Journal for Clinical Studies

FDA Expands RulesOn the Disqualification of Clinical Investigators

Paediatric Regulations are Permanent: Approaches for Overcoming the Challenges of Paediatric Drug Development

The Potential Use of Vaccines for Type 1 Diabetes

Developing Stem Cell Therapy for ALSThe Challenge

PEER REVIEWED

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Volume 4 - Issue 5

Contents

Journal for Clinical Studies 1www.jforcs.com

06 FOREWORD

WATCh PAgES

08 FDA Expands Rules on the Disqualification of Clinical Investigators

In April 2012, the US Food and Drug Administration announced in the Federal Register the publication of a final rule to amend the investigational new drug application and investigational device exemption regulations regarding the clinical investigator disqualification process. Alejandra Muntañola at Thomson Reuters provides an overview of the final rule, from May 30, 2012, and how the clinical investigator is ineligible to receive any test article if he/she is disqualified by the Commissioner of Food and Drugs.

10 Cardiovascular Safety Watch Column The assessment of off-target blood pressure responses

to non-cardiovascular drugs has been touched upon in previous columns in this series. Recently, however, there has been concerted activity in this area. It is clear that non-cardiovascular drugs can raise or lower BP in an off-target manner. While increases in BP probably attract more attention, unwanted decreases in BP can also be serious. Rick Turner at Quintiles provides an update on how it is also possible that interactions between non-cardiovascular drugs and drugs intended to lower blood pressure may either negate or potentiate the BP-lowering action of antihypertensives.

12 good Distribution Practices – Why and to What Detail gDP-contracts between Sponsors/Manufacturers and Distributors are Needed

A revision of the European GDP-guideline has been published for public consultation on December 31, 2011. Although defining the requirements for the wholesale distribution of medicinal products, the guideline is a useful guide for defining rules and roles in the distribution chain of investigational medicinal products. Claudio Lorck at Temmler Werke GmbH describes the reasons for having quality agreements with distribution/transport companies, and the main topics to be described for distribution of IMPs without usage of a depot.

REgULATORy

14 Paediatric Regulations are Permanent: Approaches for Overcoming the Challenges of Paediatric Drug Development

Global regulators have, for many years, put in place provisions and regulations to ensure that children’s specific medical needs are addressed through structured clinical research, in order to advance the development of safer and effective drugs and to generate information to guide prescribers in using these medicines in children. Philippa Smit-Marshall at PharmaNet/i3 provides an overview of how these measures have resulted in 445 drugs having paediatric labelling, with the conduct of over 400 studies in more than 170,000 patients.

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 Anthony Stewart

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 5 September 2012 PHARMA PUBLICATIONS

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Contents

Volume 4 Issue 52 Journal for Clinical Studies

16 Maximising the Role of Statisticians and Programmers to Reduce Timelines in Integrated Summaries of Safety and Effectiveness

An ISS is an Integrated Summary of Safety, and an ISE is an Integrated Summary of Effectiveness. An ISS combines the safety results from different studies conducted in a compound; while the ISE combines efficacy results. The regulatory authorities state both the ISS and ISE are critical components of a submission. David Underwood at Quanticate explains the combining of data in integrated summaries helps to address safety and efficacy concerns that are difficult to address using the data from individual trials.

18 Proactive Planning for Subject Recruitment and Retention are Critical to Modern Clinical Trial Success

Despite countless industry efforts to improve efficiency in the planning and execution of clinical trials, 80 per cent of studies are delayed in their completion by a third or more of their intended durations. Patient enrolment, or lack thereof, is frequently cited as the primary reason for clinical trial delays. Nicholas Spittal at Chiltern International discusses the widespread adoption of new technologies and services such as social media, electronic medical records, and remote data capture, which bring many opportunities to boost protocol participation, but also introduce many new challenges.

ThERAPEUTICS

26 Risk-based Monitoring: The New Regulatory Landscape, and Conjectures on the Future of Clinical Trial Execution

In early August 2011 the European Medicines Agency released a draft document entitled Reflection Paper on Risk Based Quality Management in Clinical Trials. Later the same month the US Food and Drug Administration released a draft Guidance for Industry entitled Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring. In this paper Amanda Sax, Margaret Keegan, Dan White, and Rick Turner at Quintiles will focus on the draft document from the FDA, and offer conjectures on the implications of the new regulatory landscape it engenders, assuming that the final document remains similar in spirit to that of the current drafts.

36 The Potential Use of Vaccines for Type 1 Diabetes Type 1 diabetes mellitus is an autoimmune disease. As well as

T1D, latent autoimmune diabetes in adults is also included in autoimmune diabetes. Latent autoimmune diabetes in adults (LADA) is similar to and is frequently confused with type 2 diabetes. But LADA is distinguished by the presence of autoantibodies, mainly glutamic acid decarboxylase autoantibodies. LADA patients usually become insulin-dependent at much faster rates in contrast to classic type 2 diabetes. Sandeep Kumar Gupta at Sanofi discusses why LADA has been put as a distinct entity and type of diabetes by some; others believe that LADA is just a mild variant of T1D and should be treated as such.


Contents

IT & LOgISTICS

40 Direct to the ePharma Consumer - In the Age of Connectivity

It is not a passing fad but a permanent shift. ePharma consumers are here to stay. It means that pharmaceutical and medical device companies must adapt to the new digital environment. While change is inevitable in any industry, this may be the first time that neither industry nor regulators but rather patients are driving this shift. Liz Moench, President and CEO of MediciGroup® Inc discusses how patients are already leading the charge and doctors, medical centres and clinical researchers are joining them across the globe.

44 CRA: The eClinical Persona Like many of us working in the clinical world today, the

Clinical Research Associate is confronted with a dizzying array of technology solutions, all designed to make the job easier. Corporate systems like email and time management, eClinical applications like electronic data capture, interactive web response systems and clinical trials management systems and myriad smaller applications to manage trial-specific data all contribute to technology chaos. Liz Love at Perceptive Informatics discusses when it comes to the management of eClinical data, which single product is the right one?

48 Tipping Point of Risk-Based Site Monitoring – Is it Within Reach?

With the recent 2011 release of the FDA’s draft guidance on risk-based approaches to monitoring, the agency has sought to correct a long-standing misconception that 100 per cent source document verification (SDV) is a regulatory requirement. Additionally, in issuing this draft guidance, the FDA took the further step of encouraging alternate, risk-based monitoring approaches while reaffirming that 100 per cent SDV is not a regulatory mandate. Sean Cheng at Medidata Solutions discusses that there are more efficient strategies to ensure the safety and integrity of patients and data.

54 Then and Now: Is Clinical Trial Technology Provider Selection and Implementation Becoming Easier?

The drug development industry has seen significant changes in the last ten years. Amongst those changes, pharmaceutical and biotechnology sponsor companies are outsourcing more drug development activities to third party clinical research organisations. Alongside this, clinical trial technology is playing an increasingly critical role in drug development, as the range of technologies in the market increases and as those technologies become more effective and refined. As technology choices expand and relationships between sponsors and CROs deepen, Julian de Brés at Medidata Solutions and Chris Cramer at Quanticate provide an overview of why CROs need to alter their technology provider selection process to consider market drivers that didn’t exist just a few years ago.

SPECIAL FEATURE

56 Developing Stem Cell Therapy for ALS: The Challenge ALS is a devastating disease affecting a wide range of

individuals, from young adults to senior citizens. The progressive and highly debilitating nature of the disease, combined with the lack of effective therapeutics, makes it a prime target for stem cell therapy. The unique functional properties of stem cells make them particularly promising for neurodegenerative diseases, and as a result, a number of stem cell clinical trials are underway in this area, both allogeneic and autologous. While these trials are only in their early stages, and there is still much work to be done, Adrian Harel at BrainStorm Cell Therapeutics explores how the challenges lying ahead will be overcome, bringing us closer each day to conquering ALS.



Foreword

The demand to include additional patient data, and the competitive nature of clinical development, have also led to a more global outlook for clinical trials and associated research activities of the pharmaceutical industry.

The lower cost of R&D and the increasing availability of skilled staff have led to companies

opening research facilities in emerging markets. The European Federation of Pharmaceutical Industries and Associations (EFPIA) have noted that some major pharmaceutical companies are exhibiting a preference for these regions when establishing new facilities. For example, it documented that during 2010-2012, while 14 research sites were closed in Europe, 11 were opened in Asia.

Since regulatory agencies such as the FDA and EMEA are starting to accepting clinical data generated in these regions, this also helps companies support their global marketing objectives. This has further significance given that these emerging regions are themselves also becoming important markets for new products. Through clinical trials, local physicians gain experience of new products and therefore it is in a company’s interests to base some clinical research in these locations.

The field of clinical trials is highly competitive, and companies often face situations where their preferred initial locations in the established markets do not result in the necessary number of patients being recruited. In contrast, emerging regions have large, growing populations and there is often a sizeable group of patients affected by diseases of interest to pharmaceutical companies, but not on current therapies. It is generally considered that the diseases characteristic of urban communities in major industrialised countries also typify the population of cities in emerging markets.

In this issue of Journal for Clinical Studies, I would just like to highlight some of the very pertinent topics we are bringing to you.

Alejandra Muntañola of Thomson Reuters updates FDA’s Expansion

of Rules on the Disqualification of Clinical Investigators. Rick Turner of Quintiles advances our thoughts on Cardiovascular Safety. Meanwhile, Dr Claudio Alexander Lorck of Temmler asks why, and at what level of detail, GDP-contracts between Sponsors/Manufacturers and Distributors are needed.

The Regulatory section starts with the much talked-about subject of Paediatric Regulations. Philippa Smit-Marshall of pharmanet-i3 identifies the approaches for overcoming the Challenges of Paediatric Drug Development. Another article in this section I would like to highlight is by Nicholas Spittal, Director, Strategic Clinical Development at Chiltern International, who examines the notion that Proactive Planning for Subject Recruitment and Retention are Critical to Modern Clinical Trial Success.

The Therapeutics section commences with Risk-based Monitoring: The New Regulatory Landscape, and Conjectures on the Future of Clinical Trial Execution.

Dr Sandeep Kumar Gupta contributes a piece on The Potential Use of Vaccines for Type 1 Diabetes.

I would like to direct everybody’s attention to one particular article: ePharma Consumer –

In the Age of Connectivity by Liz Moench of Medici Global. As we all know, patient empowerment, patient engagement is the talk of the town nowadays. Liz’s article gives some excellent examples as to why engaging patients in their healthcare will lead to a win-win situation for everybody.

Our Special Feature in this issue is Developing Stem Cell Therapy for ALS: The Challenge, which is written by Dr Adrian Harel of BrainStorm Cell Therapeutics.

I hope you all enjoy this issue, and I look forward to meeting everybody both at ICSE Madrid, and at Partnership in Clinical Trials in Hamburg.

Mark A. 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


In April 2012, the US Food and Drug Administration (FDA) announced in the Federal Register the publication of a final rule1 to amend the investigational new drug application and investigational device exemption regulations regarding the clinical investigator disqualification process. Under the final rule, from May 30, 2012, a clinical investigator (including a sponsor-investigator) is ineligible to receive “any test article” if he/she is disqualified by the Commissioner of Food and Drugs. Specifically, the individual is not able to conduct any investigation that supports an application for a research or marketing permit for drugs, biologics, devices, new animal drugs, foods (including dietary supplements that bear a nutrient content claim or a health claim), infant formulas, food and color additives, and tobacco products.

In the US, physicians and other qualified experts who conduct clinical studies may be disqualified if they have repeatedly or deliberately failed to comply with applicable regulations of 21 CFR 312 and 21 CFR 812, among others, related to drugs and devices. The purpose of the disqualification is to preserve the integrity of data needed to assess the safety and effectiveness of an FDA-regulated product before the product is made available to the public and to protect the safety of study subjects during the trial and patient safety after approval of the marketing application.

The disqualification regulations had a loophole identified by a report2 from the Government Accountability Office (GAO) published in September 2009. The FDA authority to debar a clinical investigator involved in research with drugs did not extend to devices and vice versa. This meant that the FDA’s oversight of clinical investigations was limited. For example, one disqualified investigator (who, among other things, falsely reported that investigational vaccines had been administered to infants when they had not, and failed to report that some clinical trial participants had been hospitalised) was prohibited from being an investigator for drugs or biologics, but was not disqualified from receiving medical devices or other FDA-regulated investigational products, and so could serve as a investigator for research on these products should this individual chose to do so. In order to correct this gap and to harmonise product-specific disqualification rules, the FDA started a regulatory process that concluded with the publication of the final rule in the Federal Register.

The new regulation adds a notification to the reviewing institutional review boards (IRBs) about a clinical

investigator being disqualified. Previous to the publication of the final rule only the sponsor and the investigator were sent a statement of the basis for the disqualification. The notification will explain that an investigator determined to be ineligible to receive test articles will be ineligible to conduct any clinical trial that supports an application for research or marketing for products regulated by the FDA.

Another amendment introduced by the final rule is that the sponsor is not exempted from submitting to the FDA the results of the investigation in the case that the agency determines that an investigation may not be considered in support of a research or marketing application, or a notification or petition submission. In such cases the sponsor will be notified and have the opportunity of a hearing before the agency.

Some other elements being regulated include: the withdrawal of the product if the Commissioner determines, after the unreliable data submitted by the investigator are eliminated from consideration, that the continued approval of the product for which the data were submitted cannot be justified; and the reinstatement of an investigator who has been disqualified if the FDA determines he/she has presented adequate assurances regarding the conduct of the investigation in compliance with the applicable regulations and provisions concerning regulatory hearings before the FDA.

Reference1. Federal Register: April 30, 2012 (Volume 77, Number 83/

Pages 25353-25361)2. GAO Report to Congressional Requesters—Oversight of

Clinical Investigators, Action Needed to Improve Timeliness and Enhance Scope of FDA’s Debarment and Disqualification Processes for Medical Product Investigators; GAO–09–807. See http://www.gao.gov/assets/300/296030.pdf

Alejandra Muntañola, RPh, MS Project Manager, Thomson Reuters. Alejandra Muntañola graduated as a pharmacist from Complutense University, Madrid and further specialised in European Regulatory Affairs. She has worked for the pharmaceutical industry in

regulatory affairs and is currently Senior Project Manager for the IDRAC United States (US) Module at Thomson Reuters.Email: [email protected]

Watch pages

FDA Expands Rules on the Disqualification of Clinical Investigators

Watch pages

10 Journal for Clinical Studies Volume 4 Issue 5

The assessment of off-target blood pressure (BP) responses to non-cardiovascular drugs has been touched upon in previous columns in this series. Recently, there has been concerted activity in this area, and therefore this column provides an update on this topic. Various publications have now made it clear that non-cardiovascular drugs can raise or lower BP in an off-target manner. While increases in BP probably attract more attention, unwanted decreases in BP can also be serious. Moreover, it is also possible that interactions between non-cardiovascular drugs and drugs intended to lower blood pressure (antihypertensive agents) may either negate or potentiate the BP-lowering action of antihypertensives. More research is needed in this regard.

As O’Brien and Turner1 recently noted, “the clinical relevance of small and transient off-target drug-induced changes in BP to symptomatology, morbidity, or mortality is not known because the subject has not been systematically studied.” However, as Grossman and Messerli2 also recently observed, “severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported.” The increasing scientific and regulatory interest in off-target BP responses led to a Cardiac Safety Research Consortium (CSRC) Think Tank meeting on this topic being held at the US Food and Drug Administration (FDA) headquarters in July of this year.3 A CSRC White Paper is currently being written following this meeting, which will be submitted to the American Heart Journal, and all readers interested in this topic are encouraged to look out for the paper’s publication in due course. For now, this column will focus on just one aspect of a more rigorous and systematic investigative strategy for assessing off-target BP responses during an investigative drug’s clinical development programme, namely the employment of ambulatory blood pressure monitoring (ABPM).

Blood pressure measurement is a central part of many medical procedures, including regular physical check-ups at doctors’ offices. On those occasions, conventional clinic BP measurement (CBPM) using the technique introduced into clinical medicine in 1896 by Riva-Rocci and Korotkoff is typically employed.4 However, ABPM can provide much more information than the single ‘snapshot in time’ reading provided by CBPM by providing a profile of BP behaviour over a 24-hour period. As well as facilitating assessment of the effects of a non-cardiovascular drug aggregated over the entire 24-hour period, ABPM also allows more fine-tuned assessments during specific windows of this time cycle. The circadian cycle can be divided into various periods, including daytime, siesta, vesperal (evening), night-time, and matinal (morning) windows. Consider night-time BP, one of the most important measures of circadian variation in BP. Nocturnal hypertension (i.e., a non-dipping pattern) is strongly associated with increased cardiovascular morbidity and mortality. The terms dipping (a decrease in BP) and non-dipping (no decrease) are used to describe the most common nocturnal patterns of BP behaviour. Around 70% of people

show reduced BP at night (i.e., show dipping), and about 30% of people have non-dipping patterns, when BP remains similar to daytime BP, or occasionally rises above daytime BP (reverse dippers). Thus, the effects of non-cardiovascular drugs on night-time BP can be examined.

Another important parameter of BP assessment that is facilitated by ABPM is the morning surge, when BP increases from night-time levels. There is a tendency for adverse cardiovascular events to occur more frequently in the early morning period, and so it is important to assess the possibility that non-cardiovascular drugs might induce or accentuate this phenomenon.

For the successful implementation of ABPM, both hardware and software considerations are important. First, ABPM devices should be validated according to internationally accepted protocols.1 Second, to obtain the most information from a 24-hour recording period, appropriate software that can collate, interpret, analyse, and electronically transmit the data to a core laboratory for centralised review of the data is recommended. Custom-designed software systems are available that provide visual printouts on a standardised plot that shows various time windows of the 24-hour profile (as discussed earlier), normal bands for systolic BP (SBP) and diastolic BP (DBP), and the recorded levels of SBP and DBP throughout the 24-hour period.

Moving to the next level of sophistication, it is also possible to collect simultaneous heart rate and rhythm information by using concurrent Holter monitoring, and then to analyse cardiac and vascular information in an integrative manner.

References1. O’Brien E, Turner JR. Assessing blood pressure responses to

noncardiovascular drugs: The beneficial role of ambulatory blood pressure monitoring. Journal of Clinical Hypertension, in press.

2. Grossman E, Messerli FH. Drug-induced hypertension: An unappreciated cause of secondary hypertension. American Journal of Medicine. 2012;125:14-22.

3. https://www.cardiac-safety.org/think-tanks/july-2012/assessment-of-pharmacologic-induced-increases-in-bp-during-clinical-development (Accessed 10th September 2012).

4. O’Brien E. Why ABPM should be mandatory in all trials of blood pressure-lowering drugs. Drug Information Journal. 2011:45:233-239.

J. Rick Turner, PhD, is Senior Scientific Director, Clinical Communications. He is an author/co-author of 130 papers, an editor/co-editor of 14 books, and Editor-in-Chief of the Drug Information Journal.Email: [email protected]

Watch pages

Cardiovascular Safety Watch column


Watch pages

A revision of the European gDP guideline (Commission guideline on gDP of Medicinal Products for human Use) was published for public consultation on December 31, 2011. Although defining the requirements for the wholesale distribution of medicinal products, the guideline is a useful guide for defining rules and roles in the distribution chain of investigational medicinal products (IMPs).

The following Watch Page describes the reasons for having quality agreements with distribution/transport companies and the main topics to be described for distribution of IMPs without usage of a depot. The topics to be covered in agreements for distribution including depots will be described in the next edition of JCS.1. Reasons for Quality Agreements between the Sponsor/

Manufacturer and the Distribution CompanyICH E6 (R1) requests the sponsor to ensure that investigational products be manufactured, handled, and stored in accordance with applicable good manufacturing practice. National authorities (e.g. Germany) nominate manufacturers to be responsible for storage and distribution.Distribution companies are generally not supervised by national or supra-national authorities for compliance with GDP unless they are wholesale distributor with a formal wholesale distributor licence.Additionally it is a matter of fact that many distribution companies do not have a worldwide net of own distribution vehicles with their own employees, but often subcontract parts of their distribution chain to smaller and nation-specific carrier companies. It is therefore important for the sponsor or the manufacturer (depending on who is taking responsibility for the IMP distribution) that there are quality agreements in place, clearly defining the level of GDP to be applied during transport of IMPs, addressing the responsibilities of the parties involved and being authorised by duly responsible personnel.

2. Quality Agreement: The Distribution Company Confirms by Signing Off that• Quality system – there is a quality system in place

ensuring that IMPs are handled and transported GDP-compliant, defining the responsibilities of the management, ensuring that deviations are documented and investigated and appropriately addressed by CAPAs (corrective action, preventive action);

• Personnel – there is sufficient GDP-qualified personnel available and responsibilities of the personnel are

clearly defined, there are job descriptions for key personnel, a training programme is in place for all personnel involved in distribution activities, the organisational structure of the distribution company is reflected in an organisation chart, and there are appropriate personnel hygiene procedures in place;

• Equipment – equipment used to control or monitor transport conditions is calibrated and maintained in regular intervals, transport containers including their packaging configurations are qualified and alarm systems are verified; transport containers are appropriately labelled; cleaning procedures for transport containers and vehicles are in place;

• Transport – the transport throughout the whole transport chain from collecting IMPs at, for example, the manufacturer’s site until delivery at the clinical site maintains the conditions as informed by the contract giver and protects the IMP against breakage, manipulation and theft; occurrences of deviations are investigated and informed to the contract giver without delay; cleaning procedures,

• Documentation – records of important processes (e.g. pick-up, delivery, traceability data, temperature records, alarms, deviation reports, change control records, complaint records, etc.) are collected, reviewed, safely archived and accessible;

• Subcontracting – any subcontractor is qualified according to established procedures and in compliance with all requirements as agreed between the contract giver and the distribution company; the distribution company remains fully responsible for all processes subcontracted;

• Change Control – the contract giver has to inform the contract giver and/or ask for his approval of changes before implementation; additionally that there is a system to document and trace changes of important procedures;

• Deviations – the distribution company will inform the contract giver without delay on any deviations which occur during transport and delivery;

• Complaint – the distribution company has a system in place to document, investigate and respond to complaints received from either the IMP recipient or the contract giver;

• Recalls – the distribution company will cooperate with the contract giver or the sponsor as regards recalls;

• Audit – the distribution company agrees to allow the contract giver to perform GDP-audits at the distribution company and its subcontractors regularly and upon reasonable notice;

good Distribution Practices (gDP) – Why and to What Detail gDP-contracts between Sponsors/Manufacturers and Distributors are Needed

3. Additional Documents of the Quality Agreement• List of subcontractors• List of contact persons/responsible persons• Tick list of responsibilities (incomplete example given below)

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]

Watch pages


Regulatory

global regulators have, for many years, put in place provisions and regulations to ensure that children’s specific medical needs are addressed through structured clinical research, in order to advance the development of safer and effective drugs and to generate information to guide prescribers in using these medicines in children.

In the early 1990s the US government introduced legislation in order to generate labelling information for medicines used in children. Subsequently, the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) were introduced to provide incentives or mandate, respectively, clinical research in children. Since 1997, these measures have resulted in 445 drugs having paediatric labelling, with the conduct of over 400 studies in more than 170,000 patients.

In July of 2012, BPCA and PREA were permanently reauthorised as part of the FDA Safety and Innovation Act (FDASIA) with the continuing objective to encourage earlier paediatric study planning by drug manufacturers, including paediatric rare diseases.

Under FDASIA, the FDA acquires new authority not only to ensure that PREA requirements are met on time but also to improve the transparency of data from paediatric studies conducted prior to 2007, to address drug shortages and to increase FDA expertise in drug studies in neonates. There is a recognised need for neonatal expertise in paediatric drug development, and to that end the FDASIA recommends that the Office of Pediatric Therapeutics and the Pediatric Review Committees have members with neonatal expertise.

In Europe, the European Paediatric Regulation was introduced to provide a framework of obligations and rewards for pharmaceutical companies and academia to conduct studies in children with the objective of increasing labelling advice and suitable formulations for medicines that are of therapeutic value for children. The Paediatric Committee (PDCO) have agreed around 1000 PIPs since its introduction, the majority for not yet registered medicines.

Recently, the European Medicines Agency (EMA) has begun its first public consultation on its inventory of needs for children’s medicines starting with cardiovascular medicines. The EMA continue to review and revise procedures to facilitate the extension or merger of an agreed Paediatric Investigation Plan (PIP) if more than one condition will be applied for and also allows companies to reduce or split a PIP if it intends to apply

for fewer conditions than planned.These changes clearly indicate the desire to collaborate

more closely with companies producing medicines for children and to focus more clearly on actual needs.

Paediatric research is here to stay and several challenges still remain in respect of their execution. The need for rigorous scientific standards must be set off against the high number of studies required as a result of the legislation and the competition for patients in rarer indications.

Innovative approaches to modelling and simulation techniques may allow more accurate estimation of doses and allow sparse sampling in pharmacokinetic studies. The EMA has developed a Concept Paper on the extrapolation of Efficacy and Safety Data in Medicine Development (June 2012) in order to develop a framework for scientifically valid and reliable extrapolation approaches.

(http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129285.pdf)

Extrapolation is essentially applying data and conclusions from subgroups of the population (source population), or in related conditions or with related medicinal products, to make inferences for another subgroup of the population (target population), or condition or product. In this way the need to generate additional information (types of studies, design modifications, number of patients required) to reach conclusions for the target population, or condition or medicinal product is reduced. Extrapolation from adults to children is a typical example and might avoid unnecessary studies.

Other approaches to overcome drug evaluation challenges in children may be applying sample size sparing statistical techniques to early studies and Phase III studies such as sequential and adaptive designs.

There may also be a place for different types of studies to gain more information on medicines use in children, such as observational studies, provided the data is scientifically valid and reliable.

Nonetheless one of the greatest hurdles for recruitment remains patient recruitment and particularly gaining parental consent and the child’s assent (where applicable). Feasibility studies to determine epidemiological characteristics of the condition, and assess suitability of investigational sites and accessibility to the appropriate patient populations, are becoming increasingly more important, especially in diseases which are currently still being defined in children e.g. multiple sclerosis.

Paediatric Regulations are Permanent: Approaches for Overcoming the Challenges of Paediatric Drug Development.

Sponsors have an opportunity and responsibility to educate and motivate study participants through investment in well-written educational material and close interactions with investigational sites, to ensure that patients can be entered into clinical trials that will ultimately benefit the whole paediatric population.

The field of paediatric medicines research is exciting. The regulations have resulted in an increase in rigorous scientific research in children, resulting in safer and more effective medicines. The need for new approaches to study design and utilisation of less conventional approaches to the generation of useful data represent future trends in paediatric medicines development.

Philippa Smit-Marshall is a UK qualified physician and pharmacologist with twenty four years experience in the pharmaceutical and CRO industry. Throughout her career she has been involved in clinical development planning, clinical trial management,

medico-marketing activities and medical monitoring including Pharmacovigilance. She has worked for companies such as Glaxo, Smith Kline Beecham, Novo Nordisk and Quintiles in both medical and operational leadership roles. She is currently Vice President of Medical Affairs responsible for the General Medicine therapy area and leads the Paediatrics Division. The dedicated Paediatric Division at PharmaNet/i3 which is a multi-disciplinary team providing paediatric-specific services to clients and is also responsible for education and the dissemination of information on global paediatric research.She provides consulting support to clients on development planning, protocol development, regulatory submissions and evaluation of drug candidates. In addition se supports clinical studies as a medical monitor. She has published and presented widely on topics in these areas. Her therapeutic areas of interest include paediatrics, cardiovascular medicine, endocrinology and neurology. She has acted as chairman of the Institute of Clinical Research’s Paediatric Advisory Board, and is a member of the European Federation of CROs Working Party on paediatrics.Email: [email protected]

Regulatory

Regulatory


What is an ISS and an ISE?An ISS is an ‘Integrated Summary of Safety’ and an ISE is an ‘Integrated Summary of Effectiveness’. An ISS combines the safety results from different studies conducted in a compound; while the ISE combines efficacy results. The regulatory authorities state both the ISS and ISE are critical components of a submission.

Why are an ISS and an ISE Considered Necessary?The combining of data in integrated summaries helps to address safety and efficacy concerns that are difficult to address using the data from individual trials. However, the regulators make it clear that a statistically significant result in an ISE is not sufficient to replace positive results in individual trials.

Combining the results from a number of different studies provides considerably more power for these important comparisons of safety and efficacy, while not taking away from a study’s primary endpoint. The increased power in an ISS enables identification of rarer adverse events (AEs) that may not be evident from a single study.

Planning the Analyses and Summaries Required in the ISS/ISEEarly planning of the ISS and ISE, and the use of a statistician in the planning, can help to identify and resolve potential problems at an early stage. This will make the process as efficient and cost-effective as possible. Planning an ISS and ISE prior to starting your pivotal studies enables you to introduce efficiencies, allowing data to be collected to answer specific questions. Producing a submission that is complete, consistent and easy to follow will make the review process for the regulatory authorities easier and therefore quicker.

For the statisticians and programmers working on the integrated summaries, one of the most time-consuming tasks is the production of a database containing the combined study data. Differences in how the data are collected may determine if it is sensible to combine the data, or what the results of the combined analyses actually mean.

As each submission is different, there are key messages that you will need to address, or specific statistical methodologies that are required and are unique to your submission.

Early identification enables the statistician to address them prior to combining the results.

Including a statistician in the pre-submission meetings with the regulatory authorities is important. Their expertise is vital for discussing issues around sample size and other statistical considerations during the design phase. The statistician can also help to identify solutions to specific concerns that the regulatory authorities raise, enabling rapid agreement.

Combining results from independently designed studies that often address slightly different objectives is always going to be difficult. For example, Study A may dose patients for three weeks, compared to Study B that doses patients for six weeks. A combined summary of the number of patients who reported an AE may not be appropriate, as one group of patients was ‘at risk’ and followed up for a greater time period. The statistician can help identify an appropriate methodology for addressing such issues. In this example, a solution may be to present AEs based using a denominator that adjusts for time at risk.

Reporting of the StudyOnce planning of the integrated analyses is complete, the statisticians and programmers will be involved in the production of the results based on the planned analyses. At this stage, close collaboration between the biometrics team and the rest of the study team is still vital to ensuring a successful submission.

It is surprising how difficult it can sometimes be to locate the validated datasets and full supporting documentation. Production of combined derived datasets can be a lengthy task, and you should take into consideration the standards of older studies compared to newer.

In a well-planned submission, once the datasets are

Maximising the Role of Statisticians and Programmers to Reduce Timelines in Integrated Summaries of Safety (ISS) and Effectiveness (ISE)

Regulatory


final you can use macros to reduce the complexity of the output production for the ISS and ISE. If the biometrics of the ISS/ISE and pivotal studies has been centralised, then these macros can be used to produce the results from the pivotal studies as well. As well as significantly reducing the time to reporting once the pivotal studies unblind, this can help to ensure consistency in the presentation of the results.

The integrated database is also essential for allowing rapid turnaround of questions from the regulatory authorities, as it simplifies production of outputs from the central database.

ConclusionThe planning of your ISS and ISE should start as early as possible to ensure consistency, allowing efficient planning of the integrated summaries and the submission process. Careful planning of the appropriate analyses is vital for reducing timelines and enables you to show that the decisions made did not introduce bias.

A well-constructed statistical analysis plan and integrated dataset help to front-load the production of the integrated summaries, and with efficient reporting tools can significantly reduce timelines to submission.

In addition, the successful planning and implementation of the ISS and ISE helps reduce review times and questions, and results in a shorter time to approval.

David Underwood is CEO and Chairman of Quanticate. He has been in the pharmaceutical industry for over 30 years, starting his career at GlaxoSmithKline as a statistician and began his own company 15 years ago to provide specialist biometrics services.

Karen Ooms, Head of Statistics for Quanticate., Statistical Consultancy Team of Quanticate (www.quanticate.com). The statistical consultancy team consists of leading experts that support pharmaceutical, biotechnology and device companies across many

therapeutic areas and all phases of drug development. In addition to supporting the development of ISE and ISS, the team are also providing general statistical support in protocol design, calculating sample sizes and providing expertise around adaptive design methodology, Bayesian methodology and risk based monitoring. Email: [email protected]

Regulatory


Despite countless industry efforts to improve efficiency in the planning and execution of clinical trials, 80 per cent of studies are delayed in their completion by a third or more of their intended durations8. Protracted study delivery has staggering financial and clinical implications for both biopharmaceutical companies (lost revenues of $8 million per day delayed8) and the patients they serve. The Manhattan Research Institute has developed a formula showing that a setback of just one year in availability for new drugs for AIDS/HIV, breast cancer, and non-Hodgkin’s lymphoma alone is estimated as costing $27 billion31. Achieving enrolment milestones can literally be the sole determining factor in the survival of small biotech organisations with only one or a few therapies in their pipelines. For many patients, it is literally life or death4.

Patient enrolment, or lack thereof, is frequently cited as the primary reason for clinical trial delays. As such, there is growing fervour for the implementation of robust subject recruitment and retention initiatives in research studies. The widespread adoption of new technologies and services, such as social media, electronic medical records (EMRs), and remote data capture, brings many opportunities to boost protocol participation, but also introduces many new challenges. The key takeaway for today’s study environment is that subject management, from pre-screening through study completion, must be carefully planned and closely supervised; it cannot be taken for granted to proceed on its own1. And even with technological advancements, the industry cannot underestimate the importance of interpersonal relationships30.

Recruiting the Modern-day Patient is a Difficult Task There is widespread interest in clinical trial participation with 94 per cent of the public agreeing that research involvement is “very important to advance medical science”5, and similar metrics support research and its funding in general8. When it comes to actually recruiting clinical trial participants, however, the industry is facing an uphill struggle. A 2008 survey revealed that only 17 per cent of 1000 respondents believed clinical trials to be “very safe” and 14 per cent revealed that they had no knowledge of the topic whatsoever8. Seventy per cent of those questioned for a recent industry white paper indicated having no awareness of the most common online clinical trial databases (e.g. ClinicalTrials.gov)12, further sustained by 74 per cent admitting “no ‘real’ knowledge of the clinical research process” and nearly everyone

stating they don’t have the tools to appropriately evaluate potential studies5.

With the proliferation of online communication methods, the rapid expansion of social networks, the “always-on” 24-hour news stream, and expanded access to mobile media, we are inundated with data at a pace never before seen. The typical person is exposed to the equivalent of an entire novel’s worth of information every single day6. It should come as no surprise that even the most targeted messages may get lost in the fold. Despite uptake of social media, its use for engaging patients is still in its infancy due to privacy concerns and lack of proper guidance from regulators. After years of debate, the FDA’s initial draft guidance issued in December 2011 for patient-initiated requests arrived with no clarity as to what may be allowable regarding engagement via social media outlets14.

Still, figuring out a way to use these newer media in a targeted and acceptable way is a potential boon for clinical research. In May 2011, 179 “e-patients” – those who rely on social media and online networks for health information – revealed that they more consistently visit a doctor, are more apt to adhere to prescribed medical schedules, and are 60% more likely than the general populace to have participated in a clinical trial12. Interestingly, this same survey showed that the vast majority – 80 per cent – read information available on healthcare websites and social networks, but are not necessarily inclined to post content in response; thus a successful social media campaign cannot rely on self-reporting from potential subjects. It is up to the industry to get the word out via these alternative venues.

Where social media shines is in its ability to reach those with similar, often unique or orphan conditions or circumstances13. Tapping into networked communities of those with rare diseases and/or similar life situations gets directly to the populations of interest for trial recruitment. By advertising or otherwise engaging in these communities, sponsors, CROs, and sites alike can reach a ready pool of potential subjects guaranteed to meet basic study criteria. Considering a broad definition of social media, there are dozens of focused and immediate opportunities with topical communities like PatientsLikeMe and the Fox Foundation’s Fox Trial Finder10,23,15. On PatientsLikeMe, for example, users can enter their conditions, gender, age and location to find relevant clinical studies nearby. From the investigation side, reviewing a specific ongoing study shows the number of registered PatientsLikeMe users who may

Proactive Planning for Subject Recruitment and Retention are Critical to Modern Clinical Trial Success

Regulatory


qualify based on their profiles. Registered users are able to directly interact by drilling down through other registered users’ profiles, making direct contact between researcher and potential subject simple, though perhaps a bit invasive when done improperly23. With a lack of regulatory guidance, it is left to sponsors to work with IRBs in determining the most appropriate means to engage patients in this fashion25. But if sponsors advertise or otherwise promote their trials in like communities, they have an immediate leg-up in gaining the attention of the high-value “e-patients.”

Yet all this talk of social media is not without its complications. Pfizer’s much-ballyhooed REMOTE study, designed to be entirely technology-driven with social media at the core of the recruitment strategy, was terminated prematurely in June 2012 due to lagging enrolment11. Rahlyn Gossen – a former research coordinator who now runs RebarInteractive.com26 which explores advancement of new means of recruiting trial patients – is firmly committed to digital methodologies, yet she remains equally critical of social media’s potential, particularly because of the long-term commitment needed to make venues like Twitter successful22. She suggests that social media today can most effectively be used to increase awareness and build rapport by creating original content and getting the word out through channels like YouTube24. Gossen sees this as a developing area as effects of traditional media wane22. So social media may very well be a means to augment, rather than revolutionise, patient accrual at the current juncture.

As a less progressive but more immediately accessible technology, increasingly routine use of electronic medical records (EMRs) provides an excellent opportunity to quickly and efficiently scan patient data that were entirely inaccessible or severely cumbersome to navigate in their previously disparate state. Use of EMRs has already shown promise to accelerate research recruitment28,3. As demonstrated in a 2011 general practice study in Germany, implementation of a study-specific “clinical trial alert” tool allowed site research coordinators to partially automate the patient identification process, such that they combed through over 16,000 potentially eligible EMRs in order to contact nearly 2000 patients leading to over 1500 enrolled subjects29. This type of rapid, automated screening process would not be possible in the ‘paper world.’ Pre-screening EMRs for potential patients has additional added benefits of confirming the viability of a potential study as described in Case Study A (see inset).

It should be noted that the proliferation of technology on its own cannot resolve the entire recruitment challenge. Given the intimacy of healthcare information, trust is primarily achieved through credibility and respect for privacy that can only be offered from physician interactions; transparency is paramount to success9,12. Patient recruitment agency Blue Chip suggests that, when considering social media as part of the accrual strategy, it is important to ensure demographics of the study requirements and the targeted communities are well-aligned, that transparency is actively maintained

with involvement of a physician, and that information is timely, accurate, and readily available for sharing within or outside the target forum12. A 2012 meta-analysis further confirms that direct physician involvement in the design and recruitment of studies is the single most important criterion in successful enrolment16.

Similarly, though it may seem obvious, proper site selection by sponsors and CROs can be the ultimate determining factor in successful recruitment. Retrospective analyses by Pfizer and Lilly have shown, perhaps not surprisingly, that strong site performance on a prior study is the most important factor in likelihood of recruitment success on a new study. This is even further amplified when investigator experience is taken into consideration17. And when other factors influence the start of a trial, as in Case Study B (see inset), additional effort is required to ensure recruitment proceeds as planned.

Recruitment is Not the End of the LineWith intense industry focus on means to bolster study accrual, patient retention often goes without planning. It costs significant capital – financial, temporal, labour, opportunity cost – to enroll each trial subject, so keeping them on a study through completion is equally as important as the initial recruitment. There will always be the unavoidable loss of subjects – unrelated adverse events, relocation, co-morbidities – so there is good reason to make certain that, barring medical reason, subjects are encouraged to remain on study. This requires creativity, flexibility and real commitment from the sponsor and the trial site.

One means of helping to retain the modern-day study subject is via the reduction of in-office requirements. Though Pfizer’s REMOTE study as discussed previously may be considered a disappointment as relates to enrolling subjects, the entirely decentralised patient-centric approach with minimal intervention from trial investigators demonstrates maximal flexibility for the modern-day study subject. Trial participants have been able to complete all their data reporting via electronic patient-reported outcomes (ePRO) tools, regardless of trial site proximity, and have been able to reach study physicians 24 hours a day to discuss participation. Whether a fully virtual trial is ‘science future’ or ‘science fiction’ remains to be seen, but certainly some of the tools, including expanded collection of remote data, is a growing trend to improve study speed and subject retention and compliance21. Sponsors need to be creative and flexible in acquiring data, particularly for long-term or highly involved studies so as to minimise disturbance of subjects’ everyday activities with commitment to patient convenience20,27.

As evidence of this, utilising ‘in-home’ study visits is another means of boosting patient retention, particularly for studies that require lengthy or frequent procedures or data collection. For example, a study nurse may visit trial participants in their homes or offices to collect blood samples or administer IV dosing, rather than requiring a subject to travel to a study site. Not only is this a

Regulatory


significant added ease for trial subjects, but it has the effect of fostering a stronger bond between participants and the trial care-givers, thus improving long-term retention20. In a case study published by Symphony Clinical Research, dropout rates across multiple Phase II/III two-year orphan drug pulmonary studies were reduced from two-thirds to just three per cent with addition of homecare services. For those planning new studies, use of decentralised patient care may be a useful and cost-effective tool in certain situations to reduce participation burden and thus improve long-term retention7.

Interestingly, whereas recruitment is evolving to include more technology-driven concepts, retention may be enhanced through significantly less evolved methods. Research shows a direct correlation between the level of involvement of the principal investigator, the approach and attitude of the research nurse, and the level of empathy for the trial subjects19. So though these facets may be perceived as less controllable by those managing studies, employing a high level of site education and training with a concerted focus on patient-centric ideologies may be the most effective means to ensure subject retention.

Finally, in cases of long-term studies, use of retention specialist organisations may significantly improve outcomes. In one example, an HIV study which had lost over 25 per cent of participants after six months was able to re-engage nearly 90 per cent of those lost subjects using concentrated outreach efforts, suggesting again that planning for retention is a necessary part of overall study planning2. Case Study C (see inset) explores a solution used to maximise patient retention over a long-term study.

Applying Lessons TodayAll told, the actionable lesson from this is that it is critical that sponsors, study investigators, and clinical monitors assess the specific qualities of each protocol and site in order to customise the best approach to recruit and retain for each given circumstance; there is rarely a “one-size-fits-all” solution to successfully enrolling and maintaining trial patients. Perhaps the most important consideration for a multisite protocol is recognition that each site will have its own unique needs, and that all stakeholders need to collaborate with each sites’ investigators and coordinators to define and implement an appropriate strategy18. Investigators’ direct involvement starting at the consultative stages is key to gaining patient buy-in. And the quantitative effect of all strategies needs to be continually assessed and recon d as the trial proceeds. Like most parts of research, subject management is a “living” process that starts and ends with humans1, and planning is essential.

The rise of social media and increase in “crowd-sourced” engagement bring new avenues to interact with and gain attention from potential and enrolled trial subjects. But use of these and all media has to be carefully planned in order to meet the rigours of ethical and regulatory guidelines, as well as to gain the trust and acceptance of the broad population. Planning, monitoring, and reacting

to subject recruitment and retention trends, are critical to ensuring trial success27. In the end, recruiting and retaining research subjects are very human endeavours, and relationships matter. Planned efforts have never been more challenging, more creative, or more necessary, and are only going to continue to evolve.

CASE STUDy A - Electronic medical records (EMRs) to pre-screen for specific protocol requirements are a useful tool to pre-select study subjects and assess protocol viability even prior to initiating a trial. A scientific roundtable was convened to finalise protocol development for an untried novel therapeutic approach. Many study design elements were assessed including prohibited medications, diagnostic requirements for enrolment, number and frequency of various study assessments and specific inclusion / exclusion criteria. There was general consensus among the research experts that the agreed elements, taken individually, would have minimal impact on the ‘enrollability’ of the study. To confirm this, the CRO enlisted three investigative sites to review their EMRs based on eight specific criteria proposed for the protocol. The results were self-evident: at best, only three per cent of patients with the target disease may initially qualify for screening. The protocol was essentially not viable in its then-current form. This inexpensive and quick appraisal demonstrates the power of EMRs and value in quantifying enrolment potential before investing significant human and financial capital. Without these results, this trial would have failed as planned, and the protocol amendments required mid-study would have significantly delayed the timelines and degraded investigator and subject motivation.

Figure 1 – Protocol criteria may seem insignificant when considered individually, but as a whole, may greatly reduce the screening pool of target subjects.


Regulatory

CASE STUDy B – Implementing multifaceted motivation and recruitment campaigns saved a Phase II respiratory study from significant delays. Initiation of a Phase II respiratory study had to be halted due to manufacturing issues just one day before screening was scheduled to commence. The sponsor and CRO immediately recognised the importance to proactively manage expectations for all stakeholders in order that the delay not become crippling. A mutual agreement was negotiated to ensure that the fully-trained CRO team remained intact and, working through the clinical monitors, there was immediate, transparent, and continuous communication to the sites about what was going on. The management team used the delay to develop and gain IRB approval for print and radio marketing tools placed locally near trial sites. The sponsor conducted direct outreach to each principal investigator and the CRAs conducted routine check-ins with the study coordinators to keep motivation high. Sites were provided with pre-printed postcards with information about the study that were sent by the hundreds to potential study subjects. Just prior to reopening the study, refresher phone initiations were conducted with all sites. In recognition of additional prescreening efforts, sites were each paid an additional non-refundable retention bonus when they screened their first subjects. The significant efforts paid off when the trial started twelve weeks behind schedule and subjects were literally lined up to

be consented. The expected recruitment period was condensed from twelve weeks to just eight days and the trial overenrolled. The transparent communication and additional emphasis on recruitment efforts helped build site rapport, maintain interest and trust, and create an environment of excitement at a time when circumstances may have otherwise had the exact opposite effect.

Figure 2 – Despite unplanned delays to initiate a Phase II respiratory study, proactive measures allowed subject recruitment to complete rapidly.

Regulatory


CASE STUDy C – Use of automated forecasts and visit tracking aids study retention efforts. For a large multisite vaccine study, the CRO and sponsor employed an electronic tracking system whereby, once a subject’s initial screening visit was entered, a full forecast of subsequent visits was generated. This allowed sites to print calendars of upcoming activities

for use in their clinics and to be included in patient charts. The system also generated automated email and SMS text message reminders to study coordinators and patients in advance of scheduled visits, and as notifications for when projected visits had not been registered. To implement such a system, direct-to-patient communications needed prior approval from ethics committees, and participation was described and approved via the informed consent process. Though not used in this case, careful planning may allow additional automation via integrations with randomisation and/or EDC applications for added notification capabilities. Patients and site coordinators agreed that this approach added significant value in aiding a busy time management process.

References1. Dyas, J. V., Apekey, T., Tilling, M. & Siriwardena, A. N.

Strategies for improving patient recruitment to focus groups in primary care; a case study reflective paper using an analytical framework. BMC Medical Research Methodology. 9, 65-73 (22 Sep 2009).

2. Sitapati, A. M., Limneos, J., Bonet-Vazquez, M., Mar-Tang, M., Qin, H. & Matthews, W. C. Retention: Building a Patient-Centered Medical Home in HIV Primary Care through PUFF (Patients Unable to Follow-up Found). Journal of Health Care Poor Underserved. 23 (3 Suppl), 81-95 (Aug 2012).

Figure 3 – An electronic patient retention system provides automation for scheduling activities resulting in improved compliance and added convenience for study subjects and research coordinators.


Regulatory

3. Lichter, A. S., Fehrenbacher, L. & Hortobagyi, G. N. Minimizing Research Delays: Identifying Successful Strategies to Keep a Clinical Trial Moving Forward. Journal of Oncology Practice. 3(6), 306-307 (Nov 2007).

4. von Eschenbach, A. & Hall, R. FDA Approvals Are a Matter of Life and Death (Editorial). (17 Jun 2012).

5. Http://ciscrp.org/professional/aware.html, visited on 22 Aug 2012.

6. Sheridan, B. Is Cue the Cure for Information Overload? Bloomberg Businessweek. (19 Jun 2012). Http://www.businessweek.com/art ic les/2012-06-19/is -cue-the-cure-for-information-overload, visited on 24 Aug 2012.

7. Case Study: Improved Patient Retention Orphan Drug Studies (White Paper). Symphony Clinical Research. (2003).

8. Http://ciscrp.org/professional/facts_pat.html, visited on 23 Aug 2012.

9. Http://ciscrp.org/professional/facts.html, visited on 24 Aug 2012.

10. Pogorelc, D. Match.coms of clinical trials make it easier to connect patients, researchers. MedCity Media. (19 Jun 2012). Http://medcitynews.com/2012/06/the-match-coms-of-cl inical-tr ials-make-it-easier-to-connect-patients-researchers/, visited on 22 Aug 2012.

11. Silverman, E. Pfizer Ends Social Media Bid for Trial Recruitment. Pharmalot. (19 Jun 2012). Http://www.pharmalot.com/2012/06/pfizer-ends-social-media-bid-for-trial-recruitment/, visited on 27 Aug 2012.

12. Engaging E-Patients in Clinical Trials through Social Media (White Paper). Blue Chip Patient Recruitment. (May 2011).

13. Meyer, E. Social media a godsend for those with rare diseases. (12 Jun 2012).

14. FDA Draft Guidance For Industry: Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices. Dec 2011.

15. Https://foxtrialfinder.michaeljfox.org, visited on 23 Aug 2012.

16. Ngune, I., Jiwa, M., Dadich, A., Lotriet, J. & Sriram, D. Effective recruitment strategies in primary care research: a systematic review. Quality in Primary Care. 20(2), 115-123 (2012).

17. Getz, K. Predicting Successful Site Recruitment. Applied Clinical Trials. (01 Nov 2011).

18. Chlan, L., Guttormson, J., Tracy, M. F. & Bremer, K. L. Strategies for Overcoming Site and Recruitment Challenges in Research Studies Based in Intensive Care Units. American Journal of Critical Care. 18(5), 410-417 (Sep 2009).

19. Good, M. & Schuler, L. Subject Retention in a controlled clinical trial. Journal of Advanced Nursing. 26 (2), 351-355 (Aug 1997).

20. Donahue, M. Bringing Trials to the Patient at Home. Applied Clinical Trials. (12 Jan 2012).

21. Donahue, M. & Henderson, L. Pfizer’s REMOTE Virtual Experience. Applied Clinical Trials. (12 Jan 2012).

22. Online Ads for Clinical Sites. ClinPage. (19 Aug 2011). Http : / /www.c l inpage .com/art ic le /on l ine_ads_for_clinical_sites/, visited on 22 Aug 2012.

23. Http://www.patientslikeme.com, visited on 22 Aug 2012.

24. Gossen, R. 3 Problems Social Media Can Solve for Research Sites. RebarInteractive. (11 Mar 2011). Http://rebarinteractive.com/3-problems-social-media-can-solve-for-research-sites/, visited on 22 Aug 2012.

25. Gossen, R. A Social Media Question IRBs Must Ask. RebarInternational. (10 May 2012). Http://r e b a r i n t e r a c t i v e . c o m / s o c i a l - m e d i a - p a t i e n t -recruitment-irb/, visited on 22 Aug 2012.

26. Http://rebarinteractive.com, visited on 22 Aug 2012.27. Falcon, R., Bridge, D. A., Currier, J., Squires, K., Hagins,

D., Schaible, D., Ryan, R. & Mrus, J. Recruitment and Retention of Diverse Populations in Antiretroviral Clinical Trials: Practical Applications from Gender, Race, And Clinical Experience Study. Journal of Women’s Health. 20 (7), (2011).

28. Baum, S. Penn Medicine to expand use of EMR software to find clinical trial candidates. MedCity Media. (31 Oct 2011). Http://medcitynews.com/2011/10/penn-medicine-to-expand-pilot-using-emr-app-for-clinical-trial-candidates/, visited on 23 Aug 2012.

29. Heinemann, S., Thuring, S., Wedeken, S., Schafer, T., Scheidt-Nave, C. & Mirko Ketterer, W. H. A clinical trial alert tool to recruit large patient samples and assess selection bias in general practice research. BMC Medical Research Methodology. 11(16), (15 Feb 2011).

30. Penckofer, S., Byrn, M., Mumby, P. & Ferrans, C. E. Improving Subject Recruitment, Retention, and Participation in Research through Peplau’s Theory of Interpersonal Relations. Nursing Science Quarterly. 24 (2), (Apr 2011).

31. Philipson, T. J. & Sun, E. Cost of Caution: The Impact on Patients of Delayed Drug Approvals (White Paper). Manhattan Institute for Policy Research. (Jun 2010).

Nicholas Spittal, MBA, PMP, Director, Strategic Clinical Development at Chiltern International, has been directing multi-national clinical research studies for more than ten years in difficult-to-enroll populations, including the then-largest programs

in three different ophthalmic indications. Chiltern International is a global full service contract clinical research organization offering consultation and drug development services to the biopharmaceutical industry. Mr. Spittal may be reached at Email: [email protected].

Regulatory


Therapeutics


IntroductionIn early August 2011 the European Medicines Agency (EMA) released a draft document entitled “Reflection Paper on Risk Based Quality Management in Clinical Trials.”1 Later the same month the US Food and Drug Administration (FDA) released a draft Guidance for Industry entitled “Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring.”2 As for other draft guidances issued by both agencies, there followed a period of public consultation during which individuals and companies could submit comments and suggestions to shape the agency’s preparation of the final versions of the guidelines. The final guidances will be issued in due course. This paper will focus on the draft document from the FDA and offers conjectures on the implications of the new regulatory landscape it engenders, assuming (as seems reasonable to presume at this time) that the final document remains similar in spirit to those of the current drafts. Moreover, it is also appropriate to review the EMA reflection paper, since the language and spirit of the two documents is strikingly similar.

EMA’s Reflection Paper on Risk-based Quality Management in Clinical TrialsThe EMA reflection paper begins by articulating a view that too many trials have avoidable quality problems arising, and the cost of the processes involved in monitoring them are very high. This suggests that the current approach to clinical quality management is in need of review and reorientation. There is a need to find better ways to ensure that limited resources are best targeted to address the most important issues and priorities, especially those associated with predictable or identifiable risks to the wellbeing of trial subjects and to the quality of trial data. The paper notes that determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. Thus, the purpose of the EMA’s reflection paper is to facilitate the development of a more systematic, prioritised, risk-based approach to quality management of clinical trials, to support the principles of Good Clinical Practice, and to complement existing quality practices, requirements and standards.1

According to the EMA, current practices are not well-adapted to achieving the desired goals and are generally very costly, regardless of whether a trial succeeds or fails. The origins of the problem are multifactorial, and the regulatory environment may also be over-interpreted, or misunderstood, resulting in a failure to achieve its actual intent. Poor risk identification and poor risk mitigation – a lack of use or understanding of risk management tools and techniques – is often associated with a reactive, fire-fighting approach to problem management. This results

in processes largely based on corrective rather than preventive action. Lack of proportionality (one-size-fits-all) in the implementation of quality control activities (e.g., monitoring) is often related to insufficient understanding of the impact that variability in trial conduct (including measurement and data collection) has on the study results and their reliability. Hence, the paper is intended to open up discussion on innovative thinking and approaches to clinical trials to facilitate the development of proportionate clinical trial processes.1

Quality is commonly defined as fit for purpose. Clinical research is about generating information to support decision-making. The quality of information generated should therefore be sufficient to support good decisions. In this view, the adequacy of that quality should be such that the decisions made would have been no different had the quality of data and information generated been perfect.3

Since absolute perfection in every aspect of an activity is rarely achievable, or could be achieved only by a large incremental allocation of resources, clear priorities should be established to mitigate the significant and serious risks to those priorities, and to establish tolerance limits within which different processes can operate. The priorities of a trial relate to the protection of trial subjects and to its scientific objectives. They should be clear, and not cluttered with minor issues (e.g., extensive secondary objectives or processes, data collection not linked to the main trial objectives. The priorities should then be reflected in the assignment of resources and control procedures, in particular focusing on the data collection, monitoring and data management activities, and study documentation.1

The paper concludes by advocating that effective mechanisms should be in place to capture protocol and/or GCP deviations and assess their impact on the objectives of the trial. Tolerance limits could be set such that detected issues may trigger more extensive monitoring (e.g., additional site visits). There is potential to develop central monitoring systems using statistical methodology to monitor the quality of the trial conduct and data, with regular metrics reports produced to demonstrate the checks/activities being undertaken.

An Overview of the FDA’s Risk-based Monitoring guidance The foundation of this draft guidance document is the FDA’s desire to make it clear to sponsors that they do not have a one-size-fits-all formulaic view regarding the execution of monitoring activities during a clinical trial. Rather, flexibility to choose the optimal combination of monitoring strategies for a given trial is explicitly granted by the following statement: “This guidance is therefore intended to clarify

Risk-based Monitoring: The New Regulatory Landscape, and Conjectures on the Future of Clinical Trial Execution

Regulatory


Therapeutics

28 Journal for Clinical Studies

that risk-based monitoring, including the appropriate use of centralized monitoring and technological advances (e.g., e-mail, webcasts, and online training modules), can meet statutory and regulatory requirements under appropriate circumstances.”2

The guidance proposes an operational definition of the optimal combination of monitoring strategies for a given trial as the approach that maximises subject protection, the quality and integrity of clinical trial data obtained from them, and compliance with all applicable regulations. The FDA is aware that preceding documents may not clearly reflect their current recommendations regarding monitoring practices, and that they recognise that they “must clearly articulate our recognition of the value of alternative approaches to facilitate change in industry’s monitoring practices.”2

The guidance therefore describes “strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively.”2 These strategies provide sponsors with the ability to provide the required oversight of subjects’ rights, welfare, and safety, and to ensure optimal quality and integrity of clinical trial data.

Before focusing on the ‘risk-based’ component of the guidance’s title, the term ‘monitoring’ itself needs to be addressed since it can have different shades of meaning to different people and in different contexts. Therefore, the FDA commented as follows:2

For purposes of this guidance, monitoring generally refers to the methods used by sponsors of investigational studies, or CROs delegated responsibilities for the conduct of such studies, to oversee the conduct of and reporting of data from clinical investigations, including appropriate investigator supervision of study site staff and third party contractors. The findings should be used to correct investigator and site practices that could result in inadequate human subject protection and/or poor data quality.

Planning for Risk-based Monitoring from the StartPlanning for risk-based monitoring must start right at the beginning of the clinical trial process, i.e., with the preparation of the trial’s protocol. Chow and Chang4 observed that the study protocol is “the most important document in clinical trials,” and the guidance similarly observes that “The most important tool for ensuring human subject protection and high-quality data is a well-designed and articulated protocol.”2 A poorly designed protocol, or one in which the language is ambiguous, can introduce errors in the data collected that make the study’s results unreliable, no matter how rigorous the monitoring performed: the same is true for a poorly designed and articulated case report form.

When writing a study protocol, sponsors should perform “a risk assessment that generally considers the types of data to be collected in a clinical trial, the specific activities required to collect these data, and the range of potential safety and other human subject protection concerns that are inherent to the clinical investigation.”2 The findings from this risk assessment should then be considered carefully when developing the monitoring plan for the trial. While

the protocol must address all details of the study’s design and execution in detail, it has become acknowledged that certain procedures and data are critical to the reliability of the trial’s results, and hence risk-based monitoring should pay particular attention to these. Important examples include:2

• Data that are critical to the reliability of the study findings, specifically those data that support primary and secondary endpoints;

• Other data that are critical to subject safety, such as serious adverse events and events leading to discontinuation of treatment;

• Processes that underpin subject safety and ethical treatment, such as seeking appropriate medical consultation or scheduling extra visits in the event of specified clinical or laboratory findings;

• Processes that underpin the integrity of these data, such as blinding or referring specified events for adjudication.

This process as it relates to risk-based monitoring is one example of a more extensive process that can be called risk-based thinking, which also commences right at the beginning of a clinical trial’s design. Risk-based thinking is discussed in more detail in the penultimate section of this paper.

Differing Monitoring PracticesMonitoring practices vary in intensity, focus, and methodology. The traditional practice, which largely remains the one predominantly employed, is one in which clinical monitors or clinical research associates make frequent, comprehensive on-site visits to all of the investigator sites participating in a trial. The FDA believes many sponsors think that a model that includes visits to all sites, perhaps every four to eight weeks, and includes 100% verification of all data is “FDA’s preferred way for sponsors to meet their monitoring obligations.”2 However, there are certainly other viable and FDA-acceptable methodologies that qualify as the requisite “adequate monitoring”. These include centralised monitoring of clinical data by statistical and data management personnel, and an extended model of this type that also includes on-site visits to higher risk sites, i.e., personnel visits to sites identified via centralised modelling as those evidencing issues that would be best addressed by a site visit. With regard to such alternate strategies, the guidance comments as follows:

There is a growing consensus that risk-based approaches to monitoring, such as focusing on the most critical data elements, are more likely to ensure subject protection and overall study quality, and will permit sponsors to monitor the conduct of clinical investigations more effectively than routine visits to all clinical sites and 100% data verification.

On-site Monitoring The term on-site monitoring refers to in-person evaluations carried out by sponsor personnel or their representatives, typically personnel from a contact research organisation (CRO) at the sites at which a trial is being conducted. Table 1 lists tasks that can be completed via on-site monitoring.

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Centralised Monitoring The term centralised monitoring refers to a remote evaluation carried out by sponsor personnel or representatives (e.g., data management personnel, statisticians, or clinical monitors) at a location other than the sites at which the clinical investigation is being conducted. Centralised monitoring improves a sponsor’s ability to ensure the quality and integrity of clinical trial data. Publications suggest that data anomalies (e.g., fabrication of data and other non-random data distributions) may be more readily detected by centralised monitoring techniques than by on-site monitoring. Electronic data capture (EDC) systems are making it possible to implement centralised monitoring methods that can enable decreased reliance on on-site monitoring: source data verification and other activities traditionally performed by on-site monitoring can now often be accomplished remotely. There is, therefore, growing appreciation of the ability of statistical assessments to identify clinical sites that require additional training and/or monitoring. Examples of the strengths of centralised monitoring are presented in Table 2.

General RecommendationsThe guidance emphasises that “no single approach to monitoring is appropriate or necessary for every clinical trial.”2 It strongly encourages sponsors to tailor monitoring plans to all trials on a case-by-case basis, focusing on subject protection and data integrity risks in the specific context of a trial’s protocol. Typically, a risk-based monitoring plan (monitoring plans are discussed in the next section) is likely to include a combination of on-site monitoring and centralised monitoring, as just described. On-site monitoring, which is likely to be particularly important in the early phases of conducting the trial, should be devoted to the assessment of critical trial processes, data collection, and site compliance. With regard to centralised monitoring, the guidance notes that “FDA encourages greater reliance on centralized monitoring practices than has been the case historically,”2 and also notes that “Sponsors who plan to rely on centralized monitoring processes should ensure that the processes and expectations for site record keeping, data entry, and reporting are well-defined and ensure timely access to clinical trial data and supporting documentation.”2

Factors to Consider when Developing a Monitoring Plan Typically, a monitoring plan should focus on critical trial data and processes identified by a risk assessment of procedures in the protocol. The relative balance of on-site and centralised monitoring for a given trial will depend to some extent on factors considered during the risk assessment, which include the following: • Complexity of the study design; • Types of study endpoints;• Clinical complexity of the study population; • Geographic regions in which the trial will be conducted,

and the degree of established trial infrastructure in each region;

• Relative experience of the clinical investigator and of the sponsor with the investigator;

• The extent to which EDC will be utilised;• Relative safety of the investigational product.

The Nature of a Monitoring Plan The guidance notes that, for each clinical trial, sponsors “should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The plan should provide those involved in monitoring with adequate information to effectively carry out their duties.”2 Various components will be included in a monitoring plan, including the following: • Description of monitoring approaches; • Communication of monitoring results;• Management of non-compliance; • Training and study-specific information; • A strategy for creating and implementing monitoring plan

amendments to address, for example, the implementation of a protocol amendment or the identification of new risks to the trial’s integrity.

Documenting Monitoring ActivitiesSince documentation of all aspects of a trial is of critical

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importance, monitoring activities themselves must be documented. Such documentation should include the following: • The date of the activity and the individual(s) conducting

it;• A summary of the data or activities reviewed;• A description of any non-compliance, potential non-

compliance, data irregularities, or other deficiencies identified;

• A description of any actions taken, to be taken, and/or recommended, including the person responsible for completing actions and the anticipated date of completion.

Monitoring documentation should be provided to appropriate management in a timely manner for review or, as necessary, follow-up.

Conjectures on the Future of Clinical Trial Monitoring and ExecutionKeegan5 discussed the clinical execution of risk-based monitoring in the new regulatory landscape generated by their draft guidance: In this particular instance, the FDA has said publicly that the industry should not wait for the finalised guidance (which may be a long time coming), but should continue to move ahead with developing processes and procedures to implement this approach. The draft guidance therefore provides confidence to sponsors and CROs that risk-based monitoring is an acceptable method for the operation and execution of a clinical trial. Given the multiple challenges currently faced by biopharmaceutical companies, including decreasing R&D pipelines, increased trial complexity, regulatory scrutiny, development costs, competition for trial participants, post-approval commitments, and reimbursement, “the FDA’s support for risk-based monitoring is highly significant and will help to accelerate the implementation of new monitoring models.”5

It is appropriate to note here that biopharmaceutical companies and CROs have actually been implementing models that align with risk-based monitoring for some time. These models include triggered monitoring, targeted monitoring, and centralised monitoring. The important consequence of the guidance, therefore, is that it will likely accelerate the use of these ‘non-traditional’ approaches. Centrally-based monitors would manage (and be accountable for) site operations, tracking site progression and data to identify potential risks, and scaling up monitoring as appropriate to mitigate these risks. For example, on-site visits by monitors would occur when and where needed. The FDA guidance therefore “provides validation of current models and a vision for the future for balancing efficiency and quality in clinical trial monitoring.”5

Rapidly evolving innovation and enhancements in technology will enable a larger percentage of monitoring to be performed electronically. The FDA envisions that centralised monitoring “will leverage technology to help ensure consistency, identify high-risk sites, and trigger alerts that allow a quick response to unusual distribution of data.”5 For example, data indicating an atypical level of protocol deviations at a particular investigational site will trigger

a site visit. Importantly, advancements in monitoring, technology, and processes will improve the quality and efficiency of all trial monitoring elements, and facilitate their integration to permit improved decision-making.

It must be borne in mind that advancements in technology and new approaches alone cannot compensate for poor clinical trial planning and design. Therefore, “the success of risk-based monitoring begins with risk-based thinking.”5 The process of risk-based thinking begins with bringing together multiple experts, e.g., clinicians, biostatisticians, data management personnel, and operational personnel, in the earliest stages of trial design and planning. Discussions addressing both scientific and operational risk mean that risk-based thinking is being applied before a trial begins, a process that allows for the recommendation of a monitoring model that is tailored for that specific study based on the assessed risks. The monitoring model will take into account the type, frequency, and intensity of monitoring needed to guarantee participants’ safety, data integrity, and quality,

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all while meeting the study objectives. For example, risk-based monitoring would allow for an intensive focus on the 20% of investigational sites that represent the greatest risk, with the remaining 80% of sites being monitored in alternative ways.

Concluding CommentsThe two regulatory documents discussed in this paper open the way to a broader, more rational approach to monitoring clinical trials. As such, they represent a great opportunity to focus clinical trial expenditures on the issues critical to a trial: addressing key scientific issues about a product, protecting participant safety, and ensuring an adequate level of data quality and integrity. The guidances also represent a new set of challenges; they require proactive identification of risk, building of risk-based monitoring plans, and the leveraging of new information technology-based solutions to drive the execution of these plans. This represents a fundamental shift in the landscape for the conduct of clinical trials, a shift that will define how trials are executed for many years to come.

References1. EMA. Reflection Paper on Risk Based Quality Management

in Clinical Trials (Draft). August 2011. Available at: http://www.ema.europa.eu/docs/en_GB/document_l ibrary/S c i e n t i f i c _ g u i d e l i n e / 2 0 1 1 / 0 8 / W C 5 0 0 1 1 0 0 5 9 . p d f (Accessed 3rd September, 2012).

2. FDA Draft Guidance for Industry. Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring. August 2011. Available at: http://www.fda.gov/downloads/Drugs/GuidanceCompl ianceRegulatoryInformation/Guidances/UCM269919.pdf (Accessed 21st August, 2012).

3. Assuring Data Quality and Validity in Clinical Trials for Regulatory Decision Making; Workshop Report Jonathan R. Davis, Vivian P. Nolan, Janet Woodcock, and Ronald W. Estabrook, Editors; Roundtable on Research and Development of Drugs, Biologics, and Medical Devices, Institute of Medicine.

4. Chow S-C, Chang M. Adaptive design methods in clinical trials: Concepts and methodologies. Boca Raton, FL: CRC/Taylor Francis. 2007.

5. Keegan M. Clinical execution of risk-based monitoring: After the FDA guidance. R&D Directions. 2012;18(1):29.

Amanda Sax is Senior Director, Integrated Process and Technologies, Quintiles. She leads the development of Quintiles’ approach to Risk-Based Monitoring, which optimises the clinical trial execution strategy for each trial to help customers manage risk and

improve efficiency. Email: [email protected]

Margaret Keegan is Senior Vice President and Global Head of Integrated Processes and Technologies, Quintiles. She has more than 20 years of pharmaceutical industry experience, and is a Chartered Statistician.Email: [email protected]

Dan White, BSN, MBA is Vice President and Global Head of Operations of Quintiles’ Project Coordination Center (PCC), the remote monitoring arm of clinical operations. He also leads Quintiles’ Clinical Events and Adjudication (CEVA) group, which

manages the endpoint adjudications and data safety committees. Email: [email protected]

J. Rick Turner, PhD, is Senior Scientific Director, Clinical Communications. He is an author/co-author of 130 papers, an editor/co-editor of 14 books, and Editor-in-Chief of the Drug Information Journal. Email: [email protected]


Market Report

Market Report



Therapeutics

Type 1 diabetes mellitus (T1D) is an autoimmune disease.1 Both T1D and latent autoimmune diabetes in adults (LADA) are included in autoimmune diabetes. Latent autoimmune diabetes in adults is similar to and is frequently confused with type 2 diabetes. But LADA is distinguished by the presence of autoantibodies, mainly glutamic acid decarboxylase (GAD) autoantibodies (GADA). LADA patients usually become insulin-dependent at much faster rates in contrast to classic type 2 diabetes. LADA has been put as a distinct entity and type of diabetes by some; others believe that LADA is just a mild variant of T1D and should be treated as such.2

Type 1 Diabetes: A Disorder of ImmunoregulationThe selective destruction of the insulin-producing ßcells in the pancreatic islets of Langerhans leads to T1D. An autoimmune response mediated by T lymphocytes (T cells) that react specifically to one or more ß cells proteins (autoantigens) results in destruction of pancreatic islets ß cells. Genetic and environmental factors interact and confer either susceptibility or resistance to disease, depending on the gene/allele possessed by the individual and the environmental agent to which that individual is exposed. Disease susceptibility leads to a pathogenic immune response whereas disease resistance leads to a protective immune response.1

Role of Cytokine in Immune ResponseThe T cells can be further classified into different subpopulations based on their expression of CD4 and CD8, which defines T helper (Th) and cytotoxic T cells (Tc), respectively. The Th cells can be divided into Th1 and Th2 cells based on their cytokine profile. An imbalance between Th1 and Th2 associated cytokines have been suggested to be of importance in mediating the ß-cell destruction, seen in T1D.3

Th1-secreted cytokines [e.g. interferon (IFN)] are thought to initiate and propagate the inflammatory process in early diabetes and Th2-secreted anti-inflammatory cytokines [e.g. interleukin (IL)-4, IL-10] to suppress it. This has led to the hypothesis that diabetes can be prevented by using Th2-secreted cytokines. The Th1-Th2 shift occurs via a change in the type of cytokine-signalling molecules being released by regulatory T-cells. Instead of pro-inflammatory cytokines, the regulatory T-cells begin to release cytokines that inhibit inflammation.4 Another approach that can skew the cytokine cascade from a Th1 to a Th2 response is the use of a non-depleting anti-CD3 antibody.5

Prediction of T1DThe development of T1D can be predicted with the combined use of genetic, islet autoantibody and metabolic testing.

Genetic prediction of T1DHuman leucocyte antigen (HLA) genes in the major histocompatibility complex (MHC), specifically alleles at the HLA DR and DQ loci, are the single most important genetic determinants of T1D. Risk is highest with the HLA DR3,4; DQ

2,8 haplotype, whereas the HLA DR2; DQ6 haplotype give protection against T1D.1,6

Autoantibodies for prediction of T1DWe can detect autoantibodies against ß-cell antigens well in advance before the clinical onset of T1D but their role in human disease is not clear. By the immunofluorescence technique, islet cell autoantibodies (ICA) were the first T1D associated autoantibodies detected in human pancreas sections. Today, the major autoantibodies used for prediction of T1D are those directed against insulin [i.e. anti-insulin antibodies (IAA)], the tyrosine phosphatases insulinoma antigen (IA)-2 and IA-2 ß, and glutamic acid decarboxylase (GAD). More recently, antibodies against the zinc transporter (ZnT8) were discovered and are now used for the prediction and diagnosis of diabetes. We can identify individuals at high risk of developing T1D with the presence of multiple antibodies.6

Prevention of T1DVarying degrees of success in suppression of ß-cell autoimmunity in NOD mice have been shown by current options for treatment of autoimmunity, such as immunosuppressive drugs (e.g. cyclosporine) and anti T-cell antibodies (e.g. anti-CD3 antibodies). But the drawback with these methods is that they requires repeated administration and may lead to non-specific harmful effects such as interference with normal immune system functions. However, antigen specific immunotherapy (ASI) uses inverse vaccination for a specific auto-antigen. The advantage with the ASI is selective inactivation of auto-reactive T cells without interference in normal immune function.7

A basic requirement in drug development is the demonstration of efficacy and safety in animal models. The NOD mouse is the most commonly used animal model for T1D and it has contributed immensely to our knowledge of disease mechanisms and prevention theory of T1D. Human T1D and autoimmune diabetes in the NOD mouse share features such as polygenic inheritance dominated by genes for the antigen-presenting molecule in the MHC autoimmune responses to (pro) insulin and GAD65, transfer of disease by bone marrow and the protracted preclinical phase. But in contrast to humans, the NOD mouse is inbred and responds to many immune and other interventions. However, most interventions prevent disease in only a proportion of NOD mice. In considering autoantigen-specific, ‘negative’ vaccination strategies for inducing immune tolerance, the NOD mice has been the ‘proof-of-concept’ model.1

Various Interventions of Immune PreventionImmunomodulatorsAnti-CD3 monoclonal antibodyThe monoclonal antibody OKT3, directed against CD3, inhibits T cell mediated lysis of target cells. But OKT3 has a strong mitogenic activity and induces massive amounts of cytokines, leading to adverse events.8 A majority of patients experienced some degree of cytokine release syndrome.

The Potential Use of Vaccines for Type 1 Diabetes

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A number of side-effects are seen in most patients, such as chills, nausea, hypotension, breathing difficulties, fever, muscle pain, thrombocytopenia with risk of bleedings, leukocytopenia with increasing frequency of infections, and anemia.2

Modified anti-human CD3 monoclonal antibody was thought to be the next alternative to the previously-used OKT3 antibody for the prevention of T1D in NOD mice. Modified non-Fc receptor (FcR) binding CD3 antibodies have been tested in clinical trials. They have been found to be less mitogenic and were equally tolerogenic compared to function Fc CD3 antibody.8

The preservation of endogenous insulin secretion assessed by C-peptide response with concomitant reduction in haemoglobin A1c levels and insulin requirement in the treated group over two years in new-onset T1D have been reported in two Phase II trials using the two different humanised anti-CD3 (teplizumab and otelixizumab).9

Anti-CD20 monoclonal antibody (Rituximab)Initially, B cells were considered to play an important role in priming T cells. But, recently it has been shown that B cells promote the survival of CD8+T cells in the islets and thus promote the disease. All mature B cells express a cell surface marker CD20. Rituximab is a humanised anti-CD20 monoclonal antibody. Rituximab has been shown to successfully deplete human B cells from peripheral circulation by mechanisms involving Fc and complement mediated cytotoxicity and via proapoptotic signals.8

A four-dose course of rituximab (an anti-CD20) partially preserved beta-cell function over a period of one year in a Phase II trial in patients with newly diagnosed T1D.9

Antigen-based ImmunotherapyVaccination by Exogenous AntigensThe diabetes development can be suppressed by vaccination with ‘non-specific’ immunostimulatory agents such as BCG (Bacillus Calmette-Guerin) vaccination in NOD mice. These agents stimulate the innate immune pathway and reset immune homeostasis. But an initial human trial of BCG vaccination has not shown benefit to demonstrate residual ß-cell function.1

Vaccination by Endogenous AntigensThe purpose of “negative” vaccination against the autoantigens that enhances ß-cell pathology is to induce disease-specific immune tolerance. This is based on the idea that self-antigen-specific immunoregulatory mechanisms are physiological and can be boosted or restored to prevent pathological autoimmunity.1

Glutamic acid decarboxylase (GAD)Vaccination by glutamic acid decarboxylase modulates the immune system and thus prevents the destruction of beta cells. GAD65 isoform has been shown to prevent autoimmune destruction of beta cells in studies of non-obese mice with diabetes.2

GAD vaccine with aluminum hydroxide (alum) as adjuvant to enhance the presentation of antigens to antigen-presenting cells has been produced. Antigen-presenting cells

process the injected GAD65 to provide peptide fragments recognised by T cells. This leads to a Th1/Th2 shift consisting of induction and proliferation of a subset of GAD65-specific regulatory T cells. These specific T cells down-regulate antigen-specific killer T cells that would otherwise attack the beta cells.2

The administration of recombinant human GAD with or without adjuvants did not induce adverse side-effects or exacerbate T1D in man and mice in preclinical studies and a Phase I clinical trial. A subsequent Phase II trial in LADA (Latent Autoimmune Diabetes in Adults) patients further supported clinical development of alum-formulated GAD vaccine.10,11

Subjects received placebo or GAD/alum (4, 20, 100, or 500µg) subcutaneously, twice in clinical trials of GAD/alum vaccination, first conducted in individuals with LADA (LADA describes adults with a slowly progressive form of type 1 diabetes. The diagnosis of LADA is based on 1) adult onset of diabetes, 2) circulating islet autoantibodies, and 3) insulin independence at diagnosis. About 10% of adults with non–insulin-requiring diabetes have LADA. The CD4+CD25+/CD4+CD25- cell ratio, as well as serum C-peptide levels, increased from baseline only in the 20µg–dose group after 6 months and only the 500µg dose boosted GAD autoantibody levels. Evidently, antigen-based therapy (ABT) can have a beneficial immunomodulatory effect without changing humoral responses to the administered antigen, at least in LADA patients. No significant study-related adverse effects were reported in a five-year follow-up, and C-peptide levels were significantly higher only in the 20µg–dose group.2,11

A subsequent larger clinical trial with newly diabetic children has further supported the beneficial effect of the 20µg GAD/alum dose. GAD/alum (20µg) vaccination preserved ß-cell function in patients treated within six months of type 1 diabetes onset but not in those treated >6 months after type 1 diabetes onset. The effectiveness of treatment in more recently diagnosed patients is likely to reflect greater remaining ß-cell mass. This parallels findings with anti-CD3 treatment in which the treatment was most effective in those with the highest residual ß-cell function at the time of treatment. The treatment induced higher levels of IL-5, IL-10, and IL-13 GAD-specific responses accompanied by higher frequency of Foxp3+ and TGF-ß secreting T-cells, even after 15 months.11

The only antigen-based vaccine candidate which has been shown to be effective in both T1D and LADA is alum-formulated GAD.8 However, in two recent Phase II/III studies performed independently by Diamyd and TrialNet, the alum-formulated GAD vaccine failed to meet a primary efficacy endpoint in preserving insulin production.10

Heat shock protein and peptide 277Another important self-antigen in the pathogenesis of diabetes is heat shock protein (Hsp). In NOD mice that were developing insulitis, antibodies directed against Mycobacterial Hsp65 and its human variant Hsp60 were found. These autoantibodies disappeared as diabetes developed and were not present in NOD mice that did not develop diabetes. Anti-Hsp60 T-cell clones transplanted into healthy mice induced insulitis. The Hsp60 epitope recognised

by T cells was identified as a 24 amino acid peptide termed peptide 277 (p277).5

Both insulitis and diabetes were prevented in NOD mice or mice exposed to low-dose streptozotocin injected with p277 in incomplete Freund’s adjuvant. The splenic population of Th1 cells shifted to the Th2 immune-modulating phenotype, accompanied by a decrease in leukocyte numbers and Th1-produced cytokines in the islets following vaccination. T cells recovered from islets of the p277-treated mice had reduced capacity to transfer diabetes into NOD recipient mice. Even after the onset of the disease, the vaccine prevented deterioration of diabetes in NOD mice.5

A human p277 vaccine, DiaPep277, has been developed based on the protective and therapeutic effects of p277 in animal models as well as the findings in the human disease. In a double-blind study in patients with recently diagnosed type 1 diabetes the efficacy of this vaccine was tested. Thirty-five patients received a subcutaneous injection of either DiaPep277 or placebo at 0, 1, 6 and 12 months. The preservation of beta cell function detected by a halt in the loss of C-peptide production was the primary endpoint of the study. A decreased need for exogenous insulin, a reduced hemoglobin A1c (HbA1c) level, and a shift in the T cell cytokine phenotype of the immune reaction to Hsp60 and p277 were secondary endpoints. C-peptide levels rapidly declined in the control group but were preserved in the DiaPep277 group (n=15) at the 10-month follow-up. At the 7- and 10-month follow–up, and also after 18 months, this difference was statistically significant. Moreover, significantly less exogenous insulin to achieve the same level of HbA1c (7%) at the end of the trial was required in the DiaPep277 intervention group. The cytokine response of T cells exposed to Hsp60 significantly shifted from a Th1-IFN response to a Th2, IL-10,IL-13 response by the end of the trial (Raz I et al., 2005). The results of this vaccine from clinical trials performed in LADA patients were inconclusive.10

Insulin Insulin was the major ßcell autoantigen selected for its therapeutic potential. The biologically active form of insulin is processed from its precursor, preproinsulin (PPIns), by sequential enzymatic cleavages that release the leader peptide (to make proinsulin; PIns) and the C-peptide.10

Following oral administration of porcine insulin, protection from diabetes was first reported in NOD mice by Zhang et al., 1991.12 Many subsequent studies reported that proinsulin/insulin or epitopes from insulin could partially protect NOD mice from developing diabetes when administered orally. The proliferation of CD4+ T regulatory cell that protect pre-diabetic mice from onset of diabetes can be induced by oral administration of human insulin to NOD mice. The ability of insulin to promote an anti-inflammatory state in dendritic cells (DCs), ultimately leading to immunological suppression of T cell function was thought be the reason behind expansion of Th2 cell population. Also, insulin can inhibit diabetes onset when administered by different routes of entry into the body i.e. proinsulin inoculated intraperitoneally or intranasally or insulin B chain peptide B:9-23 delivered subcutaneously were reported to be effective in partially suppressing diabetes onset in NOD mice.7 Till now, the

results have been disappointing in human clinical trials conducted using insulin as a therapeutic or prophylactic immunotherapy.13

Disclaimer: The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of his employer.

References1. Harrison LC. The prospect of vaccination to prevent type 1

diabetes. Hum Vaccin. 2005; 1: 143-50.2. Ludvigsson J. The role of immunomodulation therapy in

autoimmune diabetes. J Diabetes Sci Technol. 2009; 3: 320-30.

3. Hjorth M. Immunological profile and aspects of immunotherapy in type 1 diabetes. Linköping University Medical Dissertations. 2010; No. 1161. Available from liu.diva-portal.org/smash/get/diva2:279876/FULLTEXT01. Last accessed on 26/08/2012

4. Gupta SK. Vaccines for type 1 diabetes in the late stage of clinical development. Indian J Pharmacol. 2011; 43: 485.

5. Raz I, Eldor R, Naparstek Y. Immune modulation for prevention of type 1 diabetes mellitus. Trends Biotechnol. 2005; 23: 128-34.

6. Zhang Li, Eisenbarth GS. Prediction and prevention of Type 1 diabetes mellitus. J Diabetes. 2011; 3: 48–57.

7. Nicholas D, Odumosu O, Langridge WH. Autoantigen based vaccines for type 1 diabetes. Discov Med. 2011; 11:293-301.

8. Sanjeevi CB. Type 1 diabetes research: Newer approaches and exciting developments. Int J Diab Dev Ctries. 2009; 29: 49-51.

9. Cernea S, Dobreanu M, Raz I. Prevention of type 1 diabetes: today and tomorrow. Diabetes Metab Res Rev. 2010; 26: 602–605.

10. Clemente-Casares X, Tsai S, Huang C, Santamaria P. Antigen-specific therapeutic approaches in type 1 diabetes. Cold Spring Harb Perspect Med. 2012; 2:a007773.

11. Tian J, Kaufman DL. Antigen-based therapy for the treatment of type 1 diabetes. Diabetes. 2009; 58:1939-46.

12. Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci USA. 1991; 88: 10252-10256.

13. Petrovsky N, Silva D, Schatz DA. Vaccine therapies for the prevention of type 1 diabetes mellitus. Paediatr Drugs. 2003; 5:575-82.

Dr Sandeep Kumar GuptaDr Sandeep Kumar Gupta is a clinical pharmacologist with around 5 years of pharmaceutical industry experience. He completed MD (Pharmacology) from RIMS, Ranchi (India) in 2007 and started his career in Ranbaxy Research

Lab as Senior Research Scientist. His job responsibility in Ranbaxy included clinical trial designing, medical writing for regulatory submissions, new product evaluations and training of team members. Currently he is working as Regional Medical Advisor with Sanofi (India). He is a life member of India Pharmacological Society and has got around 10 publications in indexed and peer reviewed journals. Email: [email protected]

Therapeutics


IT & Logistics


It is not a passing fad but a permanent shift. ePharma consumers are here to stay. It means that pharmaceutical and medical device companies must adapt to the new digital environment. While change is inevitable in any industry, this may be the first time that neither industry nor regulators but rather patients are driving this shift. To understand the hesitancy of the pharma industry and FDA toward direct-to-ePharma consumers, it is helpful to look back 30 years ago to the advent of direct-to-patient advertising in 1983 in the US, by British-based Boots Pharmaceuticals. The campaign was for its prescription brand of ibuprofen [Rufen]. At the time, US regulators and major pharma companies resisted the direct-to-consumer approach. A two-year moratorium was immediately enacted by the Food and Drug Administration (and initially supported by most major pharma companies). The moratorium was intended to allow regulators time to more fully explore the ‘risks and benefits’ of going direct to consumer. While industry and FDA viewed it as risky, patients on the other hand viewed it as necessary. AIDS and breast cancer activists at the time were the most vocal patients in voicing their demands for the right to become actively involved in their healthcare knowledge and decision-making, and ironically the then US Surgeon General, C. Everett Koop, publicly called for patients to become “empowered healthcare consumers”.

Today, three decades later, in the face of digital marketing, some of the same hesitancy by regulators and industry surrounds the direct-to-ePharma consumer approach in Europe and the US. But this time in the US and Europe there is a major difference: while FDA deliberates, European agencies dismiss it, and industry’s legal, regulatory and compliance teams take time to garner institutional knowledge about digital media, patients are already leading the charge and doctors, medical centres and clinical researchers across the globe are joining them.

Technology is also propelling the broader adoption of direct-to consumer strategies globally through the use of portable digital devices, and it’s happening at warp speed, leaving industry to catch up. Today, internet penetration is over 70% in the majority of countries, enabling over 90% of patients and/or their families to conduct online research before seeking medical intervention. Furthermore, over two-thirds of adults go online looking for broader health- and pharmaceutical-related information.

This trend requires industry and more doctors to embrace the most empowered ePharma consumers that either has ever encountered. Constant internet connectivity – together with the rapid adoption of mobile devices – is changing how we market prescription products and clinical trials direct to ePharma consumers, care-givers and others.

It’s not a question of if, but when … and the answer is now.

While direct selling to patients through multiple channels has been around since the US Boots’ TV and print campaign in 1983, recent technology advances have had a significant impact on consumer behaviour, not only in healthcare but in daily living as well. By 2015, it is estimated that more than 50% of all retail sales will be either online or influenced by the online channel, demonstrating the integral use of the internet in all aspects of daily living including healthcare.

In the traditional model, industry’s principal ‘customer’ remains the doctor, who serves as gatekeeper, prescriber and learned intermediary. However, as other industries have found, their customers - consumers of all ages - are leveraging the benefits of an integrated, multi-channel approach, offering mobile applications and online options that make it easy and convenient for customers to execute transactions, access information, and make informed decisions, regardless of location.

Given how quickly patient expectations are rising, direct to consumer models that include mobile-enabled digital strategies in a constantly connected future will help differentiate a product or clinical trial from competitors. Tailored messages and information are delivered by a patient’s choice of communication: SMS, email, automated voicemail, direct mail, or a combination. On the commercial side, marketers are finding success in integrating co-pay benefit programmes to individual patient needs, on-demand access to experts, and community support.

The most successful direct-to-ePharma consumer campaigns are those that foster a more effective dialogue with patients. Engaging patients online as they are looking for information, and integrating that information with programmes that are accessible offline and through mobile, is the new model for both the commercial and clinical trial sides of the industry.

It’s not just a US phenomenon either. It’s a global one, as empowerment is occurring in countries with traditional social hierarchies. And while some doctors might prefer patients not to be well-informed, patients on the other hand expect to be able to research and obtain product information any time and anywhere, using whichever channel (or combination of channels) they find most convenient. The same goes for clinical trials as well.

Direct-to-ePharma consumer marketing requires an integrated business model where all channels – digital and physical – work together seamlessly to connect with patients and guide them to diagnosis, medical specialists, treatments and or clinical trials.

Today, ePharma consumers want access to condition

Direct to the ePharma Consumer – In the Age of Connectivity

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education in innovative and engaging formats with personalised assessments. Condition-specific online videos for example, bring to life the experiences of real people living with real conditions — from allergies to Alzheimer’s — as well as care-givers and expert insights. Videos showcase challenges, questions, struggles, humour, relationships, and everyday issues of the patient and care-giver journey. For clinical trials, they ease anxiety and address concerns. Importantly, users can come back at their convenience, bookmark it, create their own playlists, rate videos, or send to a friend or family member, further expanding the reach of a direct-to-ePharma consumer campaign.

Reaching the ‘connected consumer’, today’s digital campaigns must incorporate strategies that address fundamental behaviours. These ePatient consumers are increasingly connected

• Technically through a wide array of devices,• Socially through ever-expanding social networks,• Medically through online communities of ‘consequential

strangers’ where ePatients leverage their knowledge with information exchange, and

• Economically through memberships to online pharmacies that offer discounted prescriptions and medical supplies.

The rapid growth of ePharma consumers has created new opportunities to tap into well-defined online patient communications channels for pharmaceutical marketers of prescription drugs and those promoting clinical trials directly to patients. A number of factors are driving the growth of the ePharma consumer population. Older consumers are increasingly using the internet as a search tool, with prescription drug information of particular interest in this population. In addition, many people now take multiple prescription medications; in the current economic climate ePharma consumers are carefully considering their therapeutic options. In the US, where medical costs for many are not paid for by the government, cost-conscious older consumers are heading online in search of money-


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saving coupons and free trials for FDA-approved treatments, while other consumers intentionally or by chance seek out clinical trials that offer free study-related medical care and treatment, and reimbursement for participation.

The rise in online direct advertising has been accompanied by a decline in offline advertising, with advertisers looking for more innovative, lower-cost alternatives, and the ability to more precisely reach specific patient populations, especially for clinical trial marketing. For clinical trials, marketers must find and connect with very specific subsets of patients that meet very specific medical criteria. On the commercial side this specificity is generally not required, and direct-to-consumer campaigns target patients therapeutically – diabetes, rheumatoid arthritis, irritable bowel patients. Clinical study teams who have embraced eMarketing as an integral part of their patient recruitment strategies have generally found online media costs to be significant lower, with per-patient recruitment costs up to six times less than offline advertising. But online marketing success for clinical trials requires the artful use of market data.

Succeeding at online marketing is more than simple arithmetic. Instead, a digital marketing team that is well-versed in web-based outreach must interpret various search engine analytics, and be able to translate that information into a nuanced understanding of various search engine capabilities. Even details such as the direction in which advertisements are positioned on a web page can influence the effectiveness of outreach campaigns. An effective eMarketing campaign requires constant and daily attention and assessment of performance metrics. Dedicated digital marketing managers bring a highly-defined skill set that is required to truly launch successful digital ePharma consumer campaigns that expeditiously deliver patients to clinical trials or to a branded product.

We have learned over the past several decades of launching and implementing deeply engaging, supportive, and authentic patient activation programmes, branded products and clinical trials that a continuous supply of resources needs to be readily available for patients at every decision point, from online assessment tools, to call centre support and accessing clinical research centres on demand. We also know that different types of patients behave differently. Online patient communities have provided a window into the lives of patients, providing depth of knowledge that was not possible before. Harnessing the power of digital media, data and portable technologies can take direct-to-ePharma consumer campaigns to new heights.

Liz Moench, President and CEO of MediciGroup® Inc, has developed ground-breaking patient-centric programmes for marketed products and clinical trials. Her achievements include launching industry’s first direct to consumer advertising campaign [1983], pioneering patient

recruitment for clinical trials, [1991] and optimising digital and social media for clinical recruitment, including creating some of the largest online patient comunities; Team Epilepsy, Gout Study, Lupus Team to promote clinical research. Email: [email protected].

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Like many of us working in the clinical world today, the clinical research associate (CRA) is confronted with a dizzying array of technology solutions, all designed to make the job easier. Corporate systems like email and time management, eClinical applications like electronic data capture (EDC), interactive web response system (IWRS) and clinical trials management system (CTMS) and myriad smaller applications to manage trial-specific data all contribute to technology chaos. When it comes to the management of eClinical data, which single product is the right one for them?

The answer to this question: all of them and none of them. Each solution is designed for a different purpose – ensuring patient safety, verifying patient data, producing visit reports, recording site status information, managing supplies. Although these solutions are often great at what they do, using a number of different solutions can often be burdensome to the people who have to use them.

Each system is likely to have a different username and password combination. Every system is accessed via a different web link, and in many cases the same application may be accessed by different links depending on the study to which it is linked. As these systems evolved independently, developed in many cases by small niche companies, the design of each application has a diverse “look and feel”. The latter is a particular problem, as usability of multiple systems is enhanced when the navigation and use of the systems is intuitive and consistent. Even then though, the fact is that supporting a single process with multiple systems can be problematic.

With this in mind, what is the ideal solution? To build great software, the needs of the user – often referred to as the “persona” – must be considered, to produce a single, converged solution providing an uninterrupted workflow, suited to their exact needs.

The PersonaWhat is a persona? In technology terms, it is a description of a product’s typical user. The persona may describe an assumed skill set and personality of the user, the purpose being to inform those building the software in order that they can develop the software with the end-user in mind. Of course, it’s impossible to sum up an entire profession in one description, but the important thing is to help software designers to understand the people they are building for. Understanding aspects of personality that seem unimportant may be the difference between building good and bad software. An example might be a persona which includes the words “I find it difficult to use computers”. When designing software for this user type, special attention must be paid to workflow, easy-to-understand steps and simple actions which avoid technical terminology. Conversely, a persona including the phrase “advanced technical skills” could include functionality that was more technical in nature. The key word when building a persona is “behaviour” – in their day-to-day work, how does the user react to the challenges they face.

Although the persona is a written description, it is common to include a name and picture. By referring to a fictional character, software engineers are able to make system design more personal and gain empathy with the role being described. By doing so, they might better understand the user’s day-to-day challenges and workload, and can make informed decisions regarding the implementation of new features.

The persona is also used to describe the common responsibilities of the role it describes. This is useful in designing software, as it ensures that each application includes the functionality required by the user, nothing more and nothing less. An example of this might be supplying code break functionality in an application designed for the patient. The patient doesn’t need this functionality – in fact it is entirely inappropriate! By understanding the persona (the patient in this example) and knowing how they will use the application, it can be tailored to their exact needs.

Who is the CRA?As described, it is more than simply roles and responsibilities that are important in understanding the persona. Behaviour, personality and skill set are important too. So, as we examine our CRA persona in greater depth we can look for qualities which may be shared amongst the people who work so closely with sites. Those of us who have worked with CRAs know that to succeed, a CRA must possess a huge attention to detail, enabling them to identify problems with data. This quality also helps to ensure that each site is managed through the complicated and time-consuming process of study start-up, where each regulatory document has to be in place before recruitment can begin.

Diplomacy and an ability to build relationships are both important characteristics for the CRA. They act as the main point of contact between site and sponsor, and management of that relationship can be a critical success factor. There are always hurdles to cross and problems to solve. Diplomacy is often needed to smooth the bumps in the road. The CRA who works well with site personnel – particularly the site co-ordinator – may be more likely to get those missing patient notes found, or that extra quick set of test results.

An eClinical PersonaAlthough other members of the clinical research team use multiple systems, the CRA is the epitome of an “eClinical persona”. They are involved in many different aspects of multiple studies and use many applications. In managing their sites through various stages of the study, they may spend time at site working through a mountain of source data verification in EDC and drug accountability in the supplies tracking system (RTSM), whilst dealing with a serious adverse event in the pharmacovigilance system.

When not at site, they need to jump into their clinical trial management system to track critical data about the

CRA: The eClinical Persona

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site’s progress. The CRA spends time working on visit reports, planning more site visits and dealing with the day-to-day challenges of site management.

If none of these systems are right for the CRA, what’s the solution? To answer the question, we need to go back to basics on how software is developed. In the past, software has been designed with a specific part of the study process in mind. Need to track supplies? Build an IVR/IWR system. Need to track patient data? Build an EDC system. Need to track milestones, recruitment rates and payments? Build a CTMS. To truly cater for the needs of eClinical users, software should be developed from the point of view of the “persona” – the real person behind the laptop, who has to get to grips with the different systems, different screens, different logins and the different “look and feel” of each system.

In the case of the CRA, the best approach is to design a solution that spans each of the traditional product verticals (EDC, RTSM, CTMS), giving them access to one solution that meets all their needs. But what should that solution include? What are the CRA’s responsibilities?

We know that the CRA carries out source data verification when they visit the site. But what else do they do? In short, they do more than it seems possible to fit into a single day, meaning the technology needs to help them wherever it can! At site, the CRA is responsible for reviewing safety, checking the site’s regulatory documents are in order, training users on EDC, RTSM and other technologies, drug accountability, managing data queries, tracking and resolving site issues and protocol deviations, reviewing patient numbers, reviewing recruitment strategies and more besides. After doing all of that, they are required to create a visit report which gives full detail around the visit, describing the current status at the site, work done during the visit and follow-up actions.

Buying for the PersonaSo far, we’ve concentrated on how the persona is useful to technology companies who want to develop software that provides value to their users. What about the purchasers of that software – can the persona be useful to them too? Of course, the answer is a resounding “Yes”!

When deciding on a new system, the best way to ensure the software is fit for purpose is to ensure it meets all the requirements of the user. This is nothing new, and the idea of an RFI/RFP (request for information/proposal) is used widely. However, there are usually some assumptions at the beginning of this process around the type of system to be purchased.

We see this frequently in the eClinical world. eClinical vendors will often receive requests for information on RTSM, EDC or CTMS systems, which immediately narrows the focus of what can be achieved for the user. Let’s consider a CTMS example, which is traditionally the system of choice for the CRA. When putting together the list of requirements, a buyer is likely to be swayed towards the requirements that they associate with the CTMS, such as visit report generation. It is unlikely that this set of requirements would consider the needs around drug accountability (traditionally an activity associated with

IVR) or source data verification (normally associated with EDC). By starting from the system, rather than from the point of view of the persona, many of the CRA’s needs could be missed.

A Better ApproachThe best way to ensure that a new software system will be well adopted within an organisation is to select one that has been designed with the user in mind. To ensure this, the requirements should also be built from the user’s perspective. Rather than deciding to select a new CTMS, EDC or RTSM system, a more holistic approach can yield a better result. By using the standard operating procedures (SOPs) for any given set of processes (whilst ignoring the technology that they reference), a list of tasks can be produced. By understanding the user type, a skill set can be established. Combining the two results into a list of requirements that defines a system that is completely suitable for a user’s day-to-day technology results in a great persona description. With this insight, selecting a vendor that can provide all the required functionality in a user-friendly way becomes a much more likely scenario.

A Persona from All AnglesIn summary then, something as simple as a description of a user type is hugely valuable. It helps eClinical vendors develop solutions that really meet the needs of the industry they serve. It helps sponsors and CROs select systems that truly support their users, rather than selecting something that is yet another burden on their time. Finally, it means that the CRA, our eClinical persona, really gets what they need – a single system that allows them to manage their sites from qualification through to closeout.

This single system must be designed to enable data interchange across all the applications in the eClinical suite, allow collaboration amongst CRAs from the entire chain of clinical trial process, provide comprehensive metrics reporting for transparency and tracking of trial progress and, most of all, the ability to call up functionalities of one application from another, i.e., true convergence of those disparate applications. It’s a single seamless, efficient and scalable technology platform solution that maximises the benefit of natural trial workflow, the ultimate single place where all clinical trials practitioners can go to plan, design and conduct their clinical trial programs.

Liz Love is a Product Manager with Perceptive Informatics and has over 10 years’ experience working with eClinical systems, particularly clinical trial management systems (CTMSs). In recent times, her focus has been on developing functionality designed

specifically for key personas, in particular for the clinical research associate (CRA). She helps define product strategy and ensures that the needs of the user are met when designing new features.Email: [email protected]

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With the recent 2011 release of the FDA’s draft guidance on risk-based approaches to monitoring, the agency has sought to correct a long-standing misconception that 100 per cent source document verification (SDV) is a regulatory requirement. Additionally, in issuing this draft guidance, the FDA took the further step of encouraging alternate, risk-based monitoring approaches while reaffirming that not only is 100 per cent SDV not a regulatory mandate, but that there are more efficient strategies to ensure the safety and integrity of patients and data. “…There is a growing consensus that risk-based approaches to monitoring, such as focusing on the most critical data elements, are more likely to ensure subject protection and overall study quality, and will permit sponsors to monitor the conduct of clinical investigations more effectively than routine visits to all clinical sites and 100% data verification…”1

Despite the significant interest and the myriad discussions generated by the release of FDA’s draft guidance, the general impression is that there hasn’t been widespread adoption of risk-based monitoring approaches characterised by the use of partial or targeted SDV strategies. An industry survey was conducted in June 2012 (Figure 1 and Figure 2) to better understand the myths versus facts of the industry’s adoption of risk-based practices. The survey results yielded important insights into industry awareness, maturity stage, employed approaches, adoption challenges and expected benefits around risk-based site monitoring.

Industry SnapshotBeyond the Awareness StageSixty-four per cent of respondents indicated that they are in favour of the risk-based SDV approach (Figure 3). More impressively, 58 per cent indicated

that they have been involved in the decision to adopt or implement a targeted or partial SDV strategy. These encouraging results suggest that the industry has moved beyond the mere awareness phase. Many sponsors have already progressed into varying stages of adopting or implementing the risk-based approach.

Although risk-based site monitoring is not yet mainstream among existing clinical trials, a significant number of clinical researchers have begun to seriously consider, evaluate and even implement this approach.

Simpler Approaches Mostly Used but Sophisticated Ones to Emerge Risk-based monitoring and targeted SDV strategies can be categorised into four broad groups, each with its own advantages and disadvantages2: • Random SDV: The first few visits use a low level (e.g.,

10 to 20 per cent), randomly selected subjects, sites or data points for SDV. The quality of these visits is evaluated and then guides the SDV rate level up (e.g., 50 to 100 per cent) when necessary.

• Declining SDV: The initial visits are verified at 100 per cent level and if no significant issues are identified, then the adjustment to perform less SDV is made.

• Tiered SDV: The level of SDV is commensurate with the value of the particular data points within the study.

• Mixed SDV: The initial visits are verified at 100 per cent level. The tiered approach is applied to the rest of the visits.

Tipping Point of Risk-Based Site Monitoring – Is it Within Reach?


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The survey data reveals that the two relatively simpler approaches are the most commonly used: 1) predefined set of data points and 2) 100 per cent of first X subjects and then predefined set of data points (Figure 4). Closer examination of the results also shows varying degrees of sophistication in terms of risk-based approaches used by respondents. Relatively more sophisticated approaches have started to emerge but have not gained major traction, such as approaches with randomised data points that require strong collaboration with other functional teams (e.g., statisticians). Limited system functionality and lack of industry best practices were also cited as factors prohibiting the adoption of more sophisticated risk-based approaches. Using spreadsheets to mark data points requiring SDV and to track the progress is very cumbersome for the execution of tiered SDV strategies, if at all possible.

Limited Satisfaction of Current Risk-Based ExperiencesThe satisfaction level of risk-based SDV experiences varied among respondents. Only 19 per cent of respondents are satisfied with the implementation and adoption of targeted SDV strategies (Figure 5). The top reason for dissatisfaction is the resistance from monitors who continue to perform 100 per cent SDV, most likely due to their comfort level with this approach and their concern over receiving “blame” for adverse findings in an audit. Other major reasons for dissatisfaction include the need for re-monitoring and additional site training. Feedback from monitors at industry events also pointed to the lack of adequate tools to facilitate the risk-based practice as a major challenge. Some monitors even experienced increasing workloads in order to identify what needs to be verified and track what has been verified.

Potential for More Benefits ExistNearly 60 per cent of respondents agree that with risk-based practice, monitors have more time for value-added activities while on site, such as site training and interacting with site personnel (Figure 6). Over 50 per cent of respondents recognise the financial benefits of risk-based approaches in terms of lowering site monitoring costs—typically more than 30 per cent of total trial costs3 — by reducing the number of site visits and time spent on site. Many also recognised that the financial benefits of risk-based approaches have not been fully realised—about 35 per cent of the respondents estimated that the realised saving from targeted SDV was less than 25 per cent of monitoring costs, in contrast to the expected savings of 26 to 50 per cent. Some respondents indicate skepticism around the effectiveness of risk-based SDV in terms of improving trial data quality and proactively identifying low-performing sites for intervention. Lack of effective tools for real-time monitoring and benchmarking of site performance could be the reason for such concerns.

Data Quality Concerns of Non-Adopters For respondents who have not yet adopted or implemented targeted SDV, the predominant concerns are the potential risk of reduced data quality and the ability to defend the targeted SDV approach to regulators (Figure 7).

Without 100 per cent SDV, the fear of monitors missing potential issues hampers the industry’s broader adoption of risk-based SDV. Although it is not a secret that some sponsors have been using risk-based approaches over the last decade and successfully received regulatory approval for their

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drugs, no such public records are shared given the confidentiality and conservativeness of the industry. A credible industry report comparing data quality of 100 per cent SDV versus risk-based SDV can ease much of these concerns.

hurdles to OvercomeClearly, the industry is getting closer to the tipping-point but it is not there yet. Despite broad-based industry awareness, strong belief in potential benefits and promising progresses in adoption, the survey exposed clear blockages that the industry needs to address before reaching critical mass in adopting risk-based approaches (Figure 8): • Concerns of compromising data quality • Burden of proof of controls and monitoring

adequacy • Lack of regulatory guidance on appropriate SDV

coverage • Limited support of targeted SDV from existing

system

To effectively address those blockages, strong collaboration across multiple industry players is required. Broadly acceptable evidence is not prevalent today to validate or invalidate concerns around data quality. Arguments from both camps are based mostly on perceptions or discrete cases. Sponsors and technology vendors can work collectively to establish credible quality metrics of risk-based approaches to accelerate the industry’s speed of adoption.

For early adopters, survey results are mixed when it comes to satisfaction and success. Not having complementary tools and processes in place, such as centralised monitoring and site quality management, seems to be the culprit. Unlike quality control approaches, risk-based monitoring by design is a systematic quality assurance approach aiming to proactively identify and mitigate high-risk areas. But missing critical components can lead to limited success or even unfavourable results that may mislead the industry.

ConclusionClinical researchers are under unprecedented pressure to improve R&D efficiencies. Risk-based site monitoring and SDV represent significant opportunities to effectively control clinical trial costs without compromising quality. A recent article based on industry-aggregated EDC data shows that the overall eCRF data correction rate across all data points is less than three per cent after the initial capture session4. These statistics demand us to take a closer look at the cost and benefit equation, as well as more efficient alternatives to conduct 100 per cent SDV, that results in less than three per cent data correction rates. The potential benefits to the industry can be substantial if key stakeholders move in concert towards reaching the tipping-point of risk-based site monitoring and SDV adoption.

Reference List:1. US Department of Health and Human Services,

Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Devices and Radiology Health (CDHR), Guidance for Industry Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring (2011).

2. Vadim T., Imogene G., Jules M., Kaye F., Sergiy S., Joel W., Jim C., Barbara T., Risk-based Source Data Verification Approaches: Pros and Cons, Drug Information Journal, Vol. 44, pp. 745-756 (2010).

3. Rebecca E., Yeonwoo L., Robert G., Transforming Clinical Research in the United States: Challenges and Opportunities, IOM Workshop Summary, Washington DC (2010).

4. www.appliedclinicaltrials.com, visited on 27 July 2012. Medidata Solutions, Industry Metric Indicates Low ROI with Full Source Document Verification.

Sean Cheng has over 10 years of diversified experience in the life science and technology industries. He currently serves as senior manager of product marketing at Medidata Solutions and is responsible for part of the Medidata

platform, including electronic data capture (EDC), clinical data management (CDM), safety data capture and transfer, medical coding and site monitoring. Email: [email protected]

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IntroductionThe drug development industry has seen significant changes in the last ten years. Amongst those changes, pharmaceutical and biotechnology sponsor companies are outsourcing more drug development activities to third party clinical research organisations (CROs)1. Alongside this, clinical trial technology is playing an increasingly critical role in drug development, as the range of technologies in the market increases and as those technologies become more effective and refined2.

As technology choices expand and relationships between sponsors and CROs deepen, CROs need to alter their technology provider selection process to consider market drivers that didn’t exist just a few years ago, including:

go Big or go home – The era of CROs implementing a technology on a “study-by-study” basis is over, as the industry realises the advantages of developing a truly strategic partnership between CROs and technology providers. The resulting cost- and time-saving benefits drive CROs instead to find a technology partner who can deliver on an enterprise-level commitment—regardless of phase or speciality—with a scalable product solution and shared investment in a mutually beneficial, long-term relationship.

It Takes a Village – Developing a strategic relationship between a CRO and a technology provider involves a range of stakeholders from many functions. Not only must technical and operational specialists address their functional needs and concerns, but C-level management must also guide the strategic needs of the discussions. Involving executive level players is the only way to ensure that each party’s longer-term visions are accounted for and become aligned.

Plays Well with Others – Implementing multiple technologies should be synergistic; however, this is only possible if those technologies can be integrated. The degree of integration with other systems should be one of the central success factors when evaluating technology providers.

This article will examine the planning, communication and support required for successful clinical trial technology implementation in the current state of the industry compared to previous years. The article will also outline keys to success for a mutually beneficial CRO and technology provider relationship.

A Brief historyWhen the use of electronic data capture (EDC)

systems as a means of collecting clinical trial data was in its infancy, many CROs created, developed and implemented their own in-house systems. The scope and functionality of such systems ranged from the most basic setups featuring data capture via the web to fully functional data management systems that incorporated import/export facilities, dictionary coding tools and laboratory management modules. The increasing need to incorporate additional functionality to manage ancillary trial-related activities—such as randomisation, trial supply management, automatic medical event and concomitant medication coding—and the challenge of maintaining and upgrading these systems has fostered an environment that rewards CROs taking a renewed focus on their core business area: conducting clinical trials.

Thus, many CROs have strategically decided to abandon their in-house EDC systems in favour of those offered by commercial technology providers3. This shift has enabled CROs to encourage customers to use a preferred technology choice—one that may be more favourable to the specific study.

Many CROs have evaluated the commercial EDC systems available and selected one or more technology providers as preferred partners. Following the selection process, successful implementation of the technology becomes the next critical step.

Collaboration Facilitates a Painless and Efficient Process of Technology ImplementationThe partner selection process tends to be driven by higher-level management or a technology expert, with the more “hands-on” operational staff having little, if any, involvement. In some cases, a consultant may have been brought in for the short term as the latter role, their contract coming to an end once the formal agreement between the CRO and technology provider has been established.

So once a partner has been selected, how does the CRO implement the solution? The process followed may differ according to company size. In a substantial organisation such as a large pharmaceutical company or CRO, a team might then be assigned to coordinate the necessary training, determine the workflow to be adopted within the organisation’s clinical and data management teams, and conduct the steps necessary to achieve either a fully operational system or accredited partnership status. A member of the training department manages scheduling webinars and e-learning modules that should be attended by an appropriate mix and number of members of each department. This group

Then and Now: Is Clinical Trial Technology Provider Selection and Implementation Becoming Easier?


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should include a member of the quality assurance (QA) department—who then updates the standard operating procedures (SOPs) and ensures due diligence—and data managers and programmers assigned to perform necessary validation. The team may be allowed to concentrate all their attention to these tasks until they are completed.

A smaller CRO or virtual pharmaceutical company might not have the necessary dedicated resources for such a formal in-depth process. In such scenarios, assistance from the technology provider can provide invaluable support and guidance for the new partner to facilitate a smooth pathway toward full adoption of the system.

As an example of a formal implementation process for CRO partners, a dedicated individual may be appointed by the EDC vendor to oversee the process, leading a team of personnel to guide the CRO through the implementation process—analogous to the support that a CRO would provide to a sponsor when implementing a full clinical trial. In such a partnership, the teams hold a kick-off meeting to set expectations, establish timelines, assign tasks and draw up a communication plan. Following this, the EDC vendor and the CRO partner’s core development team meet weekly to discuss status updates, capturing agendas and minutes just as they would for any important project. Thus, both parties remain focussed on their respective part of contributing to the ultimate goal of conducting an effective clinical trial. During these meetings, the team organises the sequence and timing of webinars and the release of e-learning modules, maintaining a comprehensive tracker to ensure that staff attend the training most appropriate to their functional role, be it data management, medical monitoring, QA or biostatistics. The EDC vendor should offer guidance as to the workflow the partner should adopt with a master template in place as a starting model, which can be taken on board in its entirety if so desired. However, the final decision rests with the partner to determine how they will operate according to their SOPs and infrastructure.

Effective System Integration is a Key Success FactorAs more and more clinical data in the clinical research environment is captured electronically, the benefits of automatic integration of ancillary data into electronic case report forms (eCRFs) become increasingly apparent.

The ancillary data may arise from a multitude of sources: interactive voice response systems (IVRS),

interactive web response systems (IWRS), serious adverse event (SAE) reports, clinical notes, patient diaries, electrocardiography (ECG) and imaging technology, to name a few. A successful EDC solution is one which can, when required, provide an interface with other electronic sources, enabling all data to be integrated, viewed and interrogated from a single point of access. Such an integrated system will facilitate the reconciliation of data on an ongoing basis, reducing the workload for investigative sites, CROs and sponsor stakeholders.

ConclusionIn conclusion, the relative size of the company will dictate the best approach for the implementation process. Such formal partnerships between CROs and clinical technology providers enable an environment in which clinical data acquisition, entry and access are effected in the most efficient, cost-effective and mutually beneficial way.

References1. www.outsourcing-pharma.com/Preclinical-Research/

Cut-in-house-R-D-and-increase-outsourcing-says-GBI visited 6 Sept 2012

2. http://www.iom.edu/~/media/Files/Perspectives-Files/2012/Discussion-Papers/HSP-Drugs-Transforming-the-Economics.pdf visited 7 Sept 2012

3. http://www.contractpharma.com/issues/2009-11/view_features/edc-focus-cros-amp-edcs/ visited 7 Sept 2012

Chris Cramer is Vice President, Clinical Data Management for Quanticate. She has over 25 years experience in the CRO and pharmaceutical industries, with specific knowledge in data management, electronic data

capture and late phase clinical trials. Email: [email protected]

Julian de Bres is Director, CRO Partnerships at Medidata Solutions Worldwide. He is responsible for oversight of all collaborations between Medidata Solutions and CROs in the EMEA region. Julian is a graduate of the University of

Nottingham, UK, and has 15 years of experience in the clinical research industry; having held positions in the following sectors: CRO, technology providers and large pharma. Email: [email protected]


Special Feature

IntroductionALS is a devastating disease affecting a wide range of individuals, from young adults to senior citizens. The progressive and highly debilitating nature of the disease, combined with the lack of effective therapeutics, makes it a prime target for stem cell therapy. The unique functional properties of stem cells make them particularly promising for neurodegenerative diseases, and as a result, a number of stem cell clinical trials are underway in this area, both allogeneic and autologous. While these trials are only in their early stages, and there is still much work to be done, we believe that the challenges lying ahead will be overcome, bringing us closer each day to conquering ALS.

ALS OverviewAmyotrophic lateral sclerosis (ALS) or “Lou Gehrig’s Disease” is a highly debilitating neurodegenerative disease characterised by progressive degeneration of the motor neurons, and the resultant inability of the brain to control muscle movement. The classic form of sporadic ALS usually starts as weakness in one part of the body and spreads gradually to the rest of the body. ALS affects motor neurons at several levels supplying multiple regions of the body. It affects lower motor neurons that reside in the anterior horn of the spinal cord and in the brain stem; corticospinal upper motor neurons that reside in the precentral gyrus; and, frequently, prefrontal motor neurons that are involved in planning or orchestrating the work of the upper and lower motor neurons. Loss of lower motor neurons leads to progressive muscle weakness and wasting (atrophy), and eventual paralysis and death. ALS was first described in 1869 by French neurologist Jean-Martin Charcot. Currently there are around 30,000 ALS patients in the US, with another 5000 diagnosed each year. Only 50% of patients survive 18 months and 20% survive five years1. Onset of ALS may occur from the teenage years to the late 80s, but peak age at onset occurs from 55-75 years. Treatments for patients are limited, with only one approved drug, Rilutek (riluzole), which is thought to reduce damage to neurons by decreasing glutamate release. However, Rilutek increases survival by an average of only three months2. Other treatments for ALS are palliative in nature– they are designed to relieve symptoms and improve the quality of life for patients. The cost of patient management to the healthcare system is significant, with in-home treatment costing $160,000/year and institution-based treatment costing over $400,000/year3,4. In summary, there is tremendous unmet need in patients with ALS and no treatments that truly change the disease outcome5,6.

ALS PathogenesisIdentifying the underlying etiology of ALS is challenging, with only 10% of ALS cases being hereditary, although at least thirteen different Mendelian mutations have been linked to ALS7. The most common (identified to

date) mutation that causes adult-onset familial ALS is via mutations in superoxide dismutase 1 (SOD1) with over 100 disease-causing mutations identified to date8. However the vast majority of ALS has yet to be linked to any underlying genetic abnormality, further complicating disease understanding. This is one of the primary reasons for limited numbers of successful drugs or clinical trials in ALS patients9.

It is known that motor axons die by Wallerian degeneration in ALS, and large motor neurons are affected to a greater extent than smaller ones. This process occurs as a result of the death of the anterior horn cell body, leading to degeneration of the associated motor axon. As the axon breaks down, surrounding Schwann cells catabolise the axon’s myelin sheath and engulf the axon, breaking it into fragments. This forms small ovoid compartments containing axonal debris and surrounding myelin. However, the underlying mechanisms to this axonal death is not clear, with current research into the mechanisms resulting in sporadic and familial types of ALS focusing on excitotoxicity10. This may occur secondary to overactivation of glutamate receptors, autoimmunity to calcium ion channels, oxidative stress linked to free radical formation, or even cytoskeletal abnormalities such as intracellular accumulation of neurofilaments11. Apoptosis has emerged as a significant pathogenic factor, and evidence suggests that insufficient vascular endothelial growth factor may also be a risk factor for ALS in humans12. Oxidative damage, mitochondrial dysfunction, caspase-mediated cell death (apoptosis), defects in axonal transport, growth factor expression, glial cell pathology, and glutamate excitotoxicity may all mediate the pathways that cause death in ALS13,14.

However, no direct mechanism has been identified to date, and most researchers and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of ALS15.

Translatability of Animal Models In ALSAnimal models play a crucial role in disease research and a number of ALS animal research models have been developed, but their translatability into positive human trials has been limited16. Many of these including: zebrafish, fruit flies, worms, rats and mice all have been created around the SOD1 gene. There have been over 50 publications showing the extension of lifespan in the SOD1 transgenic mice; yet, riluzole has been the only agent to show clinical efficacy in ALS patients17. In summary, all study teams noted, the underpinnings of ALS remain unclear, and drugs/treatments tested in ALS mice and other animal models have produced benefits that scientists and clinicians are unable to fully replicate in humans. Despite the limitations in the current animal models, significant learnings in the underlying biology of ALS have occurred18,19,20.

Stem cells have the ability to grow into all of the body’s cell types, including motor neurons. But research

Developing Stem Cell Therapy for ALS: The Challenge

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with stem cells derived from embryos has been hampered due to ethical controversies. With the discovery of induced pluripotent stem (iPS) cells in 2006, the potential to improve current translatability of animal research by supplementing with the use of iPS cells became possible with minimal ethical concerns21. These new human stem cell research models could eliminate some of the difficulties associated with using mice and other animal models to recapitulate the human disease. The first generation of motor neurons derived from iPS cells from an ALS patient was reported in 200822. The potential of iPS cells in ALS moves beyond improved translation of pre-clinical research, to include better understanding of the underlying pathophysiology, improved drug discovery efforts, and, finally, the potential for use of iPS cells as an autologous treatment option (albeit many years in the future)23. In fact, assay based screening of motor neurons derived from ALS patient derived iPS cells has demonstrated the potential to enable drug discovery efforts, although it is still unproven24. While the promise of stem cells as therapeutics is exciting, there are some challenges to be overcome25.

The Promise Of Cell Based TherapiesCell based therapies have been used for many years to treat patients with blood disorders and specific cancers. In fact, inherited disorders of the blood and immune system and acquired loss of bone marrow function can now be cured with stem cell transplantation26. The promise of a cure is driving the significant interest in treating many additional diseases beyond oncological and hematological malignancies.

There are two overall types of stem cell therapies: autologous (self-self donation) and allogeneic (non-self donor). Within each of these two groups, there are adult and embryonic forms of stem cells. Adult stem cells, predominantly mesenchymal stem cells (MSCs) derived from bone marrow (or some derivation of these cells), are increasingly being explored as a potentially powerful source of cells for cell therapy. MSCs can become muscle, bone, cartilage or fat and, appear to have some ability to modify immune function in certain experimental models and clinical studies27. They have, therefore, become a cell of interest for treating musculoskeletal abnormalities, cardiac disease and some abnormalities of immunity (such as graft-versus-host disease after bone marrow transplant)28. In fact, Osiris’ MSC-based drug, Prochymal, was approved in Canada in 2012 for GvHD29.

Stem Cell Based Therapies for Neurodegenerative DiseasesWhile stem cells offer tremendous promise in both their ability to identify novel drug targets and potentially provide significant efficacy to patients, there are currently no stem cell treatments approved for treating a neurodegenerative disease such as ALS. However, stem cell based therapies are ideally suited for neurodegenerative diseases for several reasons. These include: their high unmet need and complex pathophysiology (e.g., severity of the diseases, lack of

understanding of the causes and/or risk factors, lack of effective drug treatments) ,which has resulted in failure of traditional small and large molecule based drug discovery efforts to discover novel medicines for these diseases. In addition, some of these diseases are autoimmune, and stem cells are both immunoprivileged and immunomodulators. Furthermore, these cells display homing properties – that is, they can “travel” to the motor neurons or sites of injury, whereas traditional drugs do not have these properties.

In the ideal situation, stem cell treatment would restore the microenvironment by delivering neurotrophic factors that protect existing motor neurons, promote growth of new motor neurons, and re-establish nerve-muscle interaction. The sum total of these effects would provide significant benefits to the ALS patient, including greatly improved survival. This is something no single small molecule or biologic could ever accomplish using today’s technologies.

ALS Clinical PipelineThe pipeline for ALS contains 37 compounds from pre-clinical development through to Phase III (only one compound in Phase III). While most of the compounds in development are targeting symptomatic or minor improvements in survival, only one modality in development has the potential to significantly improve patient outcomes30. These are treatments using stem cells or their downstream progenitors. Cell based approaches are a new modality to potentially treating ALS patients. While there have been no readouts of large Phase III studies with cell based approaches to date, there have been small studies completed to demonstrate safety of the cells in ALS patients. Readouts of the larger Phase II studies are expected in the next 18-24 months.

Seven clinical studies in ALS patients have been published to date. The first study was published in 2006 demonstrating that MSCs were safe when injected into seven ALS patients31. Subsequent published clinical studies of small trials (<20 patients) have further built the case that stem cells are safe when used in patients, with some hints of efficacy seen, although no definitive efficacy has been proven to date32,33,34,35,36,37.

Cell Based Approaches In The Clinic For ALSThere are nine cell-based assets in clinical development (Table 1). Of these nine assets in development, five are being developed by companies (Corestem, Brainstorm, Neuralstem, TCA Cellular and Q Therapeutics) and four by academic institutions (one Italian hospital, one Spanish hospital, the Mayo Clinic in the US, and a Chinese Hospital). Five of the cell based assets are autologous in nature (3 corporate owned and 2 owned by hospitals), while four are allogeneic in nature (2 corporate owned and 2 hospital owned).

Of the company based approaches, Corestem, a Korean company, is running the largest study utilizing technology developed at Hanyang University38 to harvest and isolate autologous bone marrow-derived MSCs39. BrainStorm is running the next largest corporate trial


using autologous, bone-marrow derived, differentiated MSCs that secrete neurotrophic factors. Next, Neuralstem is developing an allogeneic cell-based therapy using fetal-derived neural stem cells delivered via laminectomy. TCA cellular is developing a therapeutic platform using autologous bone marrow derived MSCs, and has completed trials in the cardiac space and in critical limb ischemia, while the 6 patient ALS trial is listed as being on partial clinical hold on the company’s website40. Finally, Q Therapeutics is planning on a 2013 Phase I trial start. In summary, over the next 18-24 months, cell based approaches will demonstrate whether they are going to live up to their promise in ALS.

The Challenges of Implementing ALS Cell Based Therapies Both allogeneic and autologous based stem cell therapies have unique challenges for treatment of ALS patients41. Some of the challenges for allogeneic based therapies include: the need for donor matching and immunosuppressive agents, with their associated side effects and risks, as well as high costs of production and maintenance. Yet, autologous based therapies face their own unique challenges as well, including the need for on-site, fully dedicated sterile production facilities (cleanrooms) near or within medical centers for individual production, and the associated high manufacturing costs.

Finally, the ability to successfully commercialize these therapies requires a completely different approach to that previously taken within the biopharmaceutical industry42. Experts continue to analyze different commercialization models for cell based therapies, striving to design the optimal one43.

Looking Towards The Future – The Path to SuccessNotwithstanding the above challenges, the vision for the future could include cell therapy “pharmacies” in major medical centers that dispense appropriate cell based therapies to patients on an as-needed basis for a variety of acute and chronic conditions. Depending on an individual patient’s medical condition and needs, physicians would order either off-the-shelf allogeneic cell therapy (for example, for treatment of acute tissue injury) or personalized, autologous cell therapy (for example, for neurodegenerative disease) produced in an on-site cleanroom production facility. This approach has the potential to revolutionize healthcare and the treatment of serious diseases. Patients would then be treated and experience significant efficacy benefits over current treatments.

Thus, despite the many challenges of translating the benefits of stem cell therapies, research groups and drug development companies are beginning to form partnerships to facilitate a more aggressive approach to translating stem cell technology into actual ALS therapeutics44. Scientists around the world have made great strides in understanding basic stem cell biology and are working intensely to find ways to translate that knowledge into practical therapies for patients. Although there is still much work to be done, the collaborative model for scientific discovery is lending momentum and direction to the lofty goal of developing stem cell therapies to cure people with ALS. The current spate of ALS clinical studies using stem cell based therapies will hopefully bring us closer to achieving that goal. The challenge for each of us in this industry is to bring these new therapies to the patients as quickly as possible.

Bibliography1. http://www.alsa.org, visited in July 20122. Miller, RG, Mitchell, JD, and Moore DH. Riluzole for

amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev (2012) Mar 14;3:CD001447.

3. Ginsberg G, Lowe S. Cost effectiveness of treatments for amyotrophic lateral sclerosis: a review of the literature. Pharmacoeconomics (2002)20:367-87.

4. Wijesekera LC, Leigh PN. Amyotrophic lateral sclerosis. Orphanet J Rare Dis (2009) 4:3.

5. Morren, JA & Galvez-Jimenez, N. Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis. Expert Opin. Investig. Drugs (2012) 21(3):297-320.

6. h t t p : / / w w w . n i n d s . n i h . g o v / d i s o r d e r s /amyotrophiclateralsclerosis/ALS.htm, visited in July 2012

7. Venkova-Hristova, K, Christov,A, Kamaluddin, Z, Kobalka, P,Hensley, K. Progress in Therapy Development for Amyotrophic Lateral Sclerosis. Neurol Res Int. (2012) Published online 2012 July 4. doi: 10.1155/2012/187234PMCID: PMC3399448.

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8. Vande Velde, C, Miller, TM, Cashman, NR, Cleveland, DW. Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A. (2008) 105(10): 4022–4027.

9. Morren, JA, Galvez-Jimenez, N. Current and prospective disease-modifying therapies for amyotrophic lateral sclerosis. Expert Opin. Investig. Drugs (2012) 21(3):297-320.

10. Sasabe J, Aiso S. Aberrant control of motoneuronal excitability in amyotrophic lateral sclerosis: excitatory glutamate/D-serine vs. inhibitory glycine/gamma-aminobutanoic acid (GABA). Chem Biodivers. (2010) 7(6):1479-1490.

11. Pagani MR, Gonzalez LE, Uchitel OD. Autoimmunity in amyotrophic lateral sclerosis: past and present. Neurol Res Int. (2011):497080. Epub 2011 Aug 1.

12. Pasquali L, Ruffoli R, Fulceri F, Pietracupa S, Siciliano G, Paparelli A, Fornai F. The role of autophagy: what can be learned from the genetic forms of amyotrophic lateral sclerosis. CNS Neurol Disord Drug Targets. (2010) 9(3):268-78.

13. Pickles S, Vande Velde C. Misfolded SOD1 and ALS: zeroing in on mitochondria. Amyotroph Lateral Scler. (2012) 13(4):333-340.

14. Venkova-Hristova, K (see above)15. Duffy LM, Chapman AL, Shaw PJ, Grierson AJ. Review: The

role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. (2011) 37(4):336-352.

16. Contestabile, A. Amyotrophic Lateral Sclerosis: From Research to Therapeutic Attempts and Therapeutic Perspectives. Current Medicinal Chemistry (2011) 18 (36):5655-5665.

17. Scott S, Kranz JE, Cole J, Lincecum JM, Thompson K, Kelly N, Bostrom A, Theodoss J, Al-Nakhala BM, Vieira FG, Ramasubbu J, Heywood JA. Design, power, and interpretation of studies in the standard murine model of ALS. Amyotroph Lateral Scler. (2008) 9(1):4-15.

18. Gurney ME, Fleck TJ, Himes CS, Hall ED. Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis. Neurology. (1998) 50(1):62–66.

19. Hensley K, Mhatre M, Mou S, et al. On the relation of oxidative stress to neuroinflammation: lessons learned from the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. Antioxidants and Redox Signaling. (2006) 8(11-12):2075–2087.

20. Gurney ME, Cutting FB, Zhai P, et al. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Annals of Neurology. (1996) 39(2):147–157.

21. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell (2006) 126(4):663-676.

22. Dimos JT, Rodolfa KT, Niakan KK, Weisenthal LM, Mitsumoto H, Chung W, Croft GF, Saphier G, Leibel R, Goland R, Wichterle H, Henderson CE, Eggan K. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science (2008) 321(5893):1218-1221.

23. Papadeas ST, Maragakis NJ. Advances in stem cell research for Amyotrophic Lateral Sclerosis. Curr Opin Biotechnol. (2009) 20(5):545-51.

24. Egawa N, Kitaoka S, Tsukita K, et al. Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells. Sci Transl Med (2012) 4(145):100-104

25. Zhang W, Duan S, Li Y, Xu X, Qu J, Zhang W, Liu GH. Converted neural cells: induced to a cure? Protein Cell (2012) 3(2):91-97.

26. Thomas ED Sr. Stem cell transplantation: past, present and future. Stem Cells (1994) 12(6):539-44.

27. Popp FC, Eggenhofer E, Renner P, Geissler EK, Piso P, Schlitt HJ, Dahlke MH. Mesenchymal stem cells can affect solid

organ allograft survival. Transplantation(2009) May 15;87(9 Suppl):S57-62.

28. Feng Y, Wang Y, Cao N, Yang H, Wang Y. Progenitor/stem cell transplantation for repair of myocardial infarction: Hype or hope? Ann Palliat Med. 2012;1(1):65-77.

29. www.osiris.com, visited in July 2012 30. Pandya RS, Mao LL, Zhou EW, Bowser R, Zhu Z, Zhu Y, Wang

X. Neuroprotection for amyotrophic lateral sclerosis: role of stem cells, growth factors, and gene therapy. Cent Nerv Syst Agents Med Chem. (2012) 12(1):15-27.

31. Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Boccaletti R, Testa L, Livigni S, Fagioli F. Autologous mesenchymal stem cells: clinical applications in amyotrophic lateral sclerosis. Neurol Res. (2006) 28(5):523-526.

32. Riley J, Federici T, Polak M, Kelly C, Glass J, Raore B, Taub J, Kesner V, Feldman EL, Boulis NM. Intraspinal stem cell transplantation in amyotrophic lateral sclerosis: a phase I safety trial, technical note, and lumbar safety outcomes. Neurosurgery. (2012) 71(2):405-416.

33. Mazzini L, Mareschi K, Ferrero I, Miglioretti M, Stecco A, Servo S, Carriero A, Monaco F, Fagioli F. Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study. Cytotherapy. (2012) 14(1):56-60.

34. Gamez J, Carmona F, Raguer N, Ferrer-Sancho J, et al. Cellular transplants in amyotrophic lateral sclerosis patients: an observational study. Cytotherapy. (2010) 12(5):669-677.

35. Mazzini L, Ferrero I, Luparello V, et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: A Phase I clinical trial. Exp Neurol. (2010) 223(1):229-237.

36. Martinez HR, Gonzalez-Garza MT, Moreno-Cuevas JE, Caro E, Gutierrez-Jimenez E, Segura JJ. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Cytotherapy. (2009) 11(1):26-34.

37. Deda H, Inci MC, Kürekçi AE, Sav A, Kayihan K, Ozgün E, Ustünsoy GE, Kocabay S. Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up. Cytotherapy. (2009) 11(1):18-25.

38. Kim H, Kim HY, Choi MR, et al. Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett. (2010) 468(3):190-194.

39. www.corestem.com, visited in July 201240. http://www.tcacellulartherapy.com/fda_clinical_trials.html,

visited in July 201241. Mason C, Dunnill P: Assessing the value of autologous and

allogeneic cells for regenerative medicine. Regenerative Medicine 4, 835-853 (2009).

42. Caine B, Montgomery SA: Building a Bridge to Commercial Success. BioProcess International (2011) 9 (S1), 1-55.

43. Smith D: Commercialization challenges associated with induced pluripotent stem cell-based products. Regenerative Medicine (2009) 5, 593-604.

44. McKernan R, McNeish J, Smith D: Pharma’s Developing interest in Stem Cells. Cell Stem Cell (2010) 6, 517-520.

Dr. Adrian Harel is CEO of BrainStorm Cell Therapeutics (OTC.OB:BCLI). One of the most active entrepreneurs in the Israeli life sciences arena, Dr. Harel has been involved in the founding and management of more than ten ventures, including Proneuron Biotechnologies (Israel), Jerusalem Biotechnology Center

(JBC), Heal-Or, and Molecular Cytomics. He holds a PhD in Neurobiology from the Weizmann Institute of Science and was a postdoctoral fellow at Washington University. Dr. Harel may be reached at Email: [email protected].


Exhibitions

The CPhI Worldwide portfolio of leading pharmaceutical events are returning once again, offering pharma executives an opportunity to source new suppliers, network and learn.

CPhI and co-located events are being held at Feria de Madrid, Spain, from 9–11 October 2012.

In addition to CPhI, which focuses on Pharma Ingredients, there is ICSE for Pharma Contract Services, InnoPack for Pharma Packaging and P-MEC Europe for Pharma Technology. Together, the shows cover every stage of the pharma value chain, with exhibitors in every area from pharma ingredients, CMOs, CROs and (pre-) clinical trials through to excipients and formulation, finished dosage, technology and packaging.

The event has a genuinely global focus, attracting visitors and exhibitors from all over the world. Last year’s event, held in Frankfurt, Germany, attracted over 30,000 attendees and more than 2,200 exhibitors from over 140 countries.

All four shows are subdivided into zones, each dedicated to a different area of expertise within the sector and designed to showcase its distinct qualities. Zoning has been warmly received by attendees because it makes the event easier to navigate and enables quick movement between areas.

CPhI and co-located events are renowned within the pharma industry for the audience they attract, even in comparison to other pharma-specific events. Time and again, exhibitors report that having a stand at the event puts them in front of senior commercial decision-makers, allowing them to forge highly productive, long-lasting business relationships face to face.

For the last few years, CPhI and co-located events have hosted the Innovation Awards, which recognize outstanding innovation among the event’s exhibitors. This year, the scope of the awards has been broadened, and they’ve been renamed accordingly, becoming the CPhI Pharma Awards.

The CPhI Pharma Awards feature three categories: Best Innovation, Best Sustainable Packaging and Best Sustainable Stand Design. Best Innovation recognizes outstanding achievement in pharmaceutical R&D, highlighting pioneers in new, commercially scalable technologies.

Entry for the CPhI Pharma Awards is open to exhibitors at CPhI Worldwide, ICSE, P-MEC Europe and InnoPack. The deadline for Best Innovation and Best Sustainable Packaging is 10 August 2012, while Sustainable Stand Design is open until 31 August. The shortlist will be announced on 7 September, with

presentations being held by shortlisted exhibitors at the CPhI Speakers Corner on 9 October. Details of how to enter can be found at http://www.cphi.com/pharma-awards.

Other new and returning features include CPhI Global Meetings, a newly launched ‘Match and Meet’ service for exhibitors and visitors, as well as the Pre-Connect conference on October 8th, Lunchtime Education sessions during the show days and the popular Speakers Corners in the InnoPack, CPhI and ICSE areas.

A custom-built Mobile App is in development that will offer quick and easy access to key information about the event. More details will be published on the CPhI website (www.cphi.com) and via the various social media channels in due course.

Interested in visiting? Choose one of our 4 visitor packages: www.cphi.com/register. Prefer to exhibit? Email for options and availability: [email protected]

Are you ready for business?



Novartis Shifts Clinical Trials to Emerging Markets, hB ReportsNovartis AG (NOVN) is shifting more of its clinical trials to emerging market regions such as Asia-Pacific, the Middle East and Africa, Handelsblatt reported, citing Novartis information. The number of clinical trials rose to 44 percent of all of Novartis trials, not including trials of cancer drugs, the newspaper reported. Source: JCS Staff Reporter, Cecilia Stroe

ERT Introduces an Enhanced Platform to Streamline Data Collection, Analysis and Processing in Clinical TrialsEXPERT®3 and MyStudyPortalTM3 represent a major step forward by simultaneously processing health outcomes data across cardiac safety, respiratory and Clinical Outcome Assessment/ ePRO studies

Philadelphia, PA, 28 August 2012 – ERT, a global technology-driven provider of health outcomes services to biopharmaceutical organizations, medical device companies and contract research organizations (CROs), today announced the launch of an enhanced clinical research workflow technology designed to streamline data collection, analysis and processing in clinical trials. The new offering, which comprises the EXPERT3 workflow platform and MyStudyPortal3 reporting engine, can simultaneously process health outcomes data across cardiac safety, Clinical Outcome Assessment (COA)/ePRO and respiratory studies. The integrated platform offers users a simple way to process multiple types of data accurately, leading to fewer errors in studies, and as a result, shorter lead times. Adopting the enhanced solution can help sponsors, CROs and trial sites facilitate informed decision making throughout the drug development process, while also providing evidence and support for product approvals and labeling claims.

Built on ERT’s renowned EXPERT technology that underpins all of ERT’s data acquisition, analysis and reporting, the new integrated platform can support more studies concurrently and is able to process a combination of data seamlessly across multiple therapy areas. The solution also supports a full suite of COA/ePRO, cardiac safety and respiratory devices, as well as a range of clinical endpoint devices such as glucometers and activity monitors. As the customer interface for EXPERT3, MyStudyPortal3 is an easy-to-use web interface which enables users to view trial data generated by EXPERT3 on demand and in real time from anywhere in the world. By implementing the solution, users can view all important information relating to a trial and receive instant online support relating to the data generated.

For further information on EXPERT3 and MyStudyPortal3 please visit www.ERT.com. Source: ERT / Scott Partnership

TEAM EPILEPSy ON FACEBOOK REAChES 240,000 MEMBERSThe world’s largest online community of epilepsy patients continues to grow in popularityPHILADELPHIA & LONDON, September 20 –Team Epilepsy, the world’s largest online epilepsy community, has reached a milestone of 240,000 members from 50 countries worldwide. Team Epilepsy was established on Facebook just a year and a half ago by MediciGlobal, a company dedicated to bringing clinical research opportunities to patients around the world, and advancing new medicines through clinical trials. Team Epilepsy has three main goals: (1) overcome the stigma of epilepsy; (2) raise awareness about epilepsy; and (3) bring clinical trial opportunities to patients.

Social media platforms like Facebook play an increasingly important role in the lives of patients living with chronic medical conditions. Epilepsy patients in particular value social connectivity, since seizures preclude many epilepsy patients from driving or working, resulting in many being housebound and isolated. Team Epilepsy fosters connections through shared experiences and information exchange.

“50 million people around the world are living with epilepsy, our goal is to provide a place where this population can engage with one another in meaningful ways.” said Nick Halkitis, Global VP of Marketing at MediciGlobal’s digital subsidiary A2P (Access to Patients). “With people participating in conversations, polls, and postings every day, this global community is spreading the word about medical advances and new clinical trial opportunities across the world in real time,” he said. “Raising awareness about innovative research and informing members of current clinical trials is a key part of Team Epilepsy’s mission. To date, 15,000 people have used our online survey on Team Epilepsy’s Facebook page to find out if they qualify for one of the epilepsy clinical trials.” Nick Halkitis also observed that member posts have further raised understanding and appreciation for epilepsy, as well as its daily impact on people’s lives. “One of the most talked about postings was the photo of a young 13-year-old boy lying in a hospital bed with his service dog. This picture has been shared by several million people across more than 50 countries, serving to further increase awareness of the role of service dogs in epilepsy,” he said. Besides its awareness and community role, Team Epilepsy also plays a supportive role in fundraising. Last year in the U.S., thousands of Team Epilepsy members supported a local chapter of the Epilepsy Foundation by garnering enough votes to win a grant from Chase Community Giving. On September 6th, Team Epilepsy supported even more chapters as they competed for precious funds. “Team Epilepsy helps everyone to win in different ways – from connecting with others, advancing new medicines, and fundraising, to learning more about seizure dogs and other animals.” Source: MediciGlobal


JCS News

Disclosure May hurt The Translation Of ResearchAll major clinical trials now include disclosures detailing who funded the study to ensure transparency. However, is it possible that this transparency is actually hurting research? One might assume that the methodological rigor of the study matters to physicians more than the disclosure. However, in a new study, researchers at Brigham and Women’s Hospital (BWH) have found that pharmaceutical industry sponsorship of a research study negatively influences physicians’ perceptions of the study and their willingness to believe and act on the research findings. This study will be published in the September 20, 2012 issue of the New England Journal of Medicine (NEJM).

“We found that physicians downgraded their perceptions of industry funded research similarly for high-quality studies and low-quality studies,” explained Aaron Kesselheim, MD, JD, assistant professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics at BWH, and principal investigator of this study.Source: JCS Staff Reporter, Cecilia Stroe

10 pharmas form nonprofit TransCelerate to accelerate R&D of new medicinesTen biopharmaceutical companies have formed a non-profit organization, TransCelerate BioPharma, to accelerate the development of new medicines. Participants include Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Pfizer, Genentech and Sanofi.

TransCelerate is the largest ever initiative of its kind and will identify and solve common drug development challenges with the end goals of improving the quality of clinical studies and bringing new medicines to patients faster. Through participation in TransCelerate, each of the 10 founding companies will combine financial and other resources, including personnel, to solve industry-wide challenges in a collaborative environment. Together, member companies have agreed to specific outcome-oriented objectives and established guidelines for sharing meaningful information and expertise to advance collaboration.

“There is widespread alignment among the heads of R&D at major pharmaceutical companies that there is a critical need to substantially increase the number of innovative new medicines, while eliminating inefficiencies that drive up R&D costs,” said Garry Neil, the newly appointed acting CEO of TransCelerate, a partner at Apple Tree Partners, and former corporate vice president of science and technology for Johnson & Johnson. “Our mission at TransCelerate BioPharma is to work together across the global research and development community and share research and solutions that will simplify and accelerate the delivery of exciting new medicines for patients.”Source: JCS Staff Reporter, Cecilia Stroe

Foundation Medicine completes $42.5M Series B financingFoundation Medicine, a Cambridge, Mass.-based molecular information company focused on bringing comprehensive cancer genomic analysis to routine clinical care, has completed a $42.5 million Series B financing.

Funding came from founding investor Third Rock Ventures, Google Ventures and Kleiner Perkins Caufield & Byers, LabCorp, Roche Venture Fund and WuXi Corporate Venture Fund, as well as public crossover funds Deerfield Management, Casdin Capital, Redmile Group and an undisclosed fund. The foundation’s board of directors remains unchanged.

“In just two years, Foundation Medicine has turned promising science into an established business that is changing the way cancer is treated,” said William Slattery, partner at Deerfield Management. “While the medical world readily accepts that genomic drivers are the key to matching patients with cancer to the best treatment for their disease, Foundation Medicine has successfully brought this concept to clinical practice. Their single, comprehensive assay uncovers cancer-driving pathways in a patient’s tumor and can inform treatment decisions.”Source: JCS Staff Reporter, Cecilia Stroe :

Sanofi, TB Alliance collaborate to accelerate new treatments for TBGlobal healthcare company Sanofi and the not-for-profit organization Global Alliance for TB Drug Development (TB Alliance) have formed a new research collaboration agreement to accelerate the discovery and development of novel compounds against tuberculosis (TB).

Sanofi and TB Alliance will collaborate to further optimize and develop several novel compounds in Sanofi’s library that have demonstrated activity against Mycobacterium tuberculosis, the bacterium that causes TB. This includes in-depth research of lead compounds based upon identified chemical derivatives of natural products, which have promising potential to treat all forms of TB, and the chemical optimization of other series of compounds that have been identified as “hits” through high-throughput screening.

“By continuing our excellent partnership with the TB Alliance and leveraging our joint resources, we hope to find together new options to fight this dreaded global disease,” said Elias Zerhouni, president of Global R&D, Sanofi.Source: JCS Staff Reporter, Cecilia Stroe


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Ever wondered , why we choose flowers as the front cover of JCS? Each of the flowers we feature on the cover, represent the national flower of one of the emerging country we highlight in that particular issue. eg. In this issue we have featured a report on India. The Lotus flower is the national flower of India, which features on the front cover

I hope this journal guides you progressively, through the maze of activities and changes taking place in these Emerging Countries.

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IFC Almac Group

Page 7 Appletree AG

Page 43 Centrical Global Ltd.

IBC Chiltern International Ltd

Page 49 Cmed Clinical Services.

Page 51 CPhi India

Page 34 & 35 CRF Health

Page 5 Dora Wirth Languages

Page 45 Durbin PLC

Page 29 ECCRO – Emerging Country Contract Research Organisation

Page 11 ERT

Page 37 Eurofins

Page 15 ExCard research GmbH

Page 47 ICON PLC

Page 61 ICSE EXPO

Page 13 & 17 INTERLAB - central lab services - worldwide GmbH

OBC MediciGlobal

Page 9 Medidata Solutions Worldwide

Page 19 Medilingua BV

Page 31 MESM Ltd

Page 3 Myoderm

Page 22 & 23 PDP Couriers

Page 53 Pharma Publications

Page 27 SCA Cool Logistics

Page 25 Temmler Werke GmbH