JCS - Volume 7 - Issue 2

Volume 7 Issue 2I Journal for Clinical Studies

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Phase1 Clinical Trials In an Era of Increasing Oncologic Success

CSF Biomarkers of Disease Modification In Alzheimer’s Disease

Logistical Challenges in Orphan DrugTrialsAdopting a patient-centric,investigator-supportive approach

Community-Acquired Bacterial Pneumonia A Challenging Diagnosis in Clinical Trials

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Volume 7 - Issue 2

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Contents

06 FOREWORD

WATCH PAGES

08 FDA Recommends Testing Drugs for Impacts on Driving Ability

New US Food and Drug Administration (FDA) draft guidance addresses when and how to evaluate drugs for the potential to impair driving ability, an issue that arises during agency reviews of approved and investigational products. Megan Auderset, writer and editor from Thomson Reuters shares her thoughts on the FDA`s recommendations on drug testing.

10 CSF Biomarkers of Disease Modification in Alzheimer’s Disease

The three major brain hallmarks of Alzheimer’s disease (AD) are extracellular amyloid plaques, axonal degeneration and intraneuronal neurofibrillary tangles, which can all be monitored via changes in the cerebrospinal fluid (CSF) biomarkers amyloid beta 42 (Aβ42), total-tau (T-tau), and phosphorylated-tau (P-tau). Within this article we have an insight into the world of in Alzheimer’s Disease`s by Henry J. Riordan, from Worldwide Clinical Trials, and Neal R. Cutler of Worldwide Clinical Trials.

MANAGING DIRECTOR Martin Wright

PUBLISHERMark A. Barker

EDITOR Orsolya Balogh

EDITORIAL ASSISTANTEvelyn Rogers

DESIGNER Fiona Cleland

RESEARCH & CIRCULATION MANAGEROlga Henschke

BUSINESS DEVELOPMENTRichard Goodard

ADMINISTRATOR Barbara Lasco

FRONT COVER © istockphoto

PUBLISHED BY Pharma PublicationsUnit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DGTel: +44 0207 237 2036Fax: +0014802475316Email: [email protected]

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 7 Issue 2 April 2015PHARMA PUBLICATIONS

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Volume 7 Issue 22 Journal for Clinical Studies

Contents

12 Phase 1 Clinical Trials in an Era of Increasing Oncologic Success

Between 2010 and 2014, 37 new molecular entities were approved by the FDA for the treatment of cancer; and between 1995 and 1999, only 20 such agents were approved. Michael Kurman, MD, from INC Research shares his thoughts on Phase 1 Clinical Trials in an Era of Increasing Oncologic Success.

14 Scandinavia / Nordic: Are they just ice and snow? Denmark leads the way in clinical trials with more than 4,700 so far. Sweden has run over 3,200 trials. These numbers reflect the progressive biotech industry in the two countries, where there are over 250 companies clustered in Medicon Valley (comprising the eastern part of Denmark and southwestern part of Sweden). Sue Lee from World Courier analyses the Scandinavian /Nordic areas and the challenges faced.

16 Understanding Stroke from the Perspective of the Large Arteries

Stroke, as it has recently been redefined, is any objective evidence of permanent brain, spinal, or retinal cell death due to a vascular cause. In general, strokes are a result of either reduced blood flow caused by a thrombus or embolus or from bleeding into the brain due to vessel rupture or leak. According to the Heart Disease and Stroke Statistics it is the second leading cause of death globally. Dr. D. Winter, and Bobby Stutz of AtCor Medical, Inc. helps us to understand stroke from the perspective of the large arteries.

18 Improving the quality and accessibility of clinical data collection through patient engagement

It is widely recognised that putting the patient at the centre of a trial’s design can significantly improve the quality and

accessibility of data collection. To do this, pharmaceutical companies need to first understand patients’ needs and expectations, as well as make sure that the trial participation fits into their daily lives. Keeping the patients engaged in the study regimes allows for capturing their data more easily, which enables adapting the system responses in order to personalise content and provide target reports and summaries to all stakeholders in the clinical research. Tim Davis of Exco InTouch discusses why putting the patient at the centre of a trial’s design can significantly improve the quality and accessibility of data collection during clinical research.

REGULATORY20 Operational Challenges Associated with Biosimilar Drug Development

This article examines the current operational landscape of biosimilar clinical drug development and identifies opportunities to decrease the risks associated with increasing competition. With an emphasis on European Union and United States’ markets, it gives an overview of some of the challenges and issues that need to be considered by researchers in this increasingly crowded environment, explains Niti Goel, Rod Hepburn, Scott Davis, Deepa Dahal, Tracy Stewart, and Kamali Chance from Quintiles.

28 FDA Makes First Move on Biosimilars in the USRegina Ballinger and Deborah Komlos from Thomson Reuters are submitting an interesting editorial titled FDA Makes First Move on Biosimilars in the US, and they give us an insight into some Clinical Programs, Analytic Similarity in Biosimilars, Immunogenicity Assessments, and then they touch upon the The Future of Biosimilars in the US.


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Contents

MARKET REPORT32 Romania`s Regulatory Framework for Clinical Trials

Romania is located in Southeastern Central Europe, north of the Balkan Peninsula and on the western shore of the Black Sea. With a population of 20.1 million, it is the seventh most populous member of the European Union. Sandrine Ruaud, from CIDP explains the Romania`s Regulatory Framework for Clinical Trials.

36 Drugs’ Marketing Authorization and Clinical Trials Regulations in Ukraine

Dr. Sergiy Pakharyna, at Synergy Group Ukraine, Dr. Yuri Afonchikov of Synergy Research Group, analyses the marketing authorization and clinical trials regulations in Ukraine by showing figures, and a list of documents for clinical trial authorization with their editorial.

THERAPEUTICS

40 Community-Acquired Bacterial Pneumonia – a Challenging Diagnosis in Clinical Trials

Community-acquired bacterial pneumonia is a common and important disease which is associated with significant morbidity and mortality worldwide. Various pathogens cause the disease, but often the underlying pathogen is not identified. Early diagnosis is key to successful therapy; however, frequently the disease is misdiagnosed. In this white paper Maxim Kosov, PSI CRO AG (USA), John Riefler, PSI CRO AG (USA), Maxim Belotserkovskiy, at PSI CRO AG. discusses why close cooperation between investigative sites and medical monitors of sponsor/CRO is essential.

TECHNOLOGY

44 e-Patient Recruitment in Emerging MarketsPatient recruitment costs around 6-7% of the total and it is highest among all other cost components. Almost 80% of clinical trials are delayed due to patient recruitment challenges. This delay adds on to the cost of maintaining staff and site, and shortening the patent period. These issues are pushing clinical trials towards two major shifts. Shift from Patient recruitment to Patient engagement and shift from site centric trials to Patient centric trials. We have an insight into these shifts by Nandini Nema of Beroe Inc.

LOGISTICS

48 Analysing Trends in Global Comparator Sourcing and Distribution in 2015 – A Preview

Ann-Marie Huss of Multipharma Clinical Supplies Ltd submit a white paper on Analysing Trends in Global Comparator Sourcing and Distribution in 2015 and gives us an overview on this subject.

52 Logistical Challenges in Orphan Drug Trials - Adopting a Patient-Centric, Investigator-Supportive Approach

Clinical development programmes for orphan drugs present considerable financial and logistical challenges for pharmaceutical sponsors. Within this article we will look into some Logistical Challenges in Orphan Drug Trials by Jennifer Peters of Greenphire, discusses the rise of orphan drug, the patient experience, challenges in orphan drug trials and patient-centric approaches.

56 Drug Pooling in Clinical Trial Supply ChainGlobal clinical trials are in a need of more efficient supply chain systems that can bring more transparency and risk mitigation strategies. Currently the clinical trial supply chain is following consumption based models which is very inefficient. They need to have better models which can take care of risk mitigation strategies as well. Rahul Sodhi of Beroe Inc. Looks into Drug Pooling in Clinical Trial Supply Chain.


2013 022 VC adv A4.indd 1 20-06-2013 12:56:33


Foreword

Editorial Advisory Board

Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc.

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

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

Catherine Lund, Vice Chairman, OnQ Consulting

Cellia K. Habita, President & CEO, Arianne Corporation

Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global

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

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

Elizabeth Moench, President and CEO of MediciGlobal

Eileen Harvey, Senior VP/General Partner, PRA International

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet Development Group

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

Georg Mathis, Founder and Managing Director, Appletree AG

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

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

Janet Jones, Senior Director, ICON Clinical Research

Jerry Boxall, Managing Director, ACM Global Central Laboratory

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

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

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Patrice Hugo, Chief Scientific Officer,

Clearstone Central Laboratories

Rabinder Buttar – President & Chief Executive Officer of ClinTec International

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

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

Economic globalisation is an important development of the past half-century. Proponents of globalisation highlight the benefits of greater economic growth and prosperity; critics point to the exacerbation of economic disparities and the exploitation of workers, particularly in developing (i.e., low- and middle-income) countries. Pharmaceutical and device companies have embraced globalisation as a core component of their business models, especially in the realm of clinical trials. This phenomenon raises important questions about the economics and ethics of clinical research and the translation of trial results to clinical practice.

Who benefits from the globalisation of clinical trials? What is the potential for exploitation of research subjects? Are trial results accurate and valid, and can they be extrapolated to other settings?

Clinical trials increasingly occur on a global scale as industry and government sponsors in wealthy countries move trials to less wealthy countries. Since 2002, the number of active Food and Drug Administration (FDA)-regulated investigators based outside the United States has grown by 15% annually, whereas the number of US-based investigators has declined by 5.5%. This trend suggests that clinical research is undergoing the same globalisation process as other industries. There are clear benefits to conducting trials in developing countries. These include fostering positive relationships among clinician investigators globally and answering questions about the safety and efficacy of drugs and devices that are of interest throughout the world.

In this issue of JCS, Henry J. Riordan and Neal R. Cutler of Worldwide Clinical Trials discuss CSF biomarkers of disease modification in Alzheimer’s disease. Success of Phase I clinical trials in oncology is analysed by Michael Kurman from INC Research. Dr D. Winter and Bobby Stutz of AtCor Medical, Inc. help us to understand stroke from the perspective of the large arteries.

In the Regulatory Section, Niti Goel, Rod Hepburn, Scott Davis, Deepa Dahal, Tracy Stewart, and Kamali Chance from Quintiles examine the current operational landscape of biosimilar clinical drug development and identifies opportunities to decrease the risks associated with increasing competition.

Regina Ballinger and Deborah Komlos from Thomson Reuters, in their editorial titled FDA Makes First Move on Biosimilars in the US, give us an insight into some clinical programmes, analytic similarity in biosimilars, immunogenicity assessments, and then they touch upon the the future of biosimilars in the US.

Within the Therapeutic Section, Maxim Kosov, John Riefler and Maxim Belotserkovskiy, of PSI CRO AG., in their article Community-acquired Bacterial Pneumonia – A Challenging Diagnosis in Clinical Trials discuss why early diagnosis is key to successful therapy. Nandini Nema of Beroe Inc. discusses e-patient recruitment in emerging markets.

In the Logistics Section, Ann-Marie Huss, of Multipharma Clinical Supplies Ltd, presents a white paper on analysing trends in global comparator sourcing and distribution in 2015 and gives us an overview on this subject, and Jennifer Peters of Greenphire discusses the rise of orphan drug, the patient experience, challenges in orphan drug trials and patient-centric approaches.

We thank all our authors for their exceptionally written and thoroughly researched articles. Hope you enjoy this issue of JCS, and I look forward to seeing you again with our next edition in May.

Orsolya BaloghEditor


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FDA Recommends Testing Drugs for Impacts on Driving Ability

New US Food and Drug Administration (FDA) draft guidance addresses when and how to evaluate drugs for the potential to impair driving ability, an issue that arises during agency reviews of approved and investigational products. Next-day drug effects are of particular concern during reviews of insomnia treatments, which are, of course, intended to sedate. In mid-May 2014, for example, the FDA announced it would require Sunovion Pharmaceuticals Inc to reduce the starting dose for prescription sleep aid Lunesta (eszopiclone) after post-market study found that the recommended doses impaired some patients’ psychomotor coordination and memory for as long as 11.5 hours.

The new draft guidance, issued in January 2015, focuses on psychoactive drugs, noting particular concern for night-time products that markedly impact the central nervous system. Evaluating Drug Effects on the Ability to Operate a Motor Vehicle is the first formal guidance issued by the FDA on this topic. The document outlines the principles and goals of studies rather than specific methods or instruments. It discusses Phase I studies, Phase II/III studies, and driving studies, and addresses issues such as randomisation and endpoint analysis.

The FDA recommends a “tiered approach” to evaluating impaired driving, including pharmacological/toxicological, epidemiological, and standardised behavioural assessments. The need for and focus of later-stage tests depend on findings earlier on. Several “broad functional domains” contribute to a person’s driving ability and should be evaluated, according to the guidance, including:

• Alertness/arousal/wakefulness;• Attention and processing speed;• Reaction time/psychomotor functions;• Sensory-perceptual functioning; and• Executive functions.

While none of these domains alone thoroughly defines driving ability or impairment, if a drug causes “clinically meaningful impairment” to a single domain, that evidence may be enough to conclude the drug impairs driving, according to the guidance. The FDA specifically notes that for some products, including drugs for sleep disorders, adverse effects on the central nervous system “cannot be assumed to be absent” the following day. Focused studies, guided by blood levels, may be necessary to characterise driving risk.


The FDA reduced the Lunesta start dose to 1 mg for all adults after finding that 2 and 3 mg doses impaired alertness for as long as 11.5 hours in some patients, affecting their driving skills, coordination, and memory. The revised Lunesta product label also cautions that the drug caused some patients to perform activities they could not recall the next day, such as “sleep-driving,” making phone calls, eating, sleep-walking, and engaging in sex. While higher Lunesta doses may be appropriate for some, patients should always use the lowest effective dose, the label states. Anyone taking 3 mg “should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness the day after use.”

The Lunesta dose change followed reductions in

January 2013 to the recommended doses of products containing another sedative, zolpidem, including Ambien, by sanofi-aventis US LLC. The FDA required those reductions after data from post-market driving simulation and lab studies showed that the morning-after zolpidem blood level for some patients was high enough to impair driving, increasing the risk for accidents. The zolpidem dose change came 20 years after the product’s initial FDA approval, in December 1992.

In May 2014, the FDA convened experts to consider suvorexant, an investigational sleep aid proposed by Merck Sharp & Dohme Corp. While members of the Peripheral and Central Nervous System Drugs Advisory Committee strongly supported the drug’s efficacy, their discussions returned frequently to concerns about next-day safety, including “excessive daytime sleepiness.” An FDA review of Merck’s clinical trial data had found that suvorexant “clearly” caused dose-related, next-day effects, including sedation, as noted in the agency’s briefing materials for the meeting.

Of particular significance to the FDA were formal driving study results showing that suvorexant can cause significant driving impairment (specifically, excessive deviation in lane position) the morning after dosing. Merck had conducted two randomised, double-blind, placebo- and active-controlled, four-period crossover studies to assess the effects of suvorexant on next-day driving performance.

Merck received FDA approval for suvorexant, now marketed as Belsomra, in August 2014. Although Merck requested a recommended dose of 20 mg for non-elderly adults and 15 mg for elderly, the FDA approved a recommended dose of just 10 mg for all adults. The maximum approved dose is 20 mg once daily, far lower than Merck’s proposed recommended daily dose of 40 mg for non-elderly adults and 30 mg for elderly. In addition, the Belsomra label includes warnings for daytime somnolence, noting a dose-related risk for impaired driving. It also advises that patients taking 20 mg should be cautioned “against next-day driving and other activities requiring complete mental alertness,” and states that all Belsomra users should be warned about the risk of potential driving impairment.

Watch Pages

Meg Egan Auderset is a writer and editor of more than 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 the Cortellis Regulatory Intelligence AdComm Bulletin.Email: [email protected]


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CSF Biomarkers of Disease Modification in Alzheimer’s Disease

The three major brain hallmarks of Alzheimer’s disease (AD) are extracellular amyloid plaques, axonal degeneration and intraneuronal neurofibrillary tangles, which can all be monitored via changes in the cerebrospinal fluid (CSF) biomarkers amyloid beta 42 (Aβ42), total-tau (T-tau), and phosphorylated-tau (P-tau) 1. Amyloid, the product of amyloid precursor protein, exists in a variety of isoforms of 36 to 43 amino acids in length; however, the focus on CSF amyloid biomarkers has mostly been on the measurement of CSF Aβ42, shown to decrease in AD patients as well as those converting to AD. The underlying assumption is that CSF Aβ42 reflects increased accumulation of Aβ42 in brain forming plaques and brain beta amyloid load 2, 3, 4. Other CSF biomarkers of interest including total tau (T-tau), a generic measure of cortical axon damage associated with many neurodegenerative disorders, and phosphorylated tau (P-tau), shown to increase threefold in the CSF of confirmed AD patients4. There is a consensus from centres around the world suggesting the levels of Aβ42 in the CSF of AD patients are significantly lower than in age-matched, healthy, elderly controls, whereas the levels of total tau (T-tau) and P-tau181P (phosphorylated at threonine 181) in AD CSF are significantly higher than those of age-matched controls. These relatively simple findings have spurred a great deal of research and debate on the role of CSF biomarkers in AD drug development.

Although these CSF biomarkers have shown some degree of utility in diagnostic accuracy as biomarkers in predicting conversion to AD from mild cognitive impairment (MCI), and as a tool to enrich patients for clinical trials to increase statistical power, these biomarkers have not shown similar success in evaluating the effectiveness of therapeutic interventions in AD, especially in the development of disease-modification therapies. This is not surprising considering that confirmation of disease-modifying biomarkers occurs only when they are found useful in predicting the clinical efficacy of a novel disease-modifying agent. However, currently approved drugs in AD and other neurodegenerative disorders only provide symptomatic relief rather than modifying the core pathophysiology of the disease, and do not change disease progression. Thus, current biomarker development for disease modification must advance in the absence of gold standard treatments to validate these biomarkers.

Biomarkers for neurodegenerative disorders can be generally divided into markers of disease state (or diagnostic biomakers) and markers of disease rate or stage that can reliably track disease progression 5. As the clinical course of AD is very slowly progressive and highly variable, the treatments designed to slow the disease progression require clinical trials with very large subject numbers for much longer durations than

symptomatic treatment trials, in order to observe clinical improvement secondary to downstream therapeutic effects on the underlying pathophysiological processes. This circumstance only underscores the necessity for CSF surrogate biomarkers of disease progression.

It is clear that both CSF tau and Aβ42 biomarkers fulfill the requirements for disease state markers of AD as they both exhibit reasonably high specificity and sensitivity in both early and late stages of AD 6. However, this brief review suggests that at this point in time it can be argued that only CSF tau measures appear to satisfy criteria as a marker of disease rate. Numerous studies have shown that in various groups of AD patients there is no strong correlation between the severity of the disease stage over time with the levels of CSF Aβ42, indicating that the levels of Aβ42 do not significantly and reliably change substantially in mild to severely symptomatic AD patients. However, longitudinal studies of the levels of CSF tau in patients with AD have shown more promising results.

For example, Blennow and colleagues7 examined exploratory, post-hoc, pooled data from two Phase II international clinical trials in order to determine whether the novel disease-modifying immunotherapy drug bapineuzumab impacted the CSF levels of the downstream biomarkers T-tau, P-tau, and Aβ42. This group reported that immunotherapy reduced CSF T-tau and P-tau biomarker levels in patients with mild to moderate AD. Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (−72.3 pg/mL) and P-tau (−9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P=.03), while a similar trend for a decrease was found for T-tau (P=.09). Of note, no clear-cut differences were observed for CSF beta amyloid. This supports other studies which have also shown that the amyloid load in the brain of AD patients, as assessed with repeated amyloid positron emission tomography measurements, appears to be stable over time despite cognitive decline. Thus, CSF Aβ42 would not be considered a worthy candidate for a marker of disease stage or rate. Importantly, this was the first study to show that disease-modifying therapy results in decreases in CSF biomarkers, and suggests that CSF T-tau and P-tau, which may reflect downstream effects on the degenerative process, may have some relative utility over Aβ42 as a surrogate biomarker in tracking rate of disease-modifying trials.

Observations such as these are supported by neuropathological studies showing that tau-containing neurofibrillary tangles, but not amyloid plaques, are associated with the cognitive function of AD patients. Furthermore, when using structural imaging measures,


only P-tau has been shown to correlate with neocortical tangle pathology at autopsy. CSF P-tau has also been shown to correlate with the rate of hippocampal atrophy in the brain. Previous postmortem histopathological studies have demonstrated an association between the degree of antemortem MRI hippocampal atrophy and neurofibrillary tangle burden and a strong correlation between both CSF T-tau and P-tau levels with the presence of neocortical neurofibrillary tangles 8. Additionally, antemortem MRI hippocampal volumes of AD patients correlate with the density of neurofibrillary tangles (but not with senile plaques) at autopsy, suggesting that hippocampal volume may better correlate with CSF T-tau and P-tau levels than CSF beta amyloid levels 9. Although mean brain volumes correlated with the CSF P-tau level, no correlation was found between any brain measurement and CSF Aβ42 levels. The fact that the CSF T-tau and P-tau levels, but not CSF Aβ42 levels, correlated with hippocampal volumes, suggests that CSF tau biomarkers reflect the neuronal loss associated with the underlying pathophysiological processes of AD and are thus better suited as a marker of disease progression. The lack of Aβ42 correlation with whole brain and hippocampal volumes agree with postmortem studies by demonstrating that the rate of brain volume loss was not determined by the amount of beta amyloid. Collectively, the above suggests a comparative role for CSF tau measures over CSF beta amyloid measures as potential surrogate biomarkers of disease progression that may be “reasonably likely” to predict the clinical benefit and desired clinical outcome in clinical trials assessing disease-modifying drugs for AD, resulting in more efficient clinical trials in terms of subject numbers and study duration.

References 1. Mattsson N, Andreasson U, Persson S, Carrillo MC,

Collins S, Chalbot S, Cutler N, Dufour-Rainfray D, Fagan AM, Heegaard NH, Robin Hsiung GY, Hyman B, Iqbal K, Lachno DR, Lleó A, Lewczuk P, Molinuevo JL, Parchi P, Regeniter A, Rissman R, Rosenmann H, Sancesario G, Schröder J, Shaw LM, Teunissen CE, Trojanowski JQ, Vanderstichele H, Vandijck M, Verbeek MM, Zetterberg H, Blennow K, Käser SA. Alzheimer’s Association QC Program. CSF biomarker variability in the Alzheimer’s Association quality control program. Alzheimer’s Dement. 9(3):251-61 (2013).

2. Flood DG, Marek G, Williams M. Developing predictive CSF biomarkers - A challenge critical to success in Alzheimer’s disease and neuropsychiatric translational medicine. Biochemical Pharmacology 81 1422–1434 (2011).

3. Jack Jr CR, Wiste HJ, Vemuri P, Weigand SD, Senjem ML, Zeng G, et al. Brain beta-amyloid measures and magnetic resonance imaging atrophy both predict time-to-progression from mild cognitive impairment to Alzheimer’s disease. Brain;133:3336–48 (2010).

4. Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer’s

disease neuroimaging initiative studies. Ann Neurol;65:403–13 (2009).

5. Fox N, Growdon JH. Biomarkers and surrogates. Neurorx 1: 181 (2004).

6. Buchhave P, Blennow K, Zetterberg H, Stomrud E, Londos E, et al. Longitudinal Study of CSF Biomarkers in Patients with Alzheimer’s Disease. PLoS ONE 4(7) (2009).

7. Blennow K, Zetterberg H, Rinne JO, Salloway S, Wei J, Black R, Grundman M, Liu E. Effect of Immunotherapy With Bapineuzumab on Cerebrospinal Fluid Biomarker Levels in Patients With Mild to Moderate Alzheimer Disease. Arch Neurol. Apr 2 (2012).

8. Tapiola T, Alafuzoff I, Herukka SK, Parkkinen L, Hartikainen P, Soininen H, Pirttila T. Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch. Neurol. 66, 382–389 (2009).

9. de Souza LC, Chupin M, Lamari F, Jardel C, Leclercq D, Colliot O, Lehéricy S, Dubois B, Sarazin. CSF tau markers are correlated with hippocampal volume in Alzheimer’s disease. M Neurobiol Aging. 33(7):1253-7 (2012).

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Neal R. Cutler, MD is the CEO of Worldwide Clinical Trials. He is a board-certified psychiatrist who has authored over 250 publications, including nine books on CNS drug development. He has also been instrumental in the design and clinical development of nearly 200 compounds in numerous therapeutic areas and has particular expertise in CNS disorders, in particular lumbar puncture procedures and CSF dynabridging methodology and analyses.

Henry J. Riordan, Ph.D. is Executive Vice President of Medical and Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various CNS drugs and disorders in both industry and academia for the past 20 years. He has been the primary author of >75 CNS protocols as well as several clinical development programmes. Dr Riordan specialises in CNS clinical trials methodology and has advanced training in biostatistics, experimental design, neurophysiology, neuroimaging and clinical neuropsychology. He has over 90 publications including co-authoring two books focusing on innovative CNS clinical trials methodology. Email: [email protected]


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Although metastatic solid malignancies, particularly in adults, remain a large unmet medical need, there can be little doubt that the recent past has produced a veritable cornucopia of new drugs for the treatment of cancer. In the five years between 2010 and 2014, 37 new molecular entities were approved by the FDA for the treatment of cancer; in the five years between 1995 and 1999, only 20 such agents were approved (information courtesy of CenterWatch). Moreover, many of the newer approvals are targeted agents, either in the form of small molecules or monoclonal antibodies, which avoid many of the unpleasant side-effects associated with non-specific cytotoxic chemotherapy. Oncologists practising today may take for granted the six separate agents currently approved for metastatic melanoma, but it was not that long ago that this disease was associated with a progression-free survival of only six weeks when treated with DTIC, the only available agent at the time.

Despite this incredible progress, many, if not most, patients treated with these newer agents still succumb to their cancers. Malignant cells develop patterns of resistance to targeted agents, and there are still patients who don’t respond, for whatever reasons, at all. The search for more effective and safer agents goes on.

Phase I studies are the entry point for the testing of new drugs in humans. For drugs being developed for the treatment of cancer, these trials typically involve patients who have exhausted all established therapies known to provide clinical benefit for their cancers. In the past, this would often mean a patient may have received one, or two prior regimens before being eligible for enrolment into a Phase I clinical trial. For some diseases (like melanoma), a clinical trial often offered at least as good a probability of efficacy as the standard of care, so that it was not uncommon to find previously untreated patients with certain cancers enrolled into Phase I trials. Now, given our new-found success in cancer drug development, potential Phase I patients may have received upwards of five prior regimens, and for certain malignancies, where drugs may be “re-cycled” (i.e., used more than one time in the course of a patient’s disease), this number can approach ten prior regimens. This has resulted in a pool of Phase I candidates who have been much more heavily pre-treated than in the past, often have highly-resistant malignancies and a greater burden of metastatic disease, resulting in poor performance scores and poor tolerance of investigational agents and the rigours of an investigational trial. Such patients can easily jeopardise the success of an early-phase trial.

So how should we measure success of a Phase I cancer clinical trial? In the past, the emphasis of such trials was strictly on defining dose-limiting toxicities and

the overall adverse event profile of a new agent. The pharmacokinetic properties of the new agent would also have been determined and responses would have been reported, although the expectation of efficacy was low.

The situation, in my view, has changed. Because patients eligible for Phase I studies now may have greater disease burdens, they come into the studies “sicker” than in the past. Many are unable to remain on the study even for the duration of the first treatment cycle due to disease progression, forcing the study sponsor to have to replace subjects. Obtaining pharmacokinetic information is still important, but now there is greater emphasis on translational and pharmacodynamic studies, particularly for targeted agents, often involving tumour biopsies. In patients without superficial metastases, this can involve trying to obtain adequate tissue samples in vital organs, such as the lung or the liver. Venture-backed companies are now under pressure to demonstrate efficacy even in Phase I, or risk a loss of future funding. “Success” in Phase I now often requires the demonstration of efficacy, with proof of mechanism of action in fresh tumour biopsies, in patients with even more resistant tumours than in the past.

Given our success in raising the standard of care in general in the treatment of cancer, all of the stakeholders in cancer drug development need to re-adjust expectations for Phase I studies. Investigators should be more circumspect in who they enroll in such studies – patients with decubitus ulcers probably don’t have ECOG performance scores of 1. Sponsors should plan for longer trials to allow for the replacement of subjects who may have to drop out due to rapid disease progression. While Phase I studies with 40 per cent response rates are desirable, this should not be the benchmark of a new drug’s ultimate success.

Phase I Clinical Trials in an Era of Increasing Oncologic Success

Michael Kurman, M.D is Senior Director of Medical Affairs for INC Research, with 30 years of oncology drug development experience as both a clinical investigator and pharmaceutical executive. Dr Kurman started his career in the practice of oncology, during which he was an

investigator on several oncology clinical trials. His background also includes the successful development or launch of four oncology products. His primary interests are in early-phase oncology clinical trial design and drug development, and in strategic portfolio management. Email : [email protected].


065_JTS_Ad_FIN.indd 1 2/9/15 10:15 AM


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Scandinavia / Nordic: Are They Just Ice and Snow?

Let’s start by clarifying what we are talking about, as defining the difference between what comprises Scandinavia and what’s Nordic is as clear to most of us as the distinction between the UK and Great Britain, or the Netherlands and Holland.

Scandinavia is Sweden, Norway and Denmark. Nordic countries are Sweden, Norway, Denmark (including Greenland and the Faroe Islands, which belong to Denmark), Finland (including Åland, which belongs to Finland), Svalbard and Iceland as well. As an aside: Iceland is very green, Greenland is covered in ice.

Hopefully that’s all clear now!

The area is ripe with innovation; Swedish inventions include the zip, refrigerator, pacemaker and computer mouse. The Danes created the world’s most popular toy. Sales at Lego (now the world’s largest toy-maker) top $2 billion per annum. The Finns boast Nokia phones, named for the river Nokianvirta which flows through the town where the company began. Nokia is the world’s largest digital camera manufacturer. Not to be left out, Norway invented the cheese slicer and the spray can.

Denmark, Finland and Sweden are all members of the EU. Finland is part of the Eurozone, whilst the other three countries maintain their national version of the Kroner. All these countries have stable economies, even given the blip that Iceland experienced, and universal welfare systems with high levels of public spending on health. The four main countries take high positions at the top of league tables for economic competitiveness, social health and happiness, with Iceland topping the global life expectancy tables for men at 81.2 years.

Denmark leads the way in clinical trials, with more than 4700 so far. Sweden has run over 3200 trials. These numbers reflect the progressive biotech industry in the two countries, where there are over 250 companies clustered in Medicon Valley (comprising the eastern part of Denmark and southwestern part of Sweden). In Norway, over 2500 trials have run, and in Finland around 1980, Iceland has been quieter with just below 100 trials, despite a booming biotech industry. Danish enzyme manufacturers today produce more than 70% of the total enzyme production worldwide, and there is a very active Dansk Biotek association. In addition, Denmark holds the world’s greatest percentage of patents in biotechnology. The Danish national health system registers the entire


population “from embryo to grave”, a system that means Denmark is home to more than 500 bio banks and extensive medical records.

Norway is supporting its own biotech industry, with the Research Council of Norway investing 10 million NOK (approximately $1.3 million) in 10 companies over four years. This is supported by infrastructure, including the Oslo Cancer Cluster and the Norwegian University of Life Sciences.

The Finnish pharmaceutical industry employs about 5400 people in research and development, marketing and production and associated jobs. There are some large production facilities in Espoo, Tampere and Turku, and national pharmaceutical exports were some 935 million Euros in 2013.

Dealing with the EU countries requires interaction with a single regulatory process. Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use relates to clinical trial applications and practice, and 2013/C 343/01 Guidelines on Good Distribution Practice of medicinal products for human use is applicable for transportation and storage. This cuts down the workload tremendously, with single applications covering Europe and standardised requirements for shipping. Iceland and Norway use harmonised regulations and are both part of

the European Economic Area (EEA) and the European Free Trade Association, which makes it very straightforward to import from the EU into both countries or intra-EU into Denmark, Finland and Sweden. Bear in mind there are some local requirements once in the country. For example, Finland requires all pharmaceuticals to be sent via a licensed importer before they can be delivered to the ultimate consignee. Importing from outside the EU will require invoices and sometimes import permits, depending on the consignee for all these locations. For Finland, it could also require a statement from the consignee.

Considering the straightforward nature of the shipping processes, the most challenging consideration of logistics in this region may be the climate. In the winter across the region, the warmest temperatures are likely to hover around freezing. North of the Arctic Circle the sun barely rises in winter, and the temperatures regularly drop to -20°C. Ensuring that the packaging you select is capable of withstanding external low temperatures, or using temperature-controlled vehicles to keep your supplies warm is imperative. Consideration should be taken when choosing site locations, as there can be infrastructural challenges due to the long distances (Sweden is 2000km, by road 1574km as the crow flies north to south), and there are strict regulations on transporting dry ice on domestic flights.

Up in the chilly North of Europe, there are few problems finding colleagues to run clinical trials. English is spoken universally, research staff are keen to take part in trials, and there is considerable expertise and enthusiasm to ensure success.

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Sue Lee 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 in her capacity as Head of the Major Clinical

Trial Unit. Sue has orchestrated the shipping thousands of shipments with very specific temperature requirements to a host of challenging locations, and each presenting their own obstacles and dilemmas. More recently in her role as Regional Quality Manager, Sue has been auditing and developing procedures and systems for regulatory compliance, package and vehicle testing, as well as temperature control and mapping. Currently, Sue’s role includes delivering pertinent, technical information and updates on latest industry developments via technical presentations, articles and white papers, workshops, association and discussion group involvement and direct links with other industry professionals. This also includes direct involvement delivering and maintaining World Courier’s online presence. Email: [email protected]


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Understanding Stroke from the Perspective of the Large Arteries

Stroke, as it has recently been redefined, is any objective evidence of permanent brain, spinal, or retinal cell death due to a vascular cause.1 In general, strokes are a result of either reduced blood flow caused by a thrombus or embolus (ischemic) or from bleeding into the brain due to vessel rupture or leak (haemorrhagic). According to the Heart Disease and Stroke Statistics – 2015 Update it is the second leading cause of death globally and, in the United States, occurs once every 40 seconds. Traditional risk factors for stroke include high brachial blood pressure, smoking, physical inactivity, chronic kidney disease, and family history to name a few.2 However, puzzlingly, rarely is the state of the blood vessels considered. But as will be discussed, evaluation of arterial function has the potential to provide significantly valuable information about stroke risk and outcome.

Direct measurement of aortic stiffness, as measured by aortic pulse wave velocity (PWV), has been shown to be an independent predictor of cardiovascular (CV) morbidity and mortality in numerous clinical and population-based cohorts. When added to traditional risk assessment models, it improves the overall 10-year CV disease risk classification for intermediate-risk subjects by 13% and their overall five-year stroke risk classification by ~20%.3 This robustness for CV disease prediction and its ease-of-use have prompted professional societies to incorporate aortic PWV measurement into recent guidelines.4

Additionally, the establishment of reference values has further promoted its widespread use in both the clinical and research settings.5

In longitudinal investigations following apparently healthy adults and hypertensive patients, PWV has been found to be independently predictive of stroke6, 7 and fatal stroke.8 One study found that an elevated PWV equates to a four-times-increased risk of stroke compared to a normal PWV value.7 A recent meta-analysis showed an increased risk of stroke with elevated PWV in numerous subgroups (Figure 1).3

While the pathophysiology that relates aortic stiffness to stroke has not yet been clearly elucidated, there are various mechanisms that may explain this relationship. First, an increase in aortic stiffness results in an increase in systolic blood pressure (BP), a decrease in diastolic BP, and thus a widening of pulse pressure in the central arteries. The brain is unique in that it is one of a few organs which does not have the ability to regulate the amount of pulsatile pressure and flow to which it is exposed. As a result the increased pulse pressure is transmitted into the cerebral microvasculature, predisposing it to rupture of the arterial walls.9 Second, a widened pulse pressure can also lead to extracranial arterial remodelling, promote

atherosclerosis and increase the chance of plaque rupture. Third, increased aortic stiffness may reflect parallel lesions at the site of the cerebral vasculature. Finally, heart disease, which is also a risk factor for stroke, is closely associated with increased arterial stiffness.7,8

In addition to its predictive value, measurement of aortic stiffness has also demonstrated prognostic importance in assessing post-stroke outcome. Research has shown that PWV measured one week after stroke is an independent marker of early neurological improvement10 and predictive of functional outcome.11 Patients with an aortic PWV less than 9.4 m/s are five times more likely to achieve functional recovery at 90 days than those with PWV values above that threshold.11 Importantly, these relationships were independent of the traditional predictors of stroke outcome, suggesting aortic PWV as a novel tool for inclusion in post-stroke prognostic assessment.

In conclusion, as stroke is an event of vascular origin, it should not come as a surprise that direct measures of large artery function can improve stroke prediction and post-event outcomes. Considering the evidence, future trials investigating stroke should incorporate measures of arterial stiffness to provide a more complete understanding of the role the large arteries play in this potentially fatal event.

Figure 1: Forest plot for aortic PWV with stroke outcomes according to pre-specified subgroups3


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References1. Sacco RL, et al. (2013, July). An updated definition of

stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 44(7), 2064-89.

2. Mozaffarian D, et al. (2015, Jan 27). Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circ, 131(4), e29-e322.

3. Ben-Shlomo Y, et al. (2014, Feb 25). Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol, 63 (7), 636-46.

4. Mancia G, et al. (2013, Jul). 2013 ESC/ESH guidelines for the management of arterial hypertension. J Hypertens, 31(7), 1281-357.

5. 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.

6. Mattace-Raso FU, et al. (2006, Feb 7). Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circ, 113(5), 657-63.

7. Pereira T, et al. (2013, May). Aortic stiffness is an independent predictor of stroke in hypertensive patients. Arq Bras Cardiol, 100(5), 437-43.

8. Laurent S, et al. (2003, May). Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke, 34(5), 1203-6.

9. Stutz, B and Winter, D (2014, Jun Jul) Dementia, cognitive impairment, and arterial stiffness. J for Clinical Studies, 6(3), 10-11.

10. Gasecki D, et al. (2012, Dec). Pulse wave velocity is

associated with early clinical outcome after ischemic stroke. Atherosclerosis, 225(2), 348-52.

11. Gasecki D, et al. (2012, Feb). Aortic stiffness predicts functional outcome in patients after ischemic stroke. Stroke, 43(2), 543-4.

Bobby Stutz is currently the Senior Research Engineer for AtCor Medical, Inc. He has spent the last eight years in the medical device industry after earning his Masters and undergraduate degrees in biomedical engineering at The Catholic University of America in Washington, D.C. Bobby may be

contacted at Email: [email protected]

Dr Winter is currently the Senior Consultant – Scientific and Clinical Affairs for AtCor Medical, Inc. Prior to joining AtCor, he was Director of Bioengineering at Southwest Research Institute, where he developed the first commercial blood pressure monitor based on arterial tonometry. He

is an internationally recognised expert in physiological fluid mechanics, biomechanics and medical device development. Dr Winter may be contacted at Email: [email protected]


Improving the quality and accessibility of clinical data collection through patient engagement

It is widely recognised that putting the patient at the centre of a trial’s design can significantly improve the quality and accessibility of data collection. To do this, pharmaceutical companies need to first understand patients’ needs and expectations, as well as make sure that the trial participation fits into their daily lives. In short: the patient must feel engaged throughout the process. Keeping the patients engaged in the study regimes allows for capturing their data more easily, which enables adapting the system responses in order to personalise content and provide target reports and summaries to all stakeholders in the clinical research. Engagement, however, is more than simply providing reminders to the trials’ participants. Patients should be supplied with the most appropriate technology and features which would not only fit seamlessly into their daily routines, but which would also make their participation in a trial more rewarding. Putting the patient at the centre of a trial’s design can significantly improve the quality and accessibility of data collection during clinical research.Improving accessibility through patient engagement

How then, to ensure that patients are put at the centre of a trial’s design and are engaged throughout? Traditionally, data collection was conducted using paper diaries due to the associated hardware costs of implementing electronic solutions. However, collecting and consolidating data

this way can be resource-intensive and a burden on both timescales and budget. Additionally, data analysis is near impossible due to the difficulty of re-engaging with patients and the timeframes elapsed between recording and review. The clinical research industry is increasingly adopting a more patient-centric approach which recognises that if patients are supported throughout a study, higher levels of compliance and retention can be achieved1.

Patient engagement also goes beyond the communication plan; to truly engage patients throughout the study lifetime it is important to make their required actions as simple and non-intrusive as possible. A device inclusive approach facilitates seamless integration of clinical trial activities into the everyday lives of patients, through the flexibility to select any connected device for communication and data capture. This should be coupled with the ability to build in true mobility enabling the patients to send and receive data using different media to fit in with their lifestyle.

Listening to the patients during drug development, and partnering throughout their clinical trial experience, as well as the simplification of methods to capture and report patient data obtained during the trial, is now seen as vital to pharmaceutical R&D success. Sponsors and

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clinical research organisations (CROs) have demonstrated a growing desire to simplify clinical data collection by implementing innovative solutions that provide greater access (in real time) to better quality data, in a more cost effective way1,2 – whilst in parallel helping to facilitate continuous patient engagement for the duration of the trial3,4.

Using mobile solutions, each study can be designed to include a relevant, tailored communication plan. This is not the future – mobile technology is now being implemented as a means of communicating directly with patients across broad demographics and multiple widespread geographic locations in clinical trials. Simplicity is the key. A single system can be used to engage with patients, collect data and enable real time data review by all stakeholders. Patient outcomes can then be integrated into a single data repository which creates standard reports for instant access. As a result physicians and sponsors can address safety risks as they occur.

Reinforcing patient engagementThe rise of electronic clinical outcome assessments (eCOA) and, specifically, electronic patient reported outcome (ePRO) tools implemented through everyday mobile technology has transformed how patients can be engaged throughout a clinical trial. Through this approach each study can be designed to include a relevant, standardised and tailored communication plan, delivered through SMS messaging, emails or in-app notifications. As such, patients can be prompted to take medication, record data and attend site visits, where previously they typically would have been left with no support between the visits. In addition, through the inclusion of timely and relevant educational and informational messages, they can be better engaged throughout the duration of the study, which not only makes trials an easier and more useful experience for the patients, but also enables researchers to collect and process fuller data quickly, accurately and reliably.

With clinical trials now commonly being conducted on a global scale, increasing efficiencies in data management is critical, and a ‘device inclusive’ approach can deliver return on investment through a number of avenues, facilitating patient involvement at the same time. The BYOD (Bring Your Own Device) approach offers the eCOA market true scalability and has the potential to greatly reduce the considerable cost and logistical effort of providing and maintaining traditional ePRO devices for all patients participating in clinical studies. However, provisioning may be required for example when a validated instrument is being used to assess primary outcomes, or where Bluetooth® integration with next-generation home monitoring devices is included. Irrespective of which model is used however, the device inclusive approach can ensure that the technology used to capture and disseminate clinical assessments

is both practical and effective in addressing protocol requirements, and is also engaging and convenient for study participants.

A patient-centric ethosOne of the easiest ways to ensure that patients feel wanted and engaged throughout their participation in a clinical study is to simply thank them for their efforts and time. Appreciating their participation and involvement can have a substantial effect on the morale of the patient, and affect their decision on whether or not to enrol in future trials. There is also a growing drive in both the EU and US to allow clinical trial patients access to their own data, so that they can see physical evidence of their own contribution to the outcome of the trial. This could further strengthen their engagement in the study regimes and make them feel like part of the wider drug development story.

A commitment to putting patient engagement at the heart of your study ensures increased patient compliance to required activities. This has several benefits, including increased quality and accuracy of data, and the ability to meet tight deadlines and budgets. A patient-centric ethos will also increase retention, reduce lost-to-follow-up and improve clinical outcomes through improved adherence.

References1. M. Donahue, L Henderson, “Pfizer’s REMOTE Virtual

Experience”, (2012), Applied Clinical Trials http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=755171

2. “inVentiv Health Clinical acquires equity stake in Mytrus”, (2013) http://www.centerwatch.com/news-online/article/4535/inventiv-health-clinical-acquires-equity-stake-in-mytrus#sthash.mQoID9Pe.dpbs

3. K. Petrie et al. (2012), “A text message programme designed to modify patients’ illness and treatment beliefs improves self-reported adherence to asthma preventer medication”, (2012), British Journal of Health Psychology, 17, 74–84

4. D. L. Anderson-Foster, “Global Issues in Patient Recruitment and Retention”, (2012) Boston, Centerwatch. pp 133-146

Tim Davis is CEO and Founder of Exco InTouch, the leading provider of digital patient engagement and data capture solutions for clinical research and healthcare providers. As a widely respected clinical technology subject matter expert, Tim has been recognized through many

accolades, including the PharmaVOICE 100 annual list of the most influential people in life sciences for his vision to utilize mobile technology to engage patients during clinical studies and real world healthcare programs.Email: [email protected]

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Regulatory

Operational Challenges Associated with Biosimilar Drug Development

This article examines the current operational landscape of biosimilar clinical drug development and identifies opportunities to decrease the risks associated with increasing competition. With an emphasis on European Union and United States’ markets, it gives an overview of some of the challenges and issues that need to be considered by researchers in this increasingly crowded environment.

IntroductionThe introduction of biologics to healthcare has had a tangible effect on patients, especially in cases where they have provided the only available treatment for a disease.1,2,3,4 The success of biologics and their spiralling costs, timed with patent expiries, have led biopharmaceutical companies to develop biosimilar products. Biosimilars have the potential to increase access and provide lower-cost options for treatment of several conditions.5, 6, 7 Due to the structural complexity of biologics and their manufacture, in addition to non-clinical analytical and functional comparability data, regulatory authorities may request clinical trials to provide additional evidence of the similarity of a biosimilar product to the reference product. 8 Although there are multiple possible routes to biosimilar approval depending on a biologic’s mechanism of action (MoA) and the jurisdiction’s views, the current typical development paradigm utilised for the European Union (EU) and the United States (US) includes a Phase I pharmacokinetics (PK) study and a Phase III confirmatory similarity study.9, 10, 11 It is possible that, over time, this development paradigm will shift to increase or decrease requirements.

As there are an increasing number of biosimilar products in development, the existing competition for the requisite patient populations, and for qualified investigators interested in conducting the research necessary to get these drugs to market, is intensifying. This article examines the current operational landscape of biosimilar clinical drug development and identifies opportunities to decrease the risks both for development and commercialisation purposes.

Differences in Biosimilar vs Innovator Biologic DevelopmentBiosimilar drug development is considered unique for many reasons. In contrast to innovator biologic development which normally proceeds from Phases I to II to III, in a biosimilar development programme, the extent of clinical evaluation required is dependent on the assessment of the non-clinical analytical data package.9,10,11 If a clinical programme is recommended by the applicable regulatory authority, clinical Phase I and possibly Phase III studies would be performed to obtain

regulatory approval. Phase II dose-ranging trials are not considered required for biosimilars because it is assumed that similar efficacy will be demonstrated with the same dose regimens for the biosimilar as for the innovator biologic. A Phase I biosimilar study would be focused on demonstrating PK, and pharmacodynamic (PD) if applicable, equivalence between the biosimilar and innovator biologics as well as the initial safety of the biosimilar.9, 10, 11 If a Phase III study is required, as it is currently in many countries, our experience indicates the Phase III trial may be initiated once interim Phase I data demonstrate sufficient safety. The Phase III study typically targets a similar patient population utilised to file for an indication for the innovator biologic, although exceptions exist as described subsequently. At the time of the biosimilar’s submission for registration, if a clinical programme has been conducted, usually fewer patient years of exposure are required for a biosimilar in contrast to the large safety databases for an innovator biologic; the limited safety profile obtained for the biosimilar should appear similar and is typically associated with that of the innovator biologic.9, 10, 11

It may be possible for a biosimilar to obtain extrapolation to other indications for which the reference product is approved without a specific study being performed in those indications, provided that proper scientific rationale is provided for each indication for which extrapolation is requested.9, 10, 11 If an indication is studied, the primary indication chosen for evaluation is usually one that is considered sufficiently sensitive, and often it is the one considered most sensitive for evaluation, i.e., for the innovator biologic, has demonstrated the greatest effect size. It is not always practical to use the most sensitive indication for study if investigators are not willing to use the drug in their patients and data obtained from the study will not resonate with clinicians using the drug for a different patient population. In other situations, the most sensitive indication may not be clearly delineated.9, 10, 11

For example, for a tumour necrosis factor inhibitor (TNFi) drug, per our analyses, the most sensitive indication has often been psoriasis. Infliximab, however, is used less commonly than other biologic agents for psoriasis treatment, so infliximab biosimilar development to date has not utilised the psoriasis indication.12, 13 Similarly in oncology, for trastuzumab in breast cancer, adjuvant and neoadjuvant disease have been seen as the most sensitive settings for study.14 In contrast, for rituximab, the most sensitive indication has not been as clear as lymphomas are not homogeneous. There is evidence from clinical trial registries, e.g., ClinicalTrials.gov, that rituximab development is proceeding as monotherapy in


Regulatory

untreated low tumour burden follicular lymphoma to show similarity. In such cases, though the study might help support the approval of the rituximab biosimilar, the data would not allow the biosimilar to obtain the indication since not approved for the innovator biologic.15, 16, 17 Such a trial may serve, however, to provide data to providers and patients that the biosimilar would be effective in the treatment of off-label indications where there may also be significant use of the innovator.18

Consideration also needs to be given to the selection of endpoints in biosimilar studies which may be conducted to evaluate an indication. In these cases, some regulatory agencies may request use of sufficiently sensitive endpoints.9, 10, 11 Biosimilar trial primary endpoints do not have to be the same as those used for clinical trials of the innovator, and currently may be selected to facilitate the detection of differences between innovator and biosimilar products. Should different primary endpoints be used than those that would be most sensitive or were used for the innovator biologic pivotal studies, secondary endpoints may be recommended by some regulatory authorities to include some common endpoints as those used for the pivotal trials of the innovator biologic to ensure more complete evaluation of clinical efficacy.11

For oncology, as overall survival endpoints are not considered adequately sensitive, biosimilar trastuzumab and rituximab clinical trials have used objective response rate (ORR) as primary endpoints. This may raise concerns in terms of biosimilar efficacy with clinicians, as ORR may not always correlate sufficiently with survival.19,20 Pathological complete response (pCR) has been used as the most sensitive endpoint in a neoadjuvant setting, though again may not be predictive of overall survival.14,21,22

In autoimmune diseases, endpoints based on continuous measures rather than dichotomous measures are also considered more sensitive; e.g., in rheumatoid arthritis (RA), focus may be placed on the Disease Activity Score (DAS) results rather than American College of Rheumatology 20% (ACR20) response rates, or in psoriasis, on the mean Psoriasis Area and Severity Index (PASI) results rather than achievement of a PASI 75% response rate.23, 24 Data analysis should also focus on the steep part of the response curves rather than the plateaus in biosimilar development as differences between reference and biosimilar products may be more apparent.9, 10 Requirements to achieve an interchangeability designation for the US may also influence trial designs and endpoints. Seeking early engagement with the regulatory agencies is essential to agree the most appropriate balance in a biosimilar’s development pathway.

Phase I ProgrammesPhase I biosimilar trials may entail enrolment of large numbers of subjects if conducted to demonstrate three-way equivalence between US- and EU-sourced

innovator biologics and the biosimilar to support global development. Usually, fewer subjects are needed in first-in-human and multiple-ascending-dose Phase I studies of innovator drugs as the primary focus in these settings is to demonstrate safety of a single drug. Phase I clinical units, typically designed to house smaller numbers of subjects, may be overloaded both in terms of recruitment capabilities and available beds for scheduling when conducting a biosimilar Phase I study. To complete a Phase I biosimilar PK study, it is not uncommon for a sponsor or subcontracting entity to stagger multiple groups of subjects through a Phase I unit or to involve multiple sites to increase subject capacity to obtain the required numbers. The conduct of biosimilar studies, while guaranteeing business for the Phase I unit, may jeopardise innovator or other biosimilar development timelines if designated Phase I units have no capacity for extended periods of time. It is important to keep one’s options open regarding securing Phase I unit capabilities.

Phase I biosimilar trials, like many innovator trials, are typically conducted in healthy volunteers. This has not been considered possible for rituximab biosimilars as safety risks associated with rituximab exposure are not considered acceptable for healthy volunteers. Rituximab biosimilar Phase I studies are often conducted in RA patients,13 because the RA patient population is considered easier to recruit and tends to be a more homogeneous population for PK determinations than cancer patients. The RA patient population studied may not always be in line with the indicated use of rituximab; while rituximab is indicated for patients who have failed TNFi treatment, the RA population studied for a rituximab biosimilar Phase I study might allow TNFi-naïve patients.25 In order to support patient recruitment against other studies, including innovator studies competing for the same patients, expectations exist to provide treatment for this population for at least one year. Clearly, this potentially increases the costs of Phase I study conduct substantially. Rituximab biosimilars also pose potential hurdles for ethics and regulatory committees regarding the acceptability of interim Phase I safety data in RA patients to initiate Phase III studies in cancer populations, as rituximab differs in the doses used as well as the immunogenicity profile for RA vs cancer patients. 17

Country and Site Selection and RecruitmentCountry selection strategies for Phase III programmes are typically based on balancing high enrolment potential, start-up timelines and business strategic needs. The basis for initial country and site selection is to focus on countries with shorter regulatory start-up timelines and previously high-enrolling sites for the indication being studied. High enrolment potential is also influenced by regional prevalence and incidence of disease. Though the expectation is that previously high-enrolling countries and sites will perform similarly in future studies, there may be differences in the recruitment patterns for a biosimilar versus a novel drug.


Regulatory

Limitations in access and variations in reimbursement criteria are important considerations in choosing countries. Access to biologics may be highly variable and in RA, for example, patients may have to meet requirements for disease duration, certain levels of disease activity or the number of previously failed traditional therapies to gain access to biologic therapy.26,27 Just as for innovators, the focus for biosimilars is often on those countries, e.g., Eastern Europe, to recruit studies where start-up timelines are relatively fast and there are large numbers of untreated patients who for financial reasons cannot get access to an innovator.28, 29 Similarly, although countries in Southeast Asia or Latin America generally have somewhat longer start-up timelines than Western Europe and North America, they may recruit more quickly due to high numbers of biologic-naïve patients and poorer access to innovators. Investigators might be further motivated by opportunities to gain access overall or earlier than payer guidelines allow to the most effective biologic therapy for their patients by enrolling them in a biosimilar trial. Co-payments, co-insurance for innovators, standard of care treatment as well as income level may also influence patient participation in clinical trials in certain countries.30, 31, 32

Biosimilar studies, generally, because they do not typically involve a placebo treatment arm, may be initiated more quickly by posing fewer concerns for ethics committees and institutional review boards. As with any situation, exceptions exist, e.g., European Medicines Agency (EMA) has requested a short placebo arm for interferon beta biosimilar studies. 33 While lack of a placebo arm may influence patient recruitment, enrolment may also be impacted by the known efficacy and safety profile of the innovator biologic. In autoimmune disease and breast cancer studies, recruitment rates may be higher for biosimilar studies than innovator studies as all patients obtain a form of active therapy, i.e., the innovator biologic or biosimilar, known to be or presumed to be, respectively, efficacious. In contrast, for non-small cell lung cancer (NSCLC), discussed further subsequently, recruitment might be slower, possibly due to the innovator biologic’s perceived modest efficacy profile and multiple opportunities to participate in novel drug studies. Overall patient recruitment rates may still be affected by similar restrictive inclusion and exclusion criteria as used in the innovator programmes.

Business strategy for a biosimilar product development influences country selection, often to ensure that regulatory requirements of countries of interest are met. There are a number of countries which currently require that the biosimilar drug be studied in their patient population in order to seek approval, e.g., Mexico, Russia, China; these requirements are often in line with their regulatory requirements for innovator development, and may change with time. As it is conceivable that some studies could complete enrolment prior to initiation of a ‘required’ country, it is difficult to predict the success of a single country and site selection approach to meet

all strategic needs. There may also be a desire to allow investigators in a target country to gain experience with the biosimilar product prior to market approval. As a result, sponsors may plan to conduct additional trials to meet their anticipated needs. Many regulators will require post-approval requirements to evaluate late occurring safety events for biosimilar products. Such studies may provide the opportunity to include additional countries to meet business strategic needs. Sponsors may also focus efforts in certain countries, especially if they themselves are based in those regions.

Managing the Competitive EnvironmentPer ClinicalTrials.gov, the number of Phase III trials for biosimilars aimed at the treatment of RA and other related autoimmune conditions has increased significantly in the last five years, with 80% of the Phase III studies having been or planned to be started from 2013 onward.13 A similar scenario exists for oncology. The situation therefore exists where virtually identical studies are running with overlapping timelines. As site capacity for running competing trials is finite, historically high-enrolling sites will ultimately become saturated. Some companies are looking for new territories and sites as a potential way to broaden their access to patients for biosimilar trials. Even so, expectations regarding recruitment rates may need to be modified as this bolus of studies progresses through the clinics.

Many of these studies are focused on drugs with the same mechanism of action, e.g., TNFi agents, targeting similar patient populations, and, therefore, similar investigators. Novel drugs may also be competing for the same patient populations. This is exemplified in NSCLC trials where multiple bevacizumab biosimilars are competing directly for investigator site resources against innovator therapies. In these situations, the risk of competition from novel drug trials that may offer compelling opportunities for improved efficacy and survival should be evaluated, despite the risk of receipt of placebo (including standard of care with or without active control) in the innovator study. Such trials may threaten the enrolment of biosimilar trials, so it is important to have a clear understanding of the competitive landscape at the local level. As with any clinical trial, investigators should be supported with tools that reduce the risk of enrolment delays. Recruitment practices vary by speciality and country, so should be designed and implemented to support the needs and preferences of investigators, as well as to be culturally appropriate and acceptable to ethics committees/institutional review boards and regulatory authorities. In a global survey conducted by Quintiles in 2012, less than 45% of investigators who conduct trials in haematology-oncology, rheumatology, and dermatology reported having adequate patient numbers at their sites. Referrals from other physicians were cited as the most effective method to supplement recruitment across these specialities globally, though advertising was preferred by more than 65% of rheumatologists and 70% of dermatologists in the US.


26272-RQA-Clinical Research_GCP_Advertisement__AW(P).indd 1 26/04/2013 13:21


Regulatory

Utilising education to inform investigators regarding biosimilars may be successful in gaining their involvement in a biosimilar study where they may have previously dismissed participation due to lack of scientific interest. According to a survey of EU specialists conducted by the Alliance for Safe Biologic Medicines, over half claimed to have only a basic understanding of biosimilars and nearly one-quarter could not define or previously had not heard of biosimilars.34 Comparable results exist from other similar efforts.18, 35 Based on these results, education is needed to explain biosimilars, the unmet need for biologics to treat disease, and regulatory requirements to ensure non-clinical analytical and functional comparability to the innovator biologic before clinical testing. The importance of sponsors investing in developing relationships and instituting education earlier rather than later with investigators cannot be underestimated from the perspective of delivering on development needs for both innovators and biosimilars. These interactions might also serve to reshape standards of care and eventually prescribing patterns.

As more biologics have come into the marketplace for RA, treatment paradigms are advocating for patients to be treated sooner and more aggressively, which may make trial recruitment more difficult.36 Many RA Phase III biosimilar studies focus on recruiting biologic-naïve patients, or for rituximab, TNFi failures,37 as these were the target populations for the innovator biologic pivotal studies. Previous biologic drug exposures may also disqualify a patient from participation in subsequent innovator or biosimilar studies. Patient recruitment may become more difficult over time as the availability of additional therapies continues to improve access.

Currently, biosimilars require the collection of immunogenicity and safety data for at least one year if planning to market in both the EU and US.9, 11

Biosimilar studies rarely extend beyond this duration. Innovator Phase III studies usually involve longer-term extensions to build safety databases. As competition for patient populations increases, sponsors need to give consideration to extending treatment periods to compete not only with recruitment for innovator trials, but also with other biosimilar trials.

To appeal to patients and investigators, minimising trial complexity is important. 38 Thought should be given to the minimum clinical and laboratory data needed and collected in a case report form, and whether or not 100% source data verification is recommended based on the risk-based approach to monitoring. The burden of patient travel to sites should be reduced as much as possible. For example, for biosimilar studies in RA or psoriasis, visits should ideally be no more than monthly after the initial four weeks from randomisation, excepting more frequent visits expected by the regulators when evaluating switch or transition between innovator biologic and biosimilar products. Allowance should be made for home injection, if applicable, for interim doses. For oncology biosimilar

trials, provision of backbone chemotherapy by the sponsor must be considered to alleviate any potential burden and inconsistency within the supply chain throughout the trial.

For companies that provide full pharmaceutical and clinical trial services such as contract research organisations (CROs), it is critical to establish the timing of its sponsor’s clinical trials. This is not only important to determine potential business conflict of interest issues upfront to maintain firewalls between teams as needed, but also to determine “roll on/roll off” of studies sequentially to keep high-enrolling sites continuously active and to identify site resource constraints and potential site and country saturation issues. CROs often see many biosimilar and innovator trials in a short timespan, receiving more frequent regulatory feedback related to biosimilar and innovator development than most sponsors in the same period. Therefore, CROs are in a position to provide more ‘real-time’ evaluation of issues to inform current development and operational execution. CROs may also be able to support investigator engagement with educational materials, including proprietary websites where investigators can learn more about the role of biosimilars in a particular disease and the status of biosimilars in their region.39

Investigational Product ConsiderationsOther issues that may arise unique to biosimilar trials are related to use of the innovator biologic as a comparator. Similar to providing active controls in studies, obtaining the innovator product can be problematic for many reasons. Careful planning and attention will need to be given to sourcing innovator product. It is critical to arrange for adequate supplies of the reference product at study onset to ensure supply continuity, but with appropriate expiration dates to avoid clinical drug supply wastage. The optimal strategy should include obtaining large supplies of reference product from the same lot, if at all possible, as lot-to-lot variation can become an issue. Blinding may also cause concern, especially with the different packaging configurations often associated with subcutaneous innovator biologics, including prefilled syringes and auto-injectors, as compared to those planned for the biosimilars. Blinding strategies need to be planned, including identifying whether the need exists for an unblinded monitoring team. Third-party clinical supply vendors can assist with sourcing as well as blinding needs.

The costs and ease of sourcing of biologics from different regions may vary depending on regional supply and pricing of the innovator. The current environment is such that if either EU- or US-sourced product is being used as a sole comparator in a Phase III study, its use will need to be scientifically justified. This justification can include analytical and functional similarity data between the chosen reference comparator and the reference product approved in the country/region of interest. Both the EMA and FDA allow use of non-EU or


Regulatory

non-US reference product, respectively, as a comparator in a confirmatory clinical Phase III study once a scientific bridge has been built between the EU/US and non-EU/US reference product from an International Conference on Harmonisation (ICH) country.9, 11 Although this bridge may be built non-clinically, currently, the bridge clinically is built via the Phase I programme. Furthermore, at this time, for interchangeability assessments in the US, data will need to be provided with US-sourced reference as a comparator.

Many injectable innovator products have an auto-injector presentation, and biosimilar sponsors may provide an auto-injector to be on par for marketing against the innovator and other biosimilars where the drug is approved for self-injection. For arthritic patients specifically, sponsors should be aware that the US FDA currently requires PK evaluation in a representative patient population with the auto-injector vs. prefilled syringe to ensure adequate delivery of the drug as well as the usual human factor studies that are required for both innovator and biosimilar compounds.40 Therefore, for an injectable TNFi biosimilar, consideration should be given to evaluating the auto-injector in the subset of psoriasis patients with psoriatic arthritis and/or in RA patients with manual dexterity issues to garner the requisite PK data and patient usability data.

Other issues to consider are provision of a certificate of analysis for all investigational products in accordance with ICH guidelines and, in the EU, a qualified person to certify release of investigational product.41, 42, 43 For pharmacovigilance, appropriate adverse event reporting for the innovator itself to the respective sponsor should be implemented.

Commercial and Reimbursement ChallengesLastly, commercial and market access issues need to be considered in biosimilar development programmes.

Marketing needs may drive the conduct of biosimilar trials in more than one indication. As regulatory requirements for biosimilars continue to evolve and clinicians remain still relatively unfamiliar with them, providers may be unwilling to use biosimilars without data in the actual indications for which they see patients, e.g., a gastroenterologist may not use a TNFi biosimilar for the treatment of Crohn’s disease (CD) if the only data available for the biosimilar are in RA.35 This attitude may change over time as clinician awareness of biosimilars increases and they gain actual experience with biosimilar products.14, 18

The potential for biosimilars to reduce overall healthcare costs has led to stakeholder and payer support for biosimilar development among various countries, including the US and Western Europe.44 Market uptake of biosimilars also has not always been as significant as expected and may not be solely driven by pricing.6,45

As a result, medical and payer stakeholders may drive

generation of additional data or conditions required for adoption. For example, the Norwegian Medicines Agency (NoMA) is sponsoring a post-marketing switching study designed to demonstrate interchangeability with innovator infliximab.46 A key lesson for sponsors is to engage early with payers and key physician groups to determine the optimal dataset necessary for commercial uptake. Even if desired endpoints cannot feasibly be generated during Phase III studies due to time and cost constraints, discussions with commercial and reimbursement stakeholders can help sponsors proactively plan appropriate post-approval studies.

Another important market access consideration for sponsors as they pursue biosimilar development is that sponsors may currently have specific payer requirements for provision of cost-effectiveness evidence. Whether generated during clinical development or post-approval, cost-effectiveness data have been important for payers to decide to endorse or reimburse biosimilars; thus, sponsors could incorporate such assessments in development programmes. Although most payers and health technology assessment (HTA) agencies are generally aligned with regulatory requirements, some have demanded additional evidence as for innovator therapies. For example, the All Wales Medicines Strategy Group (AWMSG), an HTA agency based in the United Kingdom (UK), indicated in their assessment of biosimilar epoetin zeta (Retacrit®) that it was lacking in special population, economic and patient outcomes evidence and, therefore, did not recommend the biosimilar for reimbursement.47

Other important factors for sponsors to consider during development programmes include: stakeholder (physician, patient, and payer) educational/awareness efforts – beyond attracting investigators to biosimilar studies, prescribing physicians are more likely to adopt and encourage the use of biosimilars based on good understanding of biosimilars; 14, 33, 34, 35 development of innovative, user-friendly devices (e.g., easy-to-use and convenient auto-injectors for patients) – which have the potential to differentiate biosimilars; support and value-added programmes (e.g., nurse educators or co-pay assistance) for patients who have become accustomed to such services from innovator biologic manufacturers; and forming partnerships with key payers, payer-providers (e.g., disease centres of excellence or in the US, accountable care organisations), distributors (e.g., drug wholesalers or group purchasing organisations), and patient advocacy organisations, who can all support sponsors with use of their biosimilar therapies. These are important as potential cost differentials for biosimilars may be countered for the innovator biologic.48, 49

Incorporating these considerations into biosimilar

development means that commercialisation of biosimilars may be more similar to branded therapies than to generics; thus, sponsors must allocate sufficient marketing resources to these products. Such resources


Regulatory

include key medical, sales, and reimbursement personnel (e.g., medical science liaisons, sales reps, and managed care account representatives); medical education materials and events; and consumer advertising budgets.

SummaryBiosimilar clinical development offers many opportunities for sponsors, investigators and patients. It is an evolving landscape from a clinical trial, regulatory and commercial point of view, which increases the challenges associated with implementing a successful biosimilar development programme. As biosimilar development is still a relatively new endeavour, and as more experience is gained, countries continue to adapt to allow unique provisions for biosimilar development. New guidances for biosimilar development have been announced already for 2015 by regulatory agencies and government advisory bodies including the US FDA and the National Institute for Health and Care Excellence (NICE) in England.50, 51 Based on the experience gained in the past 10 years, EMA also have modified their thinking regarding biosimilar product development as shown by revisions not only to the overarching guidelines for non-clinical and clinical development, but also to product-specific guidelines. 10, 11

To bring a biosimilar to market still requires a significant investment of money, resources and time, though currently less than that required for an innovator product.5 To be successful in biosimilar development requires comprehensive, in-depth planning of the entire programme, with a global outlook. Contributions to optimise planning should be obtained not only from internal sponsor representatives including clinical operations, medical, regulatory, statistics, and marketing, but also from external representatives e.g., regulatory agencies, payers, investigators, prescribers and patients. Ultimately, the goal of biosimilar development is to provide more opportunities for patients to access potentially life-changing drugs.

AcknowledgmentsThe authors gratefully acknowledge contributions to the preparation of this paper from Dr Ray Huml and Dr Rick Turner, Quintiles.

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51. National Institute for Health and Care Excellence. NICE’s Biosimilar Position Statement. (2015). https://www.nice.org.uk/Media/Default/About/what-we-do/NICE-guidance/NICE-technology-appraisals/biosimilars-statement.pdf. Visited 7 Jan 2015.

Rod Hepburn, Scott Davis, Deepa Dahal, MBA, Tracy Stewart, MBA (Quintiles), and

Kamali Chance, MPH, Ph.D., RAC, is a Vice President, Global Biosimilars Regulatory Strategy at Quintiles, Inc. She has extensive experience in strategic development drugs/biologics/biosimilars. In her current role, she advises biotechnology companies with region specific and/or global regulatory

strategy for the development of biosimilars. Email: [email protected]

Niti Goel, MD, FACR, a board certified rheumatologist, is Head of the Rheumatology Center of Excellence at Quintiles and an Adjunct Assistant Professor of Medicine at Duke University School of Medicine in Durham, NC. With almost 20 years of academic and industry

experience in clinical development and medical affairs, she provides therapeutic and medical regulatory strategy expertise, covering areas such as trial design, patient-reported outcomes, and lifecycle planning for biosimilars and innovator products. She is also an active member of OMERACT. Email: [email protected]


Regulatory

The US Food and Drug Administration (FDA) approved Zarxio (filgrastim-sndz), the first biosimilar product (or biosimilar), on March 6, 2015, making for a quick approval decision following a meeting of the Oncologic Drugs Advisory Committee (ODAC) just two months prior. ODAC members unanimously favoured the granting of licensure to EP2006, at the time a proposed biosimilar to Amgen Inc’s Neupogen (filgrastim), for all five indications in the Neupogen labelling. Panellists commended the sponsor, Sandoz Inc, on the extensive data in support of the application, including robust results from outside the US (AdComm Bulletin, 2015). This application is the first to have been brought for review before an FDA advisory committee.

Having been classified as a biosimilar means that Zarxio was concluded to be highly similar to the reference product, Neupogen, notwithstanding minor differences in clinically inactive components; and that there are no clinically meaningful differences between the two products in terms of safety, purity, and potency. A biosimilar product can be prescribed by a healthcare provider in place of the FDA-approved reference product. The provider has to write the specific name of the product on the prescription in order to prescribe the biosimilar.

Neupogen, a human granulocyte colony-stimulating factor (G-CSF), was originally licensed in 1991. As a result of the FDA’s decision, Zarxio is now approved for the same indications as Neupogen. Since there is no precedent for naming a biosimilar in the US, the assigned name “filgrastim-sndz” will act as a non-proprietary name; the FDA has noted its intention to release guidance in the future on the standards to be applied to naming biosimilar products.

Regarding pediatric use of Zarxio, the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c) requires all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. The FDA deferred the assessment of Zarxio for

pediatric patients who weigh less than 36 kg because this product is ready for approval for use in adults and assessment in the pediatric population has not yet been completed.

Reviewing a 351(k) ApplicationThe quest for the FDA’s approval of a biosimilar product in the US was formally launched with the signing of the March 2010 Biologics Price Competition and Innovation Act of 2009 (BPCI Act), part of the Patient Protection and Affordable Care Act. Section 7002 of Title VII—Improving Access to Innovative Therapies, Subtitle A amended section 351 of the Public Health Service Act (PHS Act) to provide an approval pathway for biosimilar or interchangeable biological products in the new “subsection (k)” of the PHS Act. The application for a biosimilar under this section is known as the 351(k) application.

In reviewing available data to support biosimilarity, the FDA takes into account the “totality of the evidence” and recommends a stepwise approach to developing the data and information needed. Sponsors are required to provide information to demonstrate biosimilarity based on data directly comparing the proposed product with the US-licensed reference product. In the cases where a development programme includes data generated using a non-US-licensed comparator to support biosimilarity to the US-licensed reference product, the sponsor must provide adequate data to scientifically justify the relevance of these comparative data to an assessment of biosimilarity and establish an acceptable bridge to the US-licensed reference product. The FDA’s recommendations on data needed to support approval of biosimilars are further outlined in various FDA guidance documents.

FDA Makes First Move on Biosimilars in the US

Table 1: EP2006 Clinical Program

Trial Design Regimen Primary Endpoint

EP06-301

Open-label, single-arm, multicenter study

EP2006 (pre-filled syringes), SC, daily dose of 5 mcg/kg, from day 2 of each chemotherapy

cycle until the ANC recovered to 10 × 109/L after the nadir or up

to a maximum of 14 days

Mean DSN in cycles 1 to 4; incidence of febrile neutropenia; and time to neutrophil recovery

EP06-302

Randomized, double-blind, parallel-group, multicenter study

EP2006 and US-licensed Neupogen (supplied in vials, 480 mcg in 1.6 mL), SC, daily dose of 5 mcg/kg, from day 2 of each

chemotherapy cycle until the ANC recovered to 10 × 109/L

after the nadir or up to a maximum of 14 days (whichever

occurred first)

Mean DSN, defined as the number of consecutive days with ANC < 0.5 Gi/L during cycle 1

EP2006 Clinical Program

ANC = absolute neutrophil count; DSN = duration of severe neutropenia; SC = subcutaneous


According to the ODAC briefing materials on EP2006 (filgrastim-sndz), the FDA concluded in its review that the data submitted demonstrate that EP2006 is highly similar to US-licensed Neupogen, and that there are no clinically meaningful differences between the two products. The review further noted that the totality of the evidence supports licensure as a biosimilar for EP2006 for all five of the indications for which US-licensed Neupogen is licensed.

Clinical Programme Support for licensure of this product was submitted in the form of results from two clinical studies (EP06-301 and EP06-302) that evaluated efficacy and safety endpoints. EP06-301 (n = 170) was a non-comparative study in which patients with breast cancer were treated with chemotherapy and then one day later were given daily EP2006 until neutrophil recovery. EP06-302 (n = 218), a comparative study that enrolled women with breast cancer undergoing chemotherapy, was the pivotal trial for the evaluation of the biosimilarity of EP2006 to US-licensed Neupogen. An overview of the trial designs are provided in Table 1.

As noted in the FDA briefing materials for the January advisory committee meeting, absolute neutrophil count (ANC) is a relevant pharmacodynamic (PD) marker for G-CSF as it reflects the mechanism of action (MOA) of G-CSF. US-licensed Neupogen is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy and for other indications. Neutropenia is generally defined by abnormally low neutrophils in the blood that increases the risks for infection and other complications. Duration of severe neutropenia (DSN) was considered a clinically relevant endpoint for the approval of US-licensed Neupogen. Moreover, incidence of infection is regarded as a clinically relevant outcome in the clinical trial used to support approval of US-licensed Neupogen.

When the advisory committee was asked directly by the FDA whether it agreed with the agency’s conclusion that there are no clinically meaningful differences between EP2006 and US-licensed Neupogen, there was discussion on the pharmacokinetic (PK) results from a sub-study of trial EP06-302. The panel noted that EP2006-treated patients experienced a longer delay to recover their neutrophil counts, and for this reason they had difficulty agreeing with the FDA’s conclusion. Nonetheless, panellists acknowledged that the two agents achieved expected results that ultimately would be of benefit to patients.

Analytic Similarity in BiosimilarsA 351(k) application for a proposed biosimilar product must “include information demonstrating biosimilarity, based on data derived from, among other things, analytical studies that demonstrate that the biological product is highly similar to the reference product

notwithstanding minor differences in clinically inactive components.” This statement and recommendations for achieving analytic similarity are explained in the FDA Draft Guidance for Industry: Quality Considerations in D e m o n s t r a t i n g Biosimilarity to a Reference Protein Product.

Analytical similarity of EP2006, US-licensed Neupogen, and European Union (EU)-approved Neupogen was assessed by evaluating lots of each of the three products. A total of 20 lots of EP2006 drug product, six lots of EP2006 drug substance, 10-15 lots of US-licensed Neupogen, and 34-52 lots of EU-approved Neupogen were evaluated. The sponsor tested several quality attributes to evaluate analytical similarity of the three products. Based on these results, the FDA concluded that EP2006 is analytically highly similar to the reference product, notwithstanding minor differences in clinically inactive components.

In addition, EP2006, US-licensed Neupogen, and EU-approved Neupogen met the pre-specified criteria for analytical similarity. Sandoz provided a sufficiently robust analysis for the purposes of establishing an analytical bridge between the three products to support the relevance of data generated from clinical and non-clinical studies using EU-approved Neupogen, to support a demonstration of biosimilarity of EP2006 to the US-licensed reference product.

In its review of the application, the FDA explained that the analytical data support the scientific bridge based on the relatively simple structure of the protein, the lack of post-translational modifications, and the robustness of the analytical characterisation, and do not raise residual uncertainty of the results of the analytical similarity studies, when taken together with the other data and information submitted, to support the demonstration of biosimilarity.

Immunogenicity AssessmentsIn the briefing materials for the January 2015 advisory committee meeting, the FDA explained that immune

Regulatory

Analytical similarity of EP2006, US-licensed Neupogen, and European Union (EU)-approved Neupogen was assessed by evaluating lots of each of the three products. A total of 20 lots of EP2006 drug product, six lots of EP2006 drug substance, 10-15 lots of US-licensed Neupogen, and 34-52 lots of EU-approved Neupogen were evaluated. The sponsor tested several quality attributes to evaluate analytical similarity of the three products. Based on these results, the FDA concluded that EP2006 is analytically highly similar to the reference product, notwithstanding minor differences in clinically inactive components. In addition, EP2006, US-licensed Neupogen, and EU-approved Neupogen met the pre-specified criteria

for analytical similarity. Sandoz provided a sufficiently robust analysis for the purposes of establishing an analytical bridge between the three products to support the relevance of data generated from clinical and non-clinical studies using EU-approved Neupogen, to support a demonstration of biosimilarity of EP2006 to the US-licensed reference product. In its review of the application, the FDA explained that the analytical data support the scientific bridge based on the relatively simple structure of the protein, the lack of post-translational modifications, and the robustness of the analytical characterisation, and do not raise residual uncertainty of the results of the analytical similarity studies, when taken together with the other data and information submitted, to support the demonstration of biosimilarity. Immunogenicity Assessments In the briefing materials for the January 2015 advisory committee meeting, the FDA explained that immune reactions to therapeutic biological products are mostly caused by antibodies against the drug (anti-drug antibodies [ADA]). Therefore, immunogenicity assessment for therapeutic biological products focuses on ADA. Within the context of the development programme for EP2006, the agency advised that a multi-dose parallel-arm study design would allow for the clearest comparison of the immunogenicity of EP2006 to the US-licensed Neupogen and EU-approved Neupogen comparators. ADA to EP2006, US-licensed Neupogen, and EU-approved Neupogen were assessed in study EP06-302. Results from this study, as well as additional information on ADA incidence from study EP06-301, support a demonstration of no clinically meaningful differences between EP2006 and US-licensed Neupogen. Approaches used in assessing animal and human immunogenicity are outlined in the draft guidance Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. In general, the clinical programme for a 351(k)

application must include a clinical study or studies (including an assessment of immunogenicity and PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used, and for which licensure is sought for the biological product, as set forth in the PHS Act. The Future of Biosimilars in the US The FDA expects additional approvals of biosimilar products. Advisory committees will likely play a role in providing the FDA with expert opinions on the data presented to support the approval of biosimilar applications. One such meeting that was originally scheduled for March 17th was cancelled by the FDA,

Biosimilar Guidance from the FDA

The FDA has developed several guidance documents, all currently in

draft form, to assist sponsors in bringing new biosimilars to market:

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009, February-2012

Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, February-2012

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, February-2012

Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants, March-2013

Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, May-2014

Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act, August-2014


Regulatory

reactions to therapeutic biological products are mostly caused by antibodies against the drug (anti-drug antibodies [ADA]). Therefore, immunogenicity assessment for therapeutic biological products focuses on ADA.

Within the context of the development programme for EP2006, the agency advised that a multi-dose parallel-arm study design would allow for the clearest comparison of the immunogenicity of EP2006 to the US-licensed Neupogen and EU-approved Neupogen comparators. ADA to EP2006, US-licensed Neupogen, and EU-approved Neupogen were assessed in study EP06-302. Results from this study, as well as additional information on ADA incidence from study EP06-301, support a demonstration of no clinically meaningful differences between EP2006 and US-licensed Neupogen.

Approaches used in assessing animal and human immunogenicity are outlined in the draft guidance Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. In general, the clinical programme for a 351(k) application must include a clinical study or studies (including an assessment of immunogenicity and PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used, and for which licensure is sought for the biological product, as set forth in the PHS Act.

The Future of Biosimilars in the USThe FDA expects additional approvals of biosimilar products. Advisory committees will likely play a role in providing the FDA with expert opinions on the data presented to support the approval of biosimilar applications. One such meeting that was originally scheduled for March 17th was cancelled by the FDA, the agency referring to a request for additional information from the sponsor. The Arthritis Advisory Committee was to discuss biologics license application (BLA) 125544 for CT-P13, a proposed biosimilar to Janssen Biotech Inc’s Remicade (infliximab), submitted by Celltrion, Inc. In August 2014, Celltrion had submitted a 351(k) application in the US for CT-P13; at that time, the sponsor had also submitted additional clinical trial data, along with the established global clinical trial data, as part of the application and approval was expected within one year.

Filgrastim-sndz has not been approved for interchangeability. Specifically, section 351(k) of the PHS Act sets forth the requirements for an application for a proposed biosimilar product and an application or a supplement for a proposed interchangeable product. This requires some experience in humans prior to earning the approval. To meet the higher standard of “interchangeability,” an applicant must:

• provide sufficient information to demonstrate biosimilarity, and also to demonstrate that the biological product can be expected to produce the same clinical result as the

reference product in any given patient; and• if the biological product is administered more than

once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

The question of the impact on the market and on the health of patients of products that are ultimately deemed interchangeable has yet to be answered. Until a product is deemed interchangeable, substitutions cannot be made automatically if an original prescription indicates Neupogen. Once that classification happens, the patient may receive the interchangeable instead of the reference product, even if the healthcare provider writes the prescription for the reference product.

The US medical reimbursement structure will also be impacted by this new approval and any future biosimilar products that are licensed in the US. The largest payer for medical care in the US is the Center for Medicare and Medicaid Services (CMS). CMS issued a question and answer guide through its Medicare Learning Network to address the many questions regarding how and when it will manage coverage it has received regarding reimbursement for filgrastim-sndz. Interestingly, the CMS policy may contradict the condition of interchangeability established by the FDA.

Deborah Komlos, MS, is the Senior Medical & Regulatory Writer for the Cortellis US Module at Thomson Reuters. In addition to writing and editing related to FDA advisory committee meetings and product approvals, Ms Komlos has managed several regulatory affairs projects including a newsletter and

Cortellis AdComm Profiles. Her previous experience has included writing and editing for magazines, newspapers, online venues, and scientific journals, as well as publication layout and graphic design work. Email: [email protected]

Regina Ballinger, RN, MS, is a Senior Manager of Regulatory Intelligence with Thomson Reuters. She currently manages US regulatory content for Cortellis, and is the executive editor of the AdComm Bulletin. Ms Ballinger has specialised experience in public health, pharmaceutical regulatory

affairs, health communications, and nursing. She has had numerous articles published on topics related to new drug approvals and drug regulatory issues. Ms Ballinger was educated at the University of Maryland in law and nursing. She holds an MS degree in healthcare systems management.Email: [email protected]

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Market Report

Romania’s Regulatory Framework for Clinical Trials

Romania is located in Southeastern Central Europe, north of the Balkan Peninsula and on the western shore of the Black Sea. With a population of 20.1 million, it is the seventh most populous member of the European Union. Its capital and largest city, Bucharest, is the sixth largest city in the European Union.

Historically, Romanian researchers and inventors are well known and have made notable contributions to the scientific field. Henri Coandă discovered the Coandă effect of fluidics. Victor Babeș discovered more than 50 types of bacteria; biologist Nicolae Paulescu discovered insulin, while Emil Palade received the Nobel Prize for his contributions to cell biology. Lazăr Edeleanu was the first chemist to synthesize amphetamine, while Costin Nenițescu developed numerous new classes of compounds in organic chemistry.

After the fall of communism in 1989, the country experienced a decade of economic instability and decline, led in part by an obsolete industrial base and a lack of structural reform. From 2000 onwards, however, the Romanian economy was transformed into one of relative macroeconomic stability, characterised by high growth, low unemployment and declining inflation. Since 2000, Romania has attracted increasing amounts of foreign investment, becoming the single largest investment destination in Southeastern and Central Europe. In 2014, economic growth was at 1.8% with Romania preceding countries like France, Germany and the United Kingdom, and unemployment was at 6.4%, which is very low compared to other EU countries.

With the current favourable economic trend, and well-established and clear regulations, we thought about sharing with you some insights into the regulatory framework for clinical trials in Romania.

Clinical trials are experimental research on the administration of a drug or cosmetic product in humans. These studies must be conducted in accordance with GCP (good clinical practice) and the applicable law in the state where it takes place.

GCP is a set of rules of good clinical practice, which is an international standard for ethical and scientific quality in the design, management, recording and reporting of clinical trials involving human subjects, facilitating mutual acceptance of data by the competent authorities in the field of medication.

In Romania, according to Regulation (EC) Nr. 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products, clinical trials in human volunteers do not represent a requirement for

placing these products on the market. For products that do not fit into the category of cosmetics, approval must be requested from the National Agency for Medicines and Medical Devices (NAMMD) in accordance with law 95/2006 on reform in the field of health, Title XVII - Drug, with subsequent modifying.

The Cosmetic Directive 76/768/EC which has been replaced by the Cosmetic Products Regulation 1223/2009 and which harmonises and simplifies the cosmetics regulations across the EU member states including Romania, provides strict guidelines controlled by authorities in each member state, harmonising the requirements for cosmetics in the European Community. A “cosmetic product “means any substance or preparation intended for placing in contact with the various external parts of the human body (epidermis, hair system, nails, lips and external genital organs) or with the teeth and mucous membranes of the oral cavity with the view exclusively or principally to cleaning them, perfuming them or protecting them in order to keep them in good condition, change their appearance or correct body odours” (Cosmetic Directive 76/768/EC).

Studies involving skin measurement methods and testing of cosmetic products on humans are similar to medical research. They involve the use of humans as research subjects and also deal with pure scientific research, whose primary purpose is to contribute to generalised knowledge about the human skin physiology and active substances, and with applied research, aimed to evaluate the safety and efficacy of new cosmetic ingredients and finished products. In both studies, the ethical considerations are related to the relationship between the physician/the investigator and the human subject/the healthy or sick volunteer and their main objective is the protection of the human being. So, the ethical considerations for cosmetic testing and use of skin measurements are similar to those for medical research on humans, particularly non-therapeutic research. They are subject to the ethical principles of the Declaration of Helsinki and the guidelines for good clinical practice (GCP), and are integrated into the research design.

There are several guidelines for testing cosmetics on human subjects, whose indication is found in the guidance DG - Health and Consumer Protection - Scientific Committee on Consumer Product (SCCP). The SCCP’s Notes of Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation.

As previously mentioned, in Romania, the competent authorities in the field of medicine are the NAMMD and Ethics Committee.


Market Report

Clinical trials on drugs are regulated in Romania in accordance with international law (Order MS no. 904 of 25 July 2006) “approving the Rules relating to the implementation of good practice in the conduct of clinical trials on medicinal products for human use” transposing Directive 2001/20 / EC of the European Parliament and of the Council of 4 April 2001; MS Order no. 903 of 25 July 2006 “Principles and detailed guidelines for the approval of good clinical practice for medicinal products for human investigational, and requirements for the manufacture and importation of these drugs”, transposing Directive 2005/28 / EC of 8 April 2005; Order no. 905 of 25 July 2006 “on the approval of the principles and guidelines of good manufacturing practice for medicinal products for human use, including for clinical investigation”

transposing Directive 2003/94 / EC of 8 October 2003.The NAMMD is a public institution subordinated to the

Ministry of Health, set up through Government Emergency Ordinance no. 72 of 30 June 2010 on reorganisation of certain healthcare facilities and amendment of public health legislation, as a result of the merger of the National Agency for Medicines and the Technical Office for Medical Devices. The NAMMD organisation and operation have been approved by Government Decision No. 734 of 21 July 2010.

For over 50 years now, the NAMMD has represented the medicinal product regulatory authority in Romania. Initially known as the Institute for the Control Medicines and Pharmaceutical Research on its setup in 1956, the name of the institution was further changed in 1960, to become the State Institute of Drug Control and Pharmaceutical Research (ICSMCF) and later on, between 1999 and 2010, by reorganisation of the former ICSMCF, the institution operated as the National Medicines Agency. The National Agency for Medicines and Medical Devices (NAMMD) is established through Emergency Government Decision no. 72/2010, as result of the merger of the National Medicines Agency with the Technical Office for Medical Devices.

The ICSMCF was the first institution in Romania to comply with the modern definition of a medicines regulatory authority, whose main duties were: authorisation and registration of medicinal products,


yearly development of the Product Index, complex control of medicinal products manufactured nationally and abroad, pharmaceutical inspection, development of the Romanian Pharmacopoeia and its Supplements, development of national standards and reference materials, etc.

According to Scientific Council Decision no. 2/2014 on Regulations for authorisation of units able to perform clinical trials in the field of the medicinal product for human use (approved on 22 April 2014), the applications for authorisation of units able to perform clinical trials on medicinal products for human use shall be submitted to the NAMMD.

For each approval of clinical trial on drugs, a dossier is submitted to the NAMMD after getting a favourable opinion from the National Committee of Ethics. A clinical trial on pharmaceutical products cannot start until the Ethics Committee has issued a favourable opinion and the NAMMD has not informed the sponsor of any grounds for non-acceptance. The study dossier addressed to the National Committee of Ethics and the one addressed to the NAMMD can be sent in parallel. Both the National Committee of Ethics and the NAMMD should express their opinions taking into consideration the same versions of the submitted documents. The timeframe for approval is 60 days from the submission of a complete and updated dossier.

Upon approval, the signed order indicates the

institution where the study will be conducted, and the principal investigator responsible for conducting it.

For more information about clinical trials, the links for the European Union Authorities (http://www.ema.europa.eu/ema/), USA (http://www.fda.gov/) and the World Health Organization (http://www.who.int/en/) can be accessed.

Compliance with these standards and regulations assures the public that the rights and safety of the trial subjects are protected under the principles based on the Human Rights Declaration of Helsinki, amended.

Clinical trials are conducted in a variety of locations, such as hospitals, universities, offices or clinics accredited for research by medical authorities.

A clinical trial may be mono-centric (occurs in one centre or one country), or multi-centric, taking place in several centres and countries. The multi-centric studies take place simultaneously in European Union countries, the United States, CIS countries, etc. whose volunteers contribute to international clinical research.

Clinical trials sponsors are usually companies or government agencies that investigate and produce drugs or cosmetic products. They design the strategy and finance the conduct of clinical trials. If the sponsor does

not have sufficient internal resources to organise clinical trials, they outsource (contract) the organising of clinical trials to specialised companies called clinical research organisations (CROs).

Between the organisations and clinical investigators conducting the study are contractual relationships in accordance with the rules of good clinical practice. These relationships determine the amount of funding for investigators and differ from project to project, depending on the length and complexity of each. Payment to the investigator is an international practice, a remuneration for a specific work of great scientific value which involves a major responsibility.

Even though Romania is estimated to have the fourth fastest-growing demand for travel and tourism in the world, it is also becoming a very popular destination for performing clinical trials, mainly due to its accessibility, and the availability of highly-trained medical practitioners and investigators, scientific technicians and researchers most of whom are fluent in both English and French, and last but not least, to the important availability of volunteers and patients.

Things are moving quickly in Romania, and with Bucharest being the safest city on the European continent, you may rest in peace that your clinical trial will unfold in a climate of public safety.

Christophe HAREL, Managing Director at CIDP Romania, is an Associate Member of the Chartered Institute of Secretaries and Administrators of the United Kingdom and holds a Master of Business Administration from the Business School of Edinburgh. Prior to joining CIDP Romania, he worked

in Mauritius for 12 years; seven years in a management company for global businesses, as administrative manager and company secretary, and five years as administrative manager at a motor car dealer. He has been, since 2011, the Managing Director of CIDP Romania.Email: [email protected]

Gabriela BARBULESCU, Quality Assurance Manager at CIDP Romania, graduated as a biologist from the University of Bucharest, Romania, having previous working experience in a laboratory for medical tests. She also holds a Master’s degree in consumer protection and quality

control from Politehnica University, Bucharest, Romania. Furthermore, she followed intensive training to become a specialist in quality management systems according to ISO 9001.

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Market Report

Drugs’ Marketing Authorisation and Clinical Trials Regulations in UkraineDespite the difficult political and economic situation, Ukraine is still open for pharma business and clinical trials in particular. Along with a vast population concentrated in several large cities, a wide range of investigative sites and qualified research personnel, Ukraine provides for foreign pharmaceutical companies and sponsors a regulatory environment mostly based on the principal provisions of the corresponding EU legal acts and guidance governing particular areas of drug marketing and clinical study authorisation.

Unlike Russia, which prefers to go its own way, including in terms of regulations in the sphere of drugs’ marketing authorisation (MA) and clinical trials, Ukraine moves along the beaten track and creates its legislative framework on the basis of the European legal documents. Despite that, the number of clinical trials initiated in Ukraine by European and other foreign sponsors has not yet approached the level of Russia.

Nevertheless, Ukraine is one of the most attractive regions of the post-Soviet area in terms of clinical research because of its vast population which is concentrated in several large cities (about 46 million people), well-equipped investigative sites (1476 as of January 2014), qualified and GCP-trained medical personnel, as well as a favourable legal landscape with regulations compliant with the European standards.

The competent authorities engaged in MA and clinical trial authorisation are represented by the Ukrainian Ministry of Health (MoH) and its subordinate expert advisory board – the State Expert Center (SEC). The MoH grants MA for drugs and issues clinical trials authorisations. SEC conducts expert evaluation of MA applications and clinical trial documents, and carries out clinical trial audits and drugs safety monitoring. The Ukrainian Central Ethics Committee responsible for ethical expertise of clinical trials documents and clinical trials authorisation was abolished in 2012. The ethical support for clinical trials is now provided by numerous local ethics committees (LECs) established at various medical, scientific and educational institutions2.

Pharmaceutical companies or CROs can request scientific advice, either during the initial development of a pharmaceutical product before submission of MA application, or later on, throughout the validity period of the MA certificate. Scientific advice is free of charge4.

The MA procedure includes three stages of expertise. The first stage (lasting up to 21 working days) aims to determine that the drug is not forbidden in Ukraine and to classify the type of application. After the first stage is successfully completed, the applicant should pay out the registration fee and expertise cost. The objective of the second stage expertise (preliminary expertise), the duration of which is 14 working days, is the compliance of the submitted package of documents with established legal requirements. A complete application is needed in case of claiming for an innovative drug MA. An abridged application is prepared when submission is made for MA of generic drug, fixed combination of previously registered drugs and other dosage form/therapeutic indication of previously registered drug. In the course of the second stage expertise SEC could request for additional (or missing) data and documents, and the applicant has to respond in 90 working days4.

The cost of expertise depends on the type of MA application and the nature of the drug. In case of a complete MA application (standard application) the expertise cost is about 2750 Euro, and about 2200 Euro if the chemical drug (substance) is well evaluated in Ukraine, about 2600 Euro for expertise of biosimilar drug, about 1250 Euro for expertise of orphan drugs, about 2300 Euro for expertise of single component generic drug, and 2600 Euro for a multi-component generic drug. An applicant is also obliged to pay state registration tax of 100 Euro for each dosage form, 10 Euro for each additional dosage strength, 10 Euro for each additional package of the drug (except radiopharmaceutical, diagnostic products and herbal drugs)3.

Figure 1

Clinical trials in Ukraine (1996-2013)

http://synergycro.ru/orange_paper/Synergy_Orange_Paper_Ukraine_2014H1.pdf

Figure 2

Number of Investigative Sites in Major Cities

http://synergycro.ru/orange_paper/Synergy_Orange_Paper_Ukraine_2014H1.pdf


Market Report

Specialised expertise is performed by SEC within 210 working days in case of a complete application, and 90 working days in case of an application for selected situations (some drugs for treatment of HIV, tuberculosis, hepatitis, rare diseases; generics, biosimilars, orphan drugs, some others). In the course of specialised expertise, SEC could request additional (or missing) data on quality, safety and efficacy of the assessed drug and the applicant has to respond in 60 working days. In cases where documents and data submitted by the applicant do not fully provide justification of an MA application, the SEC could request additional non-clinical or clinical testing of the drug4.

The SEC expert report prepared at the end of specialised expertise is the basis for the MoH decision whether to grant MA for pharmaceutical product or reject the MA application. Data on quality, safety and efficacy of the drug needed for expert evaluation should be presented in CTD format, which comprises five modules, according to the EU requirements CPMP/ICH/2887/99. The submission package, besides CTD, should also include:

• Proof of drug registration status (i.e. MA certificate issued by the country of applicant/manufacturer; list of countries where the drug is already registered),

• Finished product manufacturer authorisation (licence), GMP certificates or other GMP statements,

• Flowchart and description of manufacturing process and process controls,

• Qualitative and quantitative composition of the drug and proposed analytical procedures for its control,

• Summary of product characteristics (SmPC), • Mock-ups and specimens4.

The MA is initially valid for five years and may be renewed after this period on the basis of a re-evaluation of the risk-benefit balance by the SEC4.

The information contained in the MA application and its annexes shall be subject to public disclosure and protection against unfair commercial use. In case a generic drug is submitted for MA within five years since the original drug has been registered in Ukraine, an applicant has to provide MoH with document evidencing that reference drug MA holder gave consent to use its non-clinical and clinical data for MA purposes4.

The MA holder should notify SEC of all the changes in the technological process, utilised equipment or manufacturers engaged in APIs and excipients production. An appropriate type of variation should be chosen. Type 1A/1B and Type 2 variations represent minor changes (e.g. a change of MA holder name or location, a change of proprietary drug name (trade name), a change of ATC code, etc.) that have a low risk of compromising quality, safety and efficacy of the pharmaceutical product. All the variations listed above are subject to a two-stage expert evaluation that is performed by SEC on the contract

basis. The first-stage expertise, lasting five working days, represents a preliminary assessment of the submitted package of documents in terms of compliance with legal requirements and the type of variation application. The second-stage expertise, lasting 60 working days, represents specialised expertise aimed at justification of proposed changes and absence of their impact on the quality, safety or efficacy of the pharmaceutical product. In the course of specialised expertise, SEC could request additional (or missing) data, and the applicant has to respond in 30 working days. The expertise cost varies depending on type of the variation and the nature of drug: e.g. about 240 Euro in case of a Type 1A variation that doesn’t affect the primary package of biotechnological drug, or about 400 Euro in case of a Type 2 variation that affects the primary package of biotechnological drug4.

All other changes, e.g. a change of the API to a different API, inclusion of an additional API, or removal of one API from a multi-component product, a change in the dose of one or more of the APIs, a change in dosage form or route of administration, a change in the recommendations for use, etc., are so major that they constitute a new pharmaceutical product. These should be considered to be an application for a new product and should not be accepted as a variation4.

The procedure for clinical trial authorisation is the same for both international multi-centre (IMCT) and local clinical trials. Clinical trial authorisation is issued by MoH based on the results of expertise carried out by SEC. The list of documents that should be submitted to SEC for expertise is presented in Table 1. The information contained in the MA application and its annexes shall be subject to

public disclosure and protection against unfair commercial use. In case a generic drug is submitted for MA within five years since the original drug has been registered in Ukraine, an

Table 1

List of documents for clinical trial authorisation

Cover letter Ukrainian language Application form Ukrainian language

Power of attorney with Apostille that specifies CRO’s activities on behalf of sponsor

English language (notarised translation into Ukrainian language is mandatory)

Clinical trial protocol English language Protocol synopsis Ukrainian language

Investigator’s brochure English language Investigational medicinal product dossier

(IMPD) English language

Case report form (except IMCT) English language Informed consent form Ukrainian and Russian languages

Patient-related documents (diaries, checklists, questionnaires etc.) and promotional materials

needed for recruitment

Ukrainian and Russian languages

IMP labels Ukrainian and Russian languages Certificate of IMP batch analysis English language

GMP certificate English language Principle investigator’s application Ukrainian language

List of clinical sites + information on clinical sites to be involved in clinical trial

Ukrainian language

Documents confirming establishment of clinical sites’ LECs

Ukrainian language

Signed and dated investigators’ CVs Ukrainian language Investigators’ GCP certificates Compulsory insurance policy Ukrainian language

Information on measures to be taken by investigator in case of insured event

Ukrainian language

Information on payments and compensations to healthy volunteers or patients (if any)

Ukrainian language

EudraCT number (if applicable) English language List of competent authorities of other countries

involved in expertise of IMCT (if applicable) English language

Brief information on other clinical trials with use of IMP

(if applicable)

English language

TSE certificate (if applicable) English language

Duration of expertise is 50 calendar days, and time needed for MoH to authorise the results of SEC expertise is 10 calendar days. The cost of expertise is about 3300 Euro in cases where the investigational drug is not registered in the country of origin, and about 2000 Euro if it has been already registered in the country of origin. In the course of expertise, SEC could request additional (or missing) data, and the applicant has to respond in 60 calendar days [5].

The clinical trial documents should be submitted for ethical assessment at every clinical site that is going to participate in the clinical trial. Ethical assessment may be performed before, simultaneously with, or after SEC expertise. The list of documents submitted for ethical


Market Report

Duration of expertise is 50 calendar days, and time needed for MoH to authorise the results of SEC expertise is 10 calendar days. The cost of expertise is about 3300 Euro in cases where the investigational drug is not registered in the country of origin, and about 2000 Euro if it has been already registered in the country of origin. In the course of expertise, SEC could request additional (or missing) data, and the applicant has to respond in 60 calendar days5.

The clinical trial documents should be submitted for ethical assessment at every clinical site that is going to participate in the clinical trial. Ethical assessment may be performed before, simultaneously with, or after SEC expertise. The list of documents submitted for ethical expertise is shorter than the list of documents submitted to SEC: IMPD and other drug-related documents (certificates, labels, etc) are not necessary for LEC assessment. It is also not necessary to submit the full text of the protocol, and a summary of this document is absolutely enough for ethical consideration. Ethical expertise is free of charge and its duration is 30 calendar days. In the course of ethical expertise, LEC could request additional (or missing) data, and the applicant has to respond in 30 calendar days2, 5.

If involvement of children is anticipated in the clinical trial, informed consent signed by both parents is mandatory. The information on investigational drug and planned clinical trial acceptable for minors’ understanding should also be provided for the child’s personal consideration and assent (written for older children or oral for younger children). Moreover, the information on the involvement of children in a specific clinical trial should be addressed by the investigator in writing to the the Ukrainian guardianship and custody agencies at the place of permanent residence of the child5.

In case a clinical trial has been authorised by MoH, a sponsor or CRO may apply for an import license for investigational drug and study materials (laboratory kits, needed equipment, etc.). The import license is issued in a two-step procedure. At the first stage, a sponsor applies for reconciliation of the total amount of investigational drug and study materials that should be imported for the whole study period. The appropriate document – so-called “umbrella” permission – is issued by SEC in 10 business days. At the second stage, a sponsor applies for permission to import definite shipments of investigational drug or study materials within the limits specified by the “umbrella” permission. The permission to import an exact shipment of clinical study drug or materials (import license) is issued in 10 business days by the State Drug Control Agency, which is subordinate to MoH5.

All the investigational drugs, including matching placebo, are charged VAT of 20% in accordance with the provisions of the Tax Code of Ukraine. It is expected that in the first half of 2015 the VAT rate will be decreased from

20% to 7% in order to boost the country’s attractiveness in terms of conduct of IMCTs.

Licence for export of biological samples is not needed. Any medical institution can participate in conduct of clinical trial as a research (investigative) centre in the case of:

• Proof of appropriate medical qualification (medical licence and accreditation certificate issued by MoH),

• Proof of LEC availability,• Proof of metrological control implementation,• Proof of storage areas’ availability (patients’ source

documents should be stored at least 15 years after clinical trial is completed at clinical site).

An investigator has to be an employee of a clinical site that is involved in a definite clinical trial. In case an investigator is an employee of a medical educational institution based at a clinical site, a corresponding contract between the educational institution and clinical site should be in place. It is also mandatory that the investigator should be GCP-trained. Payment of the research centre’s and investigator’s services is performed under the contracts signed between the research centre and sponsor/CRO, and between investigator and sponsor/CRO5.

The volunteers or patients who participate in a clinical trial (those who have signed an informed consent form) should be insured by the local Ukrainian medical insurance company.

The essential or non-essential amendments may be implemented in the course of the clinical trial. Both types of amendments should be submitted to SEC. The essential amendment is considered by SEC in 30 calendar days and addressed to MoH for issuing of a corresponding authorisation in case of a positive result of SEC expertise. The time needed for MoH to issue an amendment authorisation is five calendar days. In the course of expertise, which costs about 370 Euro, SEC could request additional (or missing) data, and the applicant has to respond in 30 calendar days. The non-essential amendment is submitted to SEC only for notification and the procedure is free of charge. All the amendments should also be submitted to LEC; essential ones for consideration and non-essential ones for LEC notification. The essential amendments should be considered by LEC in 10 calendar days5.

SEC is the Ukrainian competent authority whose competence includes drug safety monitoring issues, and sponsors or CROs are obliged to provide SEC with appropriate information. All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting. SEC should be notified of all fatal or life-threatening unexpected ADRs occurring in a clinical trial as soon as possible, but no later than seven calendar days after first knowledge by the sponsor that


Market Report

a case qualifies, followed by as complete a report as possible within eight additional calendar days. Serious, unexpected ADRs that are not fatal or life-threatening should be reported to SEC as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting. In case of a long-term clinical trial, the sponsor should provide SEC with periodic safety update reports at least once per year. In the course of safety data expertise SEC could request additional information if the benefit/risk ratio of investigational drug has changed from its point of view. If the sponsor has not provided SEC with the requested information in seven calendar days, SEC could temporarily or completely stop the trial5.

In the current 2014 year the political situation in Ukraine has been unstable, affecting the perspectives of ongoing and future clinical trials. The Ukrainian MoH, like other state agencies, has been under intense pressure because of a severe budget shortfall and major distractions. Nevertheless, regulatory approvals have remained in line with legislative timelines and study submission and consideration procedures have not changed. Furthermore, in 2015 the VAT rate for the import of investigational drugs, medical devices and equipment for approved clinical trials is expected to be cut from 20% to 7%, which should be regarded as a substantial step forward for Ukraine to improve its international image and attract additional clinical trials.

Some CROs that are operating in the clinical research market in Ukraine suppose that the economic constraints faced by the country will lead to shortages of certain high-priced medicines and hospital supplies, such as CT/MRI intravenous contrast dyes. The other companies believe that no significant changes will affect research sites or the ways they operate. Some CROs have stated that new studies should not be authorised in Crimea, recruitment of new patients into current studies should be ceased, and monitoring should not be done there, while others propose sponsors should ask Russia for study approvals for Crimean sites. CROs are quite unanimous in their assessment of prospects of the Ukrainian South-East region: sponsors should avoid research sites in this critical area. Such measures as thorough checks of logistic partners and local banks that are carrying out site payments, in terms of their inclusion in the sanctions lists, seem to be also quite reasonable1, 6.

References1. Vladimir Bogin, Clinical trials in Ukraine: current

status and short-term outlook, Journal of Clinical Research Best Practices, Vol. 10, No. 4, April 2014, https://www.firstcl inical .com/journal/2014/1404_Ukraine.pdf

2. Clinical trials in Ukraine: legal and practical aspects, Apteka.ua online, No.854 (33), 27.08.2012, http://www.apteka.ua/article/157979

3. On the approval of drug marketing authorization procedures and fees, the Ukrainian Cabinet of

Ministers Decree No.376, 26.05.2005, http://www.dec.gov.ua/ (in Ukrainian)

4. On the approval of expert evaluation of drugs’ registration dossiers, including expertise of drugs’ dossiers variations, the Ukrainian Ministry of Health executive order No.426, 26.08.2005, http://www.dec.gov.ua/ (in Ukrainian)

5. On the conduct of clinical trials and their expert evaluation, the Ukrainian Ministry of Health executive order No.690, 23.09.2009 amended by executive order No.523,12.07.2012, http://www.dec.gov.ua/ (in Ukrainian)

6. The Ukraine crisis and its impact on the regional clinical trials’ market, April 2014, http://www.kcrcro.com/news/newsletters/2-2014/the-ukraine-cr is is-and-its-impact-on-the-regional-clinical-trials-market

Dr. Yuri Afonchikov is Chief Regulatory Officer at Synergy Research Group, a leading Russian CRO. He gained his medical degree at Pirogov Russian National Research Medical University in Moscow, before completing his PhD degree in Internal Medicine and Cardiology. Previously, Yuri

had a 10-year career at the Russian Ministry of Health and its control agency Roszdravnadzor dealing with drug marketing and trial authorizations. Email: [email protected]

Dr. Sergiy Pakharyna is Chief Country Officer at Synergy Group Ukraine, the branch of Synergy Research Group, a leading Russian CRO. Sergiy received his medical degree at National Medical University n.a. Bogomolets, Kiev, Ukraine and was

working as a hematologist in the Oncohematology Center for Children. In 2004 he joined Ukrainian branch of international CRO and was promoted soon to Medical Director, after that Sergiy joined Synergy in 2009. Email: [email protected]


Therapeutics

Community-acquired Bacterial Pneumonia –A Challenging Diagnosis in Clinical TrialsIntroductionCommunity-acquired bacterial pneumonia is a common and important disease which is associated with significant morbidity and mortality worldwide. Various pathogens cause the disease, but often the underlying pathogen is not identified. Early diagnosis is key to successful therapy, however, frequently the disease is misdiagnosed.

Community-acquired bacterial pneumonia (CABP) is a common illness affecting approximately 4.5 million adults in the United States annually1. Approximately one-third of these patients require hospitalisation1. A number of pathogens can cause the infection, including: typical bacteria (Streptococcus pneumoniae, Haemophilus influenzae, and (in selected patients) S. aureus and gram-negative bacilli such as Klebsiella pneumoniae and Pseudomonas aeruginosa), atypical bacteria such as Chlamydophilia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophilia, and respiratory viruses either singly, or in combination with typical bacteria2. While S. pneumoniae causes up to 70% of CABP, atypical bacteria are responsible for 30 to 40% of cases3. This is a well-known disease, however there is a need for more rapid diagnostic tests, which would help eliminate initial diagnostic errors. Misdiagnosis obviously leads to inadequate therapy, a complicated disease course and adverse outcome. If this occurs during a clinical trial, it may compromise the data analysis. Eligibility criteria for CABP clinical studies specifically exclude patients with pneumonia caused by atypical pathogens (Legionella), viruses, etc. Frequently, these diseases have very similar clinical findings, especially at the early stages. Since there is a limited time for screening procedures and a paucity of effective rapid tests, diagnostic mistakes are common. Herein, we present four cases which were initially diagnosed as typical CABP and the patients were enrolled in clinical trials with new antibiotics, however, the final diagnoses differed.

Case 1A previously healthy 22-year-old male was admitted to the hospital with a cough productive of sputum, chest pain, general fatigue, and fever of 40.1 degrees Celsius. His vital signs at admission were: respiratory rate 26 per minute, heart rate 120 bpm, blood pressure 100/60 mm Hg, and oxygen saturation on room air 88%. On auscultation, his respiratory sounds were attenuated without crackles. Chest X-ray revealed left-sided pneumonia with a moderate pleural effusion; thoracentesis produced 60 ml of opaque, yellowish fluid. Microscopic examination of the pleural fluid revealed: 15-20 white blood cells (WBC) per hpf and gram-positive bacteria. Haematology on admission showed WBC count of 13.4x10^9/L with 86.6% granulocytes. Erythrocyte sedimentation rate was 41 mm/hour. The patient was enrolled in the clinical trial

and started on a cephalosporin. During treatment, the patient’s condition did not improve; he remained febrile (temperature 38.8 degrees Celsius), with persistent cough and chest pain. On day 4, after the start of treatment his admission chest X-rays were reassessed and the patient was diagnosed with a pulmonary abscess presumptively due to tuberculosis. Pulmonary tuberculosis was confirmed the next day and the patient was transferred to a tuberculosis hospital for further treatment.

Case 2An 11-year-old boy was admitted to the hospital with cough, dyspnea, stomach pains, and fever of 39 degrees Celsius. Physical examination was remarkable for dull percussion sound and decreased bronchial sounds above the left lower lung. Haematology on admission showed WBC count of 19.55x10^9/L with 89.1% neutrophils. Chemistry revealed elevated liver function tests – AST of 121 U/L (reference range 1-40) and ALT of 143 U/L (reference range 1-45). Bilirubin was normal. C-reactive protein (CRP) was increased to 157.7 mg/L (reference range 0-10). Chest X-ray revealed an infiltrate in the left lower lobe. The patient was diagnosed with CABP, enrolled in clinical trial and started on an antibiotic (cephalosporin). On the sixth day of therapy, his condition improved slightly, CRP remained significantly elevated – 200 mg/L, and there was no improvement on chest X-ray. On this day, his physician received results of an admission Legionella test that was positive. Considering the positive Legionella test and lack of clinical improvement by the end of the week of antibacterial therapy, the patient was suspected to have Legionella pneumonia and the antibiotic was changed to clarithromycin. The patient’s condition improved with treatment and he was discharged from the hospital two weeks later.

Case 3An 8-year-old boy was admitted to the hospital with a fever of 39 degrees Celsius, cervical lymphadenitis, pharyngeal erythema, and cough. He had a short history of conjunctivitis. Haematology showed WBC count of 16.3x10^9/L with 75% neutrophils. CRP was elevated at 260 mg/dL. His procalcitonin level was slightly elevated – 1.0 ng/ml (normal <0.05). Chest X-ray showed a right lower lobe infiltrate with pleural effusion; these findings were consistent with typical bacterial pneumonia. The patient was enrolled in the clinical trial and administered a cephalosporin. After three days of therapy, his clinical condition did not improve. Cardiac ultrasound revealed dilated coronary arteries. The patient was diagnosed with Kawasaki disease (mucocutaneous lymph node syndrome) and intravenous immunoglobulins were administered. In addition, baseline serology was positive for Mycoplasma pneumoniae antibody (IgM).


Case 4A 74-year-old man was hospitalised with cough productive of sputum, chest pain and fever of 39.7 degrees Celsius. Haematology on admission showed leukocytosis with WBC count of 16.5x10^9/L with 82% neutrophils. Chemistry was unremarkable. Chest X-ray showed a right lower lobe infiltrate consistent with pneumonia. The patient was diagnosed with CABP, enrolled in clinical trial and started on a cephalosporin. Two days after initiation of therapy, his condition deteriorated – chest pain and cough worsened. Chemistry showed significant elevation of LFTs –ALT to 500 U/L and AST to 350 U/L. ECG revealed atrial fibrillation with heart rate of 120 bpm. A complicated course of pneumonia was suspected. However, LFTs continued to increase and the patient was diagnosed with pulmonary embolism of the medium branches of the pulmonary artery and infarction pneumonia. Anticoagulants were started but despite intensive therapy, the patient died seven days later.

DiscussionThe etiology of CABP has been constantly reviewed during the last decade. The incidence of CABP is 1.54-11 cases per 1000 population per year and it is a leading cause of mortality from infectious disease in industrialised countries4, 5. The most common pathogens associated with CABP are divided into “typical” and “atypical”, however the causative agent frequently remains unidentified 2, 6. Treatment of CABP is becoming more difficult, partly due to the growing problem of antimicrobial resistance 7 and partly due to difficulties with initial diagnosis 4, 8. Typical pathogens account for 85% of CABP cases. However aside from atypical pathogens, differential diagnosis includes: cardiac pathology, e.g., myocardial infarction and congestive heart failure, pulmonary fibrosis, pulmonary embolism or infarction, drug-induced pulmonary diseases, bronchogenic carcinomas, lymphomas etc.4, 8, 9.

Clinical presentation, especially in the beginning of the disease, sometimes is not helpful, as signs and symptoms are not specific. The most frequent clinical symptoms of pneumonia are cough (78%), dyspnea (69%), pleuritic chest pain (32%), and rậles (79%)6. Fever, like leukocytosis, may be absent in certain patients – elderly or young children and immunocompromised subjects. It is known that a typical radiographic pattern, like alveolar infiltrates and interstitial infiltrates appears some time after the disease onset, which also may lead to a misdiagnosis. It was shown that classical clinical and radiographic features of typical pneumonia were neither sensitive, nor specific for differentiation of pneumococcal and non-pneumococcal etiologies6.

All clinical trial protocols of treatment of CABP have exclusion criteria for atypical pneumonia and specific infections, like tuberculosis. However, diagnostic tests are either of insufficient sensitivity, or have a long turnaround time. Considering the screening period, when all necessary diagnostic procedures should be performed, diagnosis of CABP confirmed and treatment initiated in

such studies is limited to several hours, as in accordance with the international guidelines, treatment of CABP should be started within 3-4 hours after the diagnosis is established, the possibility of enrolling a patient who does not have CABP is significantly increased10.

The first two cases were due to atypical (Legionella) and Mycobacterium tuberculosis (tuberculosis) pathogens, respectively. Legionella pneumonia is very rare in children. For example, in Poland (total population 38 mln, children of 0-15 years of age – 5.8 mln) in 2012, 10 legionella cases (including all forms of the disease) were registered11. Legionella typically causes pneumonia that is indistinguishable from disease produced by other infectious agents. A key to diagnosis is that legionella disease is associated with extra-pulmonary signs and symptoms, including gastrointestinal (diarrhoea, abdominal pain), abnormal LFTs, hyponatremia, hypophosphatemia, and renal dysfunction12. However, none of the above is specific for legionella pneumonia. In our case, the patient had abdominal pain, which could be also seen in typical CABP, especially if the lower lobes are affected. In addition, moderately elevated LFTs could be a part of the presentation of severe CABP. Retrospectively, doctors might have suspected legionella pneumonia, but since the patient had typical symptoms of CABP and since time was limited, it was difficult.

Differential diagnosis of tuberculosis from bacterial pneumonia is not straightforward. It was noted that in Asian countries up to 7% of cases presenting as CABP were re-diagnosed as pulmonary tuberculosis 13. The majority of studies conclude that if a patient with symptoms of pneumonia responds quickly to antimicrobial therapy, they are likely to have bacterial pneumonia, and in contrast, if they don’t respond quickly tuberculosis is a possible diagnosis14. Laboratory findings that provide discrimination between CABP and pulmonary tuberculosis include: low levels of CRP and procalcitonin, but these tests are frequently not standard diagnostic procedures. Thus, differentiation between CABP and tuberculosis is usually made by observing the clinical response (ex juvantibus).

Early clinical features of Kawasaki disease mimic “febrile” illnesses and the diagnosis may be difficult. Typical Kawasaki disease symptoms include: fever, skin manifestations (rash and desquamation), erythema of oral and/or pharyngeal mucosa, cervical lymphadenopathy, and conjunctivitis15. These extra-pulmonary symptoms, which are characteristic of Kawasaki disease, unfortunately are non-specific. Our patient did not have skin pathology, and his pharyngeal erythema and cervical lymphadenopathy were attributed to the bacterial infection, and mild conjunctivitis was considered a concomitant disease. Kawasaki disease is associated with an inflammatory process, with elevation of ESR, CRP and WBC count, thus it is indistinguishable from other inflammatory diseases, like pneumonia16. Procalcitonin elevation is a typical feature of Kawasaki

Therapeutics


Therapeutics

disease, however it may also be seen in pneumonia. The most characteristic sign is dilation of coronary arteries, but to perform cardiac ultrasound one has to suspect such pathology.

When it is necessary to differentiate between bacterial pneumonia and pulmonary infarction, the best imaging for the latter is angiographic, or ultrasound demonstration of pulmonary thromoemboli. Important clues are disturbances of the cardiac rhythm, significant elevation of LFTs and unresponsiveness to antibacterial treatment.

ConclusionCommunity-acquired bacterial pneumonia is a disease that sometimes is difficult to differentiate from other infectious or non-infectious entities. This is related to similarity and lack of specificity of clinical and laboratory signs and symptoms, as well as time limits. It is especially important for clinical trials in CABP, because enrolment of “incorrect” patients will lead not only to safety issues, but also will compromise the study data, as such patients will be not evaluable and will be excluded from the statistical analysis. Our experience shows that simply following inclusion and exclusion criteria is insufficient. Furthermore, close cooperation between investigative sites and medical monitors of sponsor/CRO is essential.

References

1. Niedeman M.S., McCombs J.S., Unger A.N. et al. The cost of

treating community-acquired pneumonia. Clin. Ther. 20, 820-

837 (1998)

2. Torres A., Blasi F., Peetermans W.E. et al. The aethiology and

antibiotic management of community-acquired pneumonia in

adults in Europe: a literature review. Eur. J. Microbiol. Infect. Dis.

33, 1065-1079 (2014)

3. Green D.S., San Pedro G.S. Empiric therapy of community-

acquired pneumonia. Semin. Respir. Infect. 15, 227-233 (2000)

4. Torres A., Peetermans W.E., Vegi G., Blasi F. Risk factors for

community-acquired pneumonia in adults in Europe: a literature

review. Thorax, 68, 1057-1065 (2013)

5. Lim W.S., Baudouin S.V., George R.C. et al. Pneumonia

guidelines committee of the BTS standards of care committee.

BTS guidelines for the management of community acquired

pneumonia in adults: update. Thorax, 64 (suppl. 3), 1-55 (2009)

6. Ruiz M., Ewig S., Angeles M. et al. Etiology of community-

acquired pneumonia: impact of age, comorbidity, and severity.

Am. J. Respir. Crit. Care. Med. 160, 397-405 (1999)

7. Feldman C., Anderson R. Antibiotic resistance of pathogens

causing community-acquired pneumonia. Semin. Respir. Crit.

Care. Med. 33, 232-243 (2012)

8. Watkins R.R., Lemonovich T.L. Diagnosis and management of

community-acquired pneumonia in adults. Am. Fam. Physician,

83, 1299-1306 (2011)

9. Castro-Guardiola A., Armegou-Arxe A., Viejo-Rodriguez A-L. et al.

Differential diagnosis between community-acquired pneumonia

and non-pneumonia disease of the chest in the emergency ward.

Eur. J. Intern. Med. 11, 334-339 (2000)

10. Mandell L.A., Wunderink R.G., Anzueto A. et al. Infectious

Diseases Society of America/American Thoracic Society

consensus guidelines on the management of community-

acquired pneumonia in adults. Clin. Infect. Dis. 44, 27-72 (2007)

11. Stypulkowska-Misiurewicz H., Czerwinski M. Legionellosis in

Poland in 2012. Przegl Epidemiol. 68, 219-221 (2014)

12. Edelstein P.H., Cinaciotto N. Legionella. In: Mandell G.L., Bennet

J.E. Dolin R, ed. Principles and practice of infectious diseases, ed

6. Philadelphia: Elsevier (2005)

13. Shen G.H., Tsao T.C., Kao S.J. et al. Does empirical treatment of

community-acquired pneumonia with fluoroquinolones delay

tuberculosis treatment and result in fluoroquinolone resistance

in Mycobacterium tuberculosis? Int. J. Antimicrob. Agents. 39,

201-205 (2012)

14. Grossman R.F., Hsueh P-R., Gillespie S.H., Blasi F. Community-

acquired pneumonia and tuberculosis: differential diagnosis and

the use of fluoroquinolones. Inter. J. Infect. Dis. 18, 14-21 (2014)

15. Golshevsky D., Cheung M., Burgner D. Kawasaki disease. The

importance of prompt recognition and early referral. Austral.

Fam. Physician. 42, 473-476

16. Eleftheriou D., Levin M., Shingadia D. et al. Management of

Kawasaki disease. Arch. Dis. Child. 99, 74-83 (2014)

Maxim Belotserkovskiy, MD, PhD, MBA is Head of Medical Affairs at PSI CRO AG. He is a board-certified physician in Internal Medicine, Rheumatology, Anesthesiology and Intensive care, and Hemodialysis, a Certified Associate Professor of Pathological

Physiology. He has more than 20 years of experience in clinical research as investigator and clinical research professional. He is also the author/co-author of more than 130 publications.Email: [email protected]

John Riefler, MD, MS, is Director, Medical Monitoring & Consulting at PSI CRO AG (USA). His MS is in Microbiology and his clinical training is in Internal Medicine and Infectious Diseases. He is a Fellow, Infectious Disease Society of America (FIDSA) and Fellow, American Heart

Association (FAHA). He has 27 years experience in clinical development in big pharma and CROs. He is also the author/co-author of 22 publications.Email: [email protected]

Maxim Kosov, MD, PhD, is Director, Medical Monitoring & Consulting at PSI CRO AG (USA). He is a board certified physician in Pediatrics and Anesthesiology and Intensive Care. Maxim has more than 20 years of experience in both the medical and clinical research industry and has

experience across a board range of indications. He is also the author/co-author of more than 30 publications.Email: [email protected]

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Abstract / Business CasePatient recruitment costs around 6-7% of the total and it is higher than all other cost components. Almost 80% of clinical trials are delayed due to patient recruitment challenges. This delay adds on to the cost of maintaining staff and site, and shortening the patent period. These issues are pushing clinical trials towards two major shifts – shift from patient recruitment to patient engagement, and shift from site-centric trials to patient-centric trials. Both these shifts require some fundamental changes in the way clinical trials are performed and patient recruitment through electronic medium is expected to be one of those changes. This article will focus on changing recruitment trends within emerging markets and how these markets are bracing themselves for such inevitable changes.

IntroductionGlobal use of digital and social media in clinical trials gathered momentum after 2010. North America and Western Europe provide comparatively conducive environments for the growth of e-recruitment, whereas in emerging markets, the regulatory and cultural issues limit the use of e-recruitment. Among them Latin America is potentially a good clinical trial market to utilise e-recruitment methods.

Source: Secondary research & Beroe analysis

The table above portrays both traditional and e-recruitment methods for patient recruitment. The usage of the type of methods varies between developed and emerging markets. For example, due to regulatory concerns, emerging markets use PRO/CRO databases rather than ads, whereas in developed markets such as North America and Western Europe, search engines are preferred. Taking into consideration the emerging

e-recruitment methods, digital platforms of patient advocacy groups and patient databases contribute more than 70% of usage in emerging markets, whereas social media platforms are more preferred in developed markets.

e-Recruitment of patients is an outcome of loopholes in traditional methods. Issues like delays in patient recruitment, higher cost, less penetration towards rare disease patients, etc. have pushed the market to adopt new methods. Some other issues are mentioned as follows:

Issues for investigator referral:• Lack of information about clinical trial• Investigators do not have enough time to educate

patients about the trial

Issues for print media:• Difficult to target required subjects• Uneducated patients cannot understand • Response time by the sponsor is more• Location is the major barrier• Push strategy

Market Drivers for e-RecruitmentTherapeutic Area - Personalised Medicines, Rare DiseaseWith growing rare disease therapeutic pipelines, recruitment of patients is growing difficult owing to geographically dispersed patient pool. e-Recruitment offers targeted patient identification and screening according to the protocol requirements. This aids in better screen-to-recruitment ratios, especially in rare disease trials.

However, one must note that not all e-recruitment strategies are equally effective for all therapeutic areas.For example, patient forums and EHRs are very effective in recruitment of patients in rare disease trials; whereas, social media-based recruitment strategies work well for cancer clinical trials.

e-Patient Recruitment in Emerging Markets

Source: http://www.patientrecruitmentonline.com/


Cost Advantagee-Recruitment provides a cost advantage of 70-80% over traditional methods of recruitment.

So as per industry analysis, the cost advantage for e-Recruitment will be huge followed by higher penetration into the patient base.

Source: WCCT Global Webinar

Facebook is the widely-accepted social network media and also the most economical. So, the pharma companies and CROs are shifting gradually from broadcasting media to social media.

In developed markets, CROs use Facebook as the initial information method in a recruitment strategy mix in order to build the database of right patients that are later targeted using direct mail and call centres. This saves huge cost for the pharma companies.

TimelinesOne big issue with clinical trial planners is the unexpected delays in clinical trials due to delays in patient recruitment or patient dropout. One can pre-screen potential participants online so it can speed up the overall trial recruitment process. This can also assist in enhancing the patent time period for trials.

Demographic Advantage• In developed markets like the US and Japan there is

an increase in the population of over-60s.• Emerging markets like Asia Pacific, Eastern Europe

and the Middle East are seeing an increase in the young population.

Source: http://digital-agenda-data.eu/Statistics reveal that the population belonging to the 25-

54 years age group have more tendency to use electronic media for health information. This presents a viable opportunity to target this segment of the population through e-recruitment strategies, especially in emerging markets.

Other benefits include the following:• Help patients in finding a suitable trial in real time• Location is not a barrier• Right patients at right time can be targeted• Pull strategy - studies reveal that altruism is the

major clinical trial participation motivator. Use of e-technology will put patients’ willingness in the first place

• A good platform to raise awareness and share in detail the prospective outcomes and adverse effects of the study

• Best way to raise awareness and share adverse effects of the study

• In many developing markets like Israel, the government is providing a supportive regulatory environment for CROs to conduct clinical trials to make quality drugs available to the country’s population. This is increasing the use of digital media in China, Brazil and Mexico.

With the growth of the personalised medicines market, use of e-recruitment methods will tend to grow to reach the targeted patients.

Looking into e-recruitment from the patient’s perspective, more than 38% of the patients get know-how about recruitment status for a trial through search engines such as clinicaltrials.gov, followed by health associations such as NHS, referrals and social media contributing around 8%.

Although social media is preferred by 8% globally, patients in developed markets have faster adoption of social media compared to those in emerging markets who mostly identify recruitment areas through referrals.

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Source: Centerwatch Online Patient Survey 2012-2013


Hurdles for e-patient Recruitment in Emerging MarketsAmong the emerging markets, Latin America provides more regulatory freedom as compared to Asia, the Middle East and Eastern Europe. China provides a good friendly market for the use of e-recruitment methods but limited internet access reduces its use.

Source: http://www.centerwatch.com; worldbank.org

Regulatory Challenges:

In the flowchart above we have explained how the e-Recruitment process can overstep the need of IRB approvals for the trial. In traditional methods, sponsors need to get IRB approval for the trials whereas in the case of e-recruitment, companies might not get IRB approvals for the trials. Some partners may overstep this process. This may put the whole clinical study at great risk because in the latter cases the regulatory bodies can question the validity of the trial. In this case the sponsor will be forced to stop the clinical trial in some geography which can backfire on the overall processes. Hence companies need to work on this on a case-by-case basis, and they need to be very careful that their partners (CRO/PRO) have taken all necessary steps before using the e-Recruitment process.

Other hurdles include internet access, technology base, dynamic regulations in emerging markets, disease awareness, etc. Pharma sponsors and trial partners should consider each country as a different situation for their patient recruitment planning and execution.

Case Studies

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ConclusionDigital media cannot currently be accepted as the exclusive method of patient recruitment in both developed and emerging markets. However, the proportion of its use in emerging markets may tend to rise in future with the changing demography, regulatory and cultural environment of these regions.

References1. Pharmaphorum, http://www.pharmaphorum.com/

art i c les /pharma-gets - soc ia l -pharma- lessons - in -social-media-and-clinical-trials, December 2014

2. Acurian, https://www.acurian.com/, December 20143. John Patrick Pullen, http://archive.fortune.

c o m / 2 0 1 0 / 0 6 / 2 8 / n e w s / c o m p a n i e s / fa c e b o o k _clinical_trial_ads.fortune/index.htm, December 2014

4. Matthew Howes, http://www.centerwatch.com/news-online/article/6691/the-pulse-on-global-trials, December 2014

5. WCCT Global webinar, December 2014 6. Mary Jo Lamberti, PhD, Senior Research Fellow; Stella

Stergiopoulos, Senior Project Manager; Paulami Naik, MSPH, Research Analyst; Ken Getz, MBA, Director of Sponsored Research and Research Associate Professor, and principal investigator in this study, http://csdd.tufts.edu/files/uploads/TCSDD_Social_Media_Final.pdf, December 2014

7. Quintiles, http://www.quintiles.com/library/videos/patient-recruitment-in-latin-america, December 2014

8. SHERYL, http://www.webwhile.com/internet-marketing/2010/06/13/online-patient-recruitment/, December 2014

9. BBK Worldwide, http://www.bbkworldwide.com/_downloads/BBKWor ldwide_eBook_Soc ia lMedia .pdf?submiss ionGuid=ce738f9a-9fdd-4d3a-9ea6-7673022e22bb, December 2014

10. James Lind Institute, http://www.jli.edu.in/blog/leveraging-social-media-networks-for-clinical-trials-by-pharma-biotech/, December 2014

Nandini Nema is a Research 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.Nandini specializes in tracking various

clinical trial services. She has worked on multiple procurement research topics for Fortune 500 clients involving categories such as clinical development market in emerging nations, patient support program services, and Patient recruitment in emerging markets.Nandini is a graduate in Pharmaceutical Management from National Institute of Pharmaceutical Education & Research (NIPER), Mohali.Email:[email protected]

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Logistics

IntroductionActivity in clinical trials continues to rise unabated, despite subdued dynamics in the world economy along with severe political tensions between Russia and the West, as well as infringements in some regulatory environments.

In developed countries the requirement to meet economic and clinical standards for a new drug entering the market seems to be increasing year after year. Local bodies in Europe such as the UK’s National Institute for Health and Care Excellence (NICE) and Germany’s Institute for Quality and Efficiency in Healthcare (IQWiG), to name a couple, have been shown to be tough in their assessment of new drugs. Thus, sponsor companies have to implement appropriate clinical trials to meet requirements as well as to aim for increased efficiency.

The search for potential benefits by sponsor companies has resulted in an expansion of multinational clinical trials to involve fast-growing countries in the Latin Americas, such as Brazil and Mexico, and Asian countries, such as India and China, in addition to developed western countries. These benefits include a reduction in the associated costs, access to large patient pools, and in some cases higher recruitment rates. However, looking at the global spread of clinical trials, it has become obvious

that in a number of these countries, pharmaceutical companies face significant and in some cases rapidly changing challenges for clinical trial supply, and as such also for the sourcing and distribution of comparators.

A recent report published by the Institute for Healthcare Informatics, also forecasts that the surge in cancer drug innovation is projected to continue over the next five years, with oncology currently already making up 25% of the global late-stage pipeline1. Underlining that, the need for secure and transparent sourcing of comparator drugs and non-investigational medicinal products (NIMPs) on a global scale is likely to rise significantly.

This article aims to identify some patterns in the sourcing and distribution of comparators in the coming 12 months within this environment.

Change in ChinaChina is now the world’s second-largest pharmaceutical market, behind the US1. As has been observed for some time, an aging population coupled with a steady increase in chronic diseases and rapidly growing city-based populations means that China seems to be an ideal location for pharmaceutical research and development. Unlike other emerging or fast-growing markets, the

Analysing Trends in Global Comparator Sourcing and Distribution in 2015 – A Preview


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number of clinical trials initiated in China looks to be increasing year after year2. As can be seen by numerous investments in China by pharmaceutical companies recently, this is unlikely to decrease. With Bayer having set up a research and development facility a few years ago, 2014 saw AstraZeneca partner with the Shanghai-based Pharmaron and a number of companies set up central research laboratories in the country.

Although a move to initiate clinical trials in locations such as China offers a number of benefits, such as rapid enrolment, companies face regulatory and bureaucratic hurdles that can often cause significant delays, as the regulatory landscape in China evolves and specifications become more stringent. Although quality and supply chain expectations are increasing, in markets such as China that are still developing reliable and consistent regulatory systems, it is advisable to monitor the supply chain closely to ensure the prevention of falsified medicines entering the chain remains high by all parties at all times. Particularly since recent trends in comparator sourcing show a preference towards sourcing locally registered commercial drugs in China, if these are available.

Looking at the overall picture, the number of trials taking place in China looks set to continue to expand in the next 12 months, as the supporting regulatory system and infrastructure develops into a sustainable foundation for future work in this area, thus giving confidence to investors.

Indications for IndiaContinued change can also be viewed as a key feature of India’s complex regulatory system, making it important for sponsor companies and other clinical trial stakeholders to monitor developments to enable them to adapt to changes in a timely manner. Furthermore, positive change, such as the creation of the Indian Clinical Trials Registry, shows a shift towards greater transparency. Coupled with more robust quality overall, and thus increased safety, it appears that the gap to western developed country quality systems is shrinking. As 2014 showed, there arguably remain some uncertainties with regard to patent infringements, which may mean that some pharmaceutical sponsor organisations choose to be cautious with regard to carrying out clinical trials in India in the coming months, instead opting to observe and await stabilisation of the regulatory landscape.

Preview of Russia The implementation of Russia’s strategy of development of the pharmaceutical industry saw a move towards increased innovation in Russia in the last few years and it looks as if the regulatory landscape is opening up more to pharmaceutical research and development. Furthermore, overall increased quality, including closer GMP alignment with European standards, shows a positive shift. Yet, like in other countries that have been prominent for some time now, Russia is also going through significant change. In Russia’s case this includes restructuring of its healthcare system, but also improvements in pharmaceutical conditions including import / export and the removal of certain bureaucratic barriers. As these factors have the potential to cause long delays, they should be considered at an early planning stage when assessing the complexity of a trial’s supply chain. From a comparator perspective it is also essential to consider suitable distribution strategies early on, particularly in a vast country like Russia.

Overall it can be said that Russia’s market looks to be on the rise, but it is very likely to be constrained by the political turmoil recently affecting western relations with Russia.

Other CountriesLike the above-mentioned countries, clinical trials moving to Brazil and even countries such as Mexico, which has seen some social unrest, look to be increasing. Access to population-dense urban areas and the prospect of high patient enrolment and retention continue to make Brazil especially an attractive country, particularly with presumably more political stability after the recent presidential election. However, as in other countries with less well-established regulatory systems, it should be noted that approvals, as well as processes such as local sourcing of commercial drugs for comparator use, can be slow.

Sourcing Strategies in a Global SettingSince the sponsor organisation is arguably further away


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at times when a multi-centre trial is spread globally, the risks can increase. One example is quality within the clinical supply chain, which can become significantly more complex in the global setting. This can also be said when looking specifically at the comparator sourcing and distribution process. It is advisable to qualify any supply chain to be used for proper and safe delivery of the clinical supplies. With this in mind, it may be beneficial to work with an experienced partner that can provide a company with access to an already qualified global supply and distribution network. Furthermore, there are hurdles such as local language barriers, working in different time zones, and potential cultural differences, that can be navigated together.

When sourcing comparator drugs as well as auxiliary products, often for late-phase, multinational, multi-centre trials, there are a range of sourcing strategies for a sponsor company to consider. A sponsor may choose to source themselves, e.g. via a local affiliate, outsource completely, or use a combination of the two strategies. If a team decides to outsource the comparator sourcing component of a trial, thorough research should be conducted to confirm capabilities of an external provider. Furthermore, it is recommended that in-place quality systems are audited and it may be advantageous to request to review case-study examples. This way it should be possible to find an organisation that best matches the needs of the clinical trial. It is worth bearing in mind that working with a sourcing partner, who has a presence in developed western countries as well as an emerging markets footprint, may be advantageous. They can offer access to reliable local market intelligence on commercial products, including product availability and information on product presentations. Working with a partner that has access to commercial drugs direct from manufacturers or their authorised distributors, can lower the risk by ensuring authenticity, with the appropriate paper trail. Furthermore, having access to flexible

procurement options via a global network can enable sponsor companies to consider both local and central sourcing strategies for different products within the same trial. Looking at both small and large molecule drug development, the focus on biologics looks set to continue. With biologics making up 36% of the late-stage pipeline and 45% of the late-stage oncology pipeline in October 20141 it is important to consider areas of particular risk in a supply chain, such as transport routes when handling such temperature-sensitive products. One such factor is the range of natural temperature differences between clinical trial locations globally, as well as factoring in potential delays in import and export processes. Furthermore, in some instances, export of samples can be very straightforward yet import of a comparator drug may be much more complex, and it may be advisable to work with an experienced partner, who can offer guidance on important factors such as documentation, in such instances.

ConclusionPressures to reduce the costs of clinical trials remain high in established markets. Many pharmaceutical sponsor companies continue to opt to include fast-growing countries, in their trials, where the potential for cost-cutting is significant, but where numerous regulatory barriers must successfully be navigated. The pattern of distribution of clinical trials that has emerged is likely to continue to govern future activities, with activities in China particularly leading the way. It thus becomes more important to monitor the regulations across all applicable markets or have access to such information through third-party providers. Furthermore, it is recommended to benefit from working with companies that have strength and experience in comparator sourcing in a particular country. At a time when the process of securing clinical trial supplies has become increasingly difficult and complex worldwide, working with a knowledgeable partner may enable a sponsor to more easily realise the benefits of working across a range of countries.

References1. IMS Institute for Healthcare Informatics. Global

Outlook for Medicines Through 2018. November 2014.

2. Beth Nuskey. Overcoming Clinical Challenges in BRIC Markets: A White Paper. Thomson Reuters. April 2014.

Ann-Marie Huss is the Managing Director of Multipharma Clinical Supplies Ltd, UK, which is part of the Multipharma Group. She is focused on clinical trial supply, namely sourcing of comparators and local NIMPs. She obtained her BSc (Hons) in Biological Sciences (Pharmacology) from

the University of Edinburgh.Email: [email protected]

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Logistical Challenges in Orphan Drug Trials - Adopting a Patient-centric, Investigator-supportive Approach

Clinical development programmes for orphan drugs present considerable financial and logistical challenges for pharmaceutical sponsors. Although orphan drug incentive initiatives have increased research into the prevention, treatment and diagnoses of rare diseases with unmet medical need, enrolling patients in these types of trials poses inherent difficulties due to sparse and geographically dispersed patient populations, in addition to limited numbers of hospitals available to conduct a study. On top of this, investigators conducting orphan drug trials are less likely to have the infrastructure in place typical of more experienced clinical sites, meaning that although clinical focus is high, staff may have limited ability in arranging patient travel or managing the complexities of reimbursing patients. Because the stakes are so high with each individual subject in an orphan drug trial, managing the patient experience is paramount. Solutions that enable complete management and oversight of the logistical challenges of orphan drug trials offer huge potential to this specialised area of clinical research.

The Rise of the Orphan DrugOrphan drugs are products that are specifically developed to treat rare medical conditions and have been given a special regulatory designation by authorities in the US and the European Union. According to the Orphan Drug Act of 1982, the US defines orphan drugs and biologics as those “intended for the safe and effective treatment, diagnosis, or prevention of rare diseases that affect fewer than 200,000 persons in the U.S., or that affect more than 200,000 but are not expected to recover the costs of developing and marketing a treatment drug.”1 Similarly, the European Medicines Agency defines orphan drugs as “intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or debilitating” when the prevalence of the condition in the EU is less than five in 10,000 or the marketing of the medicine is “unlikely to generate sufficient returns to justify the investment needed for its development.”2

Between 5000 and 8000 rare diseases exist, and about 30 million people living in the EU (6-8% of the population)3 and an additional 30 million people living in the US (10% of the population)4 suffer from a rare disease. In total, an estimated 350 million people worldwide suffer from rare diseases.5 The nature of these conditions varies greatly, but there are certain trends; 80% of rare diseases have identified genetic origins, while others are the result of infections, allergies and environmental causes, with 50% affecting children.6 Certain rare diseases are more prevalent than others and 80% of all rare disease patients are affected by approximately 350 rare diseases.7

Once a drug that aims to prevent, diagnose or treat a rare disease is designated as an orphan drug, sponsors receive special incentives intended to encourage and enable the development of the product. These incentive programmes include grants, research design support, FDA fee waivers and tax incentives, as well as extended market exclusivity. Such incentive programmes have significantly increased the number

of orphan drugs in development and on the market. The US programme has successfully enabled the development and marketing of 400 drugs and biologics since 1983, compared to fewer than 10 in the 1970s.8 As of September 2014, the FDA had granted the orphan drug designation to a total of 2899 potential therapies.9 In the US alone, over 450 new medicines are currently being developed to treat rare disorders, and one-third of FDA approvals between 2008 and 2013 were for orphan drugs.10 In 2013, nine of 27 approved drugs were indicated for rare diseases.11

The Patient ExperienceRare diseases, although uncommon individually, are actually prevalent when viewed as a whole. Although the experience of each disease is unique, patients with rare diseases often face challenges specific to rare disease. Shire’s ‘Rare Disease Impact Report’ released in April 2013 surveyed 631 patients and 256 caregivers in the US and UK, representing 466 rare diseases. The survey looked at the commonalities in health, financial and psycho-social experiences, with results illuminating the challenges presented by conducting studies within this population. One of the most common was the long and difficult process to obtain a diagnosis, averaging 7.6 years in the US and 5.6 years in the UK12, with an average of two to three misdiagnoses. Lack of information or resources and conflicting information received from caregivers, as well as limited access to qualified physicians or difficulties finding appropriate medical care also created considerable challenges. Restricted or, in many cases, no treatment options mean that it is usual for patients to have to serve as the researcher, care coordinator and advocate for their own care. Treatment options that are available tend to be expensive with potential difficulties arising from getting adequate coverage from payors. In addition, patients were highly likely to suffer reduced quality of life, including depression, anxiety and isolations, as compared to both healthy people and those with more common serious diseases.

This shared experience means that patients suffering from rare diseases may face increased emotional and financial pressures and may reasonably be either very passionate about participating in clinical research, or very reluctant to do so, due to years of ineffective or negative interactions with the healthcare system.

Challenges in Orphan Drug TrialsClinical trials are more complex, and more costly, than ever. The average cost of moving a new drug from the test tube to the market is astronomical, with figures ranging from $350 million for a single drug to over $5 billion for large pharmaceutical companies that work on dozens of drug projects at once.13 The expense of running clinical trials is a significant contributor to these costs. On average, developing a new medicine takes 10 to 15 years.14

Despite the incentives created to support the development of orphan drugs, clinical trials in this area remain uniquely challenging. In fact, despite advances in treatment, only

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5% of rare diseases currently have a treatment.15 Beyond the difficulties of designing a scientific study protocol that successfully deals with a small patient population and a disease that may not be well-understood, logistical challenges in orphan drug trials are significant. These challenges stem from a range of factors, including:

• A disease that may not be well-understood• A small, geographically dispersed patient population that

often includes children• Patients who may have waited years for a diagnosis or

access to a clinical trial, and therefore, may be reluctant to participate in a trial or receive a placebo

• A small patient population that means there is little opportunity to make and learn from mistakes

• A lack of seasoned, experienced investigators with expertise in the disease or with access to patients

As a result, orphan disease studies cost 25 times more per patient on average than trials for non-orphan products.16

Patient-centric ApproachesWorking with small patient populations suffering from rare diseases often does not fit the traditional model for clinical trials employed by big pharmaceutical companies. As Shire’s Rare Disease Business Unit Head, Jeff Poulton, noted in the Financial Times, ‘Orphan drug development is centred on the individual, and to big pharma, this is a foreign cultural concept.17 Whether or not large pharma can adapt to the unique needs of patients in orphan drug trials, these comments highlight the need for a truly patient-centric approach.

While the need for a patient-centric mindset may be obvious, finding appropriate investigators is equally challenging for sponsors of orphan drug studies. According to Premier Research, 69% of sponsors find choosing a clinical site one of the toughest challenges in an orphan study.18 Orphan studies are also often quite global, even more so than typical clinical trials, the majority of which include more than one country.19 If a condition is so rare that there are only two or three hospitals in the world that can conduct a study, it is feasible that these hospitals may not be set up to manage clinical trials. It is therefore vital that the site is prepared and has sufficient support to be able to carry out the study and get it right first time. Sponsors have to work closely with clinical sites to elevate their processes and educate them on the level of rigour that needs to be applied.

Logistical Challenges As previously established, orphan drug trials have inherent difficulties and these present specific logistical challenges. With geographically dispersed patients and limited numbers of hospitals available to conduct a study, physically getting patients to a trial is difficult at best. Additionally, with a patient population that may have made personal financial outlays to obtain diagnosis or treatment throughout the course of their disease, have a caregiver or companion that has been intimately involved in their care, and need special accommodations due to their disease, this is a sensitive topic that requires careful attention. Because the stakes are so high with each individual patient, managing their experience is paramount. This can be especially difficult if sponsors hope to maintain blinded patient identities, which may prevent them from intervening directly

in logistical arrangements and carefully managing patients’ personal concerns.

Investigators conducting orphan drug trials may not have the infrastructure in place typical of more experienced clinical sites. Their relevant experience is often clinical and their staff may have limited ability to arrange for patient travel or manage the complexities of paying travel vendors or reimbursing subjects. Without support from sponsors, investigators may struggle to meet the logistical needs of patients or spend valuable staff time on logistical arrangements as opposed to aspects of the study like patient care or careful management of data.

New ApproachesImproving patient management and the various administrative processes during the course of an orphan drug trial can dramatically reduce the challenges associated with undertaking this type of study and enhance the patient experience. Advancements in technology offer the potential to break down barriers in trials, alleviating the challenges of having patients on different time zones and continents, and generally making the whole study process much more streamlined. By automating processes, global web-based payment management platforms


provide reassurance to an industry that is faced with tough logistical challenges and help manage the complexities of reimbursing patients.

These solutions provide a single, convenient resource for patients and study coordinators to access help with logistical arrangements and remove the administrative burden from investigative sites. They allow clinical research sponsors and sites to deliver patient payments in real-time, while tracking and monitoring all transactions, eliminating the potential for human error, while overcoming many of the limitations associated with the calculation and execution of global payments in orphan drug trials. As well as reducing costs to sponsors related to patient reimbursements, these solutions mean that they are now able to track payments and manage all trial-related costs from a single web-based portal, providing increased transparency and control. They are also compatible with and leverage clinical technologies, such as CTMS systems, electronic data capture (EDC) and electronic patient-reported outcome technologies (ePRO), in order to further streamline operational processes at site level. The ability to integrate with ePRO technology, and link patient reimbursement to remote data collection in real time, offers the potential to enhance patient engagement between site visits, providing oversight to study sponsors while maintaining blinded patient identities.

The wide geographic spread of orphan drug trials makes the requirement for patient travel highly likely. The best of these new systems feature specific travel modules that are designed specifically for studies that require complex travel arrangements, eliminating administrative steps necessary to manage travel and patient reimbursements. They ensure that patients can travel for a study without incurring out-of-pocket costs and that travel arrangements are aligned with sponsor travel policies and approval requirements. This capability means that no financial burden is placed on patients, meaning that costs can be managed without sacrificing patient experience. The use of new technology allows clear sponsor-defined logistical policies to be established and maintains adherence to these policies throughout the course of a trial while simultaneously allowing sponsors and sites to respond flexibly to the changing needs of patients.

ConclusionThe rise in the number of orphan drug trials, combined with the associated logistical challenges has driven demand for more effective patient-centric solutions, that at the same time improve trial processes for study investigators. Sponsors who recognise the need for improved strategies around these trials, and who implement technologies that are able to offer more patient-focused management of study logistics, will reap the benefits of enhanced patient engagement and compliance in the future. By garnering the many benefits that come from being able to track and manage all logistical, financial and administrative processes associated with an orphan drug trial in a single solution, sponsors can put in place an infrastructure that offers complete management and oversight, irrespective of the prior experience of the supporting investigative site. Organisations that embrace these solutions will not only improve their patient and site management capabilities in this unique area of clinical research, but will enhance the way they operate as a whole.

For further information on Greenphire and its innovative solutions please email: [email protected], call +1 215-609-4640 or visit www.greenphire.com.

References1. h t t p : / / w w w . f d a . g o v / f o r i n d u s t r y /

DevelopingProductsforrareDiseasesConditions/default.htm2. http://www.ema.europa.eu/ema/index.jsp?curl=pages/

regulation/general/general_content_000029.jsp3. http://www.ema.europa.eu/ema/index.jsp?curl=pages/

special_topics/general/general_content_000034.jsp&mid=WC0b01ac058002d4eb

4. http://www.rarediseases.org/about5. https://globalgenes.org/rare-diseases-facts-statistics/6. http://www.rarediseaseday.org/article/what-is-a-rare-

disease7. http://www.phrma.org/sites/default/files/pdf/Rare_

Diseases_2013.pdf8. h t t p : / / w w w . f d a . g o v / F o r I n d u s t r y /

DevelopingProductsforRareDiseasesConditions/default.htm

9. http://www.phrma.org/sites/default/files/pdf/Rare_Diseases_2013.pdf

10. http://www.orphan-drugs.org/2013/10/10/orphan-drugs-fda-approvals-5-years/#sthash.gNX5YxQO.dpbs

11. http://www.phrma.org/working-together-we-can-produce-results

12. http://www.shire.com/shireplc/dlibrary/documents/RareDiseaseImpactReportforWeb.pdf

13. Herper, Matthew. “The Cost Of Creating A New Drug Now $5 Billion, Pushing Big Pharma To Change.” Forbes. 11 August 2013.

14. Tufts study15. http://www.phrma.org/sites/default/files/pdf/Rare_

Diseases_2013.pdf16. http://www.orphan-drugs.org/2013/10/07/strategically-

m a n a g i n g - l o g i s t i c s - c o s t s - ra re - d i s e a s e - c l i n i ca l -trials/#sthash.G9s5yiwq.dpbs

17. http://www.orphan-drugs.org/2013/09/26/big-pharma-embrace-orphan-drug-development/#sthash.SbgaPFN7.dpuf

18. http://www.orphan-drugs.org/2014/02/06/rare-disease-clinical-trials-facts figures/#sthash.fXeWWlqg.KjamnSdm.dpbs

19. Ayalew, Kassa. “FDA Perspective on International Clinical Trials.” 12 December 2013. www.fda.gov

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Jennifer Peters is one of Greenphire’s founders and first investors. She currently serves as Greenphire’s Chief Experience Officer, ensuring that clients have an outstanding user experience and continuing to assess and improve Greenphire’s processes on behalf of clients.Prior to Greenphire, Jennifer spent over 10 years at a large global communications company, where

she oversaw several regional offices including Boston, Minneapolis, and Philadelphia. Primarily focused on highly-regulated industries such as life sciences and finance, Jennifer helped establish global relationships with pharmaceutical industry leaders.

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Drug Pooling in the Clinical Trial Supply Chain

AbstractGlobal clinical trials require efficient and robust supply chain which can bring more transparency and can introduce risk mitigation strategies. Currently, it is following consumption-based supply chain model where all the medication kits are initially assigned with patient information and then dispatched for clinical trials from central depots. This is followed by dispatching overage supplies to the tune of 100-150% to emerging markets. Unused patient specific medication kits coupled with unused overage supplies produce large amount of clinical trial material wastes which also include expensive comparator drugs. Drug pooling, a demand-based model, is possibly a strategic approach that could bring the clinical supply chain in parity with this evolving R&D pipeline. In this model the decision making for assignment of medication kits is brought closer to trial sites which could be initiated upon investigator’s request only.

This paper provides the impact analysis of “Clinical Drug Pooling at Depots” for various clinical trials. To understand the impact of drug pooling over various segments, Beroe conducted a survey among global clinical trial supply vendors, which hold 60-70% of the overall market for clinical trial supplies.

IntroductionToday the clinical trial supply chain is using consumption-based models. Given that the demand from the patients’ side is very volatile and unpredictable; the current model is not able to manage the clinical supplies efficiently. Clinical drug supplies are planned at the start of the trial and are run accordingly, providing less room for meeting any unexpected demand. There are some big issues which need to be fixed to make the clinical supply chain more efficient.

• Supply-demand mismatch: Most of the clinical trial sites complain about supply-demand mismatch for clinical trial materials. Forecasting actual numbers for patient enrolment is a very challenging task. This leads to issues like customs, lead time, quality issues, etc. A study across 150 clinical studies, involving almost 16,000 sites, published by Tufts Centre for the Study of Drug Development (CSDD) in 2013 states that 11% of the trial sites failed to enrol even a single patient, 37% under-enrol, 39% meet their targets and only 13% exceed their targets. So according to this study only 39-40% of sites met targets whereas the remainder, 60-61%, of sites were either not performing or they were exceeding the targets, both of which are issues for the clinical trial supply chain.

• Least flexibility: If there is a change in the study or if the forecasted supply varies with the actual need of supply this can lead to high overage and wastes, creating high wastage in investment for R&D. CTS (clinical trial supply) vendors generally follow a fixed protocol for supply chains, leaving less room for on-time changes required in supply of clinical materials. Secondly medication kits labelled with patient information can’t be used for other patients, which is again a sign of rigidity in supply chain process.

Drug pooling is a comprehensive strategy to fix many of the current clinical supply chain issues. It connects various segments of the clinical trial supply chain and makes the whole system more automated, dynamic, and forecasting-based. Here IMP or non-IMP supplies for different clinical trials are sent through a single window in a planned manner. The approach takes care of both over-supply and under-supply situations by maintaining periodic buffer stock of clinical trial materials.

Drug pooling can be implemented at various levels of the clinical supply chain according to the requirements. It will assist the R&D supply chain in the following manner:

Drug Pooling at Various LevelsCurrently there are three different approaches for drug pooling:

• Pooling prior to labelling: The pooling of packaged kits or kit components is done and they can be sent to regional depots to take care of labelling and other processes. Analysis of this approach is out of the scope of this document.

• Pooling at depots (unlabelled): One can send unlabelled packaged kits or kit components to regional or country-level depots. At depot level the pooling can be done, which takes care of the requirements of each clinical trial site which comes under its geographic scope. In this approach the kits are received at depots without any protocol number, which is mentioned only after receiving a request from the principal investigator from the clinical trial site. This is useful for a variety of different simultaneous clinical trials running under same program. Drug pooling at depots can be applied in two different scenarios which are discussed as follows:

• Same sponsor: The following are the criteria for this scenario:1. One sponsor2. Same clinical trial site3. Multiple clinical protocols but similar medication

• Different Sponsors: This scenario is based on the following criteria:1. Different sponsors2. Same or nearby clinical trial sites3. Similar clinical protocols or protocols using similar

medication

• Pooling at sites (labelled): In this approach the drug pooling is brought one step closer to the patients. Here the packaged kits are sent to clinical trial sites without any protocol number, although sometimes they do show a set of protocols, or a program code. In any case, the kits remain protocol independent, even at the clinical site, until they are dispensed. This can be a most fruitful strategy for the clinical supply chain, but currently there are many challenges which must be sorted out first to implement this step. The analysis of this segment is currently out of the scope for this document. We will discuss the impact analysis of “Pooling at depots” approach in more details.

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Pooling at depot level is achievable and some CTS vendors are indeed applying this concept for their pharma clients but in a very limited scope. There are some vendors who suggest that they have robust systems in place for effectively implementing drug pooling for sponsors. But in reality there are many issues like regulatory issues, effective technology, trust on trial sites, etc. which need to be fully resolved before its implementation.

Clinical supply chain companies are trying hard to implement technologies and strategies to reduce drug wastages, to bring more transparency, to make the process more robust and flexible, and to make the supply chain more integrated and streamlined. These reforms, if implemented effectively, can provide direct cost savings up to 30-40% of clinical drugs budget.

Benefits of Implementing Drug Pooling for Clinical TrialsAccording to industry experts, drug pooling, if implemented successfully, will definitely assist in transforming the clinical trial supply chain.

1. Cost Reduction: Almost 70% of the respondents feel that reduction in clinical material wastes will be a significant benefit for the drug pooling approach. This is due to the fact that decision-making for shipments of clinical material will come closer to trial sites, which will help supply chain companies to deal better with demand fluctuations. According to Beroe’s analysis, the approach can assist in saving 30-40% compared to the current level of waste in IMPs or non-IMP drugs. Less waste for drugs also means that pharma companies will need to pay less for the drug destruction process.

Fig 1:

Survey shows that 60-70% of the respondents are implementing drug

pooling for clinical supplies, but on a small scale.

2. More Efficiency and Transparency in Supply Chain: Drug pooling requires robust and efficient use of IVRS/IWRS, automation, forecasting, and JiT packaging and labelling technologies. For an effective and robust process, the medication kit should get dispatched within 48-72 hours after the order is placed.

3. Large Molecules: It is expected that by 2018, 45-50% of top 100 blockbuster drugs will be large molecules, also called biologics. These molecules are very sensitive and require strict protocols for handling, storage, distribution, and administration.

Current models for the clinical supply chain are just not capable of handling these molecules effectively. Due to unexpected delays these molecules often lose their nature. Depots used for the purpose of drug pooling can prove to be efficient for handling, storage and distribution purposes. In this way the exposure of these drugs out of the temperature range, 2-8⁰C for many large molecules, can be minimized. Drug pooling for large molecules can be a very significant approach for efficiently maintaining the stock inventory for longer time periods according to the shelf life of these biologics.

For more information on rising market share of large molecules please check the appendix

Fig 2Survey shows various expected benefits for pharma sponsors through clinical supply pooling process, N=15; Scale used is 1-5 where 1 shows minimum

impact and 5 shows highest impact.

4. Supply-Demand Harmonization for Clinical Trial Drugs:According to industry experts, drug pooling will bring more harmonization in the clinical trial supply chain. Decision-making will become more streamlined as it will come closer to trial sites. Requests for the medication kits will be triggered by investigators; only after the analysis and prediction of patient participation in the clinical trial. This will create more collaboration and understanding between investigators and vendors responsible for supplies of trial materials.

5. Overall R&D Results will Improve:According to the analysis it is expected that drug pooling on a big scale will impact the overall R&D outputs. This is due to the fact that the clinical supply chain will become more streamlined and robust. Drug availability to patients will become easy and can assist pharma companies in getting more accurate results for different titrations on a particular patient sample size.

Challenges and their Solutions for Implementing Drug Pooling:

1. JiT Labelling and Packaging:Medication kits sent to regional-level or country-level depots need to be labelled with protocol number, patient information, etc. only after a request from the investigator. This needs a robust Just-in-Time clinical packaging and labelling process. Once the investigator requests a medication kit, the team at depot level should be able to process and dispatch it within 48-72 hours. This will bring more flexibility in the supply chain process and will also bridge the gap between demand and supply of clinical trial materials. JiT labelling and packaging becomes a very integrated part of the drug pooling process. Many vendors

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involved in the clinical supply chain don’t have efficient JiT infrastructure in place. Some clinical packaging companies offer JiT facilities for clinical supplies and CTS vendors need to collaborate with such companies on a regional basis to have the required level of resources.

Fig 3Survey shows major challenges which arise during planning and implementation of drug pooling strategy

2. Reliable Vendor Selection:This is the biggest issue in the industry and many pharma companies want to engage with the best supply chain vendor for their service requirements. On the other hand many CTS vendors say that they do have the necessary resources for providing streamlined clinical supply services and that they can support drug pooling as well. But many of them may not have

the required experience of handling such requests. Selection of the most capable vendors should be strictly based on criteria like service requirements, their operational capabilities, operational KPIs, etc. Some of the basic factors that go into supplier selection criteria are mentioned in Table 1:

In such a scenario it becomes very significant on the part of sponsors to have very comprehensive know-how about supplier landscape on a global as well as a regional basis.

Suppliers’ strength and weakness analysis on a regional basis is very significant for pharma sponsors.

3. Technology Adaptation and Integration:Developed markets like North America and Western Europe provide technological and infrastructural advantages. But in emerging markets it is still a big issue. Adaptation and integration of technologies like IRT, IVRS/IWRS, etc. are expensive tasks for vendors.

Global vendors along with local players can provide a good technological base as well as their experience in global clinical trials. A good and integrated network of technology platforms will provide leverage to the vendor for a better prediction and decision-making process in the clinical supply chain.

4. Country-specific Pooling Strategy: One can’t implement drug pooling in all countries due to region-specific issues. For instance, implementing drug pooling is easier in the US as compared with India and China, whereas Russia

labelling and packaging becomes a very integrated part of the drug pooling process. Many vendors involved in the clinical supply chain don’t have efficient JiT infrastructure in place. Some clinical packaging companies offer JiT facilities for clinical supplies and CTS vendors need to collaborate with such companies on a regional basis to have the required level of resources.

Challenges Description

Global vs. regional supplier selection strategy

Pharma companies need to understand every geography’s supplier landscape, which is very significant for them to take decisions regarding supplier engagements like depot network, logistics players, drug destruction, etc.

In LATAM, including Brazil, one will find more involvement of 3PL players in the overall clinical supply chain.

In Russia local companies don’t have adequate infrastructure capabilities and global-local vendor partnerships are relevant.

China and India both provide a hybrid model of clinical supply chain where global CTS vendors have good collaborations with local players.

Experience Drug pooling needs good experience in managing the overall clinical supply chain. Many companies may not have experience in the overall supply chain process.

In-house infrastructure

Most of the companies subcontract some clinical supply services to third-party vendors.

Flexibility Often CTS vendors may not be flexible in terms of the requirements for effective drug pooling.

This increases the overall waste in the clinical supply chain.

KPIs Many times sponsors don’t have KPIs for effective supplier selection. Eligibility criteria can be segmented into operational and functional KPI requirements.

cGDP compliance The visibility for cGDP compliance decreases when engaging with many vendors globally in a centralised engagement model.

In such a scenario it becomes very significant on the part of sponsors to have very comprehensive know-how about supplier landscape on a global as well as a regional basis.

Suppliers’ strength and weakness analysis on a regional basis is very significant for pharma sponsors.

3. Technology Adaptation and Integration: Developed markets like North America and Western Europe provide technological and infrastructural advantages. But in emerging markets it is still a big issue. Adaptation and integration of technologies like IRT, IVRS/IWRS, etc. are expensive tasks for vendors. Global vendors along with local players can provide a good technological base as well as their experience in global clinical trials. A good and integrated network of technology platforms will provide leverage to the vendor for a better prediction and decision-making process in the clinical supply chain.

4. Country-specific Pooling Strategy: One can’t implement drug pooling in all countries due to region-specific issues. For instance, implementing drug pooling is easier in the US as compared with India and China, whereas Russia and Brazil are still tough countries for an effective clinical supply chain itself. Singapore is a logistics hub for the APAC region. A regional depot in Singapore can be used to directly send the trial supplies to trial sites in countries like Malaysia, Philippines, Taiwan, etc. whereas in countries like India and China one can adopt a model of in-country depot. This depot can be used for proper management of clinical trial supplies for


Logistics

and Brazil are still tough countries for an effective clinical supply chain itself. Singapore is a logistics hub for the APAC region. A regional depot in Singapore can be used to directly send the trial supplies to trial sites in countries like Malaysia, Philippines, Taiwan, etc. whereas in countries like India and China one can adopt a model of in-country depot. This depot can be used for proper management of clinical trial supplies for drug pooling. In these regions some companies are already using pooling for ancillary supplies and clinical drug materials for locally procured marketed products.

5. Regulatory Know-howFor import approval process of clinical trial materials, the NOC (No objection certificate) and import license need to be protocol-specific. But drug pooling is a concept where drugs are required to bring closer to clinical trial sites without putting protocol number. In-country depots can play a vital role in this process.

Still, experienced clinical supply chain vendors can manage drug pooling in this environment. Generally the protocol number provides information on various aspects like the phase of the clinical trial, therapeutic area, FDA or EMA, trial site, patient identity, clinical trial site, etc. One can import the container of medications without putting the patient’s identity number which can still be done at depot levels. This provides leverage and a window of opportunity for CTS vendors to implement drug pooling in respective countries.

Scope for Drug Pooling – An Evolutionary and Tough TaskSince drug pooling is expected to become one of the comprehensive strategies for the clinical supply chain, the overall scope is also expected to increase its horizons. Currently drug pooling is done for various trial protocols for the same pharma company. In future drug pooling for multi-sponsor clinical trials could be a possibility. Different pharma sponsors can combine their supplies for same medication for similar programs.

This needs to have many complex systems in place, e.g.-1. Robust clinical supply chain: Industry needs to decimate

most of the current issues in the clinical supply chain and must make technology, regulatory and cGDP a must and an integrated part of the overall system.

2. End-to-end services: Currently we have different types of players in the system, i.e. logistics provider (3PLs), depot provider, packaging service provider, CTS vendor, etc. Among these CTS vendors are the most experienced players with good technical know-how of managing the overall clinical supply chain. They can develop more in-house resources either by developing in-house infrastructure or by collaborating with service providers for end-to-end services. This is followed by 3PLs which are expanding their service portfolios in remote areas like Africa, LATAM and in developing markets like MENA (Middle East and North America).


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3. Pharma collaboration: This is the most complex part to deal with. But some time back the industry witnessed a group named TransCelerate Biopharma, a consortium of the top 10-15 pharma companies, which talked about working together for sourcing comparator drugs for their comparator trials. Based on these lines we can also expect this consortium to come up with a collaborative model for a strategy like drug pooling to streamline and consolidate the overall clinical supply chain. There are many issues like sharing confidential information with each other and working together on these lines. But this discussion is currently out of the scope of this document.

This practice requires a huge investment in the form of infrastructure and technology development. For the purpose of understanding the feasibility of pharma collaboration on

evolving clinical supply chain we asked the experts for their analysis and thoughts. For significance of pharma collaboration for inter-pharma drug pooling they agreed on 3.5-4 on a scale of 5, which is again very significant.

Expert: “Clinical supply chain service providers are understanding the evolution of clinical R&D and so they are working on bringing new innovative models for a more efficient clinical supply chain.”Director, clinical supply chain organisation

Procurement manager: “We are using drug pooling for some part of the clinical supply chain and indeed it is a good system for consolidating the supply chain process. In future we do expect expansion of this strategy on a global scale.”Independent drug supplier ReferencesSecondary Sources:

1. h t t p : / / w w w . a p p l i e d c l i n i c a l t r i a l s o n l i n e . c o m /appliedclinicaltrials/Articles/Drug-Pooling-Power-and-Pitfalls/ArticleStandard/Article/detail/506849

2. http://www.almacgroup.com/clinical-technologies/advanced-drug-supply-support-services/

3. h t t p : / / w w w . o u t s o u r c i n g - p h a r m a . c o m / C l i n i c a l -Deve lopment/TransCelerate-A ims-to-Ease-Tr ia l -Comparator-Sourcing

Primary Sources:Survey conducted by Beroe Inc. with industry experts

Rahul Sodhi is a Sr. Research Analyst with Beroe Inc., a global provider of customized procurement intelligence to Fortune 500 organizations. Rahul specializes in tracking various areas across R&D value chain. He has also done plenty of projects for categories like Clinical trial monitoring, RBM, Clinical supply chain, Comparator Sourcing, etc.Email: [email protected]

Appendix - Emerging state of bio-pharmaceutical products



Review Provides Further Insight into Link between Hormone Therapy and Breast Cancer

A review of data from two Women’s Health Initiative clinical trials reveals the varying effects of menopausal hormone therapy on the incidence of breast cancer over time. Hormone Replacement Therapy was once considered the standard treatment for women suffering menopausal symptoms. It involves the use of medications that contain female hormones – commonly estrogen or a combination of estrogen and progestin (a form of progesterone) - to replace those lost following menopause. But in 2002 came the results of a clinical trial as part of the Women’s Health Initiative (WHI), which found a link between uses of combined hormone therapy and increased risk of breast cancer - a finding that was supported by another WHI trial a year later.According to Dr. Rowan T. Chlebowski, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, CA, and colleagues, the results of these trials led to a significant reduction in the use of hormone therapy.

Source: Medical News Today

Chemical found in Nettles and Ants could improve Cancer Drug

A study has found that the chemical sodium formate could make a metal-based cancer drug 50 times more effective at shutting down cancer cells. Researchers from the University of Warwick, UK, combined the chemical with a compound of the metal ruthenium called JS07. Alone, the drug exploits the weaknesses of cancer cells and disrupts their energy generation. In combination with sodium formate (E-237), however, the researchers found it was far more effective.More commonly used as a preservative in items such as fruit juice and preserved vegetables; E-237 is derived from formic acid, commonly found in organisms such as stinging nettles and ants. In high concentrations, it can act as a diuretic but no side effects have been identified when E-237 is consumed in normal concentrations.Stinging nettles themselves have a long history of medicinal use. Medieval Europeans used them to rid the body of excess water and to relieve joint pain. Today, people still use them in treatment for urinary problems, urinary, aches and pains, hay fever and insect bites.

“By itself, JS07 is capable of shutting down cancer cells but when used in combination with sodium formate this ability is significantly increased,” says lead researcher Prof. Peter Sadler. “As a result, lower doses would be required to target cancer cells - reducing both the drug’s toxicity and potential side effects.”After developing a method with which to bind E-237 with JS07, the researchers discovered that the potent new form of the drug acts as a catalyst when interacting with cancer cells’ energy generation mechanism. By disrupting this mechanism, the drug causes the cells’ vital processes to cease, resulting in the cancer cells shutting down. Source: Medical News Today

Germany’s Merck KGaA sees Emerging Markets as Bigger Earnings Driver than Europe

Germany’s Merck KGaA now considers the world’s emerging markets as a group, with China a major driver, to be a greater revenue-producer than Europe, unit CEO Bernd Reckmann said in an interview.

The head of the company’s life science and performance materials unit told China’s Global Times that even as the nation’s economy has become a more normal one, he sees the country providing continued double-digit growth for the company.

The emerging markets that include Latin America and all of Asia except Japan provided 38% of the company’s total revenue of $12.5 billion last year, while Europe provided 35%, the company said.

Reckmann said China’s slower rate of growth would be more than offset by its increasing healthcare needs and its efforts to encourage more innovation. Merck KGaA, he said, has added to its own investment and manufacturing plants in China, the latest a $104.6 million facility expected to be operational in 2017 to produce drugs on the country’s list of those considered essential.

E. Allan Gabor, president and CEO of Merck Serono China, told the Global Time she still considered China a good investment climate, particularly for companies eyeing long-term development. Source: Merk KGaA

Cipla Buys Capacity in Yemen with Deal to Control Company there.

Indian drug maker says target has one plant that will come online soonIndia-based Cipla has been expanding its manufacturing footprint outside of its base in India and has now made the jump across the Arabian Sea to Yemen.

Cipla announced Monday that it has an agreement to buy a 51% stake in a pharmaceuticals manufacturing and distribution business there. It said it will pay $21 million for the stake and make milestone payments over the next three years if sales goals are hit.

Cipla spokesperson Jaisingh Krishnan said in an email Monday that the company was not identifying the target or providing many details. Krishnan said the drug maker has “one manufacturing facility which will be commissioned shortly,” and will manufacture tablets and capsules. Cipla itself is already selling in Yemen with more than 200 products approved there. It said that given its recent preference to manufacture products locally, this deal secures its place in a rapidly-growing marketDrug makers are building up partnerships and infrastructure in the region as they look for markets with more growth potential than they currently are realizing. Saudi Arabia, which sits just to the north of Yemen, has attracted a number of players.

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Boehringer Ingelheim in May struck a deal with two Saudi companies, Cigalah and Tabuk, which will manage and handle secondary packaging projects for 26 Boehringer Ingelheim products. AbbVie ($ABBV) also announced it would partner with the Arab Company for Pharmaceutical Products (Arabio) to manufacture Humira, the world’s best-selling drug, and other products in Saudi Arabia. Pfizer ($PFE) is a step ahead, having started on a plant there that is expected to be producing drugs next year. Source: Fierce Pharma Asia

Researchers make Key Malarial Drug-resistance finding

According to the World Health Organization’s 2014 World Malaria Report, there are an estimated 198 million cases of malaria worldwide with 3.3 billion people at risk for contracting the infection. Although the impact of malaria is still significant, the statistics reflect a considerable reduction in the global malaria burden. Since 2010, disease transmission has been reduced by 30 percent and mortality due to malaria has decreased by almost half.

Artemisinins are powerful drugs that have the most rapid action of all current drugs against Plasmodium falciparum, the parasite species that causes the most dangerous form of malaria. Artemisinin combination therapies (ACTs) are now standard treatment worldwide for P. falciparum malaria. Unfortunately, resistance to artemisinin has been detected in five countries across Southeast Asia. Along the Cambodia-Thailand border, P. falciparum is now resistant to most available antimalarial drugs. Artemisinin resistance poses a serious global threat to malaria control and elimination.

“There are two phases of blood stage malaria infection. In the first phase, the ‘ring’ parasite stage circulates in the bloodstream, and in the second phase, the ‘mature’ parasite stage sequesters in the tissues of the body,” explained Kasturi Haldar, the Rev. Julius A. Nieuwland Professor of Biological Sciences and the James C. Parsons and Carrie Ann Quinn Director of the Boler-Parseghian Center for Rare and Neglected Diseases. “Artemisinins are highly effective in treating malaria quickly because they target the first ring stage. When patients take the medication, their fevers reduce quickly, and the parasite is eliminated rapidly.”Source: World Pharma News

New WHO Statement on Public Reporting of Clinical Trial Results AnnouncedThe World Health Organization (WHO) have announced a new statement on the public disclosure of clinical trial results which updates and expands a previous statement that noted the “the registration of all interventional trials is a scientific, ethical, and moral responsibility.” The new statement includes timelines by which researchers are expected to report clinical trials results. In an Essay published in this week’s PLOS Medicine Vasee Moorthy and colleagues from the WHO outline the rationale behind the new statement.

A new element in the WHO statement is the definition of timelines for researchers to report the main findings of clinical trial results: by posting to the results section of the primary clinical trial registry within 12 months of study completion, and by publishing within a peer-reviewed journal within 24 months of study completion.

The authors conclude, “WHO calls for ethics committees, regulatory authorities, professional bodies, sponsors, investigators, and funding agencies to act in their jurisdictions to ensure results from all interventional clinical trials are reported and publicly disclosed.”Source: JCS News team

Teva Pharmaceutical considering bid for Mylan

Teva Pharmaceutical Industries Ltd. is considering a takeover bid for drug maker Mylan NV, according to people familiar with the matter, a sign of the jockeying for dominance among generic drug makers.

The Israeli generic drug maker hasn’t yet decided whether to make an offer, the people said.Last week Mylan made an unsolicited $28.9 billion proposal to buy Ireland-based Perrigo Co., and a Teva bid would represent an effort to disrupt that.Mylan said in a statement that it is committed to the Perrigo deal.

“We have studied the potential combination of Mylan and Teva for some time, and we believe it is clear that such a combination is without sound industrial logic or cultural fit,” Mylan said. “Further, there would be significant overlap in the companies’ businesses, and we believe that it is unlikely that any such combination could obtain antitrust regulatory clearances.”

A Mylan deal would be a big bite for Teva, as Mylan’s market capitalization is roughly half of Teva’s $66 billion market capitalization.Shares of both companies rose Friday after The Wall Street Journal reported on Teva’s deliberations. Mylan’s share price added 4.4% to $69.76, while Teva’s gained 1.7% to $64.41. Perrigo shares, meanwhile, dropped 0.8% to $197.46.

Teva has largely remained on the sidelines of a frenzied deal market in the health-care space, but it has indicated in recent months it has an appetite for entering the fray.

A tie-up would create a generic drug giant, which could use the combination to cut costs and cope with rising competition. Ruminating about a Teva-Mylan combination, J.P. Morgan has estimated such a deal could lead to more than $1 billion in annual cost savings.

Source: JCS News Team

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