journal for clinical studies

The Slow MoveTo Quadrivalent Influenza Vaccines

Shifting FocusIn Ophthalmic Clinical Research

Use of Traditional Complementary and Alternative MedicineIn the Management of HIV/AIDS and Related Complications in South Africa

The Potential of BangladeshAs a Clinical Research Hub in South Asia

PEER REVIEWED

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Your Resource for Multisite Studies & Emerging MarketsCLINICAL STUDIESU

Volume 4 - Issue 3

Contents

Volume 4 Issue 3 Journal for Clinical Studies

8 FOREWORD

WATCh PAgES

10 The Slow Move to Quadrivalent Influenza Vaccines On February 29, 2012, the US Food and Drug Administration

(FDA) approved the first seasonal influenza vaccine containing four strains of the influenza virus. The vaccine, FluMist Quadrivalent from MedImmune, LLC, contains two influenza A strains and, unlike previous multivalent influenza vaccines, two influenza B strains. The vaccine marks the end of a long journey to what is hoped will be a vaccine programme that could eventually save thousands of lives in the US each year. Walter Chalkley at IDRAC discusses the march to this new quadrivalent vaccine, and a start of a discussion one February many years ago.

12 Cardiovascular Safety Watch Column A recent meeting entitled Submission of Extended Digital

Electrocardiogram Waveform Data was held on March 14th, 2012, at the US Food and Drug Administration’s (FDA’s) headquarters. It provided insights that have contributed considerably to the material presented in this article. The purpose was to consider upcoming changes in the amount of data that will be requested by the FDA following the conduct of an ICH E14 Thorough QT/QTc (TQT) study. Rick Turner at Quintiles discusses an analysis of how the annotated waveforms are submitted to the FDA in HL7 format along with a Study Report.

14 What gMP-related Contents are to be Covered in Quality Agreements between the Sponsor, the CRO

and the Manufacturer? Claudio Lorck at Temmler Werke GmbH identifies how

the sponsor of a clinical trial has to consider a variety of Directives and Guidelines setting rules and restrictions to be considered, not only referring to good clinical practice but also good manufacturing practice. The following Watch Page shall support sponsors to address GMP-related requirements in quality agreements with CROs and manufacturers.

16 What You have to Know about Doing Oncology Clinical Trials in Russia

It’s been more than a decade now that Russia has been viewed as one of the major contributors to multinational clinical trials enrolment, especially in oncology. Indeed, Russia’s centralised healthcare system contains a large database of patients with diagnosed conditions. According to GBI Research, the top six therapeutic areas constitute 85% of the total share of clinical trials conducted in Russia. The major therapeutic areas for which clinical trials are conducted in the country are oncology with 22%, followed by endocrine and metabolic diseases, respiratory system, and circulatory system, each with shares of 14%. Alexandra Zaichenko at Global Clinical Trials discusses why this clearly indicates that oncology will lead the way for clinical trials conducted in Russia.

MANAgINg DIRECTOR Martin Wright

PUBLIShERMark A. Barker

MANAgINg EDITOR Mark A. Barker

EDITORIAL MANAgERJaypreet Dhillon

EDITORIAL ASSISTANTSCecilia Stroe, Jean Baptiste Marty

DESIgN DIRECTOR Ricky Elizabeth

RESEARCh & CIRCULATION MANAgERDorothy Brooks

BUSINESS DEVELOPMENT Farah Jamali

ADMINISTRATOR Barbara Lasco

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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]

The Journal for Clinical Studies – ISSN 1758-5678 is published by-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 4 Issue 3 May 2012 PHARMA PUBLICATIONS

JOURNAL FOR

Your Resource for Multisite Studies & Emerging Markets CLINICAL STUDIES U


Contents

REgULATORY

18 Identifying and Meeting the Challenges of Clinical Trials at Investigator Sites

The processes and procedures that guide the early development of medicinal products are radically disconnected from the manner in which drugs subsequently undergo clinical trials. The pathway from drug discovery, through non-clinical development and then into first-in-man trials, is a tightly programmed process over which the drug developer has full-time control. Brendan Buckley at Firecrest Clinical discusses why those that work in this phase all operate to tight SOPs, and are subject to rigorous repeated training and supervision.

22 Imaging Biomarkers in Oncology Drug Development Biomarkers are defined as measurements or characteristics

that are evaluated as indicators of normal biological or pathogenic processes, or responses to therapeutic interventions. Biomarkers have become increasingly important to physicians, medical product developers and regulatory agencies, impacting treatment decisions as well as drug approvals in their ability to define both efficacy and safety. In this article, Sandra Silberman and Philip Breitfeld at Quintiles, and Arnaud Butzbach at MEDIAN Technologies, focus on imaging biomarkers, as employed in efficacy assessments in oncology drug development.

MARKET REPORT

26 The Potential of Bangladesh as a Clinical Research hub in South Asia

According to the United Nations geographical region classification, South Asia comprises the countries of Afghanistan, Bangladesh, Bhutan, India, Iran, Maldives, Nepal, Pakistan and Sri Lanka. Bangladesh, Bhutan and Nepal are characterised as the least developed countries in the region. Bangladesh is the only LDC country that produces world-class pharma products, equipped with technologies and professionals. By 2015, Bangladesh aims to develop itself to compete in the free market. Nirvana Pillay at XCell Clinical Research and Hasan Mahmood at Bangladesh Association of Pharmaceutical Physician provide an overview of how the pharmaceutical industry in Bangladesh is one of the fastest growing sectors of the economy, and has made rapid strides over the years.

ThERAPEUTICS

30 Shifting Focus in Ophthalmic Clinical Research The ophthalmic research generating the most buzz over the

past two decades has been for neovascular retinal disorders with consecutive approvals of incrementally improving therapies. Though there is room for improvement with regard to reducing the frequency, decreasing the cost and developing a less invasive delivery method for treating neovascular eye disease, David Hoelscher and Nicholas Spittal at Chiltern International discuss how the reality is that there are multiple viable options available for physicians and their patients. The war to treat these diseases is all but over, with less reason to pursue new mono therapies.

Journal for Clinical Studies 7www.jforcs.com


Contents

36 Use of Traditional Complementary and Alternative Medicine in the Management of hIV/AIDS and Related Complications in South Africa: An Overview

The World Health Organization defines traditional medicine as the sum of total knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures used to maintain health, as well as prevent, diagnose, improve or treat physical and mental illness. For centuries, traditional healers have been playing a major role as providers of primary healthcare to the majority of people in Africa. Edward Mukwaya, Portia Rikhotso and Catherine Lund at OnQ Research SA highlight the negative sentiments against traditional healers in favour of the conventional medical system, and particularly in the developing world, especially Africa.

IT & LOgISTICS

40 Challenges in Central lab Logistics in India India is among the most favoured destinations for clinical

research outsourcing and conducting global clinical trials. Interest in India can be linked to a large patient pool with both infectious and chronic diseases, medical infrastructure, lower cost, qualified English-speaking manpower, global medical practices, globally acceptable regulatory environment, and consistent high-quality and on-time delivery. Raghavendra Karanth & Shabeer Ahmed of Eurofins Global Central Laboratory deliberates why India is the world’s third-largest producer of drugs by volume, with the third-largest drug research and development workforce, and how India is a major player in the pharmaceutical industry..

44 how Packaging Solutions are Easing Multi-site Challenges

Challenges experienced by multi-sites are some of the most frustrating for the clinical trial cold chain. Although trusted real-world data and profiles from around the globe have been painstakingly analysed and perfected over the years, even the most experienced and well-forecasted routes can encounter unforeseen problems. David Johnson at SCA Cool Logistics gives his viewpoint on the challenges encountered by the clinical trial cool chain sector when transporting their precious cargo across the globe, and shares the results from the business recent interactive presentations to the CT execs regarding issues encountered.

46 Unlocking the Logistics for your Multi-National Studies: Into the Brave New World

Conducting a successful clinical trial of any drug or treatment modality is always difficult. It is further complicated when one adds a multi-jurisdictional approach and then layers on emerging markets, where costs may be lower and where future product growth almost certainly is, but also where there is less experience, both in clinical trial conduct and in working within these jurisdictions. As with anything, it is much easier to maintain control and consistency with fewer parties involved, and when you do not have language, cultural and ethnic variances to be considered. Nicole Grannell at Bay Area Research Logistics & Jackie Bosch of McMaster University Hamilton describes some of the clinical trial objectives that will need to be maintained.

SPECIAL FEATURE

50 FDA and EMA Actions Regarding the Cardiovascular Safety of Drugs for Type 2 Diabetes Mellitus, 2007-2012: An Overview of Respective Regulatory Landscapes

Drug development and pharmacotherapy are both governed by regulatory science, which involves the development of new methods, standards and models we can use to speed the development, review, approval and ongoing oversight of medical products. Drug safety is an important component of the US Food and Drug Administration Strategic Priorities for 2011-2015 and the European Medicines Agency Road Map to 2015, bearing witness to the intimate relationship between regulatory science and the science of safety. While both agencies share a paramount commitment to protecting and promoting the health of citizens under their jurisdiction, decisions in individual cases can differ, leading certain medicines to be available to citizens of some countries and not others. In this paper Rick Turner and Paul Strumph at Quintiles present two case studies illustrating a lack of harmony in respective regulatory landscapes.

ExhIBITION PREVIEWS & REVIEWS

58 Paediatric Clinical Research Facility Opened at Alder hey, May 2012

Recent requirements by the European Regulation on Better Medicines for Children have led to a dramatic increase in the number of studies conducted in the paediatric population. Back in 2009, Alder Hey and the University of Liverpool recognised that a facility solely focused on paediatric research was needed. Charlie Orton at Alder Hey Hospital provides a review on a bespoke clinical research facility, solely focused on paediatric research, that was opened at Alder Hey Children’s Hospital in Liverpool on 4th May 2012. The facility was officially opened by comedian John Bishop during an all-day event attended by 100 guests.


Foreword

Welcome to the latest edition of JCS. I want to start by bringing to your

attention the feature on page 12. Although this is a regular Cardiovascular Watch Column written by Dr Rick J. Turner, this feature highlights a recent meeting entitled “Submission of Extended Digital Electrocardiogram Waveform Data”

which was held on March 14th, 2012, at the US Food and Drug Administration’s (FDA’s) headquarters. This article provides information to biopharmaceutical companies regarding the evolving cardiac safety regulatory landscape in the United States, so that they can start to prepare appropriately in advance. Additional information will be provided in due course.

To follow on, all the contributors to JCS never cease to amaze with the amount of in-depth and detailed information they provide about doing clinical trials in faraway places. In this issue, Raghavendra Karanth at Eurofins Global Central Laboratory deliberates on why India is the world’s third-largest producer of drugs by volume, with the third-largest drug research and development workforce, and how India is a major player in the pharmaceutical industry.

One can never underestimate the value of local knowledge. In this issue, Nirvana Pillay at XCell Clinical Research and Hasan Mahmood at Bangladesh Association of Pharmaceutical Physician provide an overview of how the pharmaceutical industry in Bangladesh is one of the fastest growing sectors of the economy, and has made rapid strides over the years. The potential of Bangladesh as a clinical research hub in South Asia is explored. According to the United Nations geographical region classification, South Asia comprises the countries of Afghanistan, Bangladesh, Bhutan, India, Iran, Maldives, Pakistan and Sri Lanka. Bangladesh, Bhutan and Nepal are characterised as the least developed countries in the region. Bangladesh is the only LDC country that produces world-class pharma products, equipped with technologies and professionals. By 2015, Bangladesh aims to develop itself to compete in the free market.

Nicole Grannell at Bay Area Research Logistics describes some

of the clinical trial objectives that will need to be maintained while unlocking the logistics for your multi-national studies. Meanwhile, David Johnson at SCA Cool Logistics gives his viewpoint on the challenges encountered by the clinical trial cool chain sector when transporting their precious cargo across the globe.

Dr Claudio Alexander Lorck of Temmler Werke GmbH identifies how the sponsor of a clinical trial has to consider a variety of directives and guidelines setting rules and restrictions to be considered, not only referring to good clinical practice but also good manufacturing practice.

Oncology clinical trials in Russia are examined by Alexandra Zaichenko at Global Clinical Trials, who discusses why oncology will lead the way for clinical trials conducted in Russia, while in the regulatory section, Sandra Silberman and Philip Breitfeld at Quintiles, and Arnaud Butzbach at MEDIAN Technologies, focus on imaging biomarkers, as employed in efficacy assessments in oncology drug development. Walter Chalkley at IDRAC discusses the slow march to the new quadrivalent influenza vaccine.

In the therapeutic section, Edward Mukwaya, Portia Rikhotso and Catherine Lund at OnQ Research SA highlight the negative sentiments against traditional healers in favour of the conventional medical system - particularly in the developing world, especially Africa. Meanwhile, David Hoelscher and Nicholas Spittal at Chiltern International discuss how the reality is that there are multiple viable options available for physicians and their patients. The war to treat these diseases is all but over, with less reason to pursue new mono therapies.

In the SPECIAL FEATURE, Rick Turner and Paul Strumph at Quintiles present two case studies illustrating a lack of harmony in respective regulatory landscapes with regard to the cardiovascular safety of drugs for type 2 diabetes mellitus, 2007-2012.

I hope you all enjoy this issue. I wish everyone who is attending the DIA Annual meeting in Philadelphia a successful meet.

Hope you all enjoy your summer, and see you again in July. Mark BarkerPublisher

Editorial Advisory Board

Andrew King, Managing Director, Biocair International. Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc. Bakhyt Sarymsakova - Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan Caroline Brooks - Associate Director, Logistics, ICON Central Laboratories Catherine Lund, Vice Chairman, OnQ Consulting 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 Charles Horth – Senior Life Sciences Consultant Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company Elizabeth Moench, President and CEO of Medici Global 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, M.D., 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 Kamal Shahani, Managing Director of Cliniminds - Unit of Teneth Health Edutech Pvt. Ltd. Karl M Eckl, Co-founder, Executive and Medical Director, InnoPhaR Innovative Pharma Research Eastern Europe GmbH Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRPNermeen Varawala, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation Patricia Lobo, Managing Director, Life Sciences Business Consulting 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 Rob Nichols, Director of Commercial Development, PHASE Forward 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


On February 29, 2012, the US Food and Drug Administration (FDA) approved the first seasonal influenza vaccine containing four strains of the influenza virus. The vaccine, FluMist Quadrivalent from MedImmune, LLC, contains two influenza A strains and, unlike previous multivalent influenza vaccines, two influenza B strains. The vaccine marks the end of a long journey to what is hoped will be a vaccine programme that could eventually save thousands of lives in the US each year. The march to this new quadrivalent vaccine started with a discussion one February many years ago.

Every February, shortly after the World Health Organization (WHO) convenes to discuss northern hemisphere influenza vaccine strains for the upcoming season, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) meets to recommend strains for inclusion in the FDA-approved seasonal influenza vaccines. The committee selects two influenza A strains and a single influenza B strain for use in the US beginning the next autumn. The committee is not obligated to follow the WHO recommendation, but usually does.

Strain selection is based on factors such as strain availability and manufacturer lead time requirements, but, when all is said and done, it is only slightly removed from a guess. Strains circulating at the time of the VRBPAC meeting are important, as are those circulating in the southern hemisphere. With the flu seasons reversed, strains from the south may foretell what is in store for upcoming seasons in the US. Data are crunched, vectors are analysed, and trends are investigated — so it is a well-informed, educated guess, but a guess nonetheless.

This is particularly apparent with influenza B strain selection. In recent years there have been two lineages of influenza B strains co-circulating: Victoria and Yamagata. Both mutate unpredictably; it is never clear which will be the dominant lineage when the upcoming influenza season arrives. Over the last ten years, the WHO and the VRBPAC have selected the correct B strain five times: the same odds as flipping a coin.

Influenza is a killer worldwide. As noted by the FDA, annual influenza-related deaths in the US over the last 30 years range from a low of 3000 to a high of nearly 50,000. Getting the right strain, particularly the correct influenza B strain, could save literally thousands of lives. The benefits of

including both lineages are apparent.For this reason, the notion of a quadrivalent vaccine

was introduced about a decade ago. As any member of the VRBPAC can attest, it has remained a discussion topic every year since, but to no avail. Until now. There are reasons for this delay: concerns by the committee that it is not specifically in their power to require a change of vaccines; concerns that it would be difficult for the manufacturers to produce the vaccine; and concerns that the development and approval of such a vaccine may require more regulatory oversight.

In this case, the new quadrivalent vaccine was submitted as a supplement to the original application with clinical studies in adults and children that compared the new vaccine with two trivalent formulations of the already-approved FluMist. Adverse events and immune responses demonstrated by the new vaccine were similar to those reported for the standard trivalent formulation of FluMist. The review process for the quadrivalent vaccine was generally no more regulatorily burdensome than that for the trivalent vaccine.

This first quadrivalent vaccine may set the standard for future seasonal influenza prevention. While it is not likely that all manufacturers will move to a quadrivalent formulation for the next influenza season, it is likely that the slow march, discussed at a decade’s worth of strain selection deliberations, may be nearing its final destination.

SourcePress release. February 29, 2012. “FDA approves first quadrivalent vaccine to prevent seasonal influenza” available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm294057.htm. Accessed April 4, 2012.

Walter Chalkley is a senior editorial project manager for IDRAC, a regulatory affairs information database and part of Thomson Reuters. His education was completed primarily at Virginia Commonwealth University in Richmond, Virginia. He achieved his Regulatory

Affairs Certification (RAC) and his regulatory interests are primarily focused on biologics, specifically vaccines. Email: [email protected]

Watch pages

The Slow Move to Quadrivalent Influenza Vaccines

12 Journal for Clinical Studies Volume 4 Issue 3

A recent meeting entitled “Submission of Extended Digital Electrocardiogram Waveform Data” was held on March 14th, 2012, at the US Food and Drug Administration’s (FDA’s) headquarters to consider upcoming changes in the amount of data that will be requested by the FDA following the conduct of an ICH E14 Thorough QT/QTc (TQT) study. TQT studies are conducted in an investigational drug’s preapproval clinical development programme to provide a rigorous assessment of the drug’s propensity to prolong the QT interval as seen on the surface electrocardiogram (ECG).1, 2 Currently, triplicate ECGs are extracted from 10-second strips taken from digital recordings for each subject in each treatment arm at each time point of interest in the study, perhaps 10-13, and read either manually or by semi-automated or highly automated systems. Following analysis, the annotated waveforms are submitted to the FDA in HL7 format along with a Study Report. However, this procedure is in the process of changing.

Dr Norman Stockbridge, Head of the FDA’s Cardiac Safety Interdisciplinary Review Team, noted that regulatory interest in digital ECGs a decade ago (former techniques had involved pen-and-ink chart recordings on paper) led to a lot of progress in this field. However, he also observed that 10-second ECGs do not capture an adequate characterisation of a drug’s QT effects as a function of time. Advances in biomedical engineering have led to equipment suitable for employment in TQT studies that can record ECG waveforms continuously for 24 hours. Since there are over 86,000 seconds in a 24-hour period, this represents approximately 8,600 10-second ECG strips. This provides the opportunity to conduct a much more extensive examination of any drug-induced effects on the waveforms. Such equipment is often used in current studies, but sponsors typically only ask core ECG labs to extract and analyse the appropriate 10-second strips, storing the rest of the data should they wish to revisit them at a later time. It is likely to take around two years for HL7 format technology to be adapted for this amount of data, but at that time the FDA will require sponsors to submit them.

This development will afford advantages to both regulators and sponsors. Consider first the regulators’ perspective. While certain rules influence sponsors’ choices regarding which 10-second ECG strips from a continuous recording will be chosen for analysis, these choices can be arbitrary to a certain degree. If the waveforms within a prespecified time window are of poor quality (or heart rate is not stable) it is possible to go a few seconds before or after the time window to select appropriate waveforms. The current system of submitting just the ECGs that were analysed means that regulators can only determine if these were analysed accurately: they cannot determine if the most appropriate waveforms were chosen to be analysed. Once they have access to all data, the latter determination also becomes possible.

Consider now the advantage to the sponsor, which may initially seem counterintuitive. Given that 8000 times as much information will be submitted, a sponsor may feel that

there is much more opportunity for regulators to find data of concern by having the opportunity to conduct unplanned analyses on any part of this dataset. However, the FDA’s intent is clearly not to do this: they simply wish to conduct a more extensive examination to yield an adequate characterisation of a drug’s QT effects as a function of time. Dr Stockbridge emphasised that, via exploratory analyses conducted to date, the regulators have ‘saved’ more TQT studies than they have invalidated: such unplanned analyses are not intended to “catch sponsors out.”

Editor’s Note:This article provides information to biopharmaceutical companies regarding the evolving cardiac safety regulatory landscape in the United States, so that they can start to prepare appropriately in advance. Additional information will be provided in due course.

References1. ICH E14, 2005. http://www.ich.org/fileadmin/Public_Web_

Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf

2. ICH E14: Questions & Answers (R1), 2012. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R1_step4.pdf

J. Rick Turner, PhD, is Senior Director, Integrated & Translational Cardiovascular Safety, Quintiles. He is an experimental research scientist and clinical triallist, Editor-in-Chief of the Drug Information Journal, a Senior Fellow at the Center for Medicine in the Public Interest, and a

Fellow of the Society for Behavioral Medicine. He is an author of more than 100 peer-reviewed papers and articles in professional journals, and an author of nine books. Email: [email protected]

Watch pages

Cardiovascular Safety Watch column


Watch pages

The sponsor of a clinical trial has to consider a variety of directives and guidelines setting rules and restrictions to be considered, not only referring to good clinical practice but also good manufacturing practice. The following Watch Page shall support sponsors to address gMP-related requirements in quality agreements with CROs and manufacturers.

1. Regulatory RequirementsICH E6 (R1) requests investigational products to be manufactured, handled, and stored in accordance with applicable good manufacturing practice. It makes the sponsor responsible to “ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s).”

Directive 2001/20/EC and 2005/28/EC request the sponsor to be responsible for ensuring that the conduct of the trials and the final data generated by those trials comply with the requirements described therein. The sponsor is therefore considered responsible for ensuring that manufacture and testing of the IMP is in compliance with the information notified pursuant to Article 9(2) of this Directive, and that the manufacturer and the test laboratories are suitable and authorised for these activities.

2. Quality Agreements Directive 2003/94/EC requires in its Article 12 – Work contracted out – that 1. Any manufacturing operation or operation linked thereto which is carried out under contract shall be the subject of a written contract.2. The contract shall clearly define the responsibilities of each party and shall define, in particular, the observance of GMP to be followed by the contract acceptor…Consequently a GMP-contract between the sponsor and the contract manufacturer and between the sponsor and the contract research organisation (CRO) should be established.

2.1 Quality Agreement Sponsor – ManufacturerBasically all process steps performed by the manufacturer should be addressed, starting from sourcing of starting materials until the distribution of the investigational product to the investigational site. Usually a tick list is

used to describe the responsibilities in detail. An example for distribution and returns/destruction is given below.

2.2 Quality Agreement Sponsor – CROBasically all GMP-related process steps occurring at the investigational site should be addressed, starting from receipt until destruction of the investigational product at the investigational site. Examples of tick list details are given below.

3. Conclusion Contracts are a legal requirement for contract manufacture of IPs on the one hand, and a powerful tool to address responsibilities between several parties and to prevent failures and additional costs due to misunderstanding and lack of communication on the other. The more detailed the future processes are described and addressed, the better the logistical part of a clinical trial can be performed.

Dr. Claudio Alexander Lorck has over 23 years experience in the field of Clinical Trial supply management. Having started his pharmaceutical career in Pharmaceutical Development, he held responsible positions in QC and R&D at Fujisawa Deutschland GmbH and

Astellas Deutschland GmbH. Claudio now heads the business unit of “Clinical Trial Materials” of Temmler Werke GmbH delivering supply services for clinical trials all over the world. Email: [email protected]

What gMP-related Contents are to be Covered in Quality Agreements between the Sponsor, the CRO and the Manufacturer?

It’s been more than a decade now that Russia has been viewed as one of the major contributors to multinational clinical trials enrolment, especially in oncology. Indeed, Russia’s centralised healthcare system contains a large database of patients with diagnosed conditions. And although hospitalisation costs are generally provided by the state or personal insurance, and are not added to trial expenses, patients with severe conditions like oncology do not get sufficient and timely medical treatment provided by state insurance - a factor which allows target recruitment goals to be reached faster and with fewer sites. Typically the treatment provided in oncology clinical trials is better than care available through the national health services.

According to GBI Research, the top six therapeutic areas constitute 85% of the total share of clinical trials conducted in Russia. The major therapeutic areas for which clinical trials are conducted in the country are oncology with 22%, followed by endocrine and metabolic diseases, respiratory system, and circulatory system, each with shares of 14%. This clearly indicates that oncology will lead the way for clinical trials conducted in Russia, where the recruitment potential is still one of the major time-saving factors. As per Outsourcing Pharma’s report, oncology clinical trials take 50% longer from protocol approval to randomisation of the last patient. Thus many pharma and biotech companies are turning to the emerging market countries like Russia, where the average time to complete the recruitment is usually threefold less than in the US and Europe.

Although man-hours are still much less expensive in Russia than in the West, and the pace of patient enrolment is between 2- 4 months ahead of sites in more developed areas, it is important to keep in mind that the major overlap

in costs may come from the costs of concomitant medication as well as comparator drugs, not to mention the costs of all blood tests and procedures, including radiology.

It is also important to highlight that due to very poor diagnostics, the prevalence (40-60%) in Russia are grade III/ IV cancers, especially for malignant tumours like pancreatic, non-small lung cancer and skin cancer. A 30.2% increase in patients diagnosed with the new malignant tumours has been observed during the last 10 years. 70% of these newly diagnosed patients require chemotherapy treatments, and only 30% receive such treatment in Moscow and St. Petersburg, with as little as 15% receiving relevant chemotherapy treatment in the other cities of Russia. This is to say that more trials should be placed in the outskirts of Russia where the sites are not so saturated with clinical studies, and the patient population in need of high standards of treatment may even exceed that in the central cities.

Alexandra Zaichenko Obtained a diploma in Translation and Interpreting Center from St. Petersburg State University. She joined PSI International in 2004, as a Project Coordinator. In 2006 Alexandra advanced her career from Clinical Trials Manager to Business

Development Director at OCT and further obtained an Executive MBA at Vlerick Gent Management School in 2010. Since August of 2010, she has taken a leading position of Director of Marketing at Global Clinical Trials.Email: [email protected]

Watch pages


What You have to Know about Doing Oncology Clinical Trials in Russia


Regulatory

The processes and procedures that guide the early development of medicinal products are radically disconnected from the manner in which drugs subsequently undergo clinical trials. The pathway from drug discovery, through non-clinical development and then into first-in-man trials, is a tightly programmed process over which the drug developer has full-time control. Those that work in this phase all operate to tight SOPs and they are subject to rigorous repeated training and supervision. Ultimately, bad performance can lead to the sanction of being fired. In contrast, when drugs come to clinical trial in patients, they must now enter a clinical setting in which the routine care of patients, not the conduct of drug trials, is usually the main preoccupation of investigators. With the exception of specialised commercial clinical trial sites, trials are generally a voluntary overhead on the patient care ‘day job’ of most investigators. In consequence, it is much more difficult for the trial sponsor to exercise control over this phase than over earlier phases of a drug’s development. Control of the process is now at arm’s length from the sponsor. This is complicated by the considerable sensitivities which impact the relationship between sponsors and investigators. The basic fact is that investigator sites participate in trials by choice. Sponsors often compete for the collaboration of sites that enjoy good patient access and high recruitment potential. They may be driven to include key opinion leaders as investigators, even those whose track records in conducting trials may not necessarily be good. There is a sense that it is important not to upset the investigator and that a light touch has to be employed in correcting problems, to prevent alienation of sites for future trials and to avoid driving a KOL into the arms of a competitor. It could thus cynically be said that the two main stages of development of a drug comprise initially the investing of several hundred million dollars in early development under close supervision, followed by the release of the fruit of this investment into the much looser later phase environment while struggling to control it. Thus, tight control morphs into ‘hoping for the best’, while the financial investment continues to increase.

The degree to which investigator site staffs comply with a protocol is likely to heavily influence whether a new drug succeeds or fails on trial. When a trial is designed, the power calculations, which drive details such as the number of participants and the duration of the trial, usually assume variances in endpoints that are achievable with optimal adherence to protocol. However, non-compliance and protocol violations may overwhelm the power calculations and lead to trial failure. A typical example is the phenomenon of ‘compassionate elasticity’, whereby investigators may stretch inclusion or exclusion criteria to enroll some unsuitable patients with

serious unmet needs to a trial. Further examples relate to a failure to distinguish adverse phenomena from efficacy effects, for instance where a rising level of a tumour marker in a trial of a cytotoxic is interpreted as a lack of efficacy rather than the effect of tumour cell death. This may result in inappropriate action. This is particularly evident in trials of drugs with narrow therapeutic indices. Such failures at site level may be the death-knell for a new drug that might have otherwise succeeded. They probably represent the greatest vulnerability to success in later phases of a drug’s development, beyond any intrinsic failings of the product itself. The frequency and cost of such failures is likely to be very high, not least for patients who might have benefited from the drug getting on the market.

Even with well-motivated sites, these difficulties are compounded by the annual inflation, heading to double digits, in the number and complexity of trial procedures and in the administrative burden that trial sites need to bear. Many protocols will require site staff to become expert in managing several diverse portals for EDC and IWRS from different vendors, further portals for central laboratories and other centralised assessments and a bewildering diversity of usernames and passwords (all carefully recorded on yellow Post-It notes adhering to various parts of their PC). There will be, in addition, study-specific gadgets for capturing ePRO, ECGs, skinfold thickness and hand grip strength. Site staff will have to learn to administer a series of rating scales and perform tests (like six-minute walks), which they were never trained to use in clinical practice. They have to take the right blood samples in the correct tubes and ship them at the proper temperature. They have to be able to find what to do at short notice, sometimes with the trial subject present, by hunting in a huge binder for the information they need. And they must be able to distinguish one trial from another, including equipment and procedures used, as the next patient through the door may happen to be in another trial altogether. The fact that it works more often than not is a huge tribute to the efforts of the great majority of site staff. But the process is deeply flawed.

Little has changed for years in how industry responds to these challenges. Site staff are still most commonly presented with training at investigator meetings, even though it is well known that these are ineffective, often poorly attended by key study personnel, and expensive. These often occur long before a patient is recruited and their message ebbs away with time. They do not address turnover of study staff on trial. At the end, sponsors have little insight into the competence of sites until, often, it is too late.

Slides and ‘talking head’ videos on the internet are not the answer. Intelligent online interactive tools are

Identifying and Meeting the Challenges of Clinical Trials at Investigator Sites

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now readily available which can allow tracked self-paced training, accessible throughout the duration of a trial, which returns invaluable data on site training behaviour to the sponsor, and which has been shown to greatly improve site performance for those who use it well.

Once a trial is underway, the external quality assessment performed by the study CRAs provides one of the main insights that the sponsor has into the crucial area of site performance. This occurs post-hoc, often many weeks after problems may have arisen and sometimes too late to remedy them. A monitor’s visit, occurring eight weeks after a patient has been inappropriately withdrawn, will rarely allow the re-entry of that patient into the study. Think of how you would view your local fire department if its main function was to call on you every few months to ask whether your house had gone on fire! How the wider use of targeted monitoring will impact site performance remains to be seen. But it will still occur long after damaging errors may have occurred in key areas.

EDC might be more useful in giving insight on how sites are performing, if it could produce information faster. Unfortunately, its potential to speed up data flow from sites is often not realised due to human-induced delay, so that lag times of three weeks from study visit to data entry are common even with the best EDC systems. This delay may be put in embarrassing context by the knowledge that it only took 12 days for the steamer ‘Teutonia’ to bring the news of President Lincoln’s assassination to Britain in 1865! Data delay has a real cost beyond the financial. Delay in obtaining visibility of key data on trial, particularly when there are significant sponsor concerns about potential toxicities in earlier phases, are a disincentive to even proceeding with potentially risky compounds. The existence of time lags in data flow, compounded by query resolution delays, highlights the aspirational nature of many adaptive trial designs, since adjustments to the trial can only occur when data have been reasonably secured.

The delivery of effective decision support to sites is also variable. At present, it usually depends on sites asking for it ad hoc. In general, larger and more experienced sites in smaller studies understand when they need to phone their CRA or the sponsor’s study team for advice. However, less experienced site staff may be reluctant to reveal their uncertainty, either to their patient or to study teams, for fear of appearing inexperienced or less knowledgeable and thus losing face. Ironically, it is such staff who are usually in most need of help and most prone to making errors. Failure of sites to seek assistance and the failure of trial organisations to make it easy for them impacts in particular on the identification of adverse effects and their correct management. For example, a typical oncology study may compare a new biological agent against placebo on a background of treatment with cisplatin. It is to be expected that leukopaenia will occur in a proportion of participants on both sides of the trial because of cisplatin. The challenge for site staff is to identify the phenomenon as an AE, attributing its causality between trial and background therapy and managing it appropriately. These all require that sites

adhere strictly to a protocol-specified management plan if harm is not to come to the patient, and to avoid biasing the trial by selective intervention on the intuition of the investigator staff. It is crucial that site staff do all of this strictly to the letter of the protocol, requiring that they can find the instructions quickly or can access advice from the study team. Here there is a role for easily accessed decision support for sites, using modern ICT tools to deliver it accurately and where necessary discreetely.

It is time to fundamentally re-think how we instruct site staff on performing trials, how we maintain their competence from beginning to end and how we support them visit by visit. The aspiration should be to strive for error-free trials at all sites, however far-fetched this initially sounds. Yet, in most other aspects of our lives we routinely complete difficult tasks while interacting with complex and sometimes dangerous forces, some of which were unimaginable not long ago. Modern life achieves this through engineering to eliminate the likelihood of danger and error. We can change light bulbs with minimal risk of electrocution because electrical systems are engineered to minimise risk. We can even do this without first having had two days of PowerPoint presentations at a light bulb changing course and without referring to a huge binder of instructions, simply because the systems are engineered to be intuitive as well as safe.

There is a basic question to be answered in formulating how we can move towards better clinical trial performance at sites, towards the error-free trial. Which is better: to try to teach people to perform complex tasks perfectly in a trial, or to engineer a simple intuitive user interface with the trial, which prevents them from making mistakes? Observe any six-year-old child with a computer game console. The answer is obvious.

There is now no technological barrier to achieving the complete simple engineered trial interface. We are on the brink of having systems available soon to advance this concept. However, their advance will bring a need to completely re-appraise whether our present ways of working are any longer appropriate. ICT has, as yet, barely intruded into how clinical trial sites work. When it does, it can bring substantial benefits to drug development and patient safety, but like all advances, it will achieve its potential fastest when minds are open to change.

Brendan Buckley MD DPhil FRCPI, Senior Vice President for Medical Affairs, Firecrest Clinical (an ICON plc company). Brendan Buckley is a co-founder of Firecrest Clinical, now an ICON plc company, and Senior VP of

Medical Affairs. He is also an Honorary Clinical Professor in the School of Medicine at University College Cork in Ireland. A medical graduate of the National University of Ireland and a doctoral graduate in Biochemistry of Oxford University, he has over 30 years’ experience in clinical pharmacology research. Prior to joining ICON, he was Director of the European collaborative Centre for Clinical Trials in Rare Diseases at Cork. He was a member of the EMA Committee for Orphan Medicinal Products (COMP) from 2000-2003, and a member of the EMA Scientific Advisory Committee on Diabetes and Metabolism until 2011. He was a member of the Board of Directors of the Irish Medicines Board, the national competent authority for Ireland, 2004-2011 and chaired its statutory Advisory Committee for Human Medicines. He is chairman of the independent data and safety monitoring boards for a number of large clinical trials programmes with several sponsors. He is a member of the scientific advisory boards of a number of research charities and honorary Director of the Cork Cancer Research Centre. Prof. Buckley is a Fellow of the Royal College of Physicians of Ireland, of the College’s Faculty of Pathology and a Fellow of the Faculty of Sports and Exercise Medicine. Email: [email protected]

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Imaging Biomarkers in Oncology Drug Development

IntroductionBiomarkers are defined as measurements or characteristics that are evaluated as indicators of normal biological or pathogenic processes, or responses to therapeutic interventions. Biomarkers have become increasingly important to physicians, medical product developers (both drugs and devices), and regulatory agencies, impacting treatment decisions as well as drug approvals in their ability to define both efficacy (therapeutic benefit) and safety (the likelihood and extent of undesirable off-target responses). This article focuses on imaging biomarkers as employed in efficacy assessments in oncology drug development.

Background Cancer remains one of the world’s leading public health concerns. Approximately 12.7 million cancer cases and 7.6 million cancer deaths are estimated to have occurred in 2008; of these, 56% of the cases and 64% of the deaths occurred in the economically developing world.1 For females, breast is the leading cancer site and accounts for 23% of the total cancer cases and 14% of the cancer deaths. For males, lung is the leading cancer site, comprising 17% of the total new cancer cases and 23% of the total cancer deaths. While greater international education and prevention campaigns are clearly desirable, the development, availability, and use of new pharmacotherapies are critical.

Kelloff and Sigman2 discussed the use of biomarkers in the context of drug development, citing those that are expressed as a consequence of cancer development and progression. Two categories of such biomarkers, those that are most relevant for identifying patients who are likely to respond to a given therapy and those that are most effective for measuring patient response to therapy, are of particular interest. The authors also discussed “innovative designs of clinical trials and methodologies that are used to validate and qualify biomarkers for use in specific contexts.”

Imaging BiomarkersImaging biomarkers play a key role in evaluating the efficacy of new candidate drugs and/or innovative therapeutic regimens (and can cost between 10% -15% of the total budget of clinical trials). However, their employment during clinical trials requires several issues to be addressed satisfactorily. First, image interpretation must be standardised to the greatest degree possible, meaning that reduced inter- and intra-reader variability is essential to minimise bias. Second, the volume of data generated by state-of-the-art imaging modalities requires computing facilities capable of storing, managing, and analysing the data: streamlining data management workflow, therefore, is a practical necessity. Web-based cloud computing technology that is made available at all participating sites

facilitates state-of-the-art image interpretation directly at investigator sites in an automated and standardised process, thereby reducing inter-reader variability.

Traditionally, in many cases where data from many investigator sites need to be interpreted, assessed, and analysed, employment of a central (core) laboratory has been considered the ‘gold standard.’ However, the time taken to respond by central labs and discrepancies with investigator site assessments leading to bias (e.g., wrong decisions on including, treating, or excluding subjects/censoring bias) have been critical issues. In the future, this may change in this field as individual sites and readers increase in expertise and standardisation. This would allow sponsors to access imaging biomarker data in near real time. This would therefore enable sponsors conducting Phase II trials to make go/no-go decisions more quickly, while implementing adaptive designs to collect data more efficiently and consistently employing the same imaging biomarker for Phase III trials.

Tumour Characteristics of InterestWhile evaluation of tumour characteristics via single-dimensional measurement criteria such as the Response Evaluation Criteria in Solid Tumors (RECIST) criteria,3-5 and bi-dimensional measurements (e.g., using WHO criteria6) have proved informative,7,8 newer characteristics of interest include quantitative lesion parameters such as volume9-11 and density.12 As new drugs are developed, the effects of alternative mechanisms of action (e.g., drugs that are antiangiogenic vs. cytotoxic) need to be assessed. Some effects may not be observed by size measurements alone, requiring instead assessments of changes in other characteristics such as density, pattern, and perfusion.

Use of AutomationIn the analysis of many types of data collected in clinical trials, the putative advantages of computer-aided and standardised systems include speed and reliability. Here, automated detections of lesions, organ and lesion segmentation, and assisted extraction of the parameters mentioned earlier (volume, density, and others) are of great interest. However, such systems must not only be reliable in consistently providing the same reading and interpretation of data, they must be reliable and correct. Demonstrating such characteristics is at the moment a hot topic for the medical imaging community. Several initiatives are currently promoting such systems and paradigms, and gathering academic, regulatory, and industry contributions to confirm their performances and perform validation. Attention is focusing not only on drug development activities but also on routine clinical practice.13-14

Partnerships and Alliances in Contemporary Drug DevelopmentPartnerships and alliances between different stakeholders in integrated pharmaceutical medicine15 are becoming more common, given the increasing demands and pressures of bringing new drugs to market.16,17 These include partnerships and alliances between biopharmaceutical companies and companies manufacturing companion diagnostics, and between biopharmaceutical companies and contract research organisations (CROs).

The need to incorporate companion diagnostics into development efforts is a growing demand, and one that requires companies to plan ahead to ensure that relevant companion diagnostics are brought to the marketplace along with the respective drugs and their (new) indications.16 An informative example is provided by crizotinib, which was approved by the US Food and Drug Administration (FDA) to treat patients with late-stage (locally advanced or metastatic), non-small cell lung cancers expressing an abnormal variant anaplastic lymphoma kinase (ALK) gene. It required approval along with a companion diagnostic test that determines if a patient’s tumour expresses this abnormal gene, and is therefore a suitable candidate for crizotinib therapy.

With regard to imaging biomarkers, a three-way partnership or alliance between a biopharmaceutical sponsor, a CRO, and an imaging company can prove fruitful. As Smith et al16 noted, “Involvement of a CRO or central laboratory as a facilitator between biopharmaceutical and diagnostic companies can have many benefits as these organizations have an intimate understanding of the drug development process and have significant practical experience with developing and deploying biomarker tests in a real-world setting.”

An alliance between the authors’ companies provides an instructive case study. Thanks to its experience in enabling novel imaging biomarkers, and to its system being adopted by radiology departments around the world for not only clinical trials but also routine clinical practice, MEDIAN leverages its approved software medical device, differentiated clinical trial imaging services offering, and biomarker development capabilities that are essential to such collaborative initiatives. Quintiles, in turn, leverages its comprehensive understanding of the biopharmaceutical industry in general and its expertise and experience in conducting multi-site and multi-regional clinical trials.

Biomarker Technologies and ChallengesWhile there is considerable diversity in biomarker research and development, each faces the same set of challenges: qualification, clinical validation, and hence the requirement of analysis platforms for biomarker evaluation. Various approaches may be used for these purposes. Some insight is provided by ICH Guideline E1618 which focuses on genomic biomarkers. The guideline comments as follows: “Qualification is a conclusion that, within the stated context of use, the results of assessment with a biomarker can be relied upon to adequately reflect a biological process, response or event, and support use of the biomarker during drug or biotechnology product development, ranging from discovery

through post-approval.” The extent of the difficulties of validation led Smith et al16 to comment, “The challenges of incorporating biomarkers into clinical development programs…are nearly as great as the enormous potential that such technology affords.” It will be of considerable interest to all stakeholders in pharmaceutical medicine, and also clinical practice, to see how imaging biomarkers, and biomarkers in general, continue to evolve. Additional references are provided to guide further reading.19-30.

References 1. Jemal A, Bray F, Center MM, et al. Global cancer statistics.

CA: A Cancer Journal for Clinicians. 2011;61(2):69-90. 2. Kelloff GJ, Sigman CC. Cancer biomarkers: selecting the

right drug for the right patient. Nature Reviews: Drug Discovery. 2012;11(3):201-214.

3. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) European Journal of Cancer. 2009;45(2):228–247.

4. Riaz A, Memon K, Miller FH, et al. Role of the EASL, RECIST, and WHO response guidelines alone or in combination for hepatocellular carcinoma: radiologic-pathologic correlation. Journal of Hepatology. 2011;54(4):695-704.

5. Tsao AS, Garland L, Redman M, et al. A practical guide of the Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and modified RECIST criteria. Journal of Thoracic Oncology. 2011;6(3):598-601.

6. WHO. WHO Handbook for Reporting Results of Cancer Treatment. 48th WHO offset publication; Geneva, Switzerland, WHO: 1979.

7. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute. 2000;92(3):205–216.

8. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. Journal of Clinical Oncology. 2007;25(13):1753–1759.

9. Follwell MJ, Khu KJ, Cheng L, et al. Volume specific response criteria for brain metastases following salvage stereotactic radiosurgery and associated predictors of response. Acta Oncologia. 2012, April 26 [Epublication ahead of print].

10. Buckler AJ, Miulshine JL, Gottlieb R, et al. The use of volumetric CT as an imaging biomarker in lung cancer. Academic Radiology. 2010;17(1):100-106.

11. Buckler AJ, Schwartz LH, Petrick N, et al. Data sets for the qualification of volumetric CT as a quantitative imaging biomarker in lung cancer. Optics Express. 2010;18(14):15267-15282.

12. Faivre S, Zappa M, Vilgrain V, et al. Changes in tumor density in patients with advanced hepatocellular carcinoma treated with sunitinib. Clinical Cancer Research. 2011;17(13):4504-4512.

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13. Quantitative Imaging Biomarker Alliance (QIBA) / Radiology Society of North America (RSNA). http://www.rsna.org/QIBA_.aspx

14. Quantitative Imaging Network (QIN) / National Cancer Institue (NCI) https://wiki.nci.nih.gov/display/CIP/QIN

15. Turner JR. Drug safety, medication safety, patient safety: an overview of recent FDA guidances and initiatives. Regulatory Rapporteur. 2009; 6(4):4-8.

16. Smith B, Stocum M, Verst C, Cohen O. Building value through biomarkers: the “Smarter Development” initiative [published online ahead of print April 12, 2012]. Drug Information Journal. doi: 10.1177/0092861512441392.

17. Turner JR. New Drug Development: An Introduction to Clinical Trials, 2nd Edition. New York: Springer.

18. ICH. Guideline E16. Biomarkers related to drug or biotechnology product development: context, structure and format of qualification submissions. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E16/Step4/E16_Step_4.pdf

19. Bednar B, Ntziachristos V. Opto-acoustic imaging of drug discovery biomarkers. Current Pharmaceutical Biotechnology. 2012 Feb 15. [Epub ahead of print].

20. Cortez MA, Welsh JW, Calin GA. Circulating MicroRNAs as non-invasive Biomarkers in Breast Cancer. Recent Results in Cancer Research. 2012;195:151-161.

21. James ML, Gambhir SS. A molecular imaging primer: modalities, imaging agents, and applications. Physiological Reviews. 2012;92(2):897-965.

22. Jones T, Price P. Development and experimental medicine applications of PET in oncology: a historical perspective. Lancet Oncology. 2012;13(3):e116-125.

23. Kircher MF, Hricak H, Larson SM. Molecular imaging for personalized cancer care. Molecular Oncology. 2012; March 10th. [Epublication ahead of print].

24. Matheis K, Laurie D, Andriamandroso C, et al. A generic operational strategy to qualify translational safety biomarkers. Drug Discovery Today. 2011;16(13-14):600-608.

25. Punnoose EA, Lackner MR. Challenges and Opportunities in the Use of CTCs for Companion Diagnostic Development. Recent Results in Cancer Research. 2012;195:241-253.

26. Townsend DW. Combined positron emission tomography-computed tomography: the historical perspective. Seminars in Ultrasound, CT, and MR. 29(4):232-235.

27. Tatsch K. Standardisation and harmonisation boost the credibility of nuclear medicine procedures. European Journal of Nuclear Medicine and Molecular Imaging. 2012: 39(1):186-187.

28. Mozley PD, Schwartz LH, Bendtsen C, et al. Change in lung tumor volume as a biomarker of treatment response: a critical review of the evidence. Annals of Oncology. 2010: 21(9):1751-1755.

29. Buckler AJ, Bresolin L, Dunnick NR, et al. Quantitative imaging test approval and biomarker qualification: interrelated but distinct activities. Radiology. 2011: 259(3):875-284.

30. Sistare FD, DeGeorge JJ. Promise of new translational safety biomarkers in drug development and challenges to regulatory qualification. Biomarkers in Medicine. 2011;5:497-514.

Sandra Silberman, MD, PhD, is Vice President, Translational Medicine, Quintiles. She has worked for pharmaceutical companies, including Pfizer and Novartis, developed the Oncology Clinical group at Eisai, and has been an independent industry

consultant to Bristol-Myers Squibb, AstraZeneca, ImClone, Roche, and several biotechnology companies in their various oncology programmes. She has over 50 publications and is named on several patents in the cancer drug development field. She is board certified in Internal Medicine and Hematology/Oncology, and is an attending physician at the VAMC in Durham, NC.Email: [email protected]

Philip Breitfeld, MD, is Vice President and Therapeutic Strategy Head, Oncology Therapeutic Area, Quintiles. He has over 25 years of work experience in oncology, including 20 years of experience in academic medical institutions in the US, and seven years of experience in

the pharma industry focused exclusively on oncology drug development and execution of clinical programmes. Prior to joining Quintiles he held senior oncology clinical development positions at BioCryst and Merck Serono. He has around 50 peer-reviewed publications in the scientific literature, and was a Visiting Scientist at the Whitehead Institute at MIT. Email: [email protected]

Arnaud Butzbach, MS, is Vice-President Operations and Chief Technology Officer, MEDIAN Technologies, which he co-founded back in 2002. He has been contributing to the medical device and imaging services industries with pioneering companies (such as Deemed,

Focus Imaging, Healthcenter, and MEDIAN Technologies) for more than twenty years, focusing on computer aided detection and diagnosis (CAD/CADx) and quantitative imaging for oncology. His scientific education and background in computer sciences and applied mathematics (INPG/ENSIMAG) makes him deeply involved with technology, software engineering, delivery of clinical trial imaging services, and development of imaging companion/monitoring tests. Email: [email protected]

AcknowledgementsThe authors wish to thank Hubert Beaumont, PhD, Estanislao Oubel, PhD, MEDIAN Technologies, and J. Rick Turner, PhD, Quintiles, for assistance in the preparation of this paper.

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Market Report

The Potential of Bangladesh as a Clinical Research hub in South Asia

According to the United Nations geographical region classification, South Asia comprises the countries of Afghanistan, Bangladesh, Bhutan, India, Iran, Maldives, Nepal, Pakistan and Sri Lanka.1 Bangladesh, Bhutan and Nepal are characterised as least developed countries (LDCs) in the region.

Bangladesh is the only LDC country that produces world-class pharma products, and is equipped with technologies and professionals. By 2015, Bangladesh aims to develop itself to compete in the free market.

The pharmaceutical industry in Bangladesh is one of the fastest growing sectors of the economy and has made rapid strides over the years. From being import-dependent in the 1980s, the industry has achieved self-sufficiency (97% local demand met by local companies) and gained global recognition as a producer of low-cost, high-quality finished drug formulations. Bangladesh is currently exporting to more than 87 countries all over the world. Having proved itself in the international market, Bangladesh is ready to face the challenges of proving its efficiency as the preferred destination for global clinical trials.

A number of factors favour Bangladesh as a clinical research hub. Firstly, there are numerous government-owned medical institutions with good facilities, which can serve as ideal centres for multi-centred clinical trials. Secondly, Bangladesh has well-trained and qualified manpower, well versed in English.

Moreover, Bangladesh is a land of diversity where Ayurveda, Unani, and homeopathy are practised with the same fervour as allopathy. Clinical studies for evaluation of various alternate systems of medicine can also be conducted with ease, which can attract collaborative contract proposals for conducting clinical trials, and many entrepreneurs have already come forward to set up their clinical research organisations (CROs) in Bangladesh.

Enabling Factors There are numerous enabling factors that are associated with performing clinical trials in Bangladesh. Here we highlight some of them:

SpeedFor almost all drug companies, speed is of the essence. Typically it takes 10-15 years to develop a new drug, and the 20-year-clock on a drug patent starts ticking when a new compound is discovered.3 So the quicker a product can get to market, the speedier the return on investment. The faster a drug is developed, the longer its patent protects it. Even saving a few months on the drug development timelines can mean millions of dollars in sales to a drug company. Conducting Phase III trials in Bangladesh simultaneously with trials in the west can save companies between two and five years in getting their drugs to market in Bangladesh and other Asian countries.

Patient EnrolmentBangladesh certainly has plenty of patients. Past experience has shown that in most of the multi-country trials, patient enrolment is rapid in Bangladesh. Many of them have never been treated before, and this makes them even more valuable as participants.

Generally Bangladeshi patients are very co-operative and they follow their doctor’s advice, and thanks to mobile networks, patients now have better communication with doctors.

Patients’ Rights and SafetyIn today’s scientific era, research is taking major strides in multiple areas to develop new and better drugs to cure ailments that are difficult to treat. Participation in clinical trails provides an opportunity to experience the benefits of these new drugs. Clinical trials move in phases; that is, Phase II trials are initiated only if the Phase I results are promising.

Table 1 Bangladesh at a glance2

Table 2 Common Diseases in Bangladesh

Similarly, Phase III trails are conducted only if the drug has shown required safety and efficacy in early-phase trails. Hence, a patient is at minimised risk during later phases of clinical trails. This phase process is particularly important in developing countries if carefully understood and explained to potential subjects. To identify problems and issues relating to medical and health sciences and to determine priority areas in research on the basis of healthcare needs, goals, policies and objectives, the Bangladesh Medical Research Council (BMRC) was established in 1972.5

Wide Spectrum of DiseaseApart from the sheer numbers of patients, there are other compelling reasons why multinational drug companies can look to Bangladesh to test new drugs. Diseases like multi-drug resistant pneumonia, hepatitis B, diabetes and some cancers are far more prevalent in Bangladesh than in the west.

Proficiency in English LanguageThe proficiency of Bangladeshi investigators and research professionals in the English language is an added advantage for all medical and scientific communications.

Economy Clinical trials in Bangladesh are economic. The overall cost advantage in bringing a drug to market by leveraging Bangladesh aggressively could save cost. Bangladesh is gaining good pharma contract manufacturing, and the total cost for the buyer reduces more than 50%. Clinical research

will also have the same cost advantages, as life expenditure in Bangladesh is very low by global standards.

The present day economic environment is quite favourable for foreign direct investments. The government is very much open to FDI initiatives, and has provided different facilities for the investor in different sectors, such as garments, pharmaceuticals etc.

InfrastructureBangladesh has a talented pool of clinical research professionals and investigator sites eager to take part in GCP trials. Bangladesh’s IT strength can be leveraged to gain competitive advantage in the clinical research arena, including data management. But unfortunately Bangladesh does not have sufficient investment in this sector, which needs huge foreign investment.

The Legal and Regulatory Environment in BangladeshMultinational pharmaceutical companies, and some independent institutions like International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR, B) and Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), are able to conduct good quality clinical trials in Bangladesh despite infrastructural challenges at the regulatory department level. They can do so because of required professional training and the professionals’ willingness to comply with regulations and applicable standards in a spirit that protects the rights and safety of trial subjects. In Bangladesh, no less than in the rest of the world, it is the


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Ministry of Health and Family Welfare (MOHFW) 4

responsibility of individual stakeholders (sponsors, CROs, investigators) to observe self-discipline while conducting clinical trials. No regulatory authority can ensure 100% GCP compliance unless the individual stakeholders are willing to comply with the applicable regulations.

The Directorate general of Drug AdministrationThe main body for submission of the Evaluating Safety and Efficacy of Clinical Trial Application. The body is also responsible for any drug-related permission and punishment.

Bangladesh Medical Research Council (BMRC)As per resolution of the government, the BMRC is the focal point for health research. Any research involving human subjects has to be notified to the BMRC. The objectives of the BMRC are to identify problems and issues relating to medical and health sciences, and to determine priority areas in research on the basis of healthcare needs, goals, policies and objectives.5

The BMRC coordinates with other institutions and organisations engaged in health research activities in Bangladesh. The ethical committee provides ethical clearance to research studies not funded by the BMRC involving human subjects, to be conducted in Bangladesh by Bangladeshi or foreign researchers.

Current research priority areas identified by the BMRC are mentioned below:• Safe motherhood, child healthcare, acute respiratory

infection (ARI)• Infectious diseases: tuberculosis, malaria, kalaazar,

filariasis, leprosy, viral diseases• Nutrition: malnutrition, anemia, nutrition-related diseases• Non-communicable diseases: hypertension, cardiovascular

diseases, diabetes, stroke, mental disorders, cancer• Health systems research• Occupational and environmental research.

Alignment with gATT/TRIPS/WTO In the fourth special ministerial discussion on the TRIPS agreement on 9-13 November 2001 in Doha, Qatar, Bangladesh has turned to a son of fortune. In the ministerial declarations, the least developed countries (LDCs) got some concession from implementing GATT-TRIPS-WTO regulations, which are:1. TRIPS Agreement shall not prevent Members from taking

measures to protect public health. 2. TRIPS Agreement shall not prevent Members from

establishing or maintaining marketing approval procedures for generic medicines and other healthcare products.

3. TRIPS Agreement shall not prevent Members from disclosing or using information held by its authorities or the patent holder where it is so required for reasons of public interest.

4. Members may, among others, authorise the production and export of medicines by persons other than holders of patents on those medicines to address public health needs in importing Members.

5. Each Member shall, within or beyond the framework of the WTO, refrain from imposing or threatening to impose sanctions and refrain from employing the grant of incentives or other benefits in a manner which could curtail the ability of developing and least-developed country Members to avail themselves of every possible policy option to protect and promote public health.6

6. In view of the special needs and requirements of LDC Members, their economic, financial and administrative constraints, and their need for flexibility to create a viable technological base, the transition period of the TRIPS Agreement shall be extended. And for this the time period is extended from 2005 to 2015 for LDCs.

ConclusionThe lack of technical knowledge on drug development and the habit of “copying” (mostly producing generic drug) are the major hurdles for indigenous drug research. Participation in global trials provides learning opportunities to Bangladeshi doctors and scientists, which in turn can be utilised to find the answers for the diseases that are endemic to the country, such as cholera, malaria, enteric fever and tuberculosis. The medical research intellectual base of the country has not been optimally utilised due to the absence of the basic research facilities and know-how.

However, by forming further collaborations with neighbouring countries such as India, Bangladesh may have the potential of becoming a clinical research hub among the LDC countries in South Asia.7

References1. United Nations Geoscheme Available at http://

millenniumindicators.un.org2. Health Bulletin, MOH, Bangladesh 20113. Why To Choose India For Conducting Clinical Trials,

publication from www.catalystclinicalservices.com4. Organogram of Ministry of Health and Family Welfare

(MOHFW), Bangladesh5. Bangladesh Medical Research Council (BMRC) http://www.

bmrcbd.org6. Website of Eskaef Bangladesh Ltd. www.skfbd.com7. Clinical Trial in India-Dilemmas for Developing Countries,

P.K. Julka, MD, Monitor. April 2007: 69-71

Dr. Nirvana S. Pillay PhD MBA, is the Managing Director of XCell Clinical Research, a division of XCell Group Ventures (Pty) Ltd. XCell Clinical Research, is a CRO service provider that primarily focuses on multi-cultural, genetic and dermatological clinical studies. Dr.

Pillay is currently an executive council member of the Clinical Research Society. Email: [email protected].

Dr. Hasan Mahmood, MBBS, MBA is a physician involved in pharmaceutical international business. He is the founder president of Bangladesh Association of Pharmaceutical Physician. Email: [email protected]

Market report


Therapeutics


The ophthalmic research generating the most “buzz” over the past two decades has been for neovascular retinal disorders with consecutive approvals of incrementally improving therapies. In the year 2000, photodynamic therapy (PDT) with verteporfin replaced laser photocoagulation for treatment of wet age-related macular degeneration (AMD), and this quickly became the standard of care, while still leaving huge opportunity for better treatment options. PDT did nothing to improve vision and showed only limited success for select patients in maintaining the vision loss that had already occurred at the time of therapy6,30.

So on came the vascular endothelial growth factor (VEGF) inhibitors33, led by the approval in 2004 of pegatanib sodium injection for wet AMD which briefly replaced PDT as the standard of care. This was subsequently unseated by ranibizumab in 2006, the anti-VEGF antibody fragment derived from the full molecule bevacizumab which had been studied (and is approved) for various oncology indications. Thus was launched the “great debate” over the past five years between the two monoclonal antibodies: although bevacizumab is not approved in any ophthalmic indication, its off-label use has shown similar efficacy and safety at a substantially lower cost8,37. In early 2011, ranibizumab received EU approval for a label extension to include treatment of diabetic macular edema (DME) and regulatory submissions for the same are underway with the FDA. Lastly, the newest VEGF-inhibitor, aflibercept, which has shown similar efficacy to ranibizumab and bevacizumab in clinical trials37, was approved by the FDA in November 2011 for wet AMD; it is currently under review in the EU for AMD, and under investigation globally for DME. Regardless of their formal approvals, it should be noted that physician-prescribed use of all the VEGF inhibitors has become the standard of care for DME, retinal vein occlusion, diabetic retinopathy and other retinal disorders as well27.

Though there is room for improvement with regard to reducing the frequency, decreasing the cost12 and developing a less invasive delivery method for treating neovascular eye disease, the reality is that there are multiple viable options available for physicians and their patients. The “war” to treat these diseases is all but over, with less reason to pursue new monotherapies36.

Flying below the radar during this same period, there continues to be research for new therapies in other eye diseases. We are experiencing a resurgence in clinical stage investigation for eye diseases that currently have suboptimal standard of care. This includes, in particular, glaucoma, for which new neuroprotective agents are under investigation to complement or even replace traditional intraocular pressure (IOP) lowering therapies, and dry eye disease (DED), for which there is an improved understanding of the inflammatory nature of the syndrome. Both disorders have long had methods for treating the symptoms, but there is growing research to find therapies to resolve their underlying causes.

Neuroprotection in glaucomaGlaucoma is a group of diseases resulting in damage to the optic nerve and ganglion apoptosis, which is initially manifested as visual field loss and, ultimately, irreversible blindness if left untreated1. A visual simulation of its effects is represented in Figure 1. Though typically accompanied

by elevated intraocular pressure (IOP), this is merely part of the syndrome; glaucoma is more accurately described as an optic neuropathy resulting from death of retinal ganglion cells. Damage at the optic disc may result from a buildup of fluid in the anterior chamber and/or from systemic or localized hypertension. As such medicinal, laser, and surgical options (see Figure 2) typically intend to reduce IOP and thus relieve tension within the eye21.

Standard of care pharmaceutical therapies include topical eye drops which aim to increase the outflow of aqueous fluid (prostaglandins or parasympathomimetics); hyperosmotics to decrease aqueous fluid production (beta-blockers, alpha-adrenergic agonists, carbonic anhydrase inhibitors); and epinephrine which does both. Current treatments are generally insufficient in resolving the visual consequences of the actual disease2,21.

Shifting Focus in Ophthalmic Clinical Research

Figure 1 – A scene as viewed by someone with normal vision compared to the lost visual field effects of a person suffering from optic neuropathy related to glaucoma (courtesy National Eye Institute, National Institutes of Health).

Therapeutics


The latest introduced therapies have targeted the reduction of dosing frequency to once or twice daily and to provide a broad array of treatment options to physicians and their patients. Laser trabeculoplasty may also be used to improve the fluid outflow through the trabeculary meshwork, but multiple sessions are often required and the effect is generally limited to just a few years before retreatment or alternative therapy is sought. Conventional surgery may also be considered to physically create a new opening through which fluid may flow (see Figure 2)20. Alternatively,

anti-hypertensives may be utilised to control blood pressure which may also have effects at the optic disc.

More recently there has been increasing evidence of the ability to treat the actual optic nerve that is damaged as a result of glaucoma with various neuroprotective agents including phenytoin, brimonidine, epigallocatechingallate, ciliary neurotrophic factor and other proprietary formulations. This is of keen interest because there currently is no way to improve vision for those patients who have irreversible impairment as a result of long-term and/or significant ocular hypertension.

Neuroprotection – the term for nervous system mechanisms protecting neurons from apoptosis34 – for glaucoma patients is not a new concept; published articles dating to the 1990s first introduced its viability31,35. However, the concept that has continued as a controversial pipedream for the past ten years is now gaining momentum1 and advancing to the clinic. With current understanding that IOP-lowering by itself may not retard disease progression, there is significant interest in new modalities for treating glaucoma34. In fact, VEGF agents like those developed previously for retinal disorders are now being increasingly evaluated for certain types of neovascular glaucoma and other diseases2,27.

As glaucoma is broadly of varied etiology, neuroprotective management would offer the additional benefit that the underlying cause and symptoms would become inconsequential to the treatment of the disease. That is, a universal neuroprotective treatment would, in theory, work on any glaucoma patient35. There is evidence that

neuroprotection may be achieved pharmacologically by preventing stress on nerve cells resulting from their own toxic feedback mechanisms, or more directly by boosting the body’s own immunologic abilities. Neuroprotective agents have long been under investigation for other central nervous system disorders including stroke, spinal cord injuries, Parkinson’s disease and Alzheimer’s disease, and these concepts are now trickling down into eye disease research26.With advancements in representative animal models to improve our understanding of the biochemical pathways affiliated with glaucoma, there is a growing body of laboratory and preclinical evidence for neurological targets to include glutamate receptors, autoimmune elements, neurotrophin deprivation, nitric oxide synthesis, oxidative stress products, sodium and calcium channels, heat shock proteins and apoptotic pathways7,29. Most human research, including the use of ciliary neurotrophic factor, brimonidine and siRNA technologies, is at the early stage in the clinic, often via investigator-led research, yet this has the potential to be an expanding field in the coming decade16.

Dry Eye Disease DevelopmentsKeratoconjunctivitis sicca (KCS) or dry eye disease (DED) is a multifactorial disorder of the tears and the ocular surface that results in symptoms including discomfort (burning, itching, pain), visual disturbance, foreign body sensation, light sensitivity (photophobia), and tear film instability with potential damage to the ocular surface10. Aqueous tear deficiency (ATD) is the most common cause of DED impacting the tear layer which covers the normal ocular surface and serves as a surfactant, as an aqueous barrier to retard evaporation, and provides a smooth optical surface.

DED is a common disorder whose prevalence increases with age and has been estimated to affect up to 10% of non-contact wearers and up to 50% of those who wear contact lenses4. DED can be classified as Sjogren’s syndrome-related versus other causes. DED also particularly affects postmenopausal11 or pregnant women and females taking oral contraceptives or hormone replacement therapy (especially estrogen-only pills). Also, certain systemic medications, such as antihistamines or beta-blockers, tend to decrease tear production leading to dry eye syndromes. Incidence among industrialised countries is comparable.

Dry eye is diagnosed via a combination of patient history and various tests, but no single assessment permits absolute diagnosis. Since DED is recently associated with structural or functional changes resulting from inflammation10,32, the use of topical steroids or non-steroidal anti-inflammatory medications may be prescribed, and topical antibiotics may be necessary if the dry eye syndrome is associated with corneal complications; however, to date, approved therapies have been primarily limited to artificial lubricants with no impact on the underlying causes of DED, and, in more severe cases, topical immodulating therapy (cyclsporine). Restasis cyclosporine ophthalmic emulsion remains the only approved prescription pharmaceutical specifically labelled for DED, and it is only approved in the US with moderate improvement for tested research subjects. Not surprisingly, greater than 90 per cent of ophthalmologists indicate more and better treatment options are needed for DED3.

Figure 2 – Surgical methods to relieve hypertensive IOP include creation of a physical opening at the meshwork to promote fluid egress (courtesy National Eye Institute, National Institutes of Health).

Therapeutics


With limitations in the efficacy and availability of DED therapies, there is great opportunity for improvement. Further, there is a wealth of recently developed knowledge about the underlying etiology of DED, including aspects of tear evaporation, insufficient tear production, tear film instability and the inflammatory basis for the disease allowing development of new pharmaceutical targets5,11. In addition, we are witnessing a growing wave of clinical investigational programmes targeting new methodologies of treating DED, including topical and oral anti-inflammatories, drug/device combinations, adjuvant therapies to and/or improved formulations of cyclosporine, and other novel approaches. A selection of leading clinical candidates summarised in Table 1 demonstrates over a dozen programmes that are in or approaching late-stage research13-19,22-25.

glaucoma and DED Clinical Research in Emerging MarketsLike many therapeutic areas, clinical research in eye diseases has frequently been limited primarily to North America and Western Europe. Historically, countries in these regions have trained physicians, educated and motivated patient populations and a clinical research support network to conduct eye disease trials. These countries are also utilised with consideration for the clear regulatory paths to marketing approvals with infrastructure readily in place for future sales distribution. Even today there remains an imbalance; a review of all active studies in glaucoma and DED reveals there are more ongoing trials in the US and Canada than all other countries combined, as demonstrated in Table 2.

Though there is no shortage of interested ophthalmologists or patients in the US, Canada and Western Europe, clearly the clinical research space is far more saturated in these locations. Ophthalmic investigative sites in these regions are frequently saddled with multiple ongoing studies across all indications, even concurrently running studies that may compete for the same patient enrolment, with study coordinators dividing their attentions across many protocols. Thus, there is growing commercial interest in conducting eye disease research in emerging territories28. Considering the current challenges of the global economic downturn, there are great financial incentives to conduct a higher proportion of research in markets where financial hurdles may be lower.

For glaucoma, much of the neuroprotective research is still in preclinical stages. Thus, there are significant opportunities for investigator-led research which may be initiated from any location in order to discover or advance early therapeutic candidates. As expansion to human trials continues, there is need for more comprehensive multidisciplinary sites than what has been required for glaucoma studies historically. This is because new investigational therapies may require intravitreal injections typically performed by retinal specialists, or intravenous delivery, collaboration

with other sub-specialists such as ocular immunologists and advanced diagnostics such as optical coherence tomography (OCT), confocal scanning laser tomography (CSLT), scanning laser polarimetry (SLP) and photographic imaging of the optic nerve head (ONH) for visualisation of damage and treatment effects at the back of the eye (9). Clinical sites who have been certified in protocol-conduct of diagnostic imaging and ETDRS best-corrected visual acuity assessments will have a “leg-up” at the feasibility assessment stage for new trials. As these technologies, training and expertise continue to expand to emerging markets, there will be greater interest to place industry-sponsored studies in locations that are less commonly used today.

For dry eye studies, the “barriers” to participation are typically low. Patients are frequently diagnosed and treated by general ophthalmologists, low-tech diagnostics are commonly employed, and procedures are generally non-invasive. And, with an aging global population over the next two decades, there will be a ready and growing patient pool for participation in DED clinical research; this is well-timed with the advancement in therapies as discussed previously. One technique that potential sites may consider performing regularly is measurement of tear osmolarity, as this has not been standard practice for DED in the past, but is expected to be a more frequently used assessment in future research.

Table 1 – Select clinic-stage investigational products for dry eye disease.

Table 2 – Number of recruiting trials (courtesy ClinicalTrials.gov on 24 January 2012).

Therapeutics


With the frequency and clinical diagnosis of DED higher in the Hispanic and Asian populations than in the Caucasian population, emerging markets are ideally suited for conduct of research studies for new DED therapies.

References

1. Almasieh, M., Wilson, A. M., Morquette, B., Cueva Vargas, J. L., Di Polo,

A. The molecular basis of retinal ganglion cell death in glaucoma.

Progress in Retinal and Eye Research. (2011).

2. Almasieh, M., Zhou, Y., Kelly, M. E., Casanova, C., De Polo, A. Structural

and functional neuroprotection in glaucoma: role of galantamine-

mediated activation of muscarinic acetylcholine receptors. Cell Death

& Disease. 1(2). (2010).

3. Asbell, P. A., Spiegel, S. Ophthalmologist perceptions regarding

treatment of moderate to severe dry eye: results of a physician survey.

Trans Am Ophthalmology. 107. 205-210 (2009).

4. Bartlett, H., Eperjesi, F. New perspectives on the investigation and

treatment of dry eye syndrome – Part 1. The Optician. 231. 27, 30-37

(2006).

5. Bhavsar, A. S., Bhavsar, S. G., Jain, S. M. A review on recent advances in

dry eye: Pathogenesis and management. Oman J of Ophthalmology.

4(2). 50-56 (2011).

6. Bressler, N. M. Early Detection and Treatment of Neovascular

Age-related Macular Degeneration. J of the Amer Board of Family

Medicine. 15(2). 142-152 (2002).

7. Chidlow, G., Wood, J. P., Casson, R. J. Pharmacological neuroprotection

for glaucoma. Drugs. 67(5). 725-759 (2007).

8. CATT Research Group. Ranibizumab and Bevacizumab for Neovascular

Age-Related Macular Degeneration. New England J of Medicine. 364.

1897-1908 (2011).

9. Chong, G. T., Lee, R. K. Glaucoma versus red disease: imaging and

glaucoma diagnosis. Current Opinion in Ophthalmology. (2012).

10. De Paiva, C. S., Pflugfelder, S. C. Rationale for anti-inflammatory

therapy in dry eye syndrome. Arq. Bras. Oftalmol. 71(6). X-x (2008).

11. Gayton, J. L. Etiology, prevalence, and treatment of dry eye disease.

Clinical Ophthalmology. 3. 405-412 (2009).

12. Gower, E. W., Cassard, S. D., Bass, E. B., Schein, O. D., Bressler, N. M.

A cost-effectiveness analysis of three treatments for age-related

macular degeneration. Retina. 30(2). 212-221 (2010).

13. http://acucela.com/pipeline-candidates.html, visited on 30 January

2012.

14. http://www.alcon.com/en/research-development/, visited on 30

January 2012.

15. http://www.altosvision.com/news/2009/01/altos-vision-products.

html, visited on 30 January 2012.

16. http://www.clinicaltrials.gov, visited on 26 January 2012.

17. http://www.eyegatepharma.com/therapeutics/, visited on 30 Jaunary

2012.

18. w w w . g l o b e s . c o . i l / s e r v e e n / g l o b e s / d o c v i e w . a s p ? d i d = 1 0 0 0

708825&fid=1725, visited on 01 February 2012.

19. http://www.luxbio.com/pipeline.htm, visited on 30 January 2012.

20. http://www.nei.nih.gov/health/dryeye/index.asp, visited on 30

January 2012.

21. http://www.nei.nih.gov/health/glaucoma/glaucoma_facts.asp, visited

on 23 January 2012.

22. http://www.novagali.com/en/eye-therapy/severe-dry-eye/, visited on

30 January 2012.

23. http://www.regenerx.com/wt/page/clinical_trials, visited on 30

January 2012.

24. http://www.resolvyx.com/products/, visited on 30 January 2012.

25. http://www.sarcode.com/, visited on 30 January 2012.

26. Kaushik, S., Pandav, S. S., Ram, J. Neuroprotection in glaucoma. J of

Postgraduate Medicine. 49(1). 90-95 (2003).

27. Kimoto, K., Kubota, T. Anti-VEGF Agents for Ocular Angiogenisis and

Vascular Permeability. J of Ophthalmology. 2012. X-x (2012).

28. Kudrin, A. Challenges in the clinical development requirements for the

marketing authorization of new medicines in southeast Asia. J Clin

Pharmacology. 49(3). 268-280 (2009).

29. Lambiase, A., Alow, L., Centofanti, M., Parisi, V., Mantelli, F. Experimental

and clinical evidence of neuroprotection by nerve growth factor

eye drops: Implications for glaucoma. Proceedings of the National

Academy of Science of the United States of Amer. 106(32). (2009).

30. Meads, C., Hyde, C. Photodynamic therapy with verteporfin is effective,

but how big is its effect? Results of a systematic review. British J of

Ophthalmology. 88(2). 212-217 (2004).

31. Schwartz, M., Belkin M., Yoles E., Solomon A. Potential Treatment

Modalities for glaucomatous neuropathy: neuroprotection and

neuroregeneration. J Glaucoma. 5(6). 427-432 (1996).

32. Stern., M. E., Pflugfelder, S. C., Inflammation in dry eye. Ocular Surface.

2(2). 124-130 (2004).

33. Stewart, M. W. The expanding role of vascular endothelial growth

factor inhibitors in ophthalmology. Mayo Clin Proc. 87(1). 77-88

(2012).

34. Vasudevan, S., Gupta, V., Crowston, J. Neuroprotection in glaucoma.

Indian J of Ophthalmology. 59(Suppl1). 102-113 (2011).

35. Weinreb, R. N., Leonard, A.L. Is Neuroprotection a Viable Therapy for

Glaucoma? Archives of Ophthalmology. 117(11). 1540-1544 (1999).

36. Zampros, I., Praidou, A., Brazitikos, P., Ekonomidis, P., Androudi, S.

Antivascular Endothelial Growth Factor Agents for Neovascular Age-

Related Macular Degeneration. J of Ophthalmology. 2012. (2012).

37. Zou, L., Lai, H., Zhou, Q., Xiao, F. Lasting Controversy on Ranibizumab

and Bevacizumab. Theranostics. 2011(1). 395-402 (2001).

Nicholas Spittal, MBA, PMP, Associate Director, Global Clinical Development at Chiltern International, has been leading industry studies in ophthalmology for ten years, including directing the then-largest global programmes in three different retinal indications. Chiltern

International is a global full service contract clinical research organization offering consultation and operational services to the biopharmaceutical industry, with particular expertise in eye disease research. Mr Spittal may be reached at Email: [email protected]

David Hoelscher, MD, Clinical Research Physician at Chiltern International, has worked for over 19 years as a physician, principal investigator, and clinical researcher across a broad range of therapeutic indications. He is the Global Head of Chiltern’s Therapeutic Area

Team in Ophthalmology responsible for providing internal and sponsor-directed strategic guidance in the design and execution of Phase I-IV eye disease trials. Dr Hoelscher may be reached at Email: [email protected]

Therapeutic


Therapeutics

Background The World Health Organization defines traditional medicine as “the sum of total knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures used to maintain health as well as prevent, diagnose, improve or treat physical and mental illness”. For centuries, traditional healers have been playing a major role as providers of primary healthcare to the majority of people in Africa. Plants are the biggest source of traditional medicines (TM). Whole plants or parts such as the roots, leaves, barks, bulbs, stems or tubers, and in other cases their powder or liquid extracts, have been and continue to be used to treat or prevent illnesses. Animal parts are also commonly used. Another aspect of TM is its necromantic nature; it does not separate body from spirit, thus the long-standing belief in many African communities that traditional healers have a “calling” and receive knowledge passed onto them from their ancestors or gods. Therefore, besides the fact that it is not a trade open to everyone in the community, it is also not questionable. Those requiring treatment have to believe what the traditional healer says they should receive, and in most cases have to follow specific instructions that most often go beyond quantities and times of the dose to include rituals, sacrifices and social interactions. It is common, for example, for a traditional healer to advise a patient to avoid social interactions with certain members of the community or even the family, as they may be the causes of a particular ailment.

With the advent of orthodox, scientific, medicine early in the 19th century, traditional medicine began to be viewed as unconventional because active components had not been scientifically identified and proved to be efficacious.

Market Trends and Regulation of TMs in South AfricaDespite the negative sentiments against traditional healers in favour of the conventional medical system, the developing world, especially Africa, constitutes the largest market for the production, selling and consumption of traditional medicine. An estimated 70% to 95% of citizens in the developing world use traditional and herbal medicine. In South Africa alone, there are over 200,000 traditional healers while there are only 25,000 biomedical doctors, thus making traditional healers more accessible to many people. Reports indicate that many black South Africans consult their traditional healers first upon learning that they are HIV positive. A study conducted in Soweto, South Africa reported that over 75% of patients who visit hospitals and clinics for HIV/AIDS and related illnesses admitted to visiting their traditional healers prior to a hospital or clinic visit. This was attributed to two major factors; the limited number of doctors - whose services many South Africans cannot afford - and cultural beliefs. The economic and time considerations of modern medical healthcare delivery often limit doctors’ capacity to address

the spiritual and emotional needs of their patients. Therefore many poor HIV/AIDS patients prefer traditional healers to orthodox medical system healthcare providers. Furthermore, when antiretroviral therapy (ART) was introduced, it was very expensive for individuals in many parts of Africa, and numerous patients resorted to traditional medicine, which is more affordable and more accessible.

Recent years have seen an unprecedented boom in the production of traditional medicine. In 2008 the global traditional medicine industry was estimated to be more than US dollars 83 billion annually. Some of these traditional medicines have contributed significantly to increasing the strength of the immune systems of critically ill people and improved their appetite for food, which is important for the treatment of HIV and AIDS. Given their relatively low prices, an increasing number of patients are using them along with their ART, although medical doctors continue to discourage this due to potential interactions between herbal extracts and antiretroviral drugs (ARVs) and their unproven efficacy and safety.

Traditional medicine plays an important role in the South Africa economy. According to the Draft Policy on African traditional Medicine for South Africa, published by the South African Department of Health in 2008, the estimated total contribution of TMs to the economy was more than 3 billion South African Rand (ZAR) per year, with trade in raw materials estimated at ZAR 520 million, herbal medicines worth ZAR 588 million and traditional healers prescribing TMs worth ZAR 2.6 billion per year. This market has continued to grow over the years as the demand for TMs grows. This increase in demand has led to an increase in the harvesting of plants and herbs used in the practice, thus creating jobs and a form of livelihood for many farmers and their workers.

Until recently, the production, distribution and promotion of traditional herbal medicines was unregulated. Traditional healers could be found virtually at any strategic trading centre in both the rural areas and the large commercial centres in South Africa. Many small-scale companies also sell fairly well packaged herbal products which are sometimes found in pharmacies and herbal shops or clinics. Several unproven claims are made of these products based on a plethora of sources, ranging from common local knowledge to internet articles and unauthorised publications, as well as from some published studies. The claims range from healing conditions related to HIV/AIDS to bold ones such as completely curing the disease. The most common claim made of these products is boosting the immune system. This state of affairs has created a situation where just about anyone, with or without prior training, knowledge, skills or “calling” can produce, distribute, promote and even prescribe traditional herbal medicines to patients from any facility. This has caused a lot of controversies, notably in the management of HIV/AIDS in conventional health

Use of Traditional Complementary and Alternative Medicine in the Management of hIV/AIDS and Related Complications in South Africa: An Overview

Therapeutics


facilities. Medical practitioners are unceasingly advising patients receiving ART to avoid concomitant use of herbal or traditional medicines. Researchers have even gone further, conducting studies that have demonstrated interactions between herbal medicines and ARVs that compromise the efficacy of ART.

Whereas it is illegal to prescribe conventional medicines that are not registered with the relevant national drug regulatory authorities, there seems to be no such regulatory requirement for TMs. However, it should be acknowledged that some progress has been made to regularise the practice of TM, by forming national and international organisations to register traditional healers and coordinate their activities. Although the formation of such organisations is a step towards creating ethical and regulatory frameworks that could facilitate efficient monitoring and standardisation of TM, a lot still needs to be done to bring it on a par with orthodox medicine, not only in terms of efforts to incorporate it into mainstream primary healthcare systems, but also in terms of sensitising traditional healers, policy-makers, health practitioners and ordinary people about the need to equally scrutinise TM. The WHO, the African Union (AU) and the Southern African Development Community (SADC) mandated all member states to initiate policy frameworks that not only maintain the integrity of patient safety, but also ensure that the TMs are integrated into the structure of the public health systems in those countries. In an effort to do this, the South African government established a Directorate of Traditional Medicine (DTM) in 2006 to co-ordinate and manage initiatives regarding Traditional Medicine within the Department of Health, as well as enacting the Traditional Health Practitioners Act (No. 22 of 2007). WHO, AU and SADC made several recommendations in this regard, that included research into the safety of TMs, registration of TMs with medicine regulatory authorities, protection of intellectual property rights, development of statutory bodies for traditional health practitioners, establishment of training institutes for traditional medicine, building capacity for the establishment of national ethics committees for traditional medicine research, and development of acceptable safety and quality standards for the manufacturing and handling of TMs. In addition, recommendations were made by the same organisations for member states to develop systems that will ensure sustainable cultivation and harvesting of sources of TMs, and to also ensure that information is available to their populations regarding the use of TMs.

Controversies with TM use in hIV/AIDS in South Africa While the western medical system refutes claims that there is a cure for HIV/AIDS, many traditional healers have continued to claim that they have cures for the disease. In the process they have attracted much criticism. The clashes between the western medical system and traditional medicine are both ideological and scientific in nature. Ideologically, proponents of the conventional medical system have tended to look down upon traditional healers. Most western-trained doctors view traditional healers with skepticism and disdain. On the scientific front, western conventional medicine is based on experimentation through clinical studies, an aspect seen to be absent in the TM system. Therefore, when

HIV/AIDS became prevalent in South Africa, many of the patients who turned to their traditional healers for help were discouraged by their doctors who considered TM as a practice based on superstition. On the other side, traditional healers fought back because they felt that the conventional doctors simply wanted to monopolise the market of HIV positive patients. This belief among the traditional healers was supported by the high cost of ART in its early roll-out phase, and the vehement discouragement of concomitant use of ART and TMs in HIV/AIDS patients by conventional medical practitioners. As the clashes raged on, traditional healers argued that there was little evidence from the orthodox medical system practitioners to prove, using their own methods of research, that ART was superior to TMs or that TMs compromised ART and not the other way around. This prompted proponents of western medicine to undertake studies to support the assertions.

Although the effects of interactions between TMs and ARVs are not fully known, over the last decade or so, studies have been conducted that have shown that such interactions could be detrimental to the health of people on ARV treatment. For example, garlic, which is commonly used by some people living with HIV/AIDS has been reported to lower blood levels of the antiretroviral drug saquinavir. St. John’s Wort has also been reported to negatively affect indinavir, a protease inhibitor used as an HIV drug, by reducing its blood level by about 57%. St. John’s Wort has also been reported to interact with nevirapine, a non-nucleoside reverse transcriptase inhibitor. Many proponents of TM use among people living with HIV/AIDS argue that discouragement of their practice is based on the unknown rather than what is known about these interactions. Many have gone further, discouraging their patients from enrolling onto ARV programmes. In some cases, the traditional healers have received both tacit and open support from government officials including the former South African Minister of Health, the late Mantu Tshabala-Msimang, who openly campaigned for the use of TMs among people living with HIV/AIDS.

Apart from the potential interactions between ARVs and TMs, and the unproven benefits of the TMs in the management of HIV/AIDS, proponents of western medicine have argued that bold claims made by traditional healers such as the ability to cure HIV/AIDS cause complacency and optimism, which in turn could lead to an increase in unsafe sex. However, traditional healers and their exponents argue that use of ARVs has created similar optimism and complacency. In light of the facts that some of the HIV/AIDS patients are made to believe that the TM they use can treat or cure HIV/AIDS, and that the predominant mode of transmission of HIV in South Africa is unprotected sex, the potential increase in risky sexual behaviour of people living with HIV/AIDS using TMs is a practical public health threat that could significantly fuel the spread of the epidemic. Although some traditional herbs could potentially reverse some symptoms of opportunistic infections, it is unethical to claim that they treat or cure HIV/AIDS. Another controversy is that due to the absence or laxity of regulation governing TM, many quacks are reported to be making fortunes and have taken advantage of the desperation of people living with HIV/AIDS to enrich themselves.


Therapeutics

Current Trends, Research and the Future The practice of TM is generally necromantic and therefore not based on published data, but rather on knowledge secretly and sometimes sacredly passed onto particular individuals in subsequent generations. Therefore, there is a dearth of information in the public domain on which particular plant or animal sources yield currently prescribed and used TMs. No two traditional healers will prescribe the same herb or mixture of herbs to the same patient for the same condition. It is also common practice for patients to obtain TMs from traditional healers and take them without asking for their names or sources. There are hundreds, even thousands of different concoctions and mixtures used by traditional healers to treat HIV/AIDS symptoms. It is believed that similar herbs are often used in different forms to treat different symptoms depending on their nature. A powder extract of a plant can be used for oral thrush, and at the same time a liquid extract of the same plant be taken orally for diarrhoea. However, the traditional healer is under no obligation to inform the patient of this, and in many instances the patient is not allowed to ask. However, as standardisation and regulation of the TM industry takes root in South Africa, together with the fostering of collaborations between TM and western medicine, knowledge about different plant and animal sources of potentially efficacious products is being exchanged and shared. Over the last decade, studies on certain TMs have been conducted with some promising findings, although most of these studies are in preliminary stages.

Two principal African herbal compounds used for HIV/ AIDS treatment in sub-Saharan Africa include Hypoxis hemerocallidea, commonly referred to as African potato, and Sutherlandia. These two herbal remedies are currently recommended by the South African Ministry of Health and in other SADC countries for HIV management.

hypoxis hemerocallideaAlso commonly called magic muthi, yellow stars, star lily, African potato, sterretjie, Afrika-patat, inkomfe, ilabatheka, sterblom, gifbol, lotsane, and molikharatsa, Hypoxis is a well-known genus of the family Hypoxidaceae. Easily recognisable by its bright yellow star-shaped flowers and strap-like leaves, it has a long history of medicinal use on the African continent. The South African primary healthcare community is currently using

Hypoxis as an immunostimulant for patients with HIV/AIDS. A daily dose of 2400 mg of raw plant is purported to be therapeutically effective. Within the genus, two species, H. hemerocallidea and H. colchicifolia are particularly popular both as African traditional remedies and for the preparation of herbal teas and tinctures. Rootstocks of this plant have been used by Zulu traditional healers for centuries in the treatment of urinary infections, heart weakness, internal tumours, and nervous disorders. Other unproven uses for this herb include benign prostatic hypertrophy, cancer and hyperglycaemia. The corms of H. hemerocallidea are being used for immune-related illnesses such as the common cold, flu, arthritis, cancer and HIV/AIDS. There is some indirect evidence that sterols and sterolins, which are found in the root of Hypoxis, have the potential to enhance immunity.

The popular press in South Africa is promoting preparations of Hypoxis as an agent that can boost immunity in HIV/AIDS patients. Multiple websites, popular magazines, and even the South African Ministry of Health have supported this assertion. Irrespective of the evidence, many Africans claim benefit from eating the root of H. hemerocallidea.

Sutherlandia frutescensCommonly called Insiswa, Unwele, Mukakana, Phetola, Lerumo-lamadi, cancer bush, kankerbos, kankerbossie, the flowering shrub S. frutescens is a member of the Fabaceafamily. The recommended therapeutic dose of Sutherlandia in humans is 9 mg/kg/day. Sutherlandia has been used in the treatment of cancer, tuberculosis, diabetes, chronic fatigue syndrome, influenza, rheumatoid arthritis, osteoarthritis, peptic ulcers, gastritis, reflux esophagitis, menopausal symptoms, anxiety, clinical depression and HIV infection. The South African Ministry of Health has concluded that this product is safe

based on primate safety studies. However, scientific data relating to the mechanism whereby Sutherlandia acts on the immune system has not been comprehensively documented. A recent study described the antioxidant potential of Sutherlandia frutescens where extracts from hot water possessed superoxide as well as hydrogen peroxide scavenging activities which could account for anti-inflammatory properties. Despite the limited data available on its antiretroviral properties, the South African Ministry of Health and SADC member states currently recommend the use of this herbal remedy for HIV/AIDS treatment.

References 1. WHO Traditional Medicine Strategy 2002-2005. 2002. Geneva: World Health

Organization.2. Robinson, M.M. & Zhang, X. 2011. Traditional medicines: Global situation,

issues and challenges. The World Medicines Situation, WHO.3. Truter, I. 2007. African traditional healers: Cultural and religious beliefs

intertwined in a holistic way. South Africa Pharmaceutical Journal. 4. Setswe, G. 1999. The Role of Traditional Healers and Primary Health Care in

South Africa. Health SA Gesondheid. 5. Hewson M. 1998. Traditional healers in Southern Africa. Annals of Internal

Medicine. 6. Moskovitz S. 1996. Traditional healers in modern medicine. The SA Retail

Chemist. 7. Department of Health. 2007. Operational Plan for Comprehensive HIV and

AIDS Care, Management and Treatment for South Africa. http://www.info.gov.za/otherdocs/2003/aidsplan.pdf

8. Nyika A. 2007. Ethical and regulatory issues surrounding African traditional medicine in the context of HIV/AIDS. Developing World Bioethics.

9. Mehta S., Moore R.D., & Graham, N.M. 1997. Potential factors affecting adherence with HIV therapy. AIDS.

10. Fairfield, K.M., Eisenberg, D.M., Davis RB, Libman H, Phillips RS. 1998. Patterns of use, expenditures, and perceived efficacy of complementary and alternative therapies in HIV-infected patients. Archives of Internal Medicine.

11. Mills, E.J., Foster, B.C., van Heeswijk, R.P., Wilson, K.E.P., Kosuge, K., Leonard, B. & Kanfer, I. 2005. Impact of African herbal medicines on antiretroviral metabolism. AIDS.

12. ‘Traditional medicine, culture, and health’, AIDS Foundation of South Africa, http://www.aids.org.za;

13. Matomela, N. 2004. Recognition for traditional healers. South Africa, http://www.southafrica.info

14. Liverpool, J., et al., 2004. Western medicine and traditional healers: Partners in the fight against HIV/AIDS. Journal of the National Medical Association.

15. Calixto, J.B., 2000. Efficacy, safety, quality control, marketing and regulatory

guidelines for herbal medicines (phytotherapeutic agents). Brazilian Journal of Medicine.

16. Amon, J.J., 2008. Dangerous medicines: Unproven AIDS cures and

counterfeit antiretroviral drugs. Globalization and Health.

Edward Mukwaya trained as a pharmaceutical scientist and has previously worked in both the public and private sectors in the areas of hospital pharmacy, retail/community pharmacy and logistics management in Uganda, Botswana and South Africa. Prior to

joining the clinical research industry in 2008, Edward worked in the field of pharmaceutical research and academics with the Department of Pharmaceutical Sciences, Tshwane University of Technology and the University of Limpopo (Medunsa campus). Edward is currently working with OnQ Research SA, as a Senior Clinical Research Associate, involved in the management and monitoring of various therapeutic area clinical trials in different African countries including South Africa, Tanzania, Ghana, Uganda, Burkina Faso and Rwanda. Edward is a member of the South African Clinical Research Association, Academy of Pharmaceutical Sciences of South Africa, and other professional bodies in Uganda, Botswana and South Africa. Email: [email protected]

Portia Rikhotso is a biomedical scientist currently working with OnQ Research SA as a Clinical Research Associate. Portia joined the clinical research industry in 2007. Prior to joining OnQ Research SA, she worked at Discovery Health and Criterium Clinical Research. She

is currently involved in the management and monitoring of clinical trials in South Africa and Kenya. Email: [email protected]

Catherine Lund started her career in clinical research at Quintiles UK in 1996. After specializing in neonatology and a background in nursing science, she subsequently started her own monitoring consultancy, OnQ Research SA in 1999. OnQ Research SA has evolved into a

formal CRO, offering full service functionality in 2004, and is currently one of the premier South African CRO’s. Catherine has been Vice Chairman of the South African ACRP chapter and is currently an executive committee member of the South African Clinical Research Association. Catherine is CCRA accredited and has presented at many conferences. Email: [email protected]

Therapeutics

IT & Logistics


IntroductionIndia is among the most favoured destinations for clinical research outsourcing and conducting global clinical trials. Interest in India can be linked to a large patient pool with both infectious and chronic diseases, medical infrastructure, lower cost, qualified English-speaking manpower, global medical practices, globally acceptable regulatory environment, and consistent high quality and on-time delivery.1

As the world’s third-largest producer of drugs by volume, with the third-largest drug research and development workforce, India is a major player in the pharmaceutical industry.2

With the concept of global central laboratories and the ease of managing data from such laboratories, sponsors are outsourcing work to central laboratories. Many global laboratories have set up their own facilities in India. With labs having state-of-the-art infrastructure and maintaining global standards, it’s now becoming more common to import samples to India for testing.

Logistics Requirements in a Central LabIn a central lab, effective logistic services are required to move samples from sites to lab, from lab to sponsor, shipment of sample drawing kits from lab to sites, reagents / lab commodities etc.

The characteristics of laboratory commodities affect the design and management of the logistics system. For the purpose of supply chain management, including designing and managing laboratory logistics systems, there are various ways to classify laboratory commodities. These classifications include3

• reagents, consumables, durables, and equipment • slow-moving and fast-moving • long shelf-life and short shelf-life • non-full supply and full supply

Bye and large, the handling of lab commodities such as reagents or sample collection kits within India is quite streamlined. These are handled by local courier companies.

Challenges in Central Lab Logistics in India

Current ScenarioCurrently the logistic requirement in India is fulfilled by courier agencies that are aggregators, or specialists in clinical trial logistics. Aggregators are the couriers who will club samples / packets with other consignments and make single shipments per day. On the other hand specialists are the ones who will handle clinical samples from point to point on an individual basis. Also a few labs in India use their own network of collection centres, to pick up samples from the clinical trial sites to be delivered to their own central lab.

There are advantages of the aggregators in terms of price to a tune of 50-60% reduction as compared to specialists, but with a risk of service issues which we cannot afford in many studies.

Reagent kits and sample kits are being transported with routine couriers. These imports require custom clearance, including an end user declaration / certificate. However if the kit transportation is done within India there is no clearance required. Most of the states have their own regulations on movement of materials. For instance, if a study has sites in West Bengal, then there is a requirement form ‘Form 50’ for transportation of investigational products to the sites. A few states, such as Maharashtra, have an OCTORI – a local tax- in place and a need for tax payment by the site (or local representative) before the shipment can be actually delivered to site. These can be addressed by working with a

service provider who has the requisite experience of dealing with such sites, planning the shipments and reducing both the transit time, and before-time deliveries.

All biological substances commonly handled by the lab are classified as per IATA guidelines4 and transported accordingly. This is a mandatory requirement in India if the shipments have to be airworthy.

Common Challenges of Handling Central Lab Logistics• Hot destination sites / remote sites• Handling of lab commodity / samples / kits• Regulatory• Availability of packaging material and dry ice• Turnaround time TAT of sample delivery• Site compliance• Import of reagents / sample kits• Cost

hot Destination The temperature in India soars to 45 degrees Celsius during the summer. Clinical trial materials are sensitive to temperature fluctuations and are perishable in nature. The efficiency of the clinical trials will depend on the efficiency of the supply chain in many ways, because the integrity of the clinical trial material is of supreme importance for accurate and best results. This brings the requirement of having

IT & Logistics

IT & Logistics


different temperature-controlled packaging, and providing on-site packing services. To provide this, the logistics service provider must have specialised and trained manpower to provide such services - not only in the main cities but also in remote areas.

Earlier, the sites were concentrated only in the metros, but with the increasing number of trials coming to India, there is a necessity to expand into tier 2 and 3 cities. Most of the interior locations are not connected by air, thus the transportation from these sites needs to be done through extremely reliable surface sources. In most cases, the samples are brought to the main city and then airlifted to the lab destination. In such cases the logistics service provider needs to have an on-time arrival to the main city for the next connection to happen by air. Any delay in the first leg of the transportation will delay the total transit, which might result in the sample going beyond the stability period.

handling of Lab CommoditiesMost of the specialist couriers are aware of the importance of the sample and its integrity. However the handlers in the aggregators may not be so well aware of the importance of the sample or lab commodity. In this context much detailed discussion with the courier company, and further drill-down by the courier company to its staff, will go a long way in handling logistics appropriately.

RegulatoryA while ago there was ambiguity on the approval process for export licence and import permits. Now there is clarity. For all biological samples movement outside India, where India is participating in the said trial, the Drugs Controller General of India (DCGI) will grant No Objection Certificate-NOC. This can be applied for along with the application for study approval. The usual time period for such approval is around 12 weeks. The details are provided on the DCGI website.5

If any lab wants to import samples for testing in India where India is part or not part of the study, the Indian Council of Medical Research (ICMR) will grant the approval.6

The ICMR will also grant approvals for either import or export of biological samples for research and/or commercial purpose. Such meetings of the ICMR to grant permits happen once every three months.

If reagent kits have to be imported, the lab should have a valid Import Export Code (IEC) and clearance from the Director General of Foreign Trade (DGFT). The common documents required for clearance of such shipments are the IEC, an end user letter, invoice copy, material safety data sheets (MSDS), and non-hazardous declaration / dangerous goods declaration. At times when the kits are too complex, the DGFT may refer the import application to the ICMR for opinion. These time delays have to be kept in mind and planned accordingly.

Availability of Packaging MaterialMany tier 2 and tier 3 cities in India where we have clinical sites do have ready access to packaging material and dry ice for shipment. So the shipments have to be planned well

in advance to avoid last-minute hiccups. With improved communication with the site courier agencies and labs, this gap is bridged. The packaging material and the method have to comply with the IATA guidelines on handling biological samples.4

Turnaround Time of Sample DeliveryThe turnaround time of sample delivery to lab from site does not necessarily depend on the distance, but depends on the connectivity. For example, biological sample shipments from Nagpur to Bangalore will take more time than from Delhi to Bangalore, even though the distance in the latter case is more. Some part of the transit happens by road and then by air in the former case. So it’s best to work out the least required time in conjunction with the sponsor, the lab and the courier agency.

Site ComplianceWith more and more studies reaching the tier 2 and tier 3 cities and new sites being recruited frequently, there is a bigger challenge to train the site personnel for compliance to sample and logistics handling. It’s also imperative that the sample documents like declaration, invoice and end user certification should be provided. With the experience of the sponsors and CROs in handling such new sites, this is not much of a challenge.

Import of Reagent Kits / Sample Collection KitsFor import of reagent kits by the lab which are currently marketed in India, only a customs clearance is required. If a kit which is not approved for marketing in India needs to be imported for a particular study, an application needs to be made to the ICMR and then to customs. It’s best to consult customs well in advance before the shipment is made to gain clarity.

Import of sample collection kits is fairly straightforward with minimal documentation, and is easily handled by routine custom clearing agents in conjunction with courier companies.

IT & Logistics


CostThe logistics cost using a specialist clinical trial courier is 5-10 times more as compared to a general courier. With the limitations of the general courier in handling the easily perishable items like samples / reagent kits, it’s better to use the specialist point to point courier. With the competition hotting up amongst specialist couriers, the prices are settling. In many instances, sponsors have used a combination of general couriers for accessible sites and specialists where absolutely necessary. This not only brings down the overall cost of logistics, but also brings in efficiency and favourable outcomes.

ConclusionIn conclusion, getting biological samples to lab in time, every time happens to be one of the biggest challenges in central lab logistics. With clarity in the regulatory process and cost moderation of logistics due to the combination of services, good days lie ahead of us.

References1. Borfitz, . India Becoming Favored Destination for Clinical

Trials. [Online] http://www.bio-itworld.com/BioIT_article.aspx?id=72434.

2. FICCI. The glorious metamorphosis − Compelling reasons for doing clinical research in India. s.l. : FICCI, 2009.

3. PROJECT, USAID | DELIVER. LABORATORY LOGISTICS HANDBOOK. [Online] 2009. www.jsi.com/JSIInternet/

Resources/.../DownloadDocument.cfm?....4. IATA. [Online] 2012. http://www.iata.org/whatwedo/

cargo/dangerous_goods/Documents/Guidance-Document-Infectious-Substances.pdf.

5. DCGI. [Online] http://www.cdsco.nic.in/prescreening_checklist.htm.

6. ICMR. [Online] 2012. http://www.icmr.nic.in/ihd/ihd.htm.

Dr. P Raghavendra Karanth, MD, started his career as a trained pathologist and teacher in a medical school. After having worked in diagnostic and central laboratory for over a decade, has joined as Lab Director of Eurofins Global Central Laboratory in 2011. He is responsible for

the lab operation in India. Email: [email protected]

Shabeer Ahmed worked as Medical Technologist, Scientific Support Officer, Lab Manager and as Project Manager in various Diagnostic and Global Central Laboratories for over 18 years. He has joined Eurofins Global Central Laboratory in 2011 as Project Manager.

He is responsible for the Project Management in India. Email: [email protected]


IT & Logistics

Challenges experienced by multi-sites are some of the most frustrating for the clinical trial cold chain. Although trusted real-world data and profiles from around the globe have been painstakingly analysed and perfected over the years, even the most experienced and well-forecasted routes can encounter unforeseen problems. David Johnson, from SCA Cool Logistics, gives his viewpoint on the challenges encountered by the clinical trial cool chain sector when transporting their precious cargo across the globe, and shares the results from the business’ recent interactive presentations to the CT execs regarding issues encountered.

Defining Challenges of Multi-sites En RouteThe world may be becoming an increasingly smaller place, but the different challenges it provides on every shore can be numerous, including country-specific regulations, infrastructure and customs’ attitudes, and that is before the country’s ambient temperature is bought in to the mix. Any of these could mark the end of a clinical trial when in transit if not planned with military precision. But what happens if even still, something else crops up that you couldn’t have planned for?

David Johnson, Clinical Trials Business Development Manager at SCA Cool Logistics, explains: “We have seen a number of case studies that have showed us just how unpredictable clinical trial journeys in the cold chain can be. For example, even though the service provider was fully aware of the different import and export rules for shipments into Brazil, a clinical product was held up in customs due to the country’s latest import/export quota, regardless of whether the shipment was a can of beans or a time- and temperature-sensitive pharma product. Essentially, clinical trials can unnervingly be out of your control when en route until they arrive in the safe hands of the intended receiver.

“However, the clinical trial industry is gladly seeing an increase of activity and innovation in new packaging solutions to overcome these problems. With revolutionary new technology we are seeing packaging that can think for itself when it encounters problems, and that can be trusted to make the right decision in a moment of crisis, saving the product from a costly and frustrating end.”

Conducted Interactive Research SCA Cool Logistics, the market leaders in temperature-controlled packaging, ran a series of interactive presentations in February this year at both IQPC in Basel, Switzerland, and at the VIB Cold Chain Storage & Distribution conference in London. The team took the opportunity to use interactive keyboards with all audience members, asking over 500 CTS-related execs a number of questions to identify and validate key industry trends, challenges, risks and opportunities, with specific reference to transporting healthcare product in the clinical cold chain.

Question 1: What is your top priority in your temperature-assured distribution chain (apart from patient safety)?

Answers: • Reduce or prevent product deviations or excursions = 81% • Ensure compliance with GDP regulations = 48% • Cost reduction = 41%

With millions of dollars worth of clinical trial product being spoilt every year due to product experiencing temperature excursions during the transportation, it is not surprising that top priority for healthcare, integrity, logistics and distribution managers at the conference was to reduce product deviations or excursions. The smallest temperature change for even the shortest of time can make the difference between a clinical trial reaching its intended destination as a working sample or as a destroyed product.

To meet this growing need for the clinical trial market, temperature-controlled packaging products are becoming more and more intelligent. For example, reactive technology that is thermostatically controlled and can heat and cool the payload area can reduce excursions dramatically.

Where multiple investigator-sites are also involved, it relies even more heavily on the packaging to be flexible and adaptable with its performance. For example, a study that includes both Russia and Malta would need intelligent packaging to adjust to both high and low temperature extremes, which it can do easily with its incredible in-built thermostatically controlled heating and cooling technology, maintaining the desired internal payload temperature by reacting to external ambient temperatures.

Compliance with GDP regulations is a complex and constantly evolving area of expertise.

Whether this is outsourced or you have own in-house specialist, it’s an important cost to the business. Failure to adhere to the latest regulations can significantly impact a trial’s progress, a hard cost to measure in this arena. Yet small investment in other areas such as packaging can go a long way in minimising the hidden cost of a delayed study.

Whilst the actual business of staying abreast of import and export regulations lies with the sponsor and the clinical

how Packaging Solutions are Easing Multi-site Challenges

IT & Logistics


services provider, packaging itself can play a useful part in supporting the product whilst any delays occur.

David Johnson explains: “Some sponsors opt to play safe and pay a premium by selecting a specific courier who can be in sole charge of their product whilst in transit, ensuring that it is rushed through customs and reaches its destination in the shortest time possible. With intelligent packaging, this additional attention and cost is not required as the packaging can control its own temperature for up to 5 days and even be placed into a fridge to prolong its duration. The costly 1-2-1 courier can be swapped for a 3PL yet the risk stays at a minimum.”

Hibernation is a revelation in recent packaging offerings, allowing packaging systems to save energy, enabling it to last even longer. The packaging can be placed into a fridge during its wait between sites, and the zero temperature differential between the internal and external temperatures means virtually no energy is expended by the system.

Question 2: What is your primary method of distribution method used for temperature-sensitive products?

Answers: • Air = 64%• Road = 28%

With air transport leading the way, the focus on temperature-controlled packaging is on its volume, size and weight. Packaging manufacturers understand the cost implications of freight to clinical trials distribution, and by ensuring packaging volumetric weight is reduced without impacting payload space, with some technologies now boasting up to 45% reduction in volumetric weight, can significantly reduce distribution costs.

Multi-sites can often mean multiple freight modes are required. With intelligent packaging, once packaging systems are activated it does not matter where they are put – perfect if different modes of transport are used, which in turn provide different temperature ranges. It is good to know that regardless of the transport mode the product will be in constant safe hands.

Question 4: I am more likely than in the past to adopt new technologies or services from a supplier if it showed that if could reduce my total cost of distribution even though the technology or service was at a higher price point.

Answer: • 90% agreed.

With total distribution costs being made up from packaging, freight and data loggers, there are opportunities to reduce costs through using new technologies and services, and those in the CT remit seem very open to understand these possibilities to reap the rewards.

David Johnson explains: “Knowing the full story can often help you make the most informed decision, but unfortunately this is not always the way when making decisions on distribution. For example, the sponsor may be

given a cost option of either distributing using £30 or £300 boxes without the cost of freight included. Studies involving multiple investigator sites make including freight costs an impossible task. Obviously, the sponsor will opt for the perceived cheaper option to save costs, however the total freight bill could be vastly bigger because of the cheaper boxes’ increased size and weight.

“An ideal world would see the service providers, sponsors and the packaging companies all sitting around one table to discuss the most efficient, low-cost option for distribution, but this unfortunately rarely happens.”

Conclusion It is not only multi-sites that have created these recent challenges. The pharmaceutical landscape has changed dramatically in recent years with the patent cliff and drying-up of blockbuster products reaching the market. Generic erosion and the lack of new products coming through have forced big pharma to change its ways, notably in the way it operates and distributes product to its growing global marketplace. Discovering efficiencies and applying lean principles are providing plenty of challenges for big pharma, and these operational challenges are intensified as the type of product shifts towards long chain molecules and protein-based therapies.

As well as being very difficult to replicate and manufacture to protect it from generic eyes, these therapies also come with strict temperature storage and distribution requirements. Now distributing product to the growing global marketplace has become a whole new ball game.

But if you could trust your packaging to make the right decisions at the right time to protect your product, the challenges discussed here would be significantly reduced, making intelligent packaging a very worthwhile investment. Add this to the other advantages of fewer temperature excursions, more efficiency in the supply chain and a single qualified solution to distribute to multi-sites, and intelligent temperature-controlled packaging could feasibly be one of the most attractive and cost-saving technologies around. SCA Cool Logistics might well be on to something.

David Johnson works as a Business Development Manager for SCA Cool Logistics focusing on the Clinical Trials market. A qualified Mechanical Engineer, David began his career working for a Pharmaceutical Process Engineering firm serving the oral solid dosage

pharma markets. Working with Big Pharma, David provided process knowledge and technologies used in the manufacture of OSD products from pilot scale through to full commercial production including continuous processing. Having joined SCA Cool Logistics back in 2010 David has experienced success through being able to adapt quickly and effectively to the changing market conditions providing the right solution for the right study.Email: [email protected]


IT & Logistics

Conducting a successful clinical trial of any drug or treatment modality is always difficult. It is further complicated when one adds a multi-jurisdictional approach and then layers on emerging markets, where costs may be lower and where future product growth almost certainly is, but also where there is less experience, both in clinical trial conduct and in working within these jurisdictions.

As with anything, it is much easier to maintain control and consistency with the fewer parties involved and when you do not have language, cultural and ethnic variances to be considered. All the while keeping in mind that, amongst others, these clinical trial objectives will need to be maintained: • successfully meeting the defined therapeutic end points, • achieving statistical significance at a level to meet a

multi-jurisdictional regulatory filing strategy, • exposing and gathering data on an appropriate age,

gender, racial and ethnic mix of patients, • ensuring the data set is unimpeachable and, not least of

all, this is to be completed within a defined timeframe and budget.

When it comes to the research logistics component for your multi-national clinical trial, there are many factors to consider. Critically, the research logistics company you choose to work with will need to be a full partner in the clinical trial process and should be part of the overall planning for the trial. The company must have relevant and up to date, country-specific global trial experience to help you to navigate the locks and channels and be familiar with the timeframes and specifics to ensure your success.

Many areas need to be considered and discussed with your logistics partner. The most time-consuming part of setting up the logistics for a multi-national trial are the country-specific labelling and importation requirements for your clinical trial drug. This needs to take into account: where the original drug was manufactured? Is it licensed to be used in all clinical site countries? Do additional suppliers need to be sourced? What primary and secondary packaging is taking place? Does this meet regulatory requirements in each country? The answers to these questions will impact your ability to distribute trial drug globally on time and on budget.

Working with an experienced research logistics company as early as possible, even in the protocol development phase, will help you to navigate potential roadblocks and develop solutions before they become an issue.

For many of our global trials we have found a successful way to aid in the specific labelling content, language requirements and importation specifics within each country. We now assign a country lead from one of the trial sites to be the lead country contact with our logistics team. Together they medically translate all the required labels and ensure they meet the country requirements, thus reducing the need for costly changes or supplementary labelling at a later date. We have even found that some seemingly insignificant layout and content items included in the label can dramatically increase the speed in which the drug shipments clear customs, one example of this was in Brazil, as we most recently discovered. Your logistics partner will also need to ensure the required documentation accompanies each individual shipment into the country to ensure acceptance, therefore prior experience is essential.

The next area our logistics company is instrumental in helping with is the design and implementation of the overall packaging plan, including both the formula and the procedure, along with the clinical trial kit itself. This will outline all the specifications for the packaging from the procedures for packaging and blinding the drug through to the components used. The packaging plan is imperative to maintaining the blinding of the trial. There are many logistical items that need to be considered to prevent unblinding during a trial, anything from the paperwork included with the shipments to each site, the content on the labels, the continuity between batches when packaging, timing on packaging … and the list goes on. You must have a logistics team that looks at every angle to ensure this cannot occur at any time throughout the course of your trial. As you know, trials take time to execute. People change positions and leave companies, and the consistency on your trial must remain. A good research logistics company has procedures in place to ensure systematic packaging so no variances occur over time. The packaging on one of our trials is quite interesting to look at. This is a 2 x 2 factorial design over seven years, with over 10,000 patients in more than 50 sites globally. Based on the 2 x 2 factorial design, the packaging requirement for each block is four packaging runs: active drug A/active drug B, active drug A/placebo drug B, placebo drug A/active drug B, placebo drug A/placebo drug B. Each run goes into the clean room / packaging room to be assembled and each must be assembled identically. After all four runs are completed with their individual treatment number on the labels they are then sorted in order from #1 - #xxx. This process randomises the treatment. If one run has the placement of a label just a little differently, then this can,

Unlocking the Logistics for your Multi-National Studies: Into the Brave New World


IT & Logistics

and will, indicate to the trial site nurse that they are from one particular run and therefore all the same in content, potentially adding bias and unblinding. Consistency and accuracy in packaging and labelling are the key to success.

Another packaging example, this time relating to cost, is in another trial we are running that has the drug packaging bottles donated from the sponsor overseas. After looking into this the logistics team uncovered a customs entry fee of $15,000 per receipt. Therefore the logistics team ordered the volume of bottles required for the entire length of the multi-year trial, saving a substantial amount of money. Not only does the logistics team source the packaging materials but they design the clinical trial kits for use. These kits need to be effective for multi-language, experienced, and trial-naïve patients, clinical triallists and study nurses. In addition, they need to be intuitive and designed to ensure accuracy and consistency within the trial protocol. Experienced logistics teams know the components of these kits can become separated at some sites and remain intact at others, so they must take into account all possibilities within the design itself. A good team will help you develop the most appropriate kit for your trial. Lastly, remember to include emergency and over run volumes. Every trial will need them and to plan ahead will keep you in good form.

At this stage of the trial rollout we have everything set up and ready to be shipped. What logistically is involved here? First, the process for importation and all documents need to be in order. For example, when shipping into the European Union (EU), a qualified person (QP) must accept and take responsibility for the trial drug. This means your research logistics company needs to have been audited by the QP and may also mean the original manufacturing site of the drug needs to be audited. This can become a critical bottleneck if not executed properly and needs to be planned out with sufficient timelines to meet everyone’s needs.

When shipping, there are many configurations that can be developed. This can be a costly portion of your trial. Ambient drug shipments require significantly less strenuous efforts than cold chain drug shipments. Based on experience it is often worth using multiple depots globally to move cold chain drug appropriately. This is an area of regulatory focus in most jurisdictions. Your research logistics team must be aware of the country requirements

for both ambient and cold chain shipping and need to work with the trial team to ensure compliance.

Risk management of shipments should always be a point of discussion. If your logistics team sends all of your trial drug to Hong Kong in one shipment and it is delayed in customs ... then what? Splitting the shipment into three bulk shipments can be a great way to manage the risk. It may increase shipping and receipt costs, but overall does not compromise your trial needs. We recently have worked on the logistics for a large, multi-year, over 15,000 patients, multi-national trial. The original direction was for direct shipments to over 500 sites, four times per year. On analysis, and with consultation with the clinical trial group, our team submitted a recommendation of bulk, yearly shipments to a central site in each region at a total saving of $2.45M. Once again these relatively small changes can have significant impact.

While conducting a multi-jurisdictional clinical trial in emerging markets can seem daunting, it has now become more of a given in the R&D world and opens up many new opportunities. With opportunity comes challenges. Ensuring that you have a thorough process and a carefully devised plan, and partner with an experienced research logistics company, the likelihood of a successful outcome becomes that much more certain.

Nicole Grannell works as the Business Unit Manager for Bay Area Research Logistics (BARL) focussing on logistical support for clinical trials. Nicole began her career in the pharmaceutical industry in a sales and marketing capacity, progressing

to senior management roles. Working with big pharma, Nicole developed her knowledge and interest in the clinical trial aspect of drug development and approval through to marketing and sales. Having joined Bay Area Research Logistics in 2011, she leads the Business Unit in successfully managing the logistical components of multi-national clinical trials in developed as well as emerging markets. Email: [email protected]

Jackie Bosch, PhD (Candidate), MSc, BScOT Reg (Ont) Population Health Research Institute, McMaster University Hamilton ON is an Associate Professor at the School of Rehabilitation Science, McMaster University and a Project Manager at the

Population Health Research Institute, McMaster University. She studied Occupational Therapy at Queen’s University and then completed her Masters degree in epidemiology at McMaster University. She is currently working in the area of cardiovascular and diabetes prevention as well as health services research. She has worked on several large international epidemiologic and clinical trials (HOPE, DREAM, EpiDREAM, ORIGIN, HOPE-3, TIDE, APOLLO). Her interests include trial methodology, programme evaluation, neurological rehabilitation, primary and secondary cardiovascular prevention. Email: [email protected]

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IntroductionDrug development and pharmacotherapy are both governed by regulatory science, which involves “the development of new methods, standards and models we can use to speed the development, review, approval and ongoing oversight of medical products.”1 Drug safety is an important component of the US Food and Drug Administration (FDA) Strategic Priorities for 2011-20152 and the European Medicines Agency (EMA) Road Map to 2015,3 bearing witness to the intimate relationship between regulatory science and the science of safety.4 While both agencies share a paramount commitment to protecting and promoting the health of citizens under their jurisdiction, decisions in individual cases can differ, leading certain medicines to be available to citizens of some countries and not others. This paper presents two case studies illustrating a lack of harmony in respective regulatory landscapes.

The first discusses regulatory approaches taken by the FDA and the EMA regarding rosiglitazone, a thiazolidinedione agent for the treatment of type 2 diabetes mellitus (T2DM). It should be noted that the case study does not address the voluminous discussion in the literature regarding the extent (if any) to which rosiglitazone may present a cardiovascular safety liability. Rather, with the exception of citing a paper that was a seminal influence in subsequent activities, it focuses on the respective regulatory landscapes, including statements, guidance documents, and actions taken with regard to this drug between 2007 and 2011. The second case study discusses differences from 2008 to the present in the respective and evolving regulatory landscapes for the prospective exclusion of unacceptable cardiovascular risk in the development of new antidiabetic drugs for the treatment of T2DM.5,6

Case Study 1: Rosiglitazone-related Regulatory Actions, 2007-2011Table 1 presents notable dates and events, including FDA Advisory Committees meetings and EMA Scientific Advisory Groups meetings (note: the EMA was known for part of this period of time as the EMEA).

At the joint meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and its Drug Safety and Risk Management Advisory Committee on July 30, 2007, which discussed the cardiovascular ischaemic and thrombotic risk of the thiazolidinediones with a focus on rosiglitazone,19 two votes were taken. First, the combined committee voted 20-3 that rosiglitazone increases the cardiac risk in patients with T2DM. Second, the committee voted 22-1 that rosiglitazone should not be removed from the market.

In July 2010, the two committees met again. Compared with the 2007 joint meeting, this two-day meeting had a longer and more complex list of predetermined

FDA and EMA Actions Regarding the Cardiovascular Safety of Drugs for Type 2 Diabetes Mellitus, 2007-2012: An Overview of Respective Regulatory Landscapes

Table 1 A Timeline of Notable Events in Case Study 1

questions to be voted upon by members of the combined committee.13 While 12 members voted in favour of removing rosiglitazone from the market, 20 voted against it. Of those 20, 10 voted for additional warnings and restrictions on use of the drug, and seven voted for additional warnings.

In concordance with these recommendations, FDA did not withdraw rosiglitazone from the US market. However, the drug’s sponsor was required to submit a Risk Evaluation and Mitigation Strategy (REMS) within 60 days of the agency’s announcement of its decision on September 23, 2010.14 The REMS is a tool available to the FDA to mitigate overall risk, making the drug available to certain patients under circumstances for which the treatment benefit-risk balance is favourable, while not allowing the drug’s use in other patients for whom the benefit-risk balance is likely to be unfavourable. It was introduced in Title IX of the Food and Drug Administration Amendments Act of 2007 (FDAAA), which provided the FDA with sweeping new safety authorities. Prior to approving a drug for marketing, the FDA can now require a sponsor to provide a REMS that addresses how risk will be mitigated (hence safety optimised) once the drug is marketed. Table 2 lists the components of a REMS. The timetable for submission of assessments is always required, while others are required on a case-by-case basis.

Required elements of the rosiglitazone REMS included:15

• Provision of complete risk information to each patient, and documentation in his/her medical record that this information has been received and understood;

• Documentation from healthcare providers that each patient taking rosiglitazone falls into one of two groups:

1. Patients currently taking rosiglitazone;2. Other individuals who are not able to achieve glycaemic

control on other medications, and who decide in consultation with their healthcare professional not to take pioglitazone (the other thiazolidinedione presently on the market) for medical reasons.

• Documentation from healthcare providers that the risk information has been shared with each patient;

• Physician, patient, and pharmacist enrolment.

In contrast to the FDA’s decision, and based on the same data and announced on the same day as the FDA’s decision, the EMA’s Committee for Medicinal Products for Human Use recommended the suspension of the marketing of rosiglitazone in European markets,12 and its marketing authorisation is currently suspended.

Recent reviews by Blind12 and Bourg and Bryles Phillip16 are instructive.

Case Study 2: Regulatory Landscapes for New Antidiabetic Drugs for T2DM, 2008-2012

Table 3 presents notable dates and events in this case study.

FDA guidanceIn February 2008 the FDA released a draft guidance entitled “Diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention.”17 With regard to cardiovascular safety it commented as follows:“ A premarketing recommendation to demonstrate macrovascular risk reduction in the absence of a signal for an adverse cardiovascular effect may delay availability of many effective antidiabetic drugs for a progressive disease that often requires multiple drug therapy. A reasonable approach may be to conduct long-term cardiovascular studies post-approval in an established time frame… This approach is beyond the scope of this guidance.”

A subsequent meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee in July 200819 resulted in a 14-2 yes/no vote that, even for antidiabetic drugs without a concerning cardiovascular safety signal during Phase II/Phase III development, there should be a requirement to conduct a long-term cardiovascular trial or to provide other equivalent evidence to rule out an unacceptable cardiovascular risk. In December 2008 the FDA issued, in final format, a guidance addressing this issue.5 This guidance has been reviewed previously,21 and


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Table 2 REMS Components

Table 3 A Timeline of Notable Events in Case Study 2


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therefore the central tenets only are summarised here. Risk is operationalised in terms of an estimated

relative risk ratio, with the number of Major Adverse Cardiovascular Events (MACE) composite endpoint events in the drug treatment group as the numerator, and the number in the control group as the denominator: independent adjudication22 of all events is required. A meta-analysis involving MACE data from Phase II and Phase III trials is conducted, yielding a relative risk ratio point estimate. A two-sided 95% confidence interval (CI) is then placed around this point estimate, and the threshold of regulatory concern is defined as an upper CI limit of 1.8 or greater. Three scenarios are described in the guidance:• If the upper limit of the CI is equal to or greater than

1.8, the drug would be deemed to have an unacceptable risk. In this case, “an additional single, large safety trial should be conducted that alone, or added to other trials, would be able to satisfy this upper bound before NDA/BLA submission.”5

• If the upper bound is equal to or greater than 1.3 and also less than 1.8, and the overall risk-benefit analysis presented at submission supports marketing approval, “a postmarketing trial generally will be necessary to definitively show that the upper bound of the two-sided 95 percent confidence interval for the estimated risk ratio is less than 1.3.”5

• If the upper limit is less than 1.3 and the overall risk-benefit analysis presented at submission supports marketing approval, “a postmarketing cardiovascular trial generally may not be necessary.”5

The postmarketing cardiovascular trial referred to is a large-scale cardiovascular outcomes safety trial focusing on MACE outcomes. A review by Joffe et al.23 is instructive.

EMA guidance The EMA issued a draft general guideline for diabetes drug development on January 20, 2010, which included text addressing the prospective exclusion of unacceptable cardiovascular risk.20,24 A period of public consultation occurred until the end of July 2010. Rather than moving directly to a final guideline, a revised version was released on September 16, 2011,6 this time with a shorter public consultation period lasting until November 18, 2011. While the fundamental approach to cardiovascular risk exclusion stayed the same, there are some pertinent differences in the text addressing cardiovascular safety between the two versions. These differences are summarised in Table 4. The employment of pediatric subjects as introduced in the second version is also addressed in the discussion section of this paper.

The revised EMA draft guideline makes it clear that two approaches to prospectively excluding unacceptable cardiovascular risk are conceivable. The first is a meta-analytic approach, similar in spirit to the one discussed in the FDA guidance. With regard to the second, the guidance comments as follows:

“As an alternate approach or when there is suspicion

of an adverse CV signal (from the database), a specific long-term controlled outcome study with at least 18-24 months follow-up (depending on the characteristic of a drug and baseline risk of the studied population) would be expected as part of the clinical development program of new glucose lowering agents at the time of submission of the MAA.6”

With two notable exceptions, the approaches in the FDA and EMA documents are comparable. These salient difference are: (1) there are no explicit thresholds of regulatory concern corresponding to the values of 1.8 and 1.3 as presented by the FDA; and (2) the EMA wishes to be fully satisfied at the time of granting marketing approval that there are no cardiovascular safety liabilities. This contrasts with the FDA’s approach of sponsors satisfying a regulatory threshold of 1.8 at the time of granting marketing approval, and subsequently using postmarketing data to satisfy the 1.3 threshold. (Should the 1.3 threshold be satisfied by an analysis of Phase II and Phase III data, as noted previously, a postmarketing cardiovascular trial generally may not be necessary, but this occurrence is not likely to be frequent.) The EMA

Table 4 New Text in the EMA’s 2011 Draft Guideline

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guideline employs general language as follows: “The overall results of [a drug’s] safety program should

be discussed in terms of internal and external validity and clinical justification of the safety outcomes. Acceptability of the data presented will be decided based on its overall quality, the point and interval estimates obtained for the calculation of specific risks, including cardiovascular risk, and the reliability of these estimates…Indications of increased risk of certain adverse events or unacceptable lack of precision are an important concern and may trigger the request for additional specific long-term outcome trials to exclude an unacceptable increase in CV or other identified risks associated with the new agent.”6

The magnitude of the point estimate will therefore be considered, as will the width of the confidence interval placed around it: the phrase “unacceptable lack of precision” is presumed to connote an upper limit that is judged to be too high, i.e., it falls at or above a virtual threshold of regulatory concern. No explicit point estimate of concern is provided in either document, although the FDA guidance commented that “it would not be reassuring to find a point estimate of 1.5 (a nominally significant increase) even if the 95 percent upper bound was less than 1.8.”5

In summary, the EMA intends for sponsors to demonstrate cardiovascular safety at the time of submission, while not explicitly defining a benefit/risk threshold. The FDA accepts demonstration of a certain (specified) degree of cardiovascular safety at the time of submission, but in the majority of cases will require that a greater (and again specified) degree of cardiovascular safety be demonstrated as a post-approval commitment.

Proteins, Insulin, and the Development of New Insulin Products and AnaloguesWith regard to the development of insulin drugs and insulin analogues, both the guidances of primary focus in this paper5,6 make it clear that the requirements for prospective exclusion of unacceptable cardiovascular risk do not apply to these drugs. Insulin and insulin analogues are the only antidiabetic medications to date granted this exception. The FDA document notes explicitly that “the absolute deficiency of insulin in patients with type 1 diabetes dictates the need for insulin therapy as an immediate lifesaving treatment for which evaluation of long-term cardiovascular risk may not be practical.” The EMA document conveys the information by naming Section 4 “Developing and licensing glucose lowering agents (except insulin products) for the treatment of type 2 diabetes mellitus.” The section dealing with long-term and cardiovascular safety assessments, Section 4.4.3 falls in this section. Section 5 is then entitled “Developing and licensing insulin preparations for the treatment of type 1 and type 2 diabetes mellitus.” Nevertheless, it is informative at this point to consider insulin via the example of the development of insulin analogues, which are proteins.

Proteins are perhaps the most complicated chemical entities in nature: As Wishart26 noted, “No other class of molecules exhibits the variety and irregularity in shape,

size, texture, and mobility that can be found in proteins.” Proteins are described using a model comprising primary, secondary, and tertiary structures. The primary structure represents the sequence of amino acids that comprise the protein, called residues, that are joined together to form chains. This string of residues is initially shapeless and not biologically active. However, “Proteins have a natural proclivity to form more complex structures,”26 and the residues fold into secondary structures and then even more complex tertiary structures, at which point they are biologically active.

A key characteristic of proteins is that any change to any part of their structure will have an impact on biological activity.27 Proteins can comprise hundreds to thousands of amino acid residues, and even an amino acid that is located a long way from the protein’s biologically active site (the specific region of the protein that is responsible for its biological activity) can exert a major influence on that function.

The hormone protein insulin plays a central role in regulating blood glucose levels within normal ranges throughout the day, lowering levels by inhibiting production of glucose in the liver. Endogenous insulin is formed in a multi-step process. Preproinsulin is synthesised in the endoplasmic reticulum of beta cells in the pancreas. It is rapidly converted to proinsulin, which consists of the A chain, the B chain, and a 35 amino acid intervening connecting segment known as “C-peptide”. Proinsulin to insulin conversion occurs in the Golgi apparatus when the C-peptide is cleaved out, and the A and B chains are joined by disulfide bonds. The secretory granules mature and store equimolar amounts of insulin and C-peptide, which is released in response to rising glucose levels.

Chain A has 21 amino acid residues and chain B has 30 residues. Recombinant DNA technology provides the ability to manufacture recombinant insulin, or insulin analogues. Insulin lispro is identical to human insulin except for amino acid insertions at locations B29 and B30. Insulin aspart differs from human insulin at just one location, B28, where the amino acid aspartic acid is substituted for proline. The name insulin aspart reflects the substitution of aspartic acid. Because exogenous insulin and insulin analogues do not contain C-peptide, the presence of C-peptide in a blood test allows an assessment of endogenous insulin secretion, even in the presence of exogenous insulin or insulin analogues.

Insulin aspart provides an interesting example of how a small change in a protein’s structure can have a significant impact on its function. The single amino acid substitution compared with endogenous insulin reduces the aggregation of insulin molecules, which means that this form of insulin dissociates rapidly and is therefore absorbed rapidly.28

Specific guidance for insulin analogues is provided by both agencies. The FDA’s February 2008 document17 commented that in the development of new insulin analogues, sponsors should address the following three fundamental issues in randomised, controlled trials: • The risk of hypoglycaemia under conditions of use

ultimately recommended in labelling, relative to


approved insulin products and regimens;• Pharmacokinetic variability should be evaluated,

according to injection site, thickness of fat layer, and other parameters known to affect absorption, distribution, metabolism, and excretion characteristics. Additionally, pharmacodynamic characteristics should be carefully studied to direct dosing interval (for long-acting products) and timing of dosing relative to meals (for short-acting products).

• As a complex biological protein, insulin has the potential to be immunogenic. Adequate assays should be developed that measure antibodies to the test product before the submission of an application.

The EMA’s thinking is captured in their July 2011 “Concept paper on the revision of the guideline on nonclinical and clinical development of similar biological medicinal products containing recombinant human insulin.”29 The document’s consultation period ended on 30th September 2011, and it was noted that “It is anticipated that the draft revised guideline will be released for consultation in the first semester of 2012.”

Discussion Case Study 1Rosiglitazone remains on the US market, albeit in restricted manner, while it has been removed from the EU market by a marketing authorisation suspension. This difference in regulatory stance is not the result of widely diverging assessments of the available data.15 Rather, it reflects a lack of harmony between the respective regulatory landscapes at a higher level. The FDAAA provided the FDA with a useful tool, the REMS, that can be used to facilitate the continued availability and use of a drug by a select group of patients for whom its benefit-risk balance is favourable. The EMA currently has no equivalent tool.

Case Study 2Before discussing the implications of differences in text addressing cardiovascular safety between the December 2008 FDA guidance5 and the September 2011 EMA draft guideline,6 it should be acknowledged that there is a theoretical (if unlikely) chance that the information the agencies convey could change when the February 2008 FDA draft guidance addressing antidiabetic drug

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development in general19 is finalised, and when the EMA draft guideline is finalised. When the FDA guidance is finalised, the information in its cardiovascular-specific December 2008 guidance will be incorporated into it. It is unlikely that the 1.8 and 1.3 thresholds of regulatory concern will change at that time since sponsors are currently being advised to plan their Phase II and Phase III programmes accordingly. Second, the release of the updated draft of the EMA general guideline in September 2011 occurred slightly more than one year following the end of the consultation period for the first draft, and, again, no explicit thresholds of regulatory concern were contained. It seems reasonable to think that, since such thresholds were not added during that period, it is unlikely that they will be added into the final version. It therefore seems reasonable to argue that there will eventually be final FDA and EMA guidances that adopt different approaches to the prospective exclusion of unacceptable cardiovascular risk.

Given the increased resources that must now be committed to developing a new drug, sponsors will likely wish to obtain marketing approval in the US and

the EU, and, consequently, to satisfy both FDA and EMA requirements. An initial and perhaps intuitive view is that the EMA guideline appears to leave regulators more discretionary latitude than do the explicit thresholds adopted by the FDA: since such thresholds do not need to be satisfied, an approval decision seems potentially easier. It is conceivable that the upper bound of a confidence interval placed around a relative risk point estimate following a meta-analysis of Phase II and Phase III data might be (just) too high to be acceptable to the FDA, but be acceptable to the EMA. This would allow a new drug onto the European market but not the US market. However, paradoxically, it is possible to speculate equally plausibly in the opposite direction. Consider a scenario in which an upper bound slightly above 1.3 might lead to FDA approval with the condition that a postmarketing study must be undertaken (although there is no specific information on the consequence of not being able to demonstrate an upper bound of less than 1.3 by conducting such a study), while leading the EMA to decline approval and request additional data from a cardiovascular outcomes trial. This would allow a new drug onto the US market but not the European market at the time of marketing application. Such lack of harmony may be puzzling to sponsors, and also to regulatory agencies in other countries that are developing their own guidances with harmonisation in mind.

Another difference between the two documents is that, as noted in Table 4, the more recent version of the EMA guideline makes explicit reference to children and adolescents. There is no equivalent mention of this subject population in the FDA cardiovascular-specific guidance. However, this population is discussed in some detail in the February 2008 FDA draft general guidance (Section V, Clinical Development of Antidiabetic Therapies, subsection D1, Pediatric Populations),17 and therefore (assuming the text remains) the final FDA general guidance will include discussion of both cardiovascular safety assessment and pediatric populations, although it is not currently known how closely associated these considerations will be.

Pediatric pharmaceutical medicine is clearly an important topic in itself (see Jackson and Turner30 for a review of FDA and EMA activities in this domain from 1979 to 2010: see also additional citations31-34). The International Diabetes Federation recently observed that, in 2011, there were 366 million people with diabetes globally, with this figure expected to rise to 552 million by 2030.35 Given the increasing occurrence of T2DM in children and adolescents, this subject population becomes particularly important. While ethical considerations are a core aspect of all clinical research (and non-human animal studies), they have been especially challenging with regard to the participation of infants, children, and adolescents, and this population has historically not been included. As a result, the lack of a clinical science-based foundation for pediatric pharmacotherapy has forced physicians to make best-guess estimates of appropriate doses of adult-tested drugs when prescribing them (in a necessarily off-label manner) for pediatric patients

in what can be regarded as “N of 1” clinical research case studies. Realisation that appropriately supervised clinical trials including pediatric subjects is a better approach has been increasing.36,37 As Rose38 observed, “The pendulum is swinging away from protecting children against research toward protecting their health through research…Research with children intends to improve the therapeutic armamentarium of pediatricians, physicians, parents, and all child healthcare givers to stabilize and improve children’s health and to reduce their suffering when they are ill.”

Concluding CommentsThis paper has presented two case studies: rosiglitazone-related regulatory actions by the FDA and EMA from 2007-2011; and regulatory landscapes in their respective jurisdictions for the development of new antidiabetic drugs for T2DM from 2008-2012. These studies have revealed a certain lack of harmony in the approaches taken, which can lead to differential availability of drugs across regions.

The paper has deliberately not speculated on potential ramifications for the number of new marketing applications submitted in each region in the future (others have recently done so39,40), focusing solely on regulatory science1,41 and the nature of the likely final FDA and EMA guidance documents. Given that diabetes is a disease of staggering proportions, it will be of interest to continue to monitor these regulatory landscapes, as well as those fashioned by other regulatory agencies.

References 1. Hamburg MA. Remarks at the National Press Club

speaker luncheon, October 6, 2010. http://www.fda.gov/NewsEvents/Speeches/ucm229195.htm. Accessed February 4, 2012.

2. Food and Drug Administration. Strategic priorities 2011–2015: responding to the public health challenges of the 21st century. http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM252092.pdf. Accessed February 4th, 2012.

3. European Medicines Agency. Road map to 2015. http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101373.pdf. Accessed February 4, 2012.

4. Turner JR. Editor’s Commentary: Regulatory science and the science of safety. Drug Information Journal. 2011;45(3):221-227.

5. FDA. Guidance for Industry. Diabetes Mellitus—Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. December 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf Accessed February 4, 2012.

6. EMA. Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus, draft. September 2011. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/10/WC500115945.pdf. Accessed February 4, 2012.

7. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular

causes. New England Journal of Medicine. 2007;356(24):2457-2371. [Erratum, New England Journal of Medicine 2007;357:100.]

8. EMEA. Doc. Ref. EMEA/230057/2007. Press Release: EMEA statement on recent publication on cardiac safety of rosiglitazone (Avandia, Avandamet, Avaglim). http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500013467.pdf. Accessed February 4, 2012.

9. Summary Minutes of the Joint Meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, July 30, 2007. http://www.fda.gov/ohrms/dockets/ac/07/minutes/2007-4308m1-final.pdf. Accessed February 6, 2012.

10. EMEA. Doc. Ref. EMEA/484277/2007. Press Release: European Medicines Agency confirms positive benefit-risk balance for rosiglitazone and pioglitazone. http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500011009.pdf. Accessed February 4, 2012.

11. FDA. Avandia (rosiglitazone maleate) tablets. November 2007. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm150820.htm Accessed February 11, 2012.

12. Blind E, Dunder K, de Graeff PA, Abadie E. Rosiglitazone: a European regulatory perspective. Diabetologia. 2011;54(2):213-8.

13. Summary Minutes of the Joint Meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, July 13-14, 2010. http://w w w . fd a . g o v / d o w n l o a d s / A d v i s o r y C o m m i t t e e s /C o m m i t t e e s M e e t i n g M a t e r i a l s / D r u g s /EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM241505.pdf. Accessed February 5, 2012.

14. Woodcock J, Sharfstein JM, Hamburg M. Regulatory action on rosiglitazone by the U.S. Food and Drug Administration. New England Journal of Medicine. 2010;363(16):1489-91.

15. Sutter S, Davis J. FDA, EMA decisions on Avandia reflect the power of REMS. “The Pink Sheet:” Prescription Pharmaceuticals and Biotechnology. 2010; September 27th, 1 and 4-6.

16. Bourg CA, Bryles Phillips B. Rosiglitazone, myocardial ischemic risk, and recent regulatory actions. Annals of Pharmacotherapy. 2012;46(2):282-9.

17. FDA. Guidance for Industry. Diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071624.pdf. February 2008. Accessed February 5, 2012.

18. EMEA. Concept paper on the need for revision of the [2002] note for guidance on clinical investigation of medicinal products in the treatment of diabetes mellitus. May 2008. http://www.ema.europa.eu/docs/en_GB/d o c u m e nt _ l i b ra r y / S c i e nt i f i c _ g u i d e l i n e / 2 0 0 9 / 0 9 /WC500003182.pdf. Accessed February 5, 2012.

19. Summary Minutes of the FDA’s Endocrinologic and


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Metabolic Drugs Advisory Committee, July 1 - 2, 2008. www.fda.gov/ohrms/dockets/ac/08/minutes/2008-4368m-Final.pdf. Accessed February 5, 2012.

20. EMA. Guideline on clinical investigation of medicinal products in the treatment of diabetes mellitus, draft. 2010. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/02/WC500073570.pdf. Accessed February 5, 2012.

21. Caveney E, Turner JR. Regulatory landscapes for future antidiabetic drug development (Part I): FDA guidance on assessment of cardiovascular risks. Journal for Clinical Studies. 2010. January issue, 34-36.

22. Turner JR, Somaratne R, Cabell CH, Tyner CA. Centralized endpoint adjudication in cardiovascular outcomes studies: composite endpoints, risk ratios, and clinical endpoint committees. Journal for Clinical Studies. 2011;3:46-49.

23. Joffe HV, Parks MH, Temple R. Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus. Reviews in Endocrine and Metabolic Disorders. 2010;11(1):21-30.

24. Turner JR, Caveney S. Regulatory landscapes for future antidiabetic drug development (Part II): EMA guidance on assessment of cardiovascular risks. Journal for Clinical Studies. 2010. March issue, 38-40.

25. EMA. Guideline on the need for non-clinical testing in juvenile animals of pharmaceuticals for paediatric indications. August 2008. http://www.ema.europa.e u / d o c s / e n _ G B / d o c u m e n t _ l i b r a r y / S c i e n t i f i c _guideline/2009/09/WC500003305.pdf. Accessed February 9, 2012.

26. Wishart D, 2005, Protein structure and analysis. In Baxevanis AD, Ouellette BFF (Eds), Bioinformatics: A practical guide to the analysis of genes and proteins, 3rd Edition. Hoboken, NJ: Wiley-Interscience, 223-251.

27. Thomas G, 2003, Fundamentals of Medicinal Chemistry. Chichester, UK: Wiley.

28. Brenner GM, Stevens CW, 2006, Pharmacology, 2nd Edition. Philadelphia: Sanders/Elsevier.

29. EMA. http://www.ema.europa.eu/docs/en_GB/d o c u m e nt _ l i b ra r y / S c i e nt i f i c _ g u i d e l i n e / 2 0 1 1 / 0 7 /WC500109587.pdf (Accessed 21st March, 2012)

30. Jackson C, Turner JR. Paediatric pharmaceutical medicine: Paediatric clinical research and consideration for clinical trials. Journal for Clinical Studies. 2010. November issue, 28-31.

31. Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in pediatric drug-development programs. Pediatrics. 2011;128(5):e1242-9.

32. Wasserman R, Bocian A, Harris D, Slora E. Limited capacity in US pediatric drug trials: qualitative analysis of expert interviews. Paediatric Drugs. 2011;13(2):119-24.

33. Tishler CL, Reiss NS. Pediatric drug-trial recruitment: enticement without coercion. Pediatrics. 2011;127(5):949-54.

34. Carleer J, Karres J. Juvenile animal studies and pediatric drug development: a European regulatory perspective. Birth Defects Research. Part B: Developmental and

Reproductive Toxicolology. 2011 Jun 2. [Epub ahead of print]

35. Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice. 2011;94(3):311-21.

36. Kölch M, Ludolph AG, Plener PL et al. Safeguarding children’s rights in psychopharmacological research: Ethical and legal issues. Current Pharmaceutical Design. 2010;16(22):2398-406.

37. Denburg AE, Joffe S, Gupta S, et al. Pediatric oncology research in low income countries: Ethical concepts and challenges. Pediatric Blood and Cancer. 2012;58(4):492-7.

38. Rose K. Ethical principles of pediatric research and drug development: A guide through national and international frameworks and applications to a worldwide perspective. In Mulberg AE, Silber SA, van den Anker JN (Eds), Pediatric Drug Development: Concepts and Applications. Hoboken, NJ: Wi¬ley-Blackwell, 2009, 115-129.

39. Hirshberg B, Raz I. Impact of the U.S. Food and Drug Administration cardiovascular assessment requirements on the development of novel antidiabetes drugs. Diabetes Care. 2011;34 Suppl 2:S101-6.

40. Viereck C, Boudes P. An analysis of the impact of FDA’s guidelines for addressing cardiovascular risk of drugs for type 2 diabetes on clinical development. Contemporary Clinical Trials. 2011;32(3):324-32.

41. Tominaga T, Asahina Y, Uyama, Y Kondo T. Regulatory science as a bridge between science and society. Clinical Pharmacology and Therapeutics. 2011:90(1);29-31.

J. Rick Turner, PhD, is Senior Director, Translational Cardiovascular Safety, Quintiles. He is a clinical triallist, regulatory scientist, Editor-in-Chief of the Drug Information Journal, a Senior Fellow at the Center for Medicine in the Public Interest, and a Fellow of the

Society of Behavioral Medicine. He is an author of more than 100 peer-reviewed papers and articles in professional journals, and an author/editor of 14 books. Email: [email protected]

Paul Strumph, MD, is Vice President, Therapeutic Strategy Lead, Cardiovascular and Metabolic Therapeutic Delivery Area, Quintiles. He is Board Certified in Internal Medicine, Pediatrics, Adult Endocrinology Diabetes and

Metabolism, and Pediatric Endocrinology. He is an author of more than a dozen articles in scientific journals and magazines, including Nature, Clinical Pediatrics, and the Journal of Clinical Endocrinology and Metabolism. Email: [email protected]

The authors are members of Quintiles’ Cardiovascular and Metabolic Therapeutic Delivery Area Writing Committee.

Exibition Previews & Reviews


Paediatric Clinical Research Facility Opened at Alder hey, May 2012

A bespoke clinical research facility, solely focused on paediatric research, was opened at Alder hey Children’s hospital in Liverpool on 4th May 2012. The facility was officially opened by comedian John Bishop during an all day event attended by 100 guests. In attendance were guests from local higher education institutions, other CRFs in England, the pharmaceutical industry, charities and children and young people including patients from Alder hey.

Speakers Sir Howard Newby, Vice Chancellor of University of Liverpool, delivered a keynote speech at the event about Alder Hey Hospital working in partnership with the University. Sir Howard highlighted the strengths of Liverpool as a city which has brought together the University plus six NHS trusts. The Liverpool Health Partners (LHP) focus on research, clinical services and education and training, with the aim of ensuring that medical research breakthroughs lead

to direct clinical benefits for patients. The organisations proactively collaborate to provide a world-class research infrastructure which attracts the best academics, clinicians and key opinion leaders to Liverpool. A presentation by Dr Matthew Peak, Director of Research at Alder Hey, sought to explain why the CRF is so important to the groundbreaking research being undertaken by the hospital and its partners. He demonstrated why research in children is so important due to the huge differences in the way in which children metabolise and excrete medicines compared to adults. He also demonstrated how the body changes and adapts this metabolism throughout life, therefore creating an essential need to develop age-appropriate medicines via safe and ethical research. He explained that the CRF is at the heart of Alder Hey’s collaborative partnership with University of Liverpool, and underpins the very best basic biomedical research and drug development already taking place amongst the hospital’s University, clinical academic and commercial partners nationally and internationally. Jenny

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Newman, MCRN Consumer Liaison Manager, was then joined by two young person’s representatives in discussing the importance of involving children and young people in research. Alder Hey’s Young Person’s Advisory Group have been involved in the initial design and planning of the CRF, along with the plans for its official opening. Jenny explained how she will bring a formal and structured patient and public engagement strategy to the CRF.

Comedian John Bishop, who has a background in the pharmaceutical industry, officially opened the facility. He was keen to highlight his admiration for the research achievements already taking place at Alder Hey, and stressed how important the new facility will be in advancing clinical studies. He also spoke about how important it was for research professionals and facilities to be in one place, centred around the child so that hospital visits are as short and efficient as possible. After unveiling the new CRF’s ‘Welcome Sign’, John met a number of patients participating in a research study of the new drug Tocilizumab, which has recently been licensed for use in paediatrics.

Those attending the event were given a tour of the facility, which includes: a welcoming reception, play area, meeting rooms and office space, two single-unit patient rooms, counselling and consultation room, monitoring and observation unit and two treatment rooms. It provides a six-bedded space in total, with a combination of private and communal facilities.

The Clinical Research FacilityRecent requirements by the European Regulation on Better Medicines for Children have led to a dramatic increase in the number of studies conducted in the paediatric population. Back in 2009, Alder Hey and the University of Liverpool

recognised that a facility solely focused on paediatric research was needed. A major capital investment by the hospital allowed the paediatric clinical research facility to be built, and the following year, Alder Hey Imagine Appeal provided funding for its leading edge equipment. In March 2012, the NIHR awarded a £2million grant to cover running costs and fund staffing for the facility until 2017.

The CRF will provide a world-class environment to support and enhance the delivery of the highest quality, most efficient, patient-focused research for children, young people and their families. Fully equipped and purposely-designed with direct links to laboratory and pharmacy facilities, it will significantly increase the capacity of Alder Hey to carry out essential paediatric research, including experimental medicine and early phase studies. The attractive, child-friendly environment of the facility will also enhance the experience of all those involved in research trials and help encourage greater participation. The facility enables Alder Hey to deliver safe, high-intensity studies of complex new medications and interventions, including those requiring inpatient, overnight care. The layout and location of the CRF ensures that studies are conducted to strict good clinical practice (GCP) standards. Sitting right in the heart of one of Europe’s biggest children’s hospitals, the facility is located close to critical care, medical inpatient facilities and clinical support services. This means Alder Hey is now providing the highest possible quality environment for safety, clinical and research governance.

Research taking place within the CRF will focus on investigating diseases and developing novel therapies, medicines and drugs. This will include experimental and early phase studies to establish the best route of medicine administration and correct dosages for children and young people. Early phase trials will take place in complex childhood conditions such as Hirschsprung’s disease, rheumatic disorders, cancers, diabetes, respiratory disorders and infectious diseases. The CRF will further Alder Hey’s expertise in paediatric drug development, and help Alder Hey achieve its ambition to be one of the recognised world leaders in children’s research and healthcare.

Dr Charlie Orton Ph.D CRF Business Manager. Managing the Medicines for Children research portfolio Charlie has 14yrs experience in clinical research. She oversees the strategic development of the facility ensuring its business is conducted to the highest standard.

Charlie has worked in primary, secondary and tertiary care bringing a well-rounded, diverse level of expertise to the facility. Email: [email protected]



India’s drug approvals put industry over peopleAfter a parliamentary committee criticised the bypassing of clinical trials and other irregularities in the approval of new drugs, India’s health ministry has ordered a panel of experts to look into the charges and suggest remedial measures. The three-member panel led by the director-general of the Indian Council of Medical Research, Vishwa Mohan Katoch, will submit its report within two months, according to a statement released on 11 May by the health ministry. The Katoch panel will suggest steps to institutionalise improvements in other procedural aspects of functioning of the ministry’s Central Drugs Standards Control Organisation, which was criticised by the parliamentary committee in its report on the 8th May saying that consumers interests were being ignored, the parliamentary committee suggested that CDSCO change its stated mission of meeting the demands and requirements of the pharmaceutical industry to one that will clearly protect public health. The committee’s report was based on studies conducted in the manner in which 42 randomly selected medicines were approved by the body — 38 of them between 2004 and 2010. The committee found sufficient evidence on record to conclude that there is collusive nexus between drug manufacturers, some functionaries of CDSCO and some medical experts. International drug makers named by the committee have responded to the committee’s charges saying that they had adhered to the law of the land, according to a report in the The Hindu Business Line newspaper on 11 May. One manufacturer told the Reuters news agency on 10 May that it would investigate alleged drug approval irregularities. Sourced: SciDev Net.

First Patient in Asia Regains Useful Sight After Receiving Retina Implant Ag’s Microchip 0Retina Implant AG (Retina Implant), a leading developer of subretinal implants for the visually impaired, announced that the first patient in China to be implanted with its microchip on February 13, 2012 at the University of Hong Kong Eye Institute has since regained useful sight. The University of Hong Kong Eye Institute is partnering with Retina Implant to be the leading clinical trial site in Asia to test its microchip in three patients who have been rendered legally blind from the degenerative condition retinitis pigmentosa (RP). This development expands Retina Implant’s multi-center study which involves leading sites in Germany, the UK, Hungary, Italy and the United States. The Hong Kong study site is being led by Professor David Wong, chair professor in Ophthalmology and director of the Eye Institute, University of Hong Kong.Professor Wong is a seasoned clinical researcher and has led several randomised trials in the related areas of retinal detachment and age-related macular degeneration.The patient, Mrs. Tsang Wu Suet Yun, has been legally blind for 15 years, and experienced a sharp deterioration over the last few years. Prior to the surgery, she was able to see almost no light at all. Despite this, she had adapted to her condition and continued to live a

very productive and capable life. She works as a masseuse and at home, prepares dinner for the family every day – in almost total darkness. Following the procedure in which she received Retina Implant’s microchip, she can see light and dark. In the laboratory, she was even able to read letters projected on a screen.Post-implantation, the microchip is turned on – this is when the evaluation of sight restoration begins. As patients must develop new internal processes for interpreting the images they see, it typically takes several weeks to fully realize their new sight capabilities. Sourced: Pharmiweb

Asia Pacific Pharma Companies Turning to high-Risk, high-Reward Drug Development, According to new Report from Thomson Reuters. 0Pharmaceutical companies in the Asia Pacific region are increasingly adapting their business models from the production of generic drugs towards more high-risk, high-return research and development, according to a new report released today by CMR International, a Thomson Reuters business.The changing picture is seen in the first edition of the 2010 Asia Pacific R&D Factbook, which finds increased clinical trial activity, patent challenges, and molecular development in the region. Whilst the proportion of global R&D expenditure allocated to Asia Pacific was less than 1 percent in 2009, these trends show a growing focus on these activities, said Hans Poulsen, head of life sciences consulting at Thomson Reuters. Global figures for clinical trial recruitment highlight a dramatic shift away from the United States and toward Asia Pacific. In 2002, 53 percent of patients recruited globally were in North America; in 2008 that figure was down to 32 percent. Asia Pacific saw an increase from 6 percent to 11 percent over the same period, while Europe showed marginal growth from 14 percent to 17 percent. Meanwhile, the number of new molecules in development by generic companies, particularly in India, reflects a strong inclination to invest in R&D. The number of patent challenges in the region indicates an increasingly aggressive approach to securing market share. Patent challenges raised by Indian companies, for example, increased 60 percent from 2006 to 2009, underlining the shifting business model in the region.The benefits to Asia Pacific in moving towards increased clinical trials and more drug development are clear: attracting more investment to the local pharma industry, and earlier access to innovative medicines for the local population,” Hans Poulsen said. “It is not clear however, if this trend will be seen as an opportunity for collaboration, or an increase in competition for multinational companies.”When it comes to clinical development activities in Asia Pac, location matters. The Factbook reports that Thailand is top for patient recruitment and quality, while Malaysia comes last, and Japan is top for regulatory performance while China is bottom. The information published in the Factbook is based on primary sources covering major pharmaceutical companies which account for approximately 80 percent of the industry’s global R&D expenditure. Sourced: Thomson Reuters.

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