all patients) carries a hazard ratio of 3.17. Unlocalised non-access site bleeding carries with it the greatest one-year mortality, with a hazard ratio of 4.728. What is important in these numbers is just how infrequently major and minor bleeding now occurs. Based on Freedmanâ&#x20AC;&#x2122;s data, if all

54 Journal for Clinical Studies

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Assumes a 50% reduction in events, two-sided alpha of 0.05 and three-day observation period interventions in the combined ACUITY/REPLACE-2/HORIZONS-AMI studies were performed radially, access site bleeding would be reduced to 1%. It is now reasonable to consider that bleeding rates in clinical practice and in clinical trials will become vanishingly small, certainly relatively so when compared with the 1980s. Thus, demonstrating the superiority of any single intervention (pharmaceutical or device), will become more challenging. Thus assuming a baseline bleeding rate of 1%, to demonstrate a 50% improvement would require a sample size of over 12,000 patients. To demonstrate a more realistic improvement, the study would need to be even larger. With the frequency of bleeding complications continuing to decline, accurate estimation of event rates for future trial design becomes even more critical. The SAFE-PCI trial fell victim to this. The trial was designed to assess complication rates in women undergoing percutaneous coronary intervention comparing the femoral vs. the radial approach9. The study was designed as a randomised registry trial, using the Cath-PCI database to collect follow-up data. While there are acknowledged challenges with randomised registry trials10, the design does allow trial execution for a fraction of the cost of a conventionally monitored trial, and has been used successfully11 for

other procedurally-based studies. But even with a very streamlined cost structure, the SAFE-PCI trial was not large enough to answer the question it sought to address, because event rates dropped even from the time that the study was being designed. This study was to randomise 3000 patients based on an estimated event rate of between 6.2 and 12.5%. The study was stopped early due to lower than expected event rates. While the available results were only presented in abstract form, the trends observed did mirror the findings of Feldman et al.7 showing a non-significant 1.2 vs. 2.9% rate of bleeding or vascular complication in radial vs. femoral approaches. Bleeding risk during cardiac catheterisation and percutaneous coronary intervention, particularly for acute myocardial infarction, has been largely mitigated since the first trials were performed in the 1980s. Major bleeding complications are now approaching 1%. Further study directed at further reducing the rate of these complications will require ever larger numbers of subjects. In addition, we did not discuss the progressive decrease in the number of patients actually requiring PCI12. Randomised registries may provide acceptable quality data at a fraction of the cost of a conventional trial, but are still subject to the same enrolment and outcomes accrual risk. Trials for the registration of products designed to further reduce bleeding may require even more novel design enhancements to be feasible.

Journal for Clinical Studies 55

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Definition i. Defined as any of the following occurring within 72 hours after PCI: intracranial hemorrhage, cardiac tamponade, nonbypass surgery-related blood transfusion in patients with a pre-procedure hemoglobin ≥8 g/dL, or an absolute decrease in hemoglobin value of ≥3g/dL in patients with a pre-procedure hemoglobin ≤16 g/dL References 1. D. Monagan, Journey into the Heart, New York: Penguin Books, 2007, pp. 36-37. 2. A. Rao, C. Pratt, A. Berke, A. Jaffe, I. Ockene, T. Schreiber, W. Bell, G. Knatterud, T. Robertson and M. Terrin, “Thrombolysis in myocardial infarction (TIMI) trial-Phase 1: Hemorrhagic manifestations and changes in plasma fibrinogen and fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase.,” J Am Coll Cardiol, vol. 11, pp. 1-11, 1988. 3. L. Campeau, “Percutaneous Radial Artery Approach for Coronary Angiography,” Catheterization and Cardiovascular Diagnosis, vol. 16, pp. 3-7, 1989. 4. F. Kiemeneij, G. Laarman, D. Odekerken, T. Slagboom and R. van der Wieken, “A Randomized Comparison of Percutaneous Transluminal Coronary Angioplasty by the Radial, Brachial and Femoral Approaches: The Access Study,” J American College of Cardiol, vol. 29, no. 6, pp. 1269-1275, 1997. 5. D. Tavris, Y. Wang, S. Jacobs, B. Gallauresi, J. Curtis, J. Messenger, F. Resnick and S. Fitzgerald, “Bleeding and vascular complications at the femoral access site following percutaneous coronary intervention (PCI): an evaluation of hemostasis strategies.,” J Invasive Cardiolol, vol. 24, no. 7, pp. 328-334, 2012. 6. X. Yang, K. Alexander, A. Chen, M. Roe, R. Brindis, S. Rao, B. Gibler, E. Ohman and Peterson, “The Implications of Blood Transfusions for Patients with Non-ST-Segment Elevation Acute coronary syndromes. Results from the CRUSADE National Quality Improvement Initiative,” J. Amer Coll Cardiol, vol. 46, pp. 1490-1495, 2005. 7. D. Feldman, V. Swaminathan, L. Kaltenbach, D. Baklanov, 56 Journal for Clinical Studies

L. Kim, S. Wong, R. Minutello, J. Messenger, I. Moussa, K. Garratt, R. Piana, W. Hillegass, M. Cohen, I. Gilchrist and S. Rao, “Adoption of Radial Access and Comparison of Outcomes to Femoral Access in Percutaneous Coronary Intervention An Updated Report from the National Cardiovascular Data Registry (2007–2012),” Circulation, vol. 127, pp. 2295-2306, 2013. 8. F. Verheugt, S. Steinhubl, M. Hamon, H. Darius, P. Steg, M. Valgimigli, S. Marso, S. Rao, A. Gershlick, A. Lincoff, R. Mehran and G. Stone, “Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention.,” J Am Coll Cardiol Intv, vol. 4, pp. 191-197, 2011. 9. C. Hess, S. Rao, D. Kong, L. Aberle, K. Anstrom, C. Gibson, I. Gilchrist, Jacobs, A. S. Jolly, R. Mehran, J. Messenger, L. Newby, R. Waksman and M. Krucoff, “Embedding a randomized clinical trial into an ongoing registry infrastructure: unique opportunities for efficiency in design of the Study of Access site For Enhancement of Percutaneous Coronary Intervention for Women (SAFE-PCI for Women).,” Am Heart J, vol. 166, no. 3, pp. 421-428, 2013. 10. M. Lauer and R. D’Agostine Sr, “The Randomized Registry Trial-The Next Disruptive Technology in Clinical Research,” New England Journal of Medicine, vol. 369, no. 17, pp. 15791581, 2013. 11. O. Frobert, N. Lagerqvist and G. Olivecrona, “Thrombus Aspiration During ST-Segment elevation Myocardial Infarction,” NEJM, vol. 369, no. 17, pp. 1587-1597, 2013. 12. E. Talbott, J. Rager, L. Brink, S. Benson, R. Bilonick, W. Wu and Y. Han, “Trends in acute myocardial infarction hospitalization rates for US States in the CDC tracking network,” PLoS One, vol. 8, no. 5, p. e64457, 22 May 2013.

L. Allen Kindman MD, FACC is Medical Director, Cardiovascular and Metabolic Therapeutic Delivery Unit, Quintiles. He is also a Clinical Professor of Medicine at the University of North Carolina, Chapel Hill. Until recently, he was an interventional and non-invasive cardiologist. Email:

Joshua Betcher, PhD is a Director of Statistics at Quintiles. Joshua received a doctorate of statistics at the University of Virginia and has focused these past 8 years on the planning, design, and execution of large scale cardiovascular endpoint mega-trials. Email:

Philip Galtry is Vice President and Cardiovascular Therapeutic Strategy Head, Cardiovascular and Metabolic Therapeutic Delivery Unit, Quintiles. Philip holds an Honours degree in Biochemistry from the University of Bristol, UK, and has worked in the management of cardiovascular studies for almost 25 years. Email: Volume 6 Issue 2

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Orphan Drugs: R&D Challenges with Updates from Turkey and Middle East Countries Introduction Rare diseases (RDs) are an important public-health issue and a challenge for the medical community. They are called ‘health orphans’, because RDs have been neglected for many years, mainly due to the research and development (R&D) challenges.1 In the 1960s, amendments were made to existing federal laws in the US, mandating that all drugs must be shown to be safe and effective through ‘adequate and well-controlled studies’ before receiving market approval2. Then raising the cost of drug development resulted in drugs for small disease populations being ‘orphaned’ by many major drug companies. Modern society still has a lack of options for the effective treatment of patients with RDs. As one of the consequences of this, the demand for public health protection has increased the economic burden of patients suffering from RDs3.

defined yet affecting less than 1/100,000 persons in a country.11 In the ME countries Jordan, Lebanon, Egypt and Saudi Arabia, there is no available reference for ‘rarity’ of diseases in official sources. The US FDA defines an “orphan product” as a drug, biologic, device or medical food that is used for the prevention, diagnosis, or treatment of a rare disease. 12 An orphan drug is defined in the 1984 amendments of the ODA as a drug intended to treat a condition affecting fewer than 200,000 persons in the US, or which will not be profitable within seven years following approval by the FDA.13 In Turkey, an orphan drug is stated as any drug that is used in these RDs.11 Generally speaking, an orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease.14

The interest of the pharmaceutical industry in developing OMPs is fairly low due to the challenges specific to orphan drugs. Also, big pharma is paying increased attention to the orphan drug market in this decade4. However, there are major challenges in accessing these markets with reliable and comprehensive clinical data that needs to be obtained from well-defined clinical trials. This article aims to present a review of the social and scientific need for the R&D of OMPs, discuss the management of the challenges, and propose the considerations to make the future better for meeting the medical needs in this area, with status updates from Turkey and the Middle East (ME), in an environment of rising improvement of the healthcare priority in this region.

Rare Diseases May Not Be so ‘Rare’! Although we name these disorders orphan or rare diseases based on the prevalence data, the numbers giving details on these suggest that these might be more common rather than rare. For example, there are 5000-8000 RDs known so far. There are approximately 30 million Americans and 30-40 million Europeans affected by these diseases.15 It has been reported that there are 250 new rare cases explored each year; however the acceptable treatment is available only for 200-300 orphan diseases.15 In Turkey, as there is not enough available detailed epidemiological data about individuals having orphan diseases so far, it has been estimated that approximately 5 million people have at least one RD.16

Definition of Rare Disease and Orphan Drug/Medicinal Product (OMP) There is no single orphan disease definition that is accepted all over the world, as it is outlined by the legislations adopted by each region or country. Overall, orphan diseases are often chronic, progressive, disabling, even life-threatening, and most of these have no effective or curative treatment, having low prevalence and high complexity.5 In the US, the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically “any disease or condition that affects less than 200,000 persons in the United States (US)6 or about 1 in 1500 people.7 This definition is essentially like that of the Orphan Drug Act (ODA) of 1983, a federal law that was written to encourage research into RDs and possible cures8. In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about 1 in 2500 people.9 However, the European Commission (EC) defines RDs as “life-threatening or chronically debilitating diseases which are of such low prevalence” that special combined efforts are needed to address them.10 The term low prevalence is later defined as generally meaning fewer than 1 in 2000 people. The definitions ranging from 1/1000 to 1/200,000 used in the medical literature and by national health plans are similarly divided. Looking at Turkey, an RD is defined in the Ministry of Health (MOH) Pricing Statement as a disease that has not been fully 58 Journal for Clinical Studies

It is known that the 80% of the RDs are of genetic origin, and the rest have environmental, bacterial, viral, or unknown origin. 15, 17 A number of medical disciplines with a lot of healthcare professionals are involved in the rare disease concept from diagnosis to treatment. Besides, the pharmaceutical industry has the responsibility to develop new and effective molecules to treat these diseases better in spite of the challenges of the medicinal product in this ‘niche’ area. More importantly, there are millions of patients and even more family members suffering from RDs trying to get fast diagnosis and effective treatment. Research and Development Challenges of the Medicines to cure Rare Diseases The challenges specific to OMPs, where pharmaceutical and biotech companies focus on OMP research and development, are discussed below: 1 Regulatory Framework and Scientific Approaches There is a certain need for stimulus for the OMP R&D for pharmaceutical and biotech companies.18, 19 For this purpose, several countries have implemented legislations to promote the development of medicinal products for RDs. In Table 1, the comparison of the various policies on orphan drugs worldwide is shown. Volume 6 Issue 2

Special Features In the US and EU: The successful implementation of the ODA has inspired the implementation of orphan drug legislation in other countries to address the unmet medical needs of patients suffering from RDs, hence the legislation in Singapore (1991), Japan (1993), Australia (1998), and in the European Union (EU) (2000).4 The EU Reg. (EC) No 141/2000 defines that medicines intended for the treatment, prevention or diagnosis of RDs (i.e. those conditions affecting less than 5/10,000 individuals in the EU) can be designated as orphan drugs (ODs). The EC has, on Rare Disease Day 2013, announced €144 million of new funding for 26 research projects on RDs. The projects will help improve the lives of some of the 30 million Europeans suffering from a rare disease. The goal is to pool resources and work beyond borders, to get a better understanding of RDs and find adequate treatments.20

products manufacturing is supported by governmental grants in a way specified in the relevant directive.24 This is an open channel for the orphan drug R&D steps to get the governmental driving force to enable the orphan drugs R&D processes in Turkey. Patient access to the orphan drugs, if not licensed yet, is possible in certain ways in Turkey. One of these is the ‘off-label use’ which is defined in guidelines available on the Turkish MOH official web page. This process is a patient-specific application which is initiated by the primary physician of the particular patient. The other way for rare disease patients to get access to the orphan drugs is the compassionate use programme, a very well-defined process by Turkish MOH, which is a patient-based humanitarian programme enabling the patient free of charge

In Turkey: Today, the Turkish MOH has been working on recognising a national plan with reference to “rare diseases” and “orphan drugs”. Health services are provided by the MOH (state universities, universities, private hospitals and organisations) to all citizens, mainly free of charge. Currently the work in the Turkish MOH is ongoing to outline the legal infrastructure for certain incentives and providing the guidance documents.21 Encouraging the growth of the domestic pharmaceutical industry and attracting foreign investment are good options for Turkey and the ME. In this context, from 1990 onwards Scientific and Biotechnological Research Parks have been established in Turkey; 32 of these are actively operating to achieve the purpose of providing a common research environment for universities, research institutes and industry, to enable information and technology exchange.22

Figure 1 Figure 2: Turkish Regulatory Authority Orphan Drug Trials Applications in 2012 by Therapeudic Areas Oncology-Hematology Genetic Disorders Eye Disorders Others

12 4 2 5

The Scientific and Technological Research Council of Turkey is one of the partner institutions in the E-RARE Project (ERA-Net for Research Programs on Rare Diseases) that is supported by the EC. The purpose of the project is to provide coordination of the national supporting institutions, to develop common support mechanisms in rare disease research, and to enable sustainable and long-term collaboration amongst partner countries. Being a member of this partnership, Turkey will be contributing to the global research and development of the rare disease treatment options and will extend awareness in the country.23 Turkey is planning to establish national networks for the prevention, surveillance, diagnosis and treatment of RDs. One promising example from Turkey is the first National Database Project for Pompe Disease, initiated under the coordination of industry, the Turkish Neurology Association Neuromuscular Diseases Scientific Working Group. With the 1st Pompe Disease database and follow-up study, it is planned to have 45 centres in Turkey, with the purpose of determining the prevalence, gender distribution and country-specific mutation types. At the MOH level, the high priority sustainable investment in the projects of biotechnological drugs, oncology drugs and blood

Figure 2

access to the unlicensed drug. The compassionate use programme covers the patients who are suffering from diseases that were not successfully cured by the existing licensed medications, and have no possibility of entering a clinical trial to have access to a medicinal product which the patient requires which has not been licensed in Turkey. The compassionate use programme application is made to the Ministry of Health per patient by the physician who confirms the diagnosis and maintains responsibility for patient Journal for Clinical Studies 59

Special Features care. 25 Clinical trials are also very important for patient access to unlicensed orphan drugs. According to recent data from the Turkish Medicines and Medical Devices Agency in MOH, there were 162 clinical trial applications in 2012, and 24 of these trials (14.8%) are stated as being in orphan drug research and/or the disease is stated as a rare disease. The therapeutic areas and the therapeutic indication of these trials are shown in Figures 1 and 2.26 In Some ME Countries: At the moment, there is no legal framework specifically describing RDs and orphan drug research and development in ME countries such as Lebanon, Jordan, Egypt and Saudi Arabia. In one of the ME countries, the United Arab Emirates, in Dubai, a Biotechnology and Research Park (DuBiotech) has been established and has been providing the environment for life sciences companies to set up organisations in ME and to collaborate in productive partnerships, potentially with local companies.27 2 Insufficient Cooperation between Stakeholders Centralising Patients The natural stakeholders in RD management include, but are not limited to, regulatory authorities, patient advocacy groups, academic environment, public organisations, consortiums, and governmental or private funding institutions. The organisations centralising patients suffering from RDs are considered of major importance. We will discuss two of the important ones here; Orphanet and EURORDIS. Orphanet is a database of RDs which was established in 1997 in France and has been supported by the EU Commission. The printed directory is sent to these experts, to all relevant hospital departments (public and private), healthcare authorities, and patient support groups. The directory is also available online.28 The aims of this study were (i) to determine how the directory is used to refer patients and send specimens, and (ii) to investigate its impact on patient referral. The Orphanet directory is used to refer patients and specimens, especially by experts and patient organisations.29 Turkey has been one of the Orphanet partner countries from 2007 onwards, with the academic support of Istanbul University. Turkey is joining the cooperation and collaboration activities in the organisation, aiming to increase awareness of RDs in Turkey, and to provide standardised, quality data to the Orphanet database. Turkey constitutes a unique place here, because none of the Middle East and North African (MENA) countries are involved in this collaboration, yet. Turkey is currently in the process of establishing national networks for the prevention, surveillance, diagnosis and treatment of RDs with the cooperation of the MOH, healthcare professionals, academia, patient advocacy groups, and industry. Patient registries contribute to the accelerated research and development for rare disease data, because concentrated and standardised data can be achieved from the well-managed patient registries.30 According to the Orphanet Jan 2013 Report, there are 588 disease registry studies being conducted in total in the world. Figure 3 shows the distributions of registries by country. There are four registry studies on RDs in Turkey which are seen in Table 2. There is no MENA country listed in the participant country list of 60 Journal for Clinical Studies

Figure 3 Figure 3: Turkish Regulatory Authority Orphan Drug Trials Applications in 2012 by Rare Disease Indications Hemophilia-A Multiple Myeloma Duchene's Muscular Dystrophia Uveitis Morquino-A Sydrome Idiopathic Pulmonary Fibrosis Ischemic Ulcer Secondary to Systemic Sclerosis Cushing Syndrome Factor-X Deficiency Perinatal Asphyxy Thalassemia Lysosomal Acid Lipase Deficiency Fabry Disease

6 3 2 2 1 1 1 1 1 1 1 1 1

the registries. It can be concluded from this that the RDs having respective high prevalence in this region are neglected. Local or national-level studies may be up and running in the region, but the data from these are not incorporated with the global data, and they are not serving a global dataset for researchers. EURORDIS is a patient-driven alliance of patient organisations representing 561 rare disease patient organisations in 51 countries. EURORDIS promotes information services adapted to the situations and special needs of people living with RDs31. Currently there is only one member from Turkey, the Turkish Mucoplysaccharidosis and Similar Lysosomal Storage Disorders Association (from 2009 onwards), in the member associations list in EURORDIS. Considering the fact that the very valuable information exchange and contributing to or shaping up the policies of healthcare and rare disease research within EURORDIS provides remarkable improvements, it would be reasonable to expect to have more patient advocacy groups in EURORDIS from Turkey. Currently, there is no membership from MENA countries here. Although this is a European organisation, as rare disorders have no borders it is necessary for some MENA patient associations to be members of this organisation. In this way the overall purpose of â&#x20AC;&#x2DC;adopting the scattered patients of RDsâ&#x20AC;&#x2122; is achieved by providing them with adequate, up-to-date scientific, social and medical information all over the world. In ME countries, however, there are some initiatives aiming to increase the public awareness for the RDs and to attract the attention of healthcare professionals. In Bahrain, for the first time, Al Jawhara Center for Molecular Medicine and Genetic Disorders/Arabian Gulf University, in collaboration with the MOH, celebrated Rare Disease Day in Manama on 28th of February 2013. The event included a scientific Volume 6 Issue 2

Special Features symposium at Al Jawhara Center on the 26th of February and a public awareness campaign day on the 28th of February. In Cyprus (Southern), the Cyprus Alliance for Rare Disorders, founded in 2010, has taken significant steps towards a proposal for a national strategy for RDs. This was accepted by the Ministerial Council in 2012, and the newly established National Committee on Rare Diseases has been working towards the creation of the rare disease management strategy. The Rare Disease Foundation of Iran is a four-year-old private institution that provides services for rare disease patients in Iran. Its aim is improving the life quality of rare disease patients and increasing public awareness about the burden of RDs on patients, their families and the community. It collaborates with the medical system and research centres to provide an information bank of rare disease patients, and to disseminate information about RDs to inform all health professionals and educate patients, their families and the general public. The Lebanese Association for Neuromuscular Diseases is a unique association of voluntary parents’ and professionals’ support groups that will spread awareness and help patients and families affected by neuromuscular diseases. LAND is committed to the identification, treatment, and cure of rare disorders through programmes of education, advocacy, research, development, and outreach. The Palestinian Starfish Orphaned Charity for Rare Disorders started in 2013, offering all individuals and their organisations activities and events that help in continuing the progress on rare disorders in Palestine. Some are fundraising projects that can be held in local communities; some will raise public awareness and support for rare disorders; some will educate and engage healthcare professionals, school students, families and patients; and all will help to provide opportunities for understanding and supporting rare disorders.32

replacement or gene therapies. This will contribute to scientifically and ethically well-designed clinical protocols that will eventually lead to reliable and standard clinical data from trials. 4 Low Prevalence As RDs are seen in a limited number of persons in the population due to its low prevalence, it is quite difficult to calculate the adequate sample size, in other words enrolment figures, to be included in the clinical trials. Moreover, patients are dispersed across the world as seen in the cases of Spinal Muscular Atrophy (SMA) and Duchenne Muscular Dystrophy (DMD). This also makes it difficult to organise a clinical trial. The prevalence data for RDs is of crucial importance for companies having orphan drug research and development in their pipeline while planning clinical trials. Epidemiology studies focusing on RDs have been helping companies to make decisions on the location and the number of human subjects for clinical studies of drug development. Population characteristics are important for the determination of rare disease prevalence. The population of Turkey and other parts of the ME region is characterised by large family size, older maternal and paternal age, and high rate of consanguineous marriages.35 Consanguineous marriages are one of the major risk factors in rare disease incidence, and carriage constitutes an attention point for researchers. The global distribution of consanguineous marriages data are summarised in Figure 4.36

3 Still Secret Natural Histories of Rare Diseases The natural histories of most RDs are not fully known, as seen in mucopolysaccharidosis type I, II, III and some other lysosomal disorders.33 Mucopolysaccharidosis type III is a family of autosomal recessive lysosomal storage disorders. MPS IIIB (Sanfilippo B Syndrome) is similar to other LSDs with an accumulation of substrate in a number of tissues and cell types, which results in cell and tissue dysfunction.34 As seen in most LSDs, a considerable variability has been observed in the clinical course of Sanfilippo B Syndrome. Children with the classical and more severe form of Sanfilippo B Syndrome often have normal or near normal development, and initially present with a slowing of development and behavioural problems beginning around two years of age. This is followed by progressive intellectual decline and loss of morbidity.33 There is no currently approved therapy for the treatment of Sanfilippo B Syndrome; additionally, the options for clinical symptoms management are limited due to the diversity of the phenotypes of the disease. As is the case for more RDs, the natural history of the disease needs to be clarified, including the clinical, biochemical, genetic, molecular characteristics and the course of disease progression for all phenotypes remains to be investigated to define the most adequate treatment options, such as enzyme

Figure 4

There are differences between regions in means of consanguineous marriages in the world: the lowest rates of consanguinity are found in Western Europe, North America and Oceania, where less than 1% of marriages are consanguineous (i.e. unions between couples related as second cousins or closer (F ≥ 0.0156)). In some parts of Southern Europe, South America and Japan, ∼1–5% of marriages are consanguineous, depending on local geography and social customs.37 The highest rates of consanguineous marriage have been observed in North Africa, the ME and much of Central and South Asia, where more than 25% of the world’s population lives, and unions between couples related as second cousins or closer can account for 50% of all marriages.38

Journal for Clinical Studies 61

Special Features Increased prevalence of α- and ß-thalassemia, rare complex haemoglobinopathies and other hematological disorders (including coagulation deficiencies and acute lymphocytic leukemia in childhood) have been reported for consanguineous offspring in different countries. A wide range of inborn errors of metabolism have been reported in indigenous and migrant populations, including lysosomal storage disorders and cerebral lipidoses.39 The consanguineous marriage rate in Turkey is reported as 17% in Ankara, Istanbul and Izmir. According to the evaluation of the regions in Turkey, this rate is lowest in the Western region (12.8%) and the highest in the Southeastern region (35%).40 Disease carriage is also important for RDs. Some of the RD carrier rates in MENA are shown in Table 3.41 This is especially crucial for the hemoglobinopathies. Thalassemia, an autosomal recessive hemoglobinopathy, is one of the commonest genetically transmitted disorders throughout the world. Collective measures including carrier identification, genetic counselling and prenatal diagnosis are required for preventing thalassemia.42

factor is scientific knowledge on RDs being scarce overall due to the rarity and complexity. ‘Rare doctors’ have adequate knowhow to diagnose ‘rare diseases’. Turkey has a unique place in this area, having very wellequipped medical faculties, accredited hospital laboratories, and medical genetics research centres. There are striking examples, such as Hacettepe, Ankara, Istanbul, and Ege University Medical Faculty Hospitals departments of hematology, pediatric medicine, oncology, etc. The most recent perinatal and pre-natal diagnostic techniques have been used in these clinics to obtain diagnoses in a very early phase. Genetic tests also help ‘rare doctors’ to diagnose the case correctly, thus avoiding delays in curing RDs. The other reason for diagnosis difficulties is the lack of a universally accepted special coding system for RDs. Although Orphanet has been presenting a classification on RDs45 this is only available for reference to Orphanet members. OMIM (Online Mendelian Inheritance in Man)46, and ICD-10 – the 10th

As recently reported by the Turkish Regulatory Authority, the majority of orphan drug and/or rare disease clinical trial applications are in the Hemophilia-A disease indication (six trials). This is followed by Multiple Myeloma (three trials), Duchenne Muscular Dystrophy (two trials), Uveitis (two trials), Morquio-A Syndrome, Idiopathic Pulmonary Fibrosis, Ischemic Ulcer secondary to Systemic Sclerosis, Cushing Syndrome, Factor X Deficiency, Perinatal Asphyxia, Thalassemia, Lysosomal Acid Lipase Deficiency, Fabry Disease (Figure 2).26 Genetic disorders such as hemoglobinopathy, glucose-6phosphat dehydrogenase deficiency, autosomal recessive syndromes, and several metabolic disorders have a presence throughout the Middle East.34 Other rare diseases resulting from viral or bacterial infections and allergies, or autoimmune reasons such as Behcet’s disease, Lichens Planus Pigmentosus, and Pemphigus are all seen more in the Middle East region than the rest of the world.43 Having these data in mind, the sponsor companies need to plan the locations of the potential clinical sites for the targeted clinical studies for OMPs in their pipeline. 5 Difficulties in Diagnosis of Rare Diseases The disease itself is complex and hard to diagnose, thus enrolment in a well-defined clinical trial protocol is very difficult; 30% of the patients receive the appropriate diagnosis in 3-5 years. More dramatically, 15% of the patients receive a diagnosis in 7 or more years, and some of them remain misdiagnosed or undiagnosed in their lifetime.1, 44 In a survey of eight rare diseases (Crohn’s Disease, Cyctic fibrosis, Duchenne Muscular Dystrophy, Ehlers-Danlos Syndrome, Marfan’s Syndrome, Tuberous Sclerosis, fragile x syndrome), it was shown that 40% of patients are misdiagnosed, and others had no diagnosis. This study suggested that appropriate information and medical expertise on RDs are often insufficient, and access to care is difficult. As a consequence, the risk for medical complications and late sequel is increased.44 Difficulties in diagnosis partly result from the sub-type of the diseases that have a mechanism that is not fully known. Another 62 Journal for Clinical Studies

Figure 5

International Classification of Diseases established by WHO – are other systems for coding.47 The absence of a universally recognised coding system is an obstacle for reliable registration of patients in national or international databases.47 Conclusive Remarks: Rare disease research requires a broad range of disease-related information for the discovery of causes of disorders. The rarity of cases makes it difficult for researchers and companies involved in R&D of orphan drugs to elucidate definite inception. Taking patients and their advocacy groups centrally, the industry and healthcare professionals need to collaborate to define the unmet medical needs and to develop innovative treatment alternatives, specifically orphan drugs, for these. Inevitably, initiatives, incentives and an established legal framework by the rule-makers, the regulatory authorities, is required to achieve the goal of defining RDs and adequate data being obtained from welldesigned clinical trials. Social and official media can also support public awareness of RDs and contribute to patients’ accessibility to the correct and most current treatment options. The national and transnational collaboration between the stakeholders may help to support the orphan disease research projects, funding them and providing them with reliable communication media. This would contribute to obtaining more correct prevalence and epidemiological data, helping healthcare professionals communicate more intensely, and increasing knowledge of the diseases and the diagnosis/treatment methods. Turkey is also the only example in the region of the participation Volume 6 Issue 2

Special Features of international organisations such as Orphanet and ERORDIS. Taking the recent initiatives of healthcare professionals and patient advocacy groups in ME countries, the interest of the rule-makers, and the forming phase of the fully established legal framework outlining RD and orphan drug development into consideration, we can conclude that community awareness of RDs and R&D need in this region is growing.

Cooperation and collaboration between all stakeholders in rare disease and orphan drug R&D needs to be improved nationally and transnationally to achieve the ultimate global goal of providing adequate care for patients suffering from RDs, and promoting orphan drugs R&D. Turkey and ME countries are of central importance, having certain rare patient pools seeking treatment options and having communities ready to proceed, taking steps forward to participate in developing new treatment options.

References: 1. Schieppati A. et al. Why Rare Diseases are an important medical and social issue, Essay Focus, Lancet 371:2039-41, 2008 2. Halffner, M.E. et al. Two decades of orphan product development. Nat Rev Drug Discov 2002: 1: 821-5 3. Halffner, M.E. et al. Adopting Orphan drugs: two dozen years of treating rare cases. N Engl J Med 2006; 354: 445-7 4. Kessel M. The problems with today’s pharmaceutical business—an outsider’s viewNature Biotechnology 29(1) 2011 5. Wastfelt et al. A journey of hope: lessons learned from studies on rare diseases and orphan drugs. J Internal Med 2006: 1-10 6. US Rare Disease Act (ODA), 2002 7. ucm239698.htm (Accessed 25 Mar 2013) 8. Orphan Drug Act (US) 1983. 9. Rare Diseases What we are talking about? (Accessed 25 Mar 2013) 10. (Accessed 20 Mar 2013) 11. Turkish MOH Pricing Statement, Official Gazette dated 22.09.2007 with number 26651 12. ucm239698.htm (Accessed 20 Mar 2013) 13. FDA/CDER Small Business Chronicles Jul 13, 2012. 14., (Accessed 25 Mar 2013) 15. Stakisaitis D. et al. Access to information supporting availability of medicines for patients suffering from rare diseases looking for possible treatments: the EuOrphan Service. Medicina (Kaunas) 2007; 43(6) 16. Dundar M. et al. Turkiye’de Nadir hastaliklar ve yetim ilaclar: Medikal ve sosyal problemler, Erciyes Medical Journal 2010; 32(3): 195-200 17. Fatma Atalar et al. Orphanet and Orphanet Orphanet Turkey Presentation 2011 18. Sharma A. Orphan Drug: Development, trends and Strategies. J Pram Bioallied Sci. 2010 2(4): 290-299 19. Nistico G. Orphan Drugs Assessment in the Centralized Procedure. Ann Ist Super Sanità 2011 | Vol. 47, No. 1: 98-99 20. EUROPEAN COMMISSION PRESS RELEASE Brussels, 28 February 2013 21. Ozbek U. Presentation in Fourth Eastern European Conference for Rare Diseases and Orphan Drugs “Together for Integrative Approach to Rare Diseases” 13-14 June 2009 Plovdiv, Bulgaria 22. Teknoloji Gelistirme Bolgeleri Dernegi ( (Accessed 15 Mar 2013) 23., (Accessed 21 Mar 2013) 24. Y%C3%B6nergesi_2012_12_19_b45aa8c.pdf 25. Turkish Ministry of Health Compassionate Use Guideline (1 Jan 2009) 26. Yegin E., Ciba M., Hicdurmaz E., Ilbars H. Orphan Drug Clinical Trials Applications to Turkish Medicines and Medical Devices Agency in 2012, Poster Presentation in 1st National Clinical Trials Congress, 3-4 May 2013, Istanbul, Congress Booklet Page 91 27. DuBiotech ( 28. (Accessed 15 Mar 2013) 29. Nabarette H. Use of a directory of specialized services and guidance in the healthcare system: the example of the Orphanet database for rare diseases. Rev Epidemiol Sante Publique. 2006 Feb;54(1):41-53 30. Hollak C.E.M. Limitations of drug registries to evaluate OMPs for the treatment of lysosomal storage disorders. Orphanet J Rare Dis 2011, 6:16 31. (Accessed 20 Mar 2013) 32. (Accessed 17 Mar 2013) 33. Valstar M.J. et al. Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. J Inherit. Metab. Dis 2010; 33:759-767 34. Ohmi K. et al. Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci. 2003; 100(4): 1902-1907 35. Al Gazali L., et al. Genetic disorders in the Arab world Brit Med J 2006; 333: 831-34 36. (Accessed 20 Mar 2013) 37. Saggar K.A. et al. Consanguinity and child health, Pediatrics and Child Health 18:5, 2008 38. Zlotogora J., Hujerat Y., Barges S., Shalev S.A., Chakravarti A. The fate of 12 recessive mutations in a single village. Ann Hum Genet 2007 71: 202–8 39. Bittles A.H. Consanguineous marriage and childhood health. Dev Med Child Neurol 2003; 45: 571–6 40. Turkiye Aile Sagligi Planlama Vakfi, Gorunum Dergisi Ocak 2011, sayfa 2 41. (Accessed 18 Mar 2013) 42. Ansari S.H. et al. Molecular epidemiology of β-thalassemia in Pakistan: Far reaching implications. Indian J Hum Genet. 2012 May-Aug; 18(2): 193–197 43. Almalki Z.S. et al. Access to orphan drugs in the Middle East: Challenge and perspective 2012: 1(4):139-143) 44. EurordisCare2: Survey of Diagnostic delays, (Accessed Jul 2006) 45. Orphanet Classification of Orphan Diseases- March 2013 ( cgi-bin/inc/ 46. (Accessed 20 Mar 2013) 47. (Accessed 18 Mar 2013) 48. Song P. et al. Intractable and Rare Diseases Research in Asia. Biosci Trends, 2012; 6(2):4851

Hilal İLBARS, Pharm. PhD was born in Ankara in 1970. Having completed her primary, secondary and high school education at TED Ankara College, she received her bachelor’s degree in pharmacy as well as her master’s degree in pharmaceutical toxicology from the Pharmacy of Gazi University in Ankara, Turkey. Currently, she has a PhD degree in pharmacy business administration discipline of the Pharmacy Faculty of Ankara University, Turkey. She worked in the Eğirdir Osteopathic Hospital under the Turkish Ministry of Health for one year. She has been working in the General Directorate of Drug and Pharmacy of Turkish Ministry of Health for nineteen years in various departments by order of cosmetics, licensing, pharmacovigilance and clinical trials. Currently, she has been working as a Director of Clinical Drug Trials Department in Turkish Medicinal and Medical Devices Agency. She has been involved in various national and international meetings as speaker, also contributing to publications in regards to the Pharma industry. She is the author of the book ‘Clinical Trials Dictionary’ published in 2013. Dr Ilbars is one of the founders of Clinical Research Association in Turkey. Email:

Duygu Kuyuncu Irmak, was graduated from the Uludag University Veterinary Medicine Faculty in 1990. She joined to Osmangazi University Medical Faculty in the same year and completed her MSc and PhD degrees at the Department of Histology and Embryology in 2000, while she has been working as research associate at the same time. She completed two thesis studies in reproductive medicine, and participated in multidisciplinary research studies during the academic experience. Dr Irmak was involved in various national and international scientific meetings as presenter of the studies and speaker. Dr Irmak joined the clinical research industry in 2003 and worked as Clinical Research Associate. She has been working as Clinical Operations Manager for more than 5 year as of now, and currently leading the MEK Consulting, a CRO operating in Turkey, Greece, Middle East and North Africa Region. Dr Irmak is an advisory board member of the Scientific and Technological Research Council of Turkey in ‘New Medicine R&D Program’ from July 2013 onwards. Email: Dr. Hamdi Akan is working as a Professor in the Hematology Department of Ankara University School of Medicine. He is an active member of EORTC and EBMT. He is a member of various national and international societies including, European Hematology Association (EHA), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), International Bone Marrow Transplantation Registry (IBMTR), Immunocompromised Host Society (IHS) and involved in multiple national and international clinical trials as an investigator or coordinator. He is currently the head and webmaster of Febrile Neutropenia Assocoation and Turkish Clinical Research Association (, and He is also the Editor of Clinical Trials Text Book and Turkish GCP Journal. Dr. Akan is the first ACRP certified clinical trial investigator in Turkey. He is one of the founders of Clinical Research Association and Akademika GCP Education Program in Turkey. He is the national representative of Educational Affairs of Turkish Society of Hematology in EHA. He has more than 60 manuscripts indexed in Index Medicus and SCI. Email:

Journal for Clinical Studies 63

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