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Volume 5 - Issue 6

Single Shot of DNA VaccinesA Review up on FSDA Guidance

An Overview of the Legislative FrameworkDriving Clinical Trial Costs

Under Surveillance:How Risk-Based Monitoring Improves the Success and Efficiency of Clinical Trials

Want to Better Recruit and Retain Patients?Think like one.

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Contents

Journal for Clinical Studies 1www.jforcs.com

06 FOREWORD

WATCH PAGES

08 An Overview of the Legislative Framework for FDA ‘Expedited Programs for Serious Conditions’

On June 26, 2013, the US Food and Drug Administration (FDA) announced in the Federal Register the publication of a draft guidance for industry entitled “Expedited Programs for Serious Conditions—Drugs and Biologics.” This draft guidance represents an expanded effort from the FDA to facilitate and expedite development and review of new drugs to address unmet medical need for serious conditions. Alejandra Muntañola of Thomson Reuters gives an overview of FDA’s legislative framework.

10 Our Love/Hate Relationship with Clinical Surveillance, and Why Both are Valid

CNS researchers have implemented surveillance strategies from within pharmaceutical companies, through contract research organisations, or by using one of the many innovations offered by surveillance vendors in the field. The universal goal of all surveillance systems is to increase the chance of trial success by improving patient and data quality. In this article Kari Nations at INC Research will tell about their relationship with clinical surveillance.

14 Aortic Stiffness and Chronic Obstructive Pulmonary Disease

Arterial stiffness, especially stiffness in the large elastic arteries such as the aorta, is now widely recognised as an important factor in the development and progression of heart disease. Over the past several years, the measurement of aortic stiffness has been shown to be an independent and significant predictor of future events in a wide range of cardiovascular diseases. Dr Winter at AtCor Medical, Inc will give you a guide to aortic stiffness and chronic obstructive pulmonary disease (COPD).

16 Cardiovascular Therapeutics Watch PageDrug-resistant hypertension (RHTN) is a very ‘hot topic’ in the hypertension literature. Out of the overall hypertensive population, it has been estimated that as many as 20-30% have RHTN. J. Rick Turner and Philip Galtry at Quintiles discuss what options exist for the treatment of these patients as increasing attention in the literature is focusing on interventional procedures to treat RHTN, of which renal sympathetic denervation (RDN) has reveived most attention.

REGULATORY

18 Evolution of the Trial Master File ProcessThere are a number of challenges that the pharmaceutical industry faces today, such as improving quality in your TMF documentation through a compliant centralised filing system. With the emergence of eTMFs,

MANAGING DIRECTOR Martin Wright

PUBLISHERMark A. Barker

EDITOR Cecilia Stroe

EDITORIAL MANAGERJaypreet Dhillon

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RESEARCH & CIRCULATION MANAGERDorothy Brooks

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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.

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a new challenge has developed around the electronic management of eTMF between CROs, sponsors, and vendors. Scott Grossman at ExL Pharma explains why in a global environment that there is a need to focus on ensuring confidence when providing TMF for regulatory inspection and legal discovery.

22 Patient Recruitment and Retention: Perspectives from an Industry Leader

Jaypreet Dhillon interviews Liz Moench at Medici Group Inc, on the challenges of patient recruitment and retention.

24 Under Surveillance: How Risk-Based Monitoring Improves the Success and Efficiency of Clinical Trials

The biopharmaceutical industry, reeling under the pressures of low R&D productivity and increased costs of clinical development, has been looking at ways to do more with less. Clinical trial (CT) monitoring, which contributes to over 30% of trial costs, has been a major focus area in this endeavour. Chitra Lele at Sciformix looks into smart approaches to monitoring, which can reduce the need for on-site monitoring visits and source data verification (SDV).

MARKET REPORT

28 Lebanon WatchClinical research in Lebanon is hassle-free, and approvals from the local ethics committee are quick, with short timelines. The total timeline to get a study started in Lebanon would be 2 to 4 months which includes the preparation of the documents, ethics committee approvals, and obtaining the import licence. Adhiti Sharad Kumar at Clinart provides an overview on conducting clinical research in Lebanon.

30 Vendor Management in Clinical Operations - New Opportunities for Small and Midsize CROs

Changes in global operating conditions have caused pharmaceutical and biotechnology companies to reconsider their existing practices and development strategies, as well as look for new approaches to reach their business and economic objectives. Outsourcing of different services is one of the solutions that can help the companies achieve these goals. In this article, Indra Aboltina and Janis Skards at Dokumeds provide an overview of vendor management in clinical operations.

34 Want to Better Recruit and Retain Patients? Think Like One

To understand what motivates patients to participate in a clinical trial, study coordinators and protocol designers must learn to think like a patient. This principle may sound obvious, but it is easy for clinical study designers to focus on the data and the trial budget, and to lose sight of patient needs. Ryan McGuire at Cutting Edge Information provides an overview of the most effective patient motivators and how these blend clinical trials’ emotional aspects with convenience.

THERAPEUTICS38 Single Shot DNA Vaccines - An Everlasting Immunity. A Review of FDA Guidance

DNA vaccines have been termed as ‘The Third Generation of Vaccines’ due to their versatility and potential that can also be utilised to produce vaccines against some of the fatal and incurable diseases of today. The recent successful immunisation of experimental animals against a range of infectious agents and several tumour models of disease with plasmid DNA testifies to the powerful nature of this revolutionary approach in vaccinology. V. Balamuralidhara, Shilpi Khattri and their team at JSS College of Pharmacy explain the FDA evolution of policy, regulatory guidance, and cover a wide range of topics including delivery mechanisms, safety issues, and documenting the pros and cons of DNA vaccines.

Contents

Volume 5 Issue 62 Journal for Clinical Studies

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Contents

IT & LOGISTICS

46 The United Federation or the Mafia?In theory, CRO partnerships should work perfectly well. One reason that there is so much debate about this topic is that it’s difficult to assess why they don’t. But there is some helpful thinking about this, which emphasises four key elements of a business partnership that need to be addressed in order to make it work really well. John Faulkes at Agio Interactive looks into strategic leadership, effective cross-company teamwork, relationship skills on both sides, cultural compatibility and how you can identify a problem.

50 The Importance of Communication in Life Sciences – Openness and Cultural Considerations

Full and open communication between companies working in partnership is important in all business sectors, and an awareness of cultural differences can be just as important. Dr Kevin C. Duff at Global Voices provides numerous examples of why optimising communication among members of the international community of scientists depends on elimination of obstacles, and how this is absolutely crucial in life sciences - and can indeed make or break projects.

54 A Review of Sourcing Approaches Within Clinical Development

As budgets become tighter and tighter, many pharmaceutical, biotechnology and device companies are having to continually re-assess the way that they are supporting research & development activities to ensure a cost-effective approach, whilst maintaining quality. Some companies have moved towards a full service strategic approach, and others have moved towards a more functional approach. Daniel Chapple at Quanticate discusses the different strategies that we are finding together with some considerations when assessing each type of strategy.

58 Industry Trends on Sourcing Clinical Trial Supplies Globally

Clinical trial supplies, specifically comparative agents as either investigational medicinal products or as non-investigational medicinal products, are a unique commodity. Although clinical trial supply sourcing is a small part of the overall clinical trial supply chain, its associated sourcing necessities have high quality specifications. Lekishia White and Ann-Marie Huss at Multipharma Clinical Supplies Ltd provide an overview of how due diligence with regard to the fulfilment of these needs can negatively affect trial timelines, however, this can be mitigated depending on the clinical trial specifics and flexibility of requirements.

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No question about it: our December issue is addressing many of the key topics and biggest challenges in the clinical trials industry nowadays. And what an exciting industry to be in: one that`s constantly evolving.

As the medicine industry plays a vital role in medical and health research, we start with an

overview of FDA’s legislative framework: Alejandra Muntañola of Thomson Reuters gives you the What, When and How of the draft guidance entitled “Expedited Programs for Serious Conditions—Drugs and Biologics”, which represents an expanded effort from the FDA to facilitate and speed up the development and review of new drugs designed to address unmet medical need for serious conditions.

Well established as a research tool in animal models over 15 years of experimentation, DNA vaccines have been called `The Third Generation of Vaccines` due to their versatility and potential. Despite the impressive knowledge gained, scientists still have to tackle a number of issues raised by translating their efficacy in preclinical models into clinical realities. The pros and cons of this revolutionary approach in vaccinology are explained by V. Balamuralidhara, Shilpi Khattri and their team at JSS College of Pharmacy, from the FDA evolution of policy and regulatory guidance to delivery mechanisms and safety issues.

The two leading causes of death in the developed world, myocardial infarction and stroke, are both a direct consequence of atherosclerosis and increased arterial stiffness. And while systematic scientific evaluation of arterial stiffness has only matured as a clinical and research discipline in recent times, it is now widely recognised as an important factor in the development and progression of a wide range of cardiovascular diseases.

Dr Winter at AtCor Medical, Inc brings insight into aortic stiffness and chronic obstructive pulmonary disease (COPD). Drug-resistant hypertension (RHTN) is another ‘hot topic’, a major public health problem globally, and is comprehensively covered by J. Rick Turner and Philip Galtry at Quintiles. Across the clinical development cycle there are many activities considered non-negotiable, and experts agree that one of them is the creation, collection, management and storage of the documents contained in the Trial Master File (TMF). With good reason: the TMF holds every last bit of data associated with a trial, and with the emergence of eTMFs, a new challenge has developed between CROs, sponsors, and vendors. Scott Grossman at ExL Pharma explains why in a global environment there is a need to focus on ensuring confidence when providing TMFs for regulatory inspection and legal discovery.

To increase the chance of trial success by improving patient and data quality is the ultimate goal of all surveillance systems. Kari Nations at INC Research will address the challenges associated with cognitive assessment in clinical trials.

Emerging markets are becoming increasingly competitive in terms of skills, expertise and infrastructure, whilst maintaining the much sought-after cost-competitiveness. Adhiti Sharad Kumar at Clinart tells you all you need to know about such a desirable location - Lebanon, where clinical research is hassle-free, and approvals from the local ethics committee are quick, with short timelines.

I wish you all a Very Merry Christmas and a Very Happy New Year. See you all in 2014.

Cecilia StroeEditor

Foreword

Editorial Advisory Board

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

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

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

Caroline Brooks - Associate Director, Logistics, ICON Central Laboratories

Catherine Lund, Vice Chairman, OnQ Consulting

Cellia K. Habita, President & CEO, Arianne Corporation

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

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

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

Elizabeth Moench, President and CEO of 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

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

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

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

Patrice Hugo, Chief Scientific Officer,

Clearstone Central Laboratories

Rabinder Buttar – President & Chief Executive Officer of ClinTec International

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

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

Stefan Astrom, Founder and CEO of Astrom Research International HB

Steve Heath, Head of EMEA - Medidata Solutions, Inc

T S Jaishankar, Managing Director, QUEST Life Sciences

Volume 5 Issue 6 6 Journal for Clinical Studies

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Watch Pages

An Overview of the Legislative Framework for FDA ‘Expedited Programs for Serious Conditions’

On June 26, 2013, the US Food and Drug Administration (FDA) announced in the Federal Register1 the publication of a draft guidance for industry entitled “Expedited Programs for Serious Conditions—Drugs and Biologics.” This draft guidance represents an expanded effort from the FDA to facilitate and expedite development and review of new drugs to address unmet medical need for serious conditions.

Over the past 30 years, the FDA has published several regulations and guidances to support expedited programmes. These approaches include: accelerated approval, priority review, fast track and breakthrough therapies.

In 1988, the FDA published the first piece of regulation in the US for drugs intended to treat life-threatening and severely debilitating illnesses under 21 CFR 312, Subpart E2. Four years later, the agency implemented the accelerated approval pathway for drugs as 21 CFR 314, Subpart H and for biologics as 21 CFR 601, Subpart E3. That same year, under the Prescription Drug User Fee Act (PDUFA)4, the FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times—standard review and priority review. A drug designated for priority review has its marketing application reviewed in six months (compared to ten months for standard review). With publication of the June 2013 draft guidance, the FDA introduced its first such document that addressed accelerated approval and priority review.

The Food and Drug Administration Modernization Act of 1997 (FDAMA)5 established the scope of fast track products and defined the designation as first requested by a sponsor. After a request is made to the FDA, the FDA must respond within 60 days of a request on whether they will accept the product under the fast track process. 21 CFR 312, Subpart E, contains the codification of FDAMA. In addition, an FDA guidance for industry entitled “Fast Track Drug Development Programs—Designation, Development, and Application Review,” published in 2006, provided details regarding the fast track development process and the requirements for designation, such as the criteria of intention of treatment of a serious or life-threatening condition and that the drug/biologic demonstrates the potential to address unmet medical needs.

The most recent programme to reinforce the FDA’s commitment to expedited development was created by the passage of the Food and Drug Administration Safety and Innovation Act (FDASIA)6 in 2012. Section 902 of FDASIA defines breakthrough therapies as drug products “intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition

and for which the preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” A product designated as a breakthrough therapy imparts the FDA to take action to expedite its development through accelerated review and improved communication with the sponsor.

The recently published draft guidance “Expedited Programs for Serious Conditions—Drugs and Biologics” also provides the FDA’s interpretation of the fast track and breakthrough therapy programmes. Developed by both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER), the document starts by providing some definitions that are the basis for understanding the expedited review programmes: “serious condition,” “available therapy” and “unmet medical need.” The concept of “available therapy” had already been digested in the 2004 “Guidance for industry: Available Therapy.”7

Additionally, the June 2013 draft guidance summarises the criteria applicable to concluding that a drug qualifies for one or more programmes, features of each programme, and timing for both sponsor submission and FDA response. The document also highlights general considerations for sponsors

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 Cortellis Regulatory Intelligence United States (US) Module at Thomson Reuters.Email: [email protected]

of expedited programmes, including more rapid manufacturing development programmes, early communications with the FDA for nonclinical study programmes, and anticipation of clinical inspections.

The provisions of the draft guidance relating to fast track development, when finalised, will replace the “Guidance for Industry: Fast Track Drug Development Programs—Designation, Development, and Application Review;” and the provisions pertaining to available therapy, when finalised, will replace the “Guidance for industry: Available Therapy.”

The comment period for the June 2013 draft guidance closed on August 26, 2013. The FDA received 26 comments from stakeholders.

References1. Federal Register: June 26, 2013 (Volume 78, Number 123/

Pages 38349-38351)2. Federal Register: October 21, 1988 (Volume 53/Page

41523)3. Federal Register: December 11, 1992 (Volume 57/Pages

58958-58959)4. Prescription Drug User Fee Act of October 29, 1992. Public

law 102-571, 102nd Congress.5. FDA Modernization Act of September 9, 1997. Public law

105-115, 105th Congress6. FDA Safety and Innovation Act of July 9, 2012. Public law

112-144, 112th Congress7. FDA Guidance for Industry: Available Therapy, July 2004.

Available at: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126586.htm

www.jforcs.com

10 Journal for Clinical Studies Volume 5 Issue 6

Watch Pages

Our Love/Hate Relationship with Clinical Surveillance, and Why Both are Valid.

As clinical researchers, we are continuously reminded of the threat and expense of trial failure in late stage development1,2. In CNS diseases, where surrogate biomarkers are largely absent, drug effects are modest, and nearly all FDA/EMA-sanctioned outcome measures are subjective and highly vulnerable to error, these threats are particularly real. While we anxiously await a promising future of validated biomarkers that will increase diagnostic and measurement precision, our patients’ medical need continues to grow. Clinical triallists must now focus on methods to meaningfully enhance the existing research paradigms. Innovative study designs that address runaway placebo response rates are an excellent first step3,4. Medication adherence-monitoring technologies that assess whether our trial participants are actually participating in our trials are not far behind 5. And then there is clinical surveillance. Despite the negative connotations suggested by its name, clinical surveillance can be implemented as a fully transparent, extremely collaborative, and highly creative next step in shoring up traditional research paradigms.

CNS researchers have implemented surveillance strategies from within pharmaceutical companies, through contract research organisations (CROs), or by using one of the many innovations offered by surveillance vendors in our field. The universal goal of all surveillance systems is to increase the chance of trial success by improving patient and data quality. Surveillance strategies aim to ensure that patients entered into our trials are fully qualified, that efficacy assessments are administered and scored reliably, and that unwanted heterogeneity is controlled, all of which necessarily result in preservation of statistical power6,7. Throughout industry, we find experienced clinical scientists applying years of academic research and clinical training to create innovative data oversight solutions, including expert review of recorded audio- or videotaped interviews, tandem patient and clinician ratings, evaluation of rating scale data to identify probable rater error, and web-based clinical interviews by calibrated centralised raters.

So does surveillance make a difference? The resounding answer is “yes.” Our own immediate measures of success are that we identify hundreds of inappropriate subjects before they are randomised and can negatively impact trial data, and we detect scale administration and completion problems that are immediately rectified with remediation before the next assessment is performed. We see sites sail through regulatory audits because protocol violations are minimised, and perhaps most importantly, we see positive effects on placebo response rates compared to historically similar trials. Until that day when industry is able to fund fully powered, prospective, randomised trials to assess the benefit

of surveillance vs. no surveillance on signal detection, these quality indicators are the strongest arguments we have in favour of clinical surveillance. They show irrefutable evidence that surveillance makes a difference, with real results that sponsors and investigators alike can celebrate.

Still, commitment to quality has its limitations, the most obvious of which is site burden. Clinical surveillance is always associated with some increased work for sites. However, the range of burden can span from taking a little extra time to correspond with surveillance clinicians to manoeuvring patients through multiple video interviews for outside review. We believe that the fundamental causes of patient selection and rater error are site workload and protocol complexity8, such that a guiding principle behind all surveillance should be to enhance and support site activity, not to exacerbate the workload challenge. Our experience is that surveillance is largely accepted, even embraced, when it can be deployed in a manner that respects the valuable time of site personnel, when the methods can be easily incorporated into daily clinic

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flow, when sites are compensated for their time, and when surveillance providers and sponsors are willing to adapt based on site feedback. Importantly, we find that those surveillance strategies that are reflective of clinical practice, such as consultations with other clinicians regarding individual cases, are the strategies most acceptable to investigators. The balance between surveillance-supported quality and minimal site burden is not an easy one to achieve, to be certain. We must continuously refine our processes to ensure we are maximising the yield on our own interventions, but deliver in a way that most sites find supportive. Knowing the low probability of success for new compounds, understanding the need to enhance our existing research paradigms, and realising that some departure from tradition is necessary to keep the field moving, we are highly enthusiastic about this next step. When thoughtfully executed, the surveillance interventions available in CNS have the potential to propel us far forward in terms of data quality and trial interpretability, which is progress surely everyone can support.

References1. Scannell, J.W., Blancklev, A., Boldon, H., et al. Diagnosing

the decline in pharmaceutical R&D efficiency. Nat Rev Drug Discov. 11(3):191-200 (2012)

2. Kola,I. & Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 3(8):711-5 (2004).

3. Preskorn, S.H., Baker, B., Kolluri, S., et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin

Psychopharmacol. 28(6):631-7 (2008). 4. Doros G, Pencina M, Rybin D, et al. A repeated

measures model for analysis of continuous outcomes in sequential parallel comparison design studies. Stat Med. 32(16):2767-89 (2013).

5. Czobor P, Skolnick P. The secrets of a successful clinical trial: compliance, compliance, and compliance. Mol Interv.11(2):107-10 (2011).

6. Jiang, D., Pepler D., Yao, H. The effect of population heterogeneity on statistical power in the design and evaluation of interventions. Int J of Behav Dev. 34: 473 (2010).

7. Muller, M.J. & Szegedi, A. Effects of Interrater Reliability of Psychopathologic Assessment on Power and Sample Size Calculations in Clinical Trials. J of Clin Psychopharm. 22(3): 318-325 (2002).

8. PhRMA 2012 Industry Profile. http://www.phrma.org/sites/default/files/159/phrma_industry_profile.pdf. Accessed 17Oct2013.

Watch Pages


Kari Nations, PhD, Vice President of CNS Clinical Development at INC Research, has worked in the pharmaceutical industry for more than 23 years, during which time she has accumulated significant breadth of experience

serving in multiple clinical and scientific leadership roles in both CROs and pharmaceutical companies, all of which she directly applies to her current role as head of the INC Research Clinical Surveillance Team. Email: [email protected] Website: www.incresearch.com

Return and Destruction

The effects of COPD, now recognised as a chronic inflammatory disease, are not limited to the respiratory system. In fact, the primary cause of morbidity and mortality in mild-to-moderate cases of COPD is cardiovascular disease. Even in COPD patients with greatly impaired lung function, the majority of deaths are from cardiovascular disease1,2. Thus, the evaluation and management of COPD, along with the assessment of the cardiovascular effects of new drugs, should include measurements of cardiovascular disease risk factors.

Arterial stiffness, especially stiffness in the large elastic arteries such as the aorta, is now widely recognised as an important factor in the development and progression of heart disease. Over the past several years, the measurement of aortic stiffness has been shown to be an independent and significant predictor of future events in a wide range of cardiovascular diseases. The most widely used measurement is the carotid-femoral pulse wave velocity (cfPWV), an easily performed, standardised measurement with established reference values3,4. A recent meta-analysis of over 16,000 subjects showed that hazard ratios for an elevated cfPWV ranged from 1.33 to 1.52 for all-cause mortality, CVD, CHF, and stroke5. Hazard ratios when grouped according to age showed that cfPWV is higher in younger (<51 years old) subjects than in the oldest subjects (>70 years old) – 1.75 vs. 1.24, respectively. In addition, net reclassification rates, indicating that subjects would be reclassified into higher or lower risk categories when cfPWV was included in risk classification, ranged from 18.6% for CHD and 22.4% for stroke.

Aortic stiffness has been gaining recognition as an important parameter in two aspects of COPD. It is an independent predictor of cardiovascular disease, as described above, but has also recently been shown to be associated with decreased lung function6. In a study by Cinarka et al. only FEV

1 was found to be an independent predictor of cfPWV.

These results are shown in the figure below.

Two possible mechanisms have been suggested to explain the association between aortic stiffness, COPD, and cardiovascular disease7. One is that genetic and lifestyle factors lead to parallel adverse changes in aortic stiffness and lung function. A second mechanism is that inflammatory and metabolic (insulin) changes that occur in COPD directly lead to increases in aortic stiffness.

Conceptual models examining the association between lung function and arterial stiffness: (a) early life and socioeconomic model, (b) inflammatory or metabolic model.

Bolton C E et al. Int. J. Epidemiol. 2009;38:867-876

Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2009; all rights reserved.

In either case, an increase in aortic stiffness, i.e., cfPWV, has been shown to be associated with decreased lung function and an increased severity of COPD.

The carotid to femoral pulse wave velocity is typically measured by recording the pressure waveform non-invasively at the carotid and femoral arteries, either simultaneously or with a reference time marker such as an EKG. From the two waveforms, the time interval between the arrival of the waveforms at each site (Δt) is determined and the distance between the sites (Δx) is used to compute the cfPWV4:

cfPWV = Δx/ Δt.

A number of systems are now available that allow rapid and easy measurement of cfPWV. The reproducibility of many of these systems (e.g., the SphygmoCor XCEL from AtCor Medical and the Complior from Alam Medical, the two most widely used systems) has been shown to be quite good. Mean differences of intra-observer values are less than 0.2m/s and for inter-observer values are less than 0.5m/s for both systems.

Recently, cfPWV has been used to assess vascular changes and associated CVD risk differences in COPD drugs. A study by Dransfield et al. looked at the effect of the combination of a corticosteroid and long-acting beta antagonist on aortic stiffness.


Watch Pages

Aortic Stiffness and Chronic Obstructive Pulmonary Disease

www.jforcs.com Journal for Clinical Studies 15

The figure shows the change in cfPWV from baseline in the FSC group. Values are means ± SE. Open circles denote Tertile 1. Open triangles denote Tertile 2. Open squares denote Tertile 3. Tertile 1 was defined by having baseline cfPWV measures ≤ 8.7m/s; Tertile 2: 8.7m/s < cfPWV ≤ 10.9m/s; Tertile 3: cfPWV >10.9m/s. At the 12 week endpoint, Tertile 3 cfPWV was significantly lower than placebo (p=0.05).

Other studies have confirmed that drug combinations can lower cfPWV, especially in patients with elevated cfPWV values at the start of treatment.

In summary, COPD is now often referred to as a cardiovascular disease since cardiovascular diseases are the prime contributor to morbidity and mortality, especially in people under 50 years old. Because of the significance of cardiovascular disease in COPD, patient risk assessment should include risk factors for CVD. Aortic stiffness has been shown to be an independent and highly significant predictor of CVD events, and when added to traditional risk scores, significantly improves those scores. In addition, aortic stiffness measures can be altered by drugs currently being evaluated for treatment of COPD so that these measures are useful in evaluating cardiovascular risk effects of these treatments. Aortic stiffness measures, specifically the carotid-femoral pulse wave velocity, can be useful both in the assessment of COPD patients and the assessment of new drugs to treat COPD.

References1. Huiart et al., Cardiovascular morbidity and mortality in

COPD, Chest, 2005; 128: 2640–26462. Sin, Is COPD really a cardiovascular disease?, Chest,

2009; 136: 329-3303. Boutouyrie et al., Determinants of pulse wave velocity

in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values,’ Eur Hrt J, 2010; 31: 2338–2350

4. Van Bortel et al., Expert consensus document on the measurement of aortic stiffness in daily practice using carotid-femoral pulse wave velocity, J Hypertens, 2012; 30: 445-448

5. McIniery et al., Prognostic value of carotid-femoral pulse wave velocity for cardiovascular events, presented at Artery 12, Vienna, Austria, Oct, 2012

6. Cinarka et al., Arterial stiffness measured by carotid femoral pulse wave velocity is associated with disease severity in chronic obstructive pulmonary disease, Resp Care, 2013; in press – online: July 2, 2013

7. Bolton et al., Lung function in mid-life compared with later life is a stronger predictor of arterial stiffness in men, International J Epidemiology, 2009; 38: 867–876

8. Dransfield et al., The effect of fluticasone propionate/salmeterol on arterial stiffness in patients with COPD, Resp Med, 2011;105:1322-1330

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

is an internationally recognised expert in physiological fluid mechanics, biomechanics and medical device development. Email: [email protected]

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As noted at the end of last issue’s column, drug-resistant hypertension (RHTN) is a very ‘hot topic’ in the hypertension literature. While professional societies in various regions of the world publish “Position Papers” that present their definitions, a commonly cited definition of RHTN in the United States (US) comes from an American Heart Association (AHA) Scientific Statement that discussed two components of RHTN: uncontrolled RHTN and controlled RHTN.1 Uncontrolled RHTN is defined as blood pressure (BP) above goal on an appropriate pharmacologic regimen consisting of three or more drugs with complementary mechanisms of action at optimal doses and preferably including a diuretic. The goals have been clinic (or doctor’s office) BP values of < 140/90 mm Hg in general, and < 130/80 mm Hg for patients with diabetes or chronic kidney disease. Controlled RHTN is defined by the AHA as BP that is controlled to goal by four or more drugs at optimal doses, preferably including a diuretic. The European Society of Hypertension has used a similar definition as the AHA for uncontrolled RHTN.2 Other authors have suggested the inclusion of a time dimension in the definition, for example that the treatment regimen must have been in place for at least three months before a determination of RHTN is made.3 Out of the overall hypertensive population, it has been estimated that perhaps as many as 10% of patients have RHTN.2

What options exist for the treatment of these patients? Ideally, they may be referred to hypertension specialists who are experts in sophisticated pharmacologic regimens that may benefit these hard-to-treat patients; suboptimal medication regimens are common in referred patients.4,5 Improvements to prescribed regimens can include switching standard thiazide diuretics to chlorthalidone or to a loop diuretic. In some patients, the aldosterone antagonists eplerenone and spironolactone may be beneficial (spironolactone therapy was discussed in a recent Cardiovascular Watch Column published in International Pharmaceutical Industry6). Additionally, consolidation of antihypertensive therapies using 3-drug single pill combination therapy (diuretic, angiotensin receptor blocker, and dihydropyridine calcium antagonist) is likely to both improve control and adherence (itself a major consideration) in subsets of patients with RHTN.7

Increasing attention in the literature is focusing on interventional procedures to treat RHTN, of which renal sympathetic denervation (RDN) has received most attention. In RDN, a catheter is passed via the femoral artery into both renal arteries and radiofrequency energy is then used to ablate the sympathetic nerve fibres. While

RDN has not yet received regulatory approval in the US, as of October 2013 six European Commission marked (CE-marked) RDN devices were available for use in clinical practice outside the US. In an early study of RDN in severe hypertension (in which the mean baseline BP of participants on three or more antihypertensive drugs was 177/101 mmHg), 45 patients received RDN.8 Decreases from baseline in clinic BP at 1, 3, 6, 9, and 12 months post-procedure ranged between -14/-10 and -27/-17 mm Hg. A report from the same group of investigators was published addressing BP reductions after 24 months,9

and a recent publication in the Lancet presented the final three-year report of this trial, known as the Symplicity HTN-1 trial. In this paper, complete data at 36 months were available for 88 patients, for whom the mean clinic baseline BP was 175±16/98±14 mm Hg. Mean reductions in BP were -32.0/-14.4 mmHg.10

In the Symplicity HTN-2 trial, participants were allocated in a 1:1 ratio to undergo RDN (maintaining previous antihypertensive treatment) or to maintain previous antihypertensive treatment without RDN.11 The primary efficacy endpoint of change in seated clinic systolic BP six months post-procedure was assessed in 49 patients receiving RDN and 51 patients in the control group. For the RDN treatment group, mean clinic BP was

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Cardiovascular Therapeutics Watch Page

reduced significantly by -32/-12 mmHg, while for the control group the respective values were -1/0 mmHg. The numbers of adverse events did not differ between groups, and no serious procedure- or device-related complications were noted. The results from the Symplicity HTN-3 trial12

are due to be reported early in 2014. Those results will attract a lot of attention since it is a pivotal trial that is prospective, randomised, and uses a masked procedure with observers blinded to treatment.

It should be emphasised that the BP reductions just discussed are based on clinic BP values. As discussed at an American Society of Hypertension (ASH) Interactive Forum on the Detection, Evaluation, and Management of Severe Hypertension and RHTN held on October 10th, 2013, when BP changes are assessed via 24-hour ambulatory BP monitoring (ABPM), the reductions are typically considerably smaller.3, 13, 14 Experts in pharmacological and device-based treatment of RHTN from the US, Europe, and Australia attended this meeting, which included presentations and multiple interactive discussion sessions. The proceedings from the meeting will be published in due course in the official journal of ASH, the Journal of Clinical Hypertension. We will notify readers of this column in due course when it has been published.

References1. Calhoun DA, Jones D, Textor S, et al. Resistant

hypertension: diagnosis, evaluation, and treatment–a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403–1419.

2. Schmieder RE, Redon J, Grassi G, et al. Updated ESH position paper on interventional therapy of resistant hypertension. EuroIntervention. 2013;9 (Suppl R):R58-R66.

3. Turner JR, O’Brien E. Diagnosis and treatment of resistant hypertension: the critical role of ambulatory blood pressure monitoring. J Clin Hypertens (Greenwich). 2013, Sep 19 [Epub ahead of print]

4. Yakovlevitch M, Black HR. Resistant hypertension in a tertiary care clinic. Arch Intern Med. 1991;151:1786-1792.

5. Garg JP, Elliott WJ, Folker A, Izhar M, Black HR; RUSH University Hypertension Service. Resistant

hypertension revisited: a comparison of two university-based cohorts. Am J Hypertens. 2005;18(5 Pt 1):619-626.

6. Cardiovascular Therapeutics Watch Column. International Pharmaceutical Industry. 2013;5(3):68-69.

7. Deeks ED. Olmesartan medoxomil/amlodipine/hydrochlorothiazide: fixed-dose combination in hypertension. Drugs. 2011;71:209-220.

8. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275-1281.

9. Symplicity HTN-1 Investigators. Catheter- based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011;57:911-917.

10. Krum H, Schlaich MP, Böhm M, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2013 Nov 6 [Epub ahead of print]

11. Esler MD, Krum H, Sobotka PA, et al. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903-1909.

12. Kandzari DE, Bhatt DL, Sobotka PA, et al. Catheter-based renal denervation for resistant hypertension: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol. 2012;35:528-535.

13. Campese VM. Interventional hypertension: a new hope or a new hype? The need to redefine resistant hypertension. J Hypertens. 2013;31:2118-2122.

14. Howard JP, Nowbar AN, Francis DP. Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4121 patients with focus on trial design: the CONVERGE report. Heart. 2013;99:1579-1587.

J. Rick Turner, PhD, is Senior Scientific Director, Clinical Communications, Quintiles. He is also a Senior Fellow at the Center for Medicine in the Public Interest, and a Fellow of the Society of Behavioral Medicine. Email: [email protected].

Philip Galtry is Vice President and Cardiovascular Therapeutic Strategy Head, Cardiovascular and Metabolic Therapeutic Delivery Unit, Quintiles. Philip holds an Honours degree in Biochemistry from the University of Bristol, UK, and has worked in the management of cardiovascular

studies for almost 25 years.


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Throughout the past few years I have been researching, organising and producing trial master file educational meetings. I have seen a number of challenges that the pharmaceutical industry faces today such as improving quality in your TMF documentation through a compliant centralised filing system. With the emergence of eTMFs a new challenge has developed around the electronic management of eTMF between CROs, Sponsors, and vendors. In a global environment there is a need to focus on ensuring confidence when providing TMF for regulatory inspection and legal discovery.

The main challenges industry faces include improving quality in your TMF documentation though a compliant centralised filing system. With the emergence of eTMFs, a new challenge has developed around the electronic management of eTMF between CROs, sponsors, and vendors. In a global environment there is a need to focus on ensuring confidence when providing TMF for regulatory inspection and legal discovery.

At the 2013 Trial Master File Summit in Alexandria, VA, Lisa Mulcahy, TMF Process Consultant and Co-Chair of the DIA Trial Master File reference model, led the workshop “Electronic Management of your Trial Master File.” This interactive session included over 35 participants - life science organisations, CROs, and eTMF service providers. During this workshop, a number of challenges between sponsors, CROs, and vendors were explored and best practices were shared, leading to a better understanding of ways to maintain this TMF management relationship between clinical research stakeholders.

Planning and Execution of the TMF As the paradigm for the conduct of inspection of the TMF is changing, simply having paper TMF documents on hand for a health authority inspection isn’t enough any more. It’s a reality that since TMF content exists in many formats, inspectors can and will request to see the TMF content in its original or native form. Add to this that inspectors have individual preferences on how they want to review the content during the inspection, which makes it difficult to predict how the inspection will proceed. Sponsor companies and vendors have to be ready to present their TMF content in a number of ways with multiple support mechanisms.

Aligning the departments of Quality Assurance, Information Technology, Asset Protection in addition to TMF contributing departments, to name a few, can be a difficult task. It’s important that all contributors providing TMF content are in the same frame of mind. This ensures

TMF content is prepared in an efficient manner for both announced and unannounced inspections.

Additionally, management of the TMF is a complicated process even in the simplest of clinical trials. The degree of complexity can skyrocket when components of the TMF are delegated for collection and creation, and management do not give proper attention to data filing. When you add in an electronic TMF (eTMF) system to the equation, the complexity can triple. But this doesn’t have to be the case. It’s important for the sponsor and CRO to resist the urge to quickly set up and manage the TMF at the trial startup discussions, and instead work through the key foundational principles of TMF management in an electronic environment.

Discussions primarily focused around some of the main challenges that vendors, CROs, and sponsors have with the electronic management of TMF with other stakeholders. By identifying these key issues, common trends, and best practice sharing, the industry can gain a better understanding of how to identify electronic management of a clinical trial’s eTMF.

When CROs and vendors were asked what their biggest challenges are with sponsors around electronic TMF management, they responded:

• Differences in platforms between CROs and sponsors, as well as the lack of system integrations

• Lack of a definition of index structure as well as standards and detailed SOPs

• Single point of contact for both organisations• Sponsor oversight / project management • Client access• Changing management and training expectations on

an eTMF system• Not utilising the eTMF system as designed• Reluctance to change and regulatory group

apprehension

When sponsors and vendors were asked what their biggest challenges are with CROS around electronic TMF management, they responded:

• Single point of content• Index limited to sub-set of TMF content• Processes that create TMF content that are not

integrated• Not having clearly defined roles for CROs and sponsors• Turnover rates and need for retaining• Need to make processes malleable to meet many

sponsor requirements


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Evolution of the Trial Master File Process


• Access to the eTMF system• Open access to the quality reviews conducted not

easily provided• Inspection process for inspections during a trial

When sponsors and CROs were asked what their biggest challenges are with vendors around electronic TMF management, they responded:

• Technology implementation roadmap that will ensure issues complicating implementation are addressed

• Platform differences• Scalability• Supportability• Oversell of the product• System integration• Need to customise too much

Key FindingsSome of the main categories between the three users included definition of content, TMF process to follow, responsibility for quality, and access. Additionally, some of the issues that affect electronic TMF management included use and integration of technology, training, and support.

As the TMF is often short-changed due to the contractual process between a sponsor and CRO, the attention to management of the TMF can be less than adequate. Adding into the mix an eTMF platform to manage the TMF increases the risk for decreased quality.

According to the workshop discussions, some of the main roadmap discussions between a sponsor and CRO during the contracting phases should include:

• Creating a TMF plan• Determining whose TMF structure will be used• Process and naming convention of TMF content• Initiation of the TMF at the start of the study• Transfer of content at archival and the impact of

vendors• Archival of the TMF in multiple formats• Roles and responsibilities• Maintenance during and at the conclusion of the

trial.

The addition of an eTMF can complicate the process between CROs and sponsors, so some of the new dimensions that must be addressed include:

• Helpdesk availability in multiple languages to support global trials

• Configurations and technical updates and subsequent deployment

• Multiple levels of training• System access and performance worldwide• Governance strategy that covers access, roles,

security, updates, and scope• Electronic quality review process including direct

access to content• Service level agreements of content management• User acceptance• Complexity of client and/or vendor-authored content

A number of discussions during this workshop included the process of TMF management. When a sponsor handles the eTMF, some of the ways this makes it easier include:

• Sponsor TMF consistency for all trials• Full sponsor control • Complete audit and inspection readiness and quality

review capability.

When a CRO handles the eTMF, some of the ways this makes it easier include:

• Experience of working with an eTMF across multiple studies and sites

• CRO consistency of use across multiple clients that can increase TMF quality

• Cost-burden to the CRO and not the sponsor.

The last part of the workshop was around developing an action plan if a standardised TMF management is not in place. Workshop discussions focused on presenting the benefits of action and consequences of a non-action to your leadership to start the discussion about eTMF management and how it pertains to the sponsor-CRO relationship. Final discussions focused around creating a roadmap for addressing how TMF management will be handled in a sponsor/CRO partnership.

October 22-23, 2013 in London, UK saw the 2nd

European Trial Master File summit, which included a workshop entitled “Trial Master File: Confidence in Providing TMF for Regulatory Inspection or Legal Discovery” led by Lisa Mulcahy, TMF Process Consultant and Co-Leader TMF Reference Model Initiative, Mulcahy Consulting and Eldin Rammell, Managing Director, Rammell Consulting Limited. The workshop discussed how to prepare for a health inspection. During this workshop’s records management 101 discussion, it was noted that if records have the potential to have so much value in helping people do their jobs, make good decisions, provide accountability, offer evidence in litigation, and support corporate identity, they need to be properly managed. GRMP is Good Records Management Practice. GRMP assumes that:

• The record is present, can be accessed, can be interpreted, can be trusted and can be maintained throughout time.

• In addition, a comprehensive records management policy together with a routine training and compliance programme will offer significant legal protection in the event of litigation. A variety of significant legislation establishes the importance of records management, data privacy, freedom of information, the keeping of employment records and more.

Regulatory

Regulatory


A trial master file is the “documentation referred to in Article 15(5) of Directive 2001/20/EC as the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated.” --European Directive 2005/28/EC. Essential documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with all applicable regulatory requirements. Trial master files are created by clinical trial management, medical monitors, benefit/risk professionals, vendors, data management, regulatory professionals, medical writing professionals, finance, contracts and legal professionals, events committees, investigative sites, project management professionals, quality assurance professionals and more.

• The format of trial master files can include:• Paper documents • Electronic records • Living records not to be finalised until end of trial • Databases and data listings • Emails • Audit trails and metadata of systems • UAT • Web/intranet/applications • Digital streams • SAS programs…tables and listings • Structured and unstructured data.

Problems and challenges with these differing formats include duplication and reconciliation, very large documents, email branching, forwarding and inappropriate content within the email, difficulty managing records in multiple repositories, among others. Further, trial master files can be located in myriad places, creating further organisational challenges.

• TMF records might be located in a variety of places for a study, including:

• Validated Electronic Content Management Systems • IVRS • Email folders• Databases • Held with a vendor• Central paper file room • Long-term archive at company or a vendor • eArchive or decommissioned systems • File cabinets, desks, shelves, briefcase, courier

(while en route somewhere) • Hard and C:\ drives • Collaboration sites (SharePoint sites or equivalent) • Network drives • CDs or USB drives• Backup tapes• Internet/web • CTMS • LMS (training) and quality systems

• Or not documented at all.

• During an inspection, an inspector might want to review original paper records, review copies of paper records, review electronic records directly in the system, have direct access, use a navigator, or review copies of electronic records. Further, when multiple electronic repositories hold TMF records:

• Some TMF records might not be appropriate for others outside of a function to see.

• Some systems may not have interoperability with others, so TMF records are really not in a consolidated eTMF.

• Some systems take TMF records and replicate them as part of their processing, storing the TMF content as a new single entity, making it unclear which one is the authoritative source.

• Archiving processes must be established so that all repositories holding TMF records throughout the retention period meet the minimum requirements for systems holding archived records.

Translation into TMF Management Process

• Within just one company, the following individuals/ functions might have access to electronic TMF content:

• TMF owners • Quality assurance/quality management • Records management for access to archived paper and offline archived content

• Legal • Privacy/information security officer • Systems owners • Vendors who hold content on sponsor’s behalf • Regulatory affairs • Development/strategic partners • IT and IT QA • Hardware provisioning/audit support

• When direct access is given, the following items need to change in the TMF management process:• A concrete, defined process should reach all TMF

content owners• A standard set of content should be available that

also indicates authoritative location• Real-time inspection-readiness• Quality and completeness of the TMF must be

ensured• Timely submission of TMF content into the

authoritative system to eliminate any reasons for backlog

• Oversight of processes and vendors and evidence of it in the TMF

• A concrete, defined updated process for preparation and conduct of inspections when direct access is to be provided

• War rooms must be eliminated.

An archive offers controlled access, orderly storage, controlled movement in and out, and is checked for appropriateness. They should be suitable to provide long-term retention and include meta-data and indexing. Likewise, a named archivist should be responsible for archives and access should be restricted to those individuals. Further, a system must be in place for locking

and protecting documents. A protected audit trail is also an important component of an archive.

To mitigate against obsolescence, the media used to store essential documents must remain complete and legible throughout the required period of retention, and storage conditions should ensure that essential records are maintained in a legible condition.

• It is important that future access to records and data is maintained. This could include maintaining the system (hardware and software) to access the data in its original format, or the use of a new system to emulate the old software or migration of the data into a new format to ensure continual access with new software.

• A formal preservation strategy should include periodic test retrieval.

The objective of an archive is to maintain the integrity, authenticity, reliability and accessibility of the record for the entire duration of the approved retention period.

TMF best practices have been evolving over the past few years due to the introduction of electronic systems and regulatory guidances. As the industry moves to an electronic system, the TMF process becomes more complex. However, understanding what is needed by health authorities and developing a clear understanding of your TMF process will allow you to ensure that your TMF is of high quality and inspection-ready. By staying up to date on industry trends, technology advancements and networking with your colleagues, you will be able to ensure your TMF process is efficient and compliant to regulatory standards.

Scott Grossman, Senior Conference Director – Team Leader at ExL Pharma has been working in the conference industry for 4+ years. Currently Scott manages a portfolio consisting of Trial Master File, Partnering with Accountable Care Organizations, and Medical Affairs Strategic Summit Series.

Additionally Scott manages a team of conference

producers that are responsible for the production of healthcare and pharmaceutical educational and networking events globally. His leadership spans across multiple ExL departments, ensuring conference quality and great product development. Through the last two years he has built a strong relationships with TMF experts across the country, bringing together large groups of professionals for two centralized events in the US and United Kingdom. These events have grown to become the “Largest Meeting Dedicated to the Improvement of eTMF and Paper TMF” in the industry. Email:[email protected]


Regulatory

JCS: How is strategic recruitment going to address the challenges of patient recruitment?LM: Today more than ever, companies want to maximise their recruitment investment to yield the greatest return. This can only be achieved by being strategic and precise. To be precise, you have to have tools that allow you to take the guesswork out of recruitment, and this requires data, and such data must be in real time. Strategic recruitment equates to data-driven decisions that allow clinical teams to direct recruitment investment to the most productive recruitment strategies.

JCS: So what would some of those tools be?LM: Those tools are real-time metrics coupled with online analytic data. Today this includes mapping patient pathways, and more than ever before assessing your digital recruitment strategy. In the past, for example, recruitment advertising was based on what study sites wanted; today’s model involves media forecasting, planning and modelling of traditional and online recruitment methods, and collaborating with study sites to collectively evaluate response from each strategy. This tool alone involves study sites in strategic consideration, such as what per cent of your recruitment goal will be achieved by one media method versus another, and what is the cost for achieving this? These data-driven tools are used to fine-tune the recruitment strategy throughout the recruitment programme. Metrics and modelling forecasts give a sponsor and study sites the ability to have baseline metrics against which to measure performance. It further allows us, as implementers, to have targets against which to benchmark actual performance against forecast.

JCS: What strategy do you use to disseminate the recruitment message? LM: There are several key issues to consider in responding to this question; the first is to consider how and where specific patients search for information, and where in the healthcare system they receive their treatment. The second is that getting ‘the message out’ about a study requires an understanding of the patient population because your message must resonate with your target audience. It requires that the recruitment team must affirmatively know what will make that patient population ‘tick’, and this cannot be based on opinion but fact. These are the same steps you would take for marketing a prescription product; instead we are marketing a clinical study.

JCS: How critical is recruitment-specific technology today?LM: Technology is critical today. For a recruitment specialist, technology enables us to collect data, communicate with patients using various methods, connect with patients online, and exchange data with sites securely and in real time. It takes the guesswork out of recruitment and makes it a science more than an art. Technology enables every aspect of a recruitment programme to be charted, right down to individual study sites.

Technology enables us to rapidly track the performance of both sides of recruitment: the ‘push’ and the ‘pull’. Push strategies are outreach strategies to patients and referring physicians. Pull strategies are those that ‘pull’ patients through from pre-screening to randomisation. When technology empowers us to collect this data in real time, decisions can be made for optimising push and pull strategies. Technology provides us with the flexibility to continually assess and adjust recruitment investment and methods on a site-specific level, and when speed is of the essence, the internet enables recruitment advertising to be adjusted fast; minute-by-minute on a site-by-site basis.

JCS: What about educating the patient about clinical trials; either to enroll or once they have joined a clinical trial? LM: Patient education is really very important, both from an ethical and a legal perspective. In the US, numerous lawsuits related to clinical trials have been based on the failure to educate and / or inform patients adequately. Only through patient education can patients be empowered with a sense of control about their participation in a clinical trial. Education is important for addressing patients’ fear of the unknown. When patients know what to expect, and what they experience is in line with these expectations, recruitment and retention results are positive, and overall study performance goals are met.

Regulatory


Patient Recruitment and Retention: Perspectives from an Industry Leader

Regulatory

JCS: How about the use of physicians for patient recruitment? LM: There are two ways to address this question: the role that physicians conducting the study can play in recruitment, and the role of physicians in referring patients. Today, with information at patients’ fingertips, decisions to participate in a clinical trial are driven by three things: the study, the site and the physician conducting the study. When often physician investigators are practically invisible or partially involved in a clinical trial, they fail to connect with a patient in a way that patients expect, and this can have consequences for both recruitment and retention. The role of the study physician is vital, and those who are partially involved may not fully appreciate how important their engagement is in the overall study process. Actively engaged physician investigators that host community seminars about a clinical trial, participate in advocacy events, or present at medical society meetings, play a critical role in the patient recruitment process. The success of physician referral networks is driven by several factors: the medical condition, available treatments, and the healthcare delivery system. Success is also predicated on the ability of the study site to establish close connection with the referring physician. In a recent survey conducted with physician investigators and study coordinators, for a rare medical condition and minimal access to available medications for most patients, referral networks were recognised as theoretically important, but only one out of 30 sites had implemented a referral network. The main reason cited was lack of time and resources to build and nurture such a network. In countries with public healthcare systems, privately-based clinical trial sites have been successful in establishing referral networks. In this model, referring physicians can reduce costs from the government as payor of care to clinical trials that incur treatment and care costs, and patients gain access to new potential treatments. In this scenario, everyone gains.

JCS: Pharmacy data: how important is this?LM: It’s very important for recruitment feasibility and ‘road testing’ the protocol. We actually use insurance claims and pharmacy data. Pharmacy data and claims data allow us to look at standard of care and current medical practice, and evaluate the protocol against what the data shows us. And it also allows us to evaluate where these patients are in the healthcare system or whether these patients even exist. We conducted a feasibility study where we examined co-morbid conditions for an oncology study. It was the use of these databases that allowed us to actually do critical analysis, and predictions that determined recruitment for this study would take several years. Such knowledge during the planning phase is essential to have before companies spend the millions going down a path of significant investment and then they can’t find the patients.

JCS: How important are patient advocacy groups to recruitment?LM: Many patients will trust other patients just like them. In many cases, social media facilitates information-sharing and treatment advice amongst patients. As such, social media has given rise to the prevalence of patient-based communities. Patient-based communities together with leading advocacy organisations are changing the landscape of the role of advocacy in patient recruitment. Consider lupus, for example: we

found that while 60% of lupus patients will source information from the leading lupus foundation, more than 80% visit and or participate in patient-based communities. For conditions with a social stigma, however, patients are less likely to be as visibly engaged in patient-based community or advocacy forums, but nevertheless still visit these communities to read and access information. Today, patient advocacy organisations are playing a more active role in establishing registries and providing clinical trials listings.

JCS: How about databases for patient recruitment?LM: While the role of databases on the commercial side of the industry is optimal, for clinical trials, these databases must be of significant size to make an impact. Study site locations and protocol inclusion/exclusion criteria can result in very few patients recruited from a database of several million. On the other hand, databases as registries can and will play an increasing role in clinical trial recruitment. But importantly, the integrity and the security of these databases will be more scrutinised as laws continue to evolve regarding personal privacy and data security.

JCS: Simplifying clinical trial design. Do you think some people are just afraid of clinical trials because they are too complex and time-consuming?

LM: This is where I think the industry can look outside of itself and learn from other industries. When other industries develop products and services, they go directly to their customer base to get feedback. They look at how to improve their product or service. It would be beneficial if companies considered the patient voice in clinical trial design. The only therapeutic area in which this occurred progressively was in AIDS. Back in the eighties when patients pushed for the “right to know”, the AIDS patients were demonstrating that they had a right to know about specific clinical studies and the right to understand its details. Having personally participated in a focus group where patients were brought together to review an AIDS protocol, I witnessed firsthand together with the clinical team the level of constructive insight provided. Involving patients in clinical trial design is essential for several reasons: identifying the potential logistical challenges of the study from a participant viewpoint, and substantiating certain design rationales. Both are important issues to understand in advance to ensure recruitment-retention success.


Elizabeth Moench, President and CEO Medici Global Ltd. For 22 years MediciGlobal has been supporting paediatric recruitment and retention, developing recruitment and retention programmes for fragile paediatric populations including schizophrenia, eczema, eosinophilic oesophagitis, spina bifida with voiding dysfunction, ADHD, and others. Contact MediciGlobal at +1 (484)674-6825 (US), +44 (0) 208 834 1447 (UK) or

Email: [email protected]


Regulatory

The biopharmaceutical industry, reeling under the pressures of low R&D productivity and increased costs of clinical development, has been looking at ways to do more with less. Clinical trial (CT) monitoring, which contributes to over 30% of trial costs, has been a major focus area in this endeavour. On-site monitoring of clinical trials has been identified as one of the most cost and resource-intensive components of the clinical trial industry’s global spending (over US $42 billion in 20121).

Smart approaches to monitoring, such as centralised, remote, risk-based and adaptive monitoring which are emerging, can reduce the need for on-site monitoring visits and source data verification (SDV) while achieving the objectives of monitoring more effectively. It is recognised that the traditional approach of on-site visits and 100% SDV is not optimal, and cannot, on its own, effectively achieve the primary objectives of monitoring, which are to ensure the rights and safety of participants and the reliability of safety and efficacy results. Both the US FDA and European Medicines Agency are urging greater reliance on centralised monitoring practices to identify when on-site monitoring is truly required and how on-site monitoring can be optimised through metrics collected from centralised monitoring methods. The guidance released by the FDA in August 20132

recommends a quality risk management approach to CTs that encourages greater use of centralised monitoring practices which may be better suited for the risk-based monitoring strategies the sponsors are developing.

A Risk-based Approach to MonitoringKey elements which are intrinsic to the reliability of safety and efficacy results from a clinical trial are: power of the study (which can be affected by recruitment numbers, treatment compliance, completeness of data and adequacy of follow-up information), inclusion criteria (to ensure that the study population is as intended and is homogenous), treatment allocation (randomisation and blinding) and outcomes (accurate measurement and capture of outcomes data and use of appropriate statistical methods for analysis and inference). Certain indicators of these elements are the factors for which risk assessment is performed in order to eventually determine the extent and frequency of on-site monitoring which is apt for the study. Some of these factors are: complexity of design (including study phase and types of endpoints), geographical spread, investigator experience, whether electronic data capture (EDC) is used and the safety profile of the product.

Approaches to risk assessment may be qualitative/subjective or quantitative/objective. For example, risk ratings can be qualitatively assigned based on study design, which is a major determinant of protocol complexity. Risk ratings can be assigned a priori depending on whether only non-invasive procedures are used (lowest risk – e.g., non-interventional/observational),

only approved treatments are used (mild risk – e.g., Phase IV), whether it is a Phase III trial with a new treatment and/or a new indication (moderate risk) or whether it is a Phase I or Phase II trial of a new treatment (high risk).

An optimised monitoring strategy can be determined based on these risk ratings and key risk indicators (KRIs) corresponding to other factors such as patient safety (rates of adverse events and serious adverse events), treatment compliance (percentage of patients with delayed or reduced dose or with treatment discontinuation), data management (delays in completing and sending case report forms, query rates, query resolution times) and other aspects of study conduct (actual vs target recruitment rate, percentage of patients with protocol violations, percentage of dropouts).

A report of a pilot project conducted by Pfizer and the US FDA to test a model for prospectively designing quality into CTs and managing quality during study conduct illustrates the use of statistical methods in quantitative risk assessment3. This project, based on 73 ongoing studies, applied a quantitative

Under Surveillance: How Risk-based Monitoring Improves the Success and Efficiency of Clinical Trials

approach to complement integrated quality management plan (IQMP) efforts using statistical models to identify risk factors that require more scrutiny. Factors related to eight different risk categories were considered to identify perceived risks. The risk categories were compound characteristics, subjects, protocol, locations, site operations, outsourcing, monitoring and drug supplies. A statistical test (Wilcoxon rank sum test) was used to identify association between risk factors and the occurrence of quality issues. In univariate analysis, the following risk factors had at least a marginal association (p < 0.1) with the number of quality issues: packaging/labelling, dosing complexity, biologic compound, size of planned procedures, subjectivity in measurement, use of placebo and number of exclusion criteria.

Monitoring plans formulated on the basis of such risk-based assessments may sometimes include extensive on-site monitoring, but mostly will include reduced (risk-adapted, or on a random sample of centres/patients/outcomes) or targeted (based on KRIs and statistical monitoring) monitoring. The quality of study conduct is monitored through (a) training, (b) data entry checks and discrepancy management, (c) central and on-site monitoring of data and (d) planned checks by data monitoring committees (DMCs). Central statistical surveillance (CSS) is a critical element of central monitoring.

How Central Statistical Surveillance Adds ValueCSS is a centralised monitoring technique that uses statistical tools to identify errors, outliers and abnormal trends/patterns in clinical trial data, and thus provides effective triggers and leads for targeted monitoring visits.

Sources of errors are study design, study procedures, case report form (CRF) design, data recording, data analysis and inference. Errors can be random or systematic. Random errors may impact the statistical power of the study but may not result in bias, while systematic errors will most certainly result in biased conclusions. Errors could be unintentional (e.g. unknown issue with calibration of an instrument), could be due to lack of attention to detail (data not transcribed correctly from the source to the CRF) or due to a lack of understanding (unclear about how dose titration details are to be captured on the CRF). In rare instances, there could be deliberate errors committed with the intention to fabricate or falsify data. Results of a survey conducted a few years ago suggested that erroneous analysis, reporting and interpretation due to lack of knowledge and understanding were perceived to be far more common than intention of fabrication or falsification4.

The main principles underlying the use of statistical methods to detect errors, outliers or trends are:

• Clinical trial data generated by application of a standard protocol and the same CRF at all participating centres is highly structured in the way it is collected, grouped and analysed.

• The multivariate structure and/or time dependence of the variables is sensitive to deviations and easily detected by statistical tests.

CSS is able to detect data issues that go undetected in SDV and on-site checks, e.g., identical values for vital signs over

several visits. It considers every piece of information entered in the CRF as potentially indicative of quality rather than being restricted by pre-defined KRIs. Statistical checks are performed to check randomness (first digit preference, rounding), plausibility (correlation structure, outliers, dates in range) and comparability (between treatment arms, between centres or any other covariates of interest).

Basic statistical procedures and tests such as the Chi-square test, t-test and F-test are used to compare the distribution of all variables of interest across centres for the purpose of identifying any ‘outlying’ centres or observations. Study design and CRF design issues could also be detected from such analysis. For example, low variability in data across visits (indicated through the F-test) may lead to suspicion that the same observation is being entered without actual measurements being taken at each visit. This may suggest that the CRF has too many fields and its size may need to be reduced. Plausibility checks (for correlations, outliers) may require appropriate plots and graphs, followed by statistical inferential procedures. Model-based approaches are required to check comparability across centres. Tests on means, within patient variances etc., are used to generate a high-dimensional matrix of p-values with statistical methods used to identify outliers.

A recent article provides results from actual trials to illustrate typical findings that can be expected from a CSS approach which detects abnormal patterns that were not (or could not have been) detected by on-site monitoring5. Data fabrication or falsification done with an intention to hide missing data or to make the results look more favourable for a particular treatment, may be detectable through centre or treatment-by-centre comparisons from appropriate statistical models that are fitted to the data. A recent publication illustrates the development and validation of risk scores to identify fabricated data within a multicentre trial, to be used in CSS6. The analysis was based on a database from a multicentre cardiovascular trial in which data from 9 to 109 centres was documented to be fabricated. Exploratory factor analysis was used to select from 52 possible predictors. Final models were selected from a total of 18 independent predictors and the models were converted to risk scores for each centre. Five different risk scores were identified and each had the ability to discriminate well between centres with and without fabricated data. The risk scores were validated for their false-positive rates.

CSS relies on ‘sufficient’ data being available to be able to detect abnormal trends. Hence it may not be effective in trials that have several centres with small amounts of data, or at the beginning of a trial before sufficient data is accumulated.

ConclusionResults of a survey published in 2011, based on the responses from 65 organisations performing clinical trials, indicated that 83% use centrally available data to evaluate site performance and 12% always or frequently used centralised monitoring to replace on-site monitoring7. In this survey, 87% of respondents said that they always perform on-site visits. However, the reliance on central and remote monitoring has increased significantly of late and organisations have embraced a risk-based approach to on-site monitoring.


Regulatory


Regulatory

In summary, an efficient and effective monitoring strategy is a combination of (1) targeted site visits, primarily for training, mentoring and support to site staff, (2) remote assessment through incident alerts, tracking system and statistical analysis and (3) trial oversight through steering committees and DMCs. CSS is a powerful tool which can identify unexpected or strange data patterns, making on-site monitoring much more targeted and effective. It is critical for an effective risk-based monitoring strategy. Its growing importance is indicative of the crucial role of statistics and programming in effective clinical trial monitoring and hence the need for the sponsor to ensure availability of statistical expertise while planning resources for monitoring. If the sponsor is managing the trial in-house, adequate statistics and programming resources would have to be planned for each study. If the trial is outsourced to a contract research organisation (CRO), the sponsor will have to ascertain that the CRO has the capability to perform CSS or they may have to use another vendor for this activity.

References1. PRNewswire-iReach, June 24, 20132. “Guidance for Industry Oversight of Clinical Investigations - A

Risk-Based Approach to Monitoring”, US FDA, Aug 20133. Alemayehu D., Alvir J., Levenstein M., Nickerson D., “A Data-

driven Approach to Quality Risk Management”, Perspectives in Clinical Research 2013; 4: 221-226

4. Al-Marzouki, S. et al., “The effect of scientific misconduct on

the results of clinical trials: A Delphi survey”, Contemporary Clinical Trials, 26 (2005): 331

5. Veneta, D. et al., “A Statistical Approach to Central Monitoring of Data Quality in Clinical Trials”, Clinical Trials (2012), Vol 9, No. 6: 705-713

6. Pogue, J. et al., “Central Statistical Monitoring: Detecting Fraud in Clinical Trials”, Clinical Trials (2013), Vol 10, No. 10: 225-235

7. Morrison, Briggs W. et al., “Monitoring the Quality of Conduct of Clinical Trials: A Survey of Current Practices”, Clinical Trials (2011) Vol 8, No. 3: 342-349

Chitra Lele is Chief Scientific Officer at Sciformix Corporation, with over 20 years of experience

i n the healthcare industry. She has been part of the company’s leadership from its inception and has been instrumental in establishing and growing the organisation. Prior to Sciformix,

Chitra was Executive Director responsible for Indian operations of Pfizer Global R&D. With a PhD in Statistics from Stanford University, her prior experience includes work as a biostatistician in cancer epidemiology at both Stanford and University of California.Email: [email protected]

Regulatory

Comprehensive service package for phase I-IVand Postmarketing studies

Scienti�c and medical expertise

Medical writing and translations

Pharmacovigilance

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www.dokumeds.com

EUROPEAN CLINICALRESEARCH ORGANIZATION

[email protected]+ 371 67553065


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Why conduct clinical research in Lebanon?• Much shorter start-up time for clinical studies • Untapped patient population• Quick local ethics committee approvals• Well-educated medical professionals

Facts about LebanonLocation: Lebanon is a west Asian country located in the East Mediterranean.Capital: Beirut

Lebanon Statistics Population: 4.42 million (as of 2012) 1

Healthcare expenditure: 6.3% (as of 2011) 2

IntroductionClinical research in Lebanon is hassle-free, and approvals from the local ethics committee are quick, with short timelines. The total timeline to get a study started in Lebanon would be 2 to 4 months which includes the preparation of the documents, ethics committee approvals, and obtaining the import license. However, the summer months could be considered the slow period.

Potential Sites for Clinical Research in Lebanon• Rafik Hariri University Hospital: In Rafik Hariri University

Hospital, the membership of IRB complies with the membership requirements of ICH-GCP. In addition, the IRB operates in a manner consistent with good clinical practices under the ICH guidelines, with FDA and applicable national and local regulations. All the physicians at RHUH usually attend ICH-GCP training sessions organised by local and global CROs.

• American University of Beirut (AUB): AUB has a Federal-wide Assurance (FWA) with the Office of Human Research Protection (OHRP), in the Department of Health and Human Services (DHHS), as a domestic institution. In the FWA, the Institutional Official, that is the Provost, certifies that AUB

assures that all activities related to human subjects research, regardless of the funding source, are guided by the ethical principles of the Belmont Report. In addition, research sponsored by federal sources has to abide by the corresponding federal regulations. Under the umbrella of the AUB Human Research Protection Program, institutional review boards (IRBs) are charged with the prior review and approval of all research involving human participants at AUB, unless the research was granted exempt from IRB review status, upon review of submitted relevant information. The IRB was separated into two boards: the Biomedical IRB and the Social and Behavioral IRB, the latter including faculty representation from all schools in AUB at large. Vice chairs were appointed to each board. The Biomedical IRB reviews research conducted at AUBMC and/or by the School of Medicine, excluding qualitative or quantitative research. It also reviews research by any faculty that involves FDA oversight, specifically clinical research involving an investigational device, drug or testing, research requiring an IND (investigational new drug) registration, or any other research where the data will be submitted for FDA regulatory review. Its members are nominated by the Dean of the School of Medicine and appointed by the Human Research Protection Program (HRPP) Director, in consultation with the Chair of the IRB and an institutional official, as appropriate. The Social and Behavioral IRB reviews research conducted at the School of Arts and Sciences, the School of Agriculture and Nutrition Sciences, the Olayan School of Business, the School of Engineering and Architecture, and the School of Nursing. Review of research by any of these schools that involves FDA oversight is referred to the Biomedical IRB. At least one representative from each school at AUB will be nominated to serve on the Social and Behavioral IRB by the dean at that school, and appointed by the HRPP Director in consultation with the Chair of the IRB and IO, as appropriate.3

• University Medical Centre - Rizk Hospital: All research involving human subjects under the jurisdiction of the Lebanese American University and its affiliates (UMCRH) must be submitted to the Committee of Human Subjects in Research (CHSR) for review and approval prior to initiation. The Lebanese American University (LAU) established in 2008, as part of its educational and research mandate, the Committee on Human Subjects in Research (CHSR). The responsibility of this committee is to review and approve research projects involving human subjects conducted at LAU and the University Medical Center - Rizk Hospital (UMCRH).4

Timelines for Approval• Rafik Hariri University Hospital: 3-4 weeks • American University of Beirut (AUB): 4-6 weeks • University Medical Centre-Rizk Hospital: 6-8 weeks

So the timeline varies from site to site and can be from 3-8 weeks approximately.

Lebanon Watch


Process of SubmissionAll the documents need to be submitted to the local ethics committee in advance of two weeks before the meeting date of the ethics committee, in order to be sure that all the documents are in place. In case anything is required, the local ethics committee will inform the researcher which documents need to be submitted to complete the package. The documents would be as follows: protocol, investigator brochure, informed consent form, case report form, diary cards and the manuals.

Fees for the SubmissionThe local ethics committee fees vary from site to site, and are usually in the range of USD 1000-1500.

Import Licence in LebanonThe Ministry of Health in Lebanon is the regulatory authority that controls the import and export of investigational products and biological samples.

The approval of the importation should be taken from the import/export department. If the product is registered in the Ministry of Health, the importation will be done like any other product. If the product is not registered in the Ministry of Health, the MOH should grant approval of the product to be imported.

ConclusionBecause of the start-up time being very short as compared to many other countries, Lebanon is becoming very popular for the conduct of clinical trials. Coupled with the rise in the number of medical professionals in Lebanon, it has been considered by a lot of pharmaceutical companies as a potential clinical research site.

References1. World Bank2. http://data.worldbank.org/indicator/SH.XPD.TOTL.ZS3. http://www.aub.edu.lb/IRB/Pages4. www.lau.edu.lb

Adhiti Sharad Kumar has been working for a clinical research organisation for the past three-and-a-half years, and has been involved in regulatory, training and marketing activities. Currently, she is also the Coordinator for the Gulf Chapter of the Association of Clinical Research Professionals – ACRP. This group is focused on promoting clinical research

around the Gulf, and involves training sessions, networking events, etc. Email: [email protected]

Market Report

Market Report


Changes in global operating conditions have made pharmaceutical and biotechnology companies reconsider their existing practices and development strategies as well as look for new approaches to reach their business and economic objectives. Outsourcing of different services is one of the solutions that can help the companies achieve these goals.

ICH GCP Guidelines state that the sponsor may transfer any or all of the duties and functions related to the clinical investigation, including monitoring, to an external organisation (such as a CRO or an individual contractor), but the ultimate responsibility for the quality and integrity of the clinical investigation data shall reside with the sponsor1.

In April 2012 the EMA issued the following document: “Reflection paper on ethical and GCP aspects of clinical trials of medicinal products of human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities”2. This paper addresses the challenges listed below:

1. Cooperation in the regulation of clinical trials with a specific emphasis on capacity-building initiatives for a common approach to oversight of trials;

2. The steps that EU regulators should take in order to ensure that ethical and GCP standards are applied to clinical trials for human medicines (during both the development and marketing authorisation application phases). In addition, in August 2013 the FDA published a new guidance for the industry: “Oversight of Clinical Investigations – a Risk-Based Approach to Monitoring”3. The main aim of this document has been to enhance the quality of clinical trial data by focusing on the oversight of the most important aspects of study conduct and reporting.

As the volume of business outsourced to CROs has been steadily increasing during the last years, small and midsize CROs are encouraged to look for new opportunities to cooperate with each other. Cooperation with other clinical or non-clinical service providers has always been a part of Dokumeds’ business operations, thus allowing us to extend the geographic coverage, expand the scope of services, and receive high-quality support essential for the successful execution of projects. Our first attempt to change the paradigm of vendor management was initiated back in 2006 when, together with five other small/midsize European CROs, we established the AcrossAlliance, aiming to cooperate within the framework

of international project management certified under ISO 9001:2000 standards4. This alliance has proved its ability to adapt to a constantly changing environment and remain a successful player in the business.

For a small/midsize CRO specialising in clinical operations in Central and Eastern Europe (having seven offices in Central and Eastern Europe, operating in more than 10 countries), vendor management in the regions where the company has not established itself and where the company staff is not present, as well as the opportunity to extend the services, is crucial to cover the full scope of services and expand the geographical coverage requested by the sponsors.

Dokumeds has also started the development of its own CRO strategy and approach to vendor selection and management, particularly during the last couple of years, trying to find the solution and approach which corresponds to the company’s internal culture, best business practices, sponsor expectations and regulatory requirements.

In today’s dynamically changing industry environment, it is essential that a service provider has the readiness to manage the project: upon receipt of the request for proposal (RFP) the CRO must know which vendors have to be selected for the execution of the project, and why.

Considering that not all the sponsor companies

have sufficient in-house expertise in the therapeutic area, geographic region, or the respective regulatory environment necessary to clearly define the scope of work and their expectations from a CRO, the decision and selection of vendors to be involved at this early stage is not an easy task for a CRO. During this process it is critical to keep in mind the overall responsibility for the quality of performance of a particular CRO, including the quality of vendor services, as well as the availability of internal competence, resources, tools and systems to lead and manage the vendors.

To optimise the vendor selection and the outsourcing decision, a CRO has to have an established systematic approach and procedures of vendor management in place, allowing it to evaluate and manage the quality risks.

What Does a CRO Need to Outsource Services to Vendors? First a CRO has to have a clear understanding of its own capabilities and availability of resources, as well as the current and strategic business needs. The importance of an

Vendor Management in Clinical Operations - New Opportunities for Small and Midsize CROs?

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established vendor selection and management procedure, comprising the full set of procedures—starting with the identification of business needs, vendor categorisation, identification, qualification, including the pre-selection audit, as well as the qualification maintenance plan of active vendors—has to be considered. A vendor manager or a vendor management group together with a quality manager, as well as their effective collaboration with the different internal structural units within a CRO, such as the clinical operations, business development, contract finance and other applicable structures, have a significant role in the execution of this internal “pre-outsourcing” process, as well as later during the re-qualification. It is recommended to develop and agree on the common concept and principles of pricing and cost control to be implemented while working together. During the qualification and re-qualification of vendors providing the core services, a documented proof of the financial stability of vendors, such as the annual finance reports, should not be neglected.

Based on our long-term experience, without having performed the vendor qualification a CRO will not be considered a reliable service provider by a sponsor and will not be able to respond efficiently and credibly to the sponsor’s requests concerning the vendor services, as well as assure the subsequent quality of performance. Development of mutually acceptable concept and principles of pricing and cost control is advisable.

Apart from having a clear understanding of the grounds for outsourcing services to vendors and having a database of already qualified vendors, the contracting CRO needs to know how the quality and oversight of the project will be assured. Elements of the service agreement, such as a clearly defined scope of work outsourced to vendor, as well as the milestones to be reached, incentive plans, risk-sharing, penalties and specific requirements, like staff qualification and other conditions defined by the sponsor agreement, have to be included in the vendor agreement and accepted by the vendor’s senior management before the execution of the project. However, having a service agreement with all the elements specified above in place is not enough to assure the oversight. Oversight requires commitment of the senior management of the contracting CRO, as well as the vendor. Furthermore, it should be assured on different levels starting with the project level (controlling the achievements of milestones, keeping the metrics and evaluating the risks), finance and contract department (assuring the budget and change control), human resources (assuring the appropriate resource planning and workload control, as well as the fulfilment of training requirements), quality management (harmonisation of SOPs, KPIs, following the implementation and compliance with applicable quality measures), as well as the input into the oversight of other structural and supportive units. The oversight could be assured by regular communication, evaluation and analysis of the project metrics, including the workload and cost control, as well as the procedures defining the

risk evaluation, and escalation and implementation of applicable corrective and preventive actions (CAPA), clearly defined roles, responsibilities and accountability within a project and between the parties. Attention should be paid to the clear definition of governing SOPs and training needs. Although a common presumption is that the most important factors determining the success of vendor management are the service contract and budget, Dokumeds’ ten years of experience in the management of different clinical service providers has demonstrated the importance of setting up the principles of governance, particularly the principles of communication. Early involvement of the senior management of both Dokumeds and the service providers has always been a key to successful management of the project. Unfortunately this factor is often underestimated or neglected by the management of many CROs. Our experience has proven that a meeting of the members of senior management at an early stage of the development of a contract, particularly the master service agreement, brings a real return on investment (ROI) at a later stage.

Management meetings are a good way to establish the relationship and commitment of the senior management of both parties. Meetings are also an opportunity to openly discuss the details of master service agreements, to evaluate the risks and the risk-sharing between the parties, for example the incentive plans and penalties or specific conditions, if such are defined by the sponsor service agreement. Such meetings can also help to determine the subsequent communication plans to be implemented on different levels (senior management, quality management, project level etc.), principles of decision-making, risk management and problem escalation, main metrics, strategy and management of human resources, management of conflicts and changes, and further collaboration. As the project progresses, management should participate in oversight TCs and annual oversight meetings. Based on Dokumeds’ experience, the intangible result of this approach could not be underestimated, as it comprises the established common understanding and trust between companies as well as the commitment of senior management, which influences accordingly the spirit of the whole team and the quality of performance.

Apart from simply keeping track of project metrics, the development and implementation of quality and oversight plans should also be seriously considered. These plans have to be developed at an early stage of the project by both the contracting and subcontracting parties. The communication model set up within a project has a significant impact on it’s success and efficient management. Although sponsors often limit the number of direct contact persons at a CRO to a small number of people, for example, solely the project manager or the project manager and the director of clinical operations, the CRO as the main contracted party should find the best communication model to assure efficient and complete communication within a team. The communication models

which raise the risk of delivering insufficient, delayed and even ‘’screened’’ or misinterpreted information to the sponsor or project team, thus undermining the quality of performance, should by all means be avoided.

Based on our experience, we would recommend the use of a communication model which keeps in the loop all the relevant persons of the team depending on their role and competence in the project. Such a model allows one to ensure that all the team members are informed in a timely manner, guarantees transparency and an undistorted delivery of information from the original source, as well as the efficiency and quality of the project. The major components of vendor oversight are reflected in the scheme below.

Figure 1 Vendor oversight major components

When managing vendors, apart from the routine experience in running clinical operations, the small/

midsize CRO should possess certain additional in-house competencies, such as the up-to-date knowledge of the local legislation in all the countries operated by vendors, including the regulations related to contract and payment management, pharmacovigilance, healthcare and reimbursement system, as well as the import/export regulations. These competencies that increase the CRO’s overall know-how can be obtained while managing vendors in different countries and in different fields of services. Ensuring this requires additional internal resources of the CRO, as well as the synchronisation of quality management systems and tools. There is one more factor requiring particular attention of CROs managing the vendors in different regions: the additional competencies have to be assured and the systems have to be managed efficiently in a well-planned manner to balance the overall running costs. In general the main areas of resource investment are reflected below

.

Figure 2 Governance of subcontracted CROs

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“Operating in the world’s Clinical Trial hotspots, we ensure consistent andreliabletimedefiniteandtemperaturecriticalservices.” www.pdpcouriers.com

Dokumeds’ almost 10 years of experience in working with vendors (partner CROs from AcrossAlliance or CROs outside AcrossAlliance), local warehouses, central laboratories, imaging, and ECG central reading laboratories has proved that such a model of collaboration is accepted by sponsors and could be effective in providing a high quality of services if governed by clearly defined rules of conduct, assuring the oversight and achievement of operational goals.

References1. Guideline for Good Clinical Practice E6(R1) pp 20

http://www.ich.org, visited on 03 Nov 2013. 2. Reflection paper on ethical and GCP aspects of clinical

trials of medicinal products for human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities http://www.ema.europa.eu, visited on 03 Nov 2013.

3. Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring, August 2013 http://www.fda.gov/, visited on 03 Nov 2013.

4. www.acrossalliance.com

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Janis Skards, MD, PhD – one of Dokumeds founders, teaching staff, investigator and practicing physician, since 2006 Medical Director of Dokumeds. Experienced in Regulatory, pharmacovigilance and medical affairs in Pfizer. Currently involved in business development of Dokumeds, feasibility studies, patient recruitment,

and process optimization.Email: [email protected]

Indra Aboltina MD, PhD – one of Dokumeds founders, in industry since 1995. Before – teaching staff in the Medical Academy of Latvia for postgraduates in nephrology and internal medicines; dean of faculty for public health. Since joining industry - medical monitor for

Wyeth R&D, later General Manager and CEO of Dokumeds. Main interests: company, project and finance management, partnerships and environment shaping. Email: [email protected]

“Operating in the world’s Clinical Trial hotspots, we ensure consistent andreliabletimedefiniteandtemperaturecriticalservices.” www.pdpcouriers.com

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Want to Better Recruit and Retain Patients? Think Like One.

To understand what motivates patients to participate in a clinical trial, study coordinators and protocol designers must learn to think like a patient. This principle may sound obvious, but it is easy for clinical study designers to focus on the data and the trial budget — and to lose sight of patient needs. The most effective patient motivators blend clinical trials’ emotional aspects with convenience.

Of course, if clinical teams are able to hit their enrolment targets, the next goal is to ensure that every patient completes the trial. Patient retention issues can eat into a trial’s scheduled timetable with the same voracity as early enrolment woes can. Cutting Edge Information surveyed 83 trial managers and patient recruitment specialists and interviewed a half-dozen experienced professionals to find out what really motivates patients to enrol in clinical trials in the first place and what activities help keep patients enrolled. The result was a benchmarking study titled Clinical Trial Patient Recruitment: Accelerate Enrollment, Increase Retention and Reduce Costs, from which much of the data in this article is derived.

Understanding Patient MotivatorsDetermining what factors will drive patients to join clinical trials is often difficult. Compensating patients for travel costs or childcare can be a motivating factor, but more often patients are swayed to join a trial if they have an emotional response toward clinical medicine. Perhaps the largest motivator is altruism, the overall sense of advancing science and helping others with the same disease. Yet provoking that response in prospective patients is a challenge: They either feel it or they don’t. Patients who do feel altruistic are likely to participate in multiple clinical trials. Statistics show that most patients who participated in a clinical trial stated they would participate in the future. For patients with a genuine interest in clinical trials, other incentives may not be as significant.

To convince other patients, compensation may be needed to offset any inconveniences. Ethical guidelines, however, prevent the outright use of money as an incentive for clinical trial participation outside of Phase I, healthy subject studies. But reimbursement for travel expenses, parking, childcare and lost time at work not only passes muster with ethics boards but also makes it easier for patients to participate.

Patient motivators — or sometimes demotivators, as the case may be — are products of protocol design and should be considered at the very earliest stages of study planning. Number of required office visits, invasiveness of procedures and trial duration all play a part in a patient’s decision to enrol. For example, a short, convenient trial makes for an easy sell. But a protocol that calls for frequent 10-hour office visits, with follow-up visits every year for five years, imparts far great burden on the patient. Trial staff will have to work overtime to convince patients to enrol.

This section examines these different motivators. Survey respondents rated each motivator on a scale from 1 to 10 (10 being extremely effective). Figure 1 lists the top four patient motivators in order of effectiveness. The list reveals that protocol elements and disease-related factors earned the highest effectiveness rating from surveyed trial managers. Rated most effective at 7.9 is the prospect of improved treatment. Although teams can feel that patient recruitment is a race to attract numbers, ultimately, these patients have conditions that need better treatments.

Second on the list, with an average score of 7.3, is the convenience of sites. The closer the site, the more likely a patient is to participate in a trial. The prospect of free medication and a lower number/frequency of visits received average effectiveness ratings of 6.8 and 6.6, respectively. Other incentives, such as travel compensation for patients, earned average ratings below 6.0. Although these other incentives are not thought to be effective motivators for initial trial enrolment, they are frequently used to enhance patient retention.

Figure 1: Overall Effectiveness Ratings of Patient Motivators

When trial teams are deciding which recruitment motivators will have the most impact on a given trial, it is important to consider sociodemographics, the target patients and the areas near the site. One trial manager interviewed said that he has seen patient motivators vary widely based on geography, gender and age. Ultimately, all patients want access to expert medical care. It is the responsibility of trial managers to minimise the barriers to access such care.

Recruitment managers will make better decisions with a solid understanding of the patient population’s demographics. For example, if a trial’s target patient population is age 25 to 35, this group is more likely to have young children. Offering

free childcare for each office visit would break down another barrier and could motivate someone to take part who might have otherwise declined the opportunity. On the other hand, if the trial were for prostate disease, then offering free childcare is not as important and perhaps hot coffee is a more enticing motivator.

The more you know about the patient, the better. Are patients unemployed or on disability as a result of their condition? If so, then arranging special, daytime transportation would be an important consideration. Or does their current job require that any site visits take place after 7 p.m.? Knowing the answers to these questions will enable teams to develop patient materials that highlight the trial’s features likely to impact their lives.

Receiving Improved TreatmentAccording to surveyed trial managers, the prospect of receiving improved treatment is the number one motivator. Healthcare co-insurance payments are on the rise, and many patients would probably prefer to visit their doctors more often but simply can’t afford it. Besides the additional physician visits, for many patients, the increased attention they receive during a clinical trial is appealing. Getting additional office visits for treatments and increased time with a physician are both important motivators. While boasting an overall effectiveness rating of 7.9, the idea of receiving better medical care earned effectiveness ratings of 8.5 and 8.7 in Phase II and Phase IV, respectively.

A patient’s primary motivation is treating his or her own condition. However, another aspect, if subtle, is at play: the thought of improving treatment for all future patients afflicted with the disease. An interviewed patient recruitment manager has heard patients say, “This is my way of giving back to society. It may be small, but I am doing something to further understanding for this disease.” This thought does not occur to every patient, however. Trial staff should point out that contributing to clinical research is not insignificant — it is a valuable gift that patients can provide.

Convenience of SitesConvenience of sites encompasses many factors, including distance to patients, office hours, childcare on site, free parking and first-floor office for elderly patients. All of these characteristics make for a convenient site. Convenience of sites earned consistently high effectiveness ratings across all development phases.

When selecting sites, sponsors and CROs must recognise geographic pockets of patients. Electronic medical records make it easier to accurately identify the number of patients within a physician’s practice. Patients generally view paperwork as a hassle. A streamlined patient intake procedure would add to the overall convenience of the clinical trial experience.

Free Medication/TreatmentThe word free can motivate us to do extreme things. This phenomenon applies to medical care as well. With an overall effectiveness rating of 6.8, free medication/treatment ranked third. For areas like diabetes, an ongoing but manageable

condition, the prospect of receiving free blood sugar-testing supplies and glucometers can be a strong motivator — especially for patients living on fixed incomes. For a more invasive disease, such as cancer, treatments can cost patients thousands of dollars a year. When these types of costs are involved, free treatment for several years is a tremendous motivator.

Free medication is most effective in Phase IV trials, earning a rating of 8.8. This rating makes sense, as the drug has already been approved at this stage. A patient may have been prescribed the medication by the family doctor. If the doctor shares information about a new clinical trial open to the patient, receiving the free medication is a great motivator for participation.

Number and Frequency of Office VisitsProtocol design can drive patient recruitment as well. Surveyed trial managers rated number/frequency of visits as the fourth most effective motivator, with an average of 6.6. Limiting the number of required office visits has proved to be a particularly effective motivator across three different development phases. Phase II, Phase IIIa and Phase IV earned effectiveness ratings of 7.1, 7.3, and 7.3, respectively.

Number of visits goes hand in hand with the overall convenience of a particular site. If a site is nearby, stopping in for a weekly visit may be feasible. However, if a single site covers a large geographic region, then the trial protocol should be adjusted to require fewer office visits. Extending the time spent on each visit, along with limiting the total number of visits, may be more convenient for patients in rural areas.

Strategies to Lower Dropout RatesFor trial managers, once patients enrol into a clinical trial, retaining them throughout the full duration of the study is the next most important goal. Trial protocol design features can greatly impact patient retention. Shorter trials do not have the same patient retention issues as longer trials do. Trial designers must consider these factors when deciding on patient enrolment goals to better calculate dropout statistics.

More conservative trial designers will factor in a 30% dropout rate into their enrolment goals. For longer trials, the protocol must include patient retention strategies. Many interviewed experts believe the number one way to enhance patient retention is to make participants feel engaged with the site staff. One interviewed executive even said that the best patient retention programme is a skilled study coordinator who can give patients personal attention and make them feel like a part of something bigger.

Making patients feel special is not difficult, but it does require thought and effort. Study coordinators must think about both the physical and emotional aspects of a clinical trial. They must ask themselves: How are the patients responding physically to the treatments? Is there any way to make them feel more comfortable? Do follow-up visits trigger an emotional reminder to patients that they have the disease?

Market Report


Market Report


Study coordinators with a strong grasp on how to handle those questions will be the best defence against patient dropout. In one diabetes trial, a study coordinator gave patients a special cookbook to help them manage their new dietary restrictions. Another trial manager sent birthday cards to all study participants. Small gestures like these remind patients that the staff cares for their health first and foremost.

Several interviewed executives mentioned that another retention technique is to remind trial participants that they are not alone. Newsletters that update the trial’s progress worldwide can create a sense of connection among patients. Similarly, a web portal that provides patients the ability to share their experiences with other study participants can keep them engaged in the trial process.

Making sure that each and every patient completes the trial is a key to reducing costs. Recruiting patients after a trial has completed because dropout rates ran too high can crush a budget. With that in mind, it is shocking that 50% of all surveyed trial managers do not employ formal patient retention strategies. For those forward-thinking trial managers who do use retention techniques, visit reminders by phone are the most commonly used strategy (80%), followed by printed patient support materials and transportation assistance at 51% (Figure 2).

Figure 2: Percentage of Trial Managers Using Patient Retention Activities

Visit Reminders by PhoneReminders are a simple way to ensure patients do not miss scheduled visits — or eventually drop out of the study altogether. Reminders made by phone are the most common patient retention strategy recommended by trial managers. They are inexpensive (free) and are still thought to be more effective than MMS messaging or email. New technologies can automate the calling process, further streamlining this option. More than half of surveyed trial managers deliver visit reminders by phone during each development phase. In fact, 100% of surveyed Phase II trial managers employ this technique. Phone reminders also see heavy use in Phase IIIa and Phase IIIb.Printed Patient Support

Materials Patients need to understand the elements of the protocol they are responsible for once they leave the doctor’s office. Just over half (51%) of surveyed trial managers send their patients home with printed materials such as pamphlets or brochures. Giving patients printed material that they can take home is a traditional and highly effective retention strategy. These print materials should contain daily dosing requirements, timing of follow-up visits, space for journal entries and answers to frequently asked questions about the clinical trial. The most common critique is that support materials are often better at putting patients to sleep than informing them. Experts agree that infographics can hold readers’ attention longer and increase overall understanding of the clinical process — leading to improved recall.

Transportation AssistancePatients need reliable transportation to participate in a clinical trial. If site managers are interested in having patients return for all of their scheduled visits, it is a good idea to compensate patients for their transportation. Transportation assistance is one of the most common patient retention strategies reported by trial managers. It is used by more than 50% of surveyed trial managers in most development phases. Transportation assistance is especially important in urban settings, where most patients must either pay for bridges, tolls and parking, or buses and trains. It is also crucial to extend transportation assistance to disabled patients who might not otherwise be able to travel to a site on their own. There are countless examples of trial managers employing shuttle services for special-needs patients — easing another burden for individuals already coping with so many.

Ryan McGuire is a proud graduate of Rutgers University with a degree in finance. Born and raised in New Jersey, Ryan moved to North Carolina in 2008 to start a new career with Cutting Edge Information. Since joining CEI Ryan has led research projects in topic areas such as: clinical operations,

patient recruitment, market access, medical affairs, lifecycle management, investigator initiated trials (IITs), medical publications and medical information. His most recent benchmarking study on clinical trial costs launched in November.Email: [email protected]

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Therapeutics


Single Shot Of Dna Vaccines An Everlasting Immunity A Review Up On Fda Guidance

Abstract: DNA vaccines have been termed as The Third Generation of Vaccines due to their versatility and potential that can also be utilised to produce vaccines against some of the fatal and incurable diseases of today (such as HIV/AIDS or malaria). The recent successful immunisation of experimental animals against a range of infectious agents and several tumour models of disease with plasmid DNA testifies to the powerful nature of this revolutionary approach in vaccinology. Among numerous advantages, a major attraction of DNA vaccines over conventional vaccines is that they are able to induce protective cytotoxic T-cell responses as well as helper T-cell and humoral immunity. These advances and the emerging voluminous literature on DNA vaccines highlight the rapid progress that has been made in the DNA immunisation field. This article deals with FDA evolving policy, regulatory guidance covering a wide range of topics including delivery mechanisms, safety issues, and documenting the pros and cons of DNA vaccines. Hence we conclude that the stringent rules should be made flexible, like eliminating the requirement for pre-clinical studies and reducing the necessity for performing bio-distribution etc, for the sponsors.

Introduction:DNA (deoxyribonucleic acid) vaccination is a technique for protecting an organism against disease by injecting it with genetically engineered DNA to produce an immunological response. Nucleic acid vaccines are still experimental, and have been applied to a number of viral, bacterial and parasitic models of disease, as well as to several tumour models. DNA vaccines have a number of advantages over conventional vaccines, including the ability to induce a wider range of immune response types1. DNA vaccine is a DNA sequence used as a vaccine: this DNA sequence code is used for forming antigenic proteins of pathogen. As this DNA is inserted into cells it is translated to form antigenic protein, and since this protein is foreign to cells, immune response is raised against this protein. In this way, the DNA vaccine provides immunity against that pathogen.

Objective• To describe the evolution of FDA policy over the period of

20 years.• To provide the status of regulatory guidance and

recommendations for further changes to facilitate development in the field of DNA vaccines.

History• In 1990, in the University of Wisconsin, Jon Wolff found

that injection of DNA plasmids produced a protein response in mice.2

• In 1993, in Merck Research Laboratories, Dr. Margaret Liu found that intramuscular injection of DNA from influenza

virus into mice produced complete immune response.• In 1996, trials involving T-cell lymphoma, influenza &

herpes simplex virus were started.2

Overview of DNA Vaccines:Current vaccines consist of inactive pathogens that are inserted into the body in order to activate an immune response and produce memory white blood cells. While usually effective, conventional vaccines can potentially become inert in improper environments, or trigger an actual infection in a weakened immune system. However, recent advances in DNA vaccines represent a new generation of vaccination that can bring worldwide relief with lessened probability of causing additional damage. Vaccines are considered a baseline in most medical records today, inducing an immune response against an inert pathogen to prevent future infection. DNA vaccines provide an alternative method to produce immunity in organisms. First developed during the 1990s, DNA vaccines continue to undergo clinical trial and testing today.3 Used when modified pathogenic substances are unavailable or difficult to manufacture, DNA vaccines produce immunity within an organism without ever presenting the pathogen to the subject organism.

DNA vaccines consist of bacterial plasmids with particular pathogenic gene inserts. These inserts, which code for the surface proteins that cover the infectious agent, become integrated within the cell’s DNA. The surface proteins are transcripted and displayed by the altered cells, prompting the body to produce an immune response. The plasmid also sequences a unique promoter sequence that will allow the targeted organism to successfully transcript the encoded proteins. White blood cells and lymphocytic B-cells and T-cells recognise the displayed proteins and produce the appropriate antibodies, creating a successful immune response.4, 5

The medical value of DNA vaccines is immense. They have the capability to produce a stronger and wider immunity within the organism and can be modified to cover multiple diseases. Because of their construct with specific inserts, a plasmid can encode multiple surface proteins. The versatility and potential of DNA vaccines can also be utilised to produce vaccines against some of the fatal and incurable diseases of today.6 Studies over the past decade have indicated that DNA vaccines can be used to mimic diseases such as HIV/AIDS or malaria and produce suitable immunity. These two diseases contribute to the greatest number of deaths in underdeveloped countries. By producing immunity against HIV/AIDS or malaria, the mortality rates of individuals will decrease dramatically and the population structure of many developing countries will shift to have more adults than children, effectively slowing down the population growth of those counter

Therapeutics

Methods of Delivery:

Gene gun delivery Adsorbed plasmid DNA into gold particles

Ballistically accelerated into body with gene gun.

Syringe DeliveryEither intramuscularly or intradermally

VIRAL GENE

RECOMBINATION DNA TECHNOLOGY

EXPRESSION PLASMID

PLASMID WITH FOREIGN GENE

TRANSFORM IN TO BACTERIAL CELL

BACTERIAL CELL

PLASMID DNA Gets Amplified

READY TO USE FORM

How DNA Vaccine is Made:



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DNA vaccines are administered by two methods, as follows:Endogenous: Antigenic protein is presented by the cell in which it is producedExogenous: Antigenic protein is formed in one cell but presented by a different cell

FDA Regulatory Policy:

1) Development of Regulatory Policy

Continued progress towards the clinical development of DNA vaccines is influenced by the regulatory environment created by the Center for Biologics Evaluation and Research of the US Food and Drug Administration (CBER/FDA). CBER sets and implements vaccine policy in accordance with its interpretation of relevant Federal statutes, laws and guidelines. Existing CBER guidelines reflect the agency’s experience in the regulation of other types of vaccines and biological agents. This conservative approach helps maintain consistency in product regulation, thereby insuring compliance with the US Code of Federal Regulations. CBER policy mandates that sufficient pre-clinical data be obtained in one or more “relevant” animal

Endogenous Pathway Exogenous Pathway

How DNA Vaccine Works:

When a virus enters

the body

Muscle Cells Plasma DNA

02/10/13 - JCS Publication - Sep Print final version.indd 13 04/10/2013 14:49


Therapeutics

models to conclude that a DNA vaccine is likely to be safe and immunogenic before that vaccine proceeds into human clinical studies. Typically, pre-clinical studies are performed in mice to determine whether a vaccine is immunogenic, and in rabbits to determine whether the vaccine causes acute or chronic toxicity. A variety of studies are also required to establish that the vaccine can be synthesised reproducibly, and that it remains stable under prolonged storage. Results from such pre-clinical studies influence decisions concerning the number, timing, and dose of vaccine that can be administered to humans.

The regulation of prophylactic DNA vaccines has evolved since clinical trials of these agents were initiated in the mid 1990s. The accumulation of pre-clinical and clinical experience, including information concerning plasmid manufacture, vector construction, vaccine immunogenicity, and safety, has informed changes to regulatory guidelines. In 2007, the FDA updated its guidance document concerning the manufacture and testing of DNA vaccines designed to reduce susceptibility to infectious diseases.7 DNA vaccines intended for other uses, such as the treatment of autoimmune disease or cancer, were not covered by that document. This reflected differences in the level of risk deemed acceptable for products used to treat pre-existing illnesses versus prophylactic vaccines intended for use by the general public. The FDA’s initial approval of Phase I clinical trials of prophylactic DNA vaccines relied on evidence that plasmids could be manufactured consistently, coupled with extensive pre-clinical safety data. Early recommendations concerning DNA vaccine manufacture and testing were largely based on FDA experience involving other types of vaccines and DNA-based products.8 Since that time, considerable additional information and experience has accumulated concerning DNA vaccine manufacture, activity and safety.9 That new information formed the basis for revisions in FDA regulatory guidelines.

2) Assessment of Regulatory Policy

The development of pharmaceutical products is envisioned as a linear process, wherein drugs or biologics discovered through basic research progress to pre-clinical animal testing and then into Phase I - III clinical trials. The development of DNA vaccines has not followed this linear route, as immunogenicity concerns have short-circuited efforts to progress from small Phase I to larger Phase II/III immunogenicity and efficacy studies. To date, numerous Phase I studies have been conducted to distinguish among the various plasmid components, sequence motifs, adjuvants, sites/methods of administration, and other variables in terms of their impact on vaccine immunogenicity.10 Indeed, rather than developing a single product, those involved in DNA vaccine trials commonly design multiple “candidate” constructs (simultaneously or in succession) to identify elements that can be incorporated to improve the immunogenicity of subsequent vaccines. While existing CBER guidelines seek to maintain consistency in product regulation and maximise compliance with the Code of Federal Regulations, such policy does not recognise or accommodate to the exigencies of DNA vaccine development. Thus, the conservative nature of current regulations may hinder efforts to improve vaccine performance. As noted above, most Phase I DNA vaccine trials utilise “candidate” plasmids (or plasmid/adjuvant combinations) that are unlikely to proceed further towards licensure. An optimised

regulatory policy for DNA vaccines would therefore facilitate the conduct of multiple Phase I trials, with each trial involving only a small number of human volunteers.

3) Recommended Changes to Regulatory PolicySeveral policy changes would significantly lower the cost and accelerate the initiation of Phase I studies: • CBER should require less extensive toxicology (including integration) testing for “candidate” vaccines entering Phase I trials. The requirement for such data could be shifted to vaccines intended for Phase II/III study.

Rationale: The authors recognise that this policy change might be perceived as increasing the risk to subjects participating in Phase I trials. However, even extensive pre-clinical animal testing does not necessarily reduce subject risk, as the predictive value of rodent studies for DNA vaccines used in humans is unreliable. Indeed, strong protective immune responses have been repeatedly achieved in mice but not in man. In terms of the safety and toxicity studies performed in mice and/or rabbits, such studies uniformly indicate that DNA vaccines are safe.11 In the absence of a DNA vaccine that causes toxicity, the reliability of either animal model in predicting an adverse clinical outcome cannot be ascertained. Thus, the added value of extensive toxicology testing for “candidate” vaccines is unclear. Moreover, the safety of DNA vaccines is by now well-established in human clinical trials.12

• CBER should require less demanding product manufacturing data for “candidate” vaccines entering Phase I trials. The requirement for such data could be shifted to vaccines intended for Phase II/III study.

Rationale: The safety profile of DNA vaccines has been excellent. Manufacturers need to establish that candidate vaccines used in Phase I studies are sterile and free of endotoxin. As “candidate” vaccines are administered to only a handful of volunteers, issues of lot-to-lot consistency and purity become important primarily for those plasmids that proceed into Phase II trials. Any potential risks associated with such a relaxation in regulatory requirements could be managed by conducting dose escalation studies that minimised the number of volunteers exposed to novel vaccines.

• Increase the access of biotech and academic investigators to the FDA for advice on trial design/conduct. This would include increasing the number of pre-IND meetings allowed and permitting sponsors to contact FDA reviewers for advice “on the record” concerning their product. Mirroring the European regulatory model, the FDA could receive reimbursement for such broadened access, enabling the organisation to hire and train the additional personnel needed to provide these services.

Rationale: Pre-IND meetings facilitate the open exchange of data and ideas between those producing new DNA vaccines and those regulating such agents. These meetings have proven extremely useful to manufacturers and CBER reviewers alike. The number of pre-IND meetings was restricted years ago when CBER resources were limited. New resources have been provided to the FDA, and should be channelled into supporting more of these highly effective interactions. Similarly, allowing FDA

Therapeutics


reviewers to provide reliable advice on an ongoing basis would be of considerable benefit to vaccine manufacturers.

• Define “candidate” vaccines as “well-characterised products”. This would allow the biochemical analysis of plasmids to substitute for biological potency assays of “candidate” vaccines. Similarly, the conduct of comprehensive biodistribution and integration studies could be shifted to those products entering Phase II trials, speeding and reducing the cost of Phase I studies.

Rationale: All biological agents entering clinical trial should be sterile and non-reactogenic. However most “candidate” DNA vaccines will not progress beyond Phase I study. In such cases, requirements concerning the nature and extent of product characterisation should be limited.

4) The Regulatory Status of DNA Vaccines:DNA vaccines combine the biotechnological manufacturing

aspects of a subset of gene therapeutic medical products with the mode of action of a classical vaccine. Due to this hybrid state, the regulation of DNA vaccines requires expertise from both gene therapy and vaccine experts. The regulatory authorities in Europe and the USA have established slightly different regulatory pathways for plasmid DNA vaccines for prophylaxis against infectious diseases versus for therapeutic use.13

In the European Union, a therapeutic DNA (vaccine) is

considered as a Gene Therapy Medicinal Product (GTMP), whereas vaccines against infectious diseases are explicitly excluded from the GTMP definition (2001/83/EC). The centralised procedure for the marketing authorisation application is mandatory for DNA vaccines, whether they are used for therapeutic purposes or against infectious disease (726/2004/EC).

In the USA, the distinction between the alternative usage of plasmid DNA as a medical product is similarly recognised and impacts on their regulations. DNA vaccines against infectious diseases are regulated by the Center for Biologics and Evaluation and Research (CBER) Office of Vaccines Research and Review (OVRR), whilst DNA vaccines that are intended for non-infectious therapeutic indications fall under the responsibility of CBER’S Office of Cellular, Tissues and Gene Therapies (OCTGT).

Vaccinations Guide:14

DNA vaccines offer a novel method of immunising people against not only viral and bacterial diseases, but a host of parasitic and fungal infections as well. This technique relies on the introduction of genetic material from a particular disease-causing pathogen into human cells through a specially engineered delivery system. This leads to the secretion of proteins normally expressed on the surface of pathogens from human cells, and these proteins trigger a defensive response that can immunise an individual against the actual pathogen without any need for exposure to the disease-causing agent.

While still in development, this vaccination technology offers some distinct advantages that would make it an invaluable asset in vaccination and immunisation programmes. In this article we look at some of the benefits of DNA vaccines when compared to existing vaccination techniques, and some of the obstacles we face in getting these vaccines into popular use.

Pros of DNA Vaccines:Because of a number of distinct advantages DNA vaccines can offer over existing vaccination techniques, the technology has drawn a lot of interest. It would not be under development if it didn’t offer a distinct solution to problems we face with immunisations today.

Increasing the Scope of Administering to a Variety of PopulationsFirstly DNA vaccines do not contain an actual infectious agent, whether dead or alive. One of the classic methods of vaccination is the introduction of a live but weakened version of a pathogen into a person. This has proven effective thus far, but does offer some distinct safety concerns. The risk of reversion for example, where the vaccination strain mutates and becomes virulent, is one such issue, as is the fact that these vaccines can’t safely be used in people who are pregnant, elderly, or suffering from any one of a number of chronic diseases. These concerns are not relevant to DNA vaccines, which could potentially be given to virtually anyone regardless of health status safely, and without any risk of reversion.

In Terms of Transport DNA vaccines are also less susceptible to damage due to environmental conditions, such as extreme temperatures or humidity. They can safely be administered to people who live in areas where regular vaccines are difficult to maintain or may be compromised due to the lack of proper storage facilities in unique environmental conditions (EX: India - particularly in countries where healthcare and transport infrastructure isn’t as well-established). DNA vaccines, if integrated into the body appropriately, can produce a sustained immune response, making booster vaccinations unnecessary.By receiving a DNA vaccine, an individual can have lifelong immunity towards a disease by simply receiving a single shot. One of the problems with some vaccination technologies is the fact that multiple booster doses are needed for a vaccine to effectively immunise an individual, which would decrease the demand for boosters along with the price of the vaccines.

Economical BenefitsBesides the general medical benefits, DNA vaccines can provide a large economic benefit as well. Due to the decreased restrictions in the production and storage of DNA vaccines compared to regular vaccines, the cost of producing and maintaining DNA vaccines is much lower. The prevention of disease by using DNA vaccines reduces the amount of money spent on medication. This can be especially beneficial to people in developing countries. This lower price can also be attributed to the difference in the production cost of current vaccines and DNA vaccines. According to specific case studies, it can be seen that the cost of developing and manufacturing a successful and beneficial regular vaccine can range from $500 million to $1 billion. Comparatively, the development and manufacturing of a DNA vaccine ranges between $200 and $300 million.15DNA vaccines also offer advantages in terms of their production. Once tested for efficiency and safety, a DNA vaccine can be generated in large volumes at a much lower cost than some traditional vaccine types. The DNA vaccine in question would also be easier to transport as there are no particular storage requirements (live vaccines for example need to be kept refrigerated).

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Vaccination is Not Limited to Viruses/Bacteria Finally, DNA vaccines can potentially be applied to a broader range of disease-causing pathogens like fungi and parasitic organisms. At present, most vaccination technologies are limited to viruses and bacteria.16

Cons of DNA Vaccines:14

At present there still some obstacles limiting the potential uses of DNA vaccines, including the fact that this type of vaccination would be limited to pathogens with a distinctive protein immunogen (molecule that triggers an immune response). Some pathogens possess non-protein immunogens - bacteria with sugar coats for example. DNA vaccines also present a slight risk of potentially disrupting normal cellular processes. This has yet to be shown as a major concern; however, there is a chance that the introduction of foreign DNA into the body could affect a cell’s normal protein expression pathways. Two concerns regarding the effectiveness of the vaccine itself revolve around the body’s reaction to the vaccine. The first is the chance of an immune response against the DNA itself, or the DNA delivery vector, which would defeat the point of the vaccine as a whole. If such a reaction were to occur, no protein immunogens would be expressed, and there would be no immune response to those immunogens, and hence no immunity against the pathogen in question. Secondly, there is a chance that the body develops a resistance or tolerance towards the protein the vaccine introduces. This would again defeat the purpose of the vaccine, which is to stimulate a lasting immune response against the injection.

DNA Vaccines on Infants:There is also some concern over the application of DNA vaccines on infants. Since the fetal immune system often cannot differentiate between the transformed cells and regular cells, this child essentially develops no immunity. This raises concerns that DNA vaccines may in fact be highly detrimental to the immune system of the infant. This inability of self-differentiation renders many potential, and basic, infant DNA vaccines ineffectual. Adults do not face this problem as the immune system can readily differentiate between the self and the non-self. While theoretically, and in the future, a single dosage of DNA vaccine could be applied to an infant for all common childhood diseases and produce a strong immunity, current methods of construction of DNA vaccines do not allow this to be successful. At the current stage, however, DNA vaccines cannot be administered to infants.4 Though the methodology is not foolproof as of yet, DNA vaccines could potentially become the next greatest technology of the century and give rise to further biotechnological advances in the future.

Ethical Concerns about this New Method of InoculationDespite the medical, economic, and humanitarian benefits of DNA vaccines, there are also several ethical concerns about this new method of inoculation. Because DNA vaccines alter the genome of the targeted cells, many consider DNA vaccines to be a form of genetically modifying organisms, a cause for great ethical debate. Some individuals feel that scientists are attempting to alter organisms at the molecular level and are thereby “playing God.” Others worry about the long-term

impacts of adding sequences to the human genome.4 By inserting a foreign DNA fragment into an organism’s genome, there is a concern about the possible effect that the new encoding will have on the host. If DNA can be introduced to produce specific proteins to prevent infection, could the same procedure not also be used to deliberately modify an organism? A DNA fragment could potentially be inserted into an organism’s genome at an early stage of development and could alter the organism as a whole. The long-term effects of DNA vaccines on the human genome are not yet fully understood. Theoretically speaking, the DNA vaccine should only be potent for a short amount of time due to the natural cell cycle. However, there is still not enough scientific evidence to indicate the conclusive long-term impacts of tinkering with an organism’s DNA.

Conclusion:The FDA’s guidance evolved over time, reflecting the understanding gained concerning issues associated with DNA vaccine manufacture, immunogenicity and safety. Many of those changes involved a relaxation in regulatory requirements, such as:

1. Providing sponsors with greater flexibility in the selection of potency assays for lot release testing during early clinical development,

2. Eliminating the requirement for pre-clinical studies designed to specifically evaluate whether DNA vaccines induce autoimmunity, and

3. Reducing the necessity for performing biodistribution, persistence and/or integration studies of certain DNA plasmids.

In developing countries like India, where financial conditions/growth are at a much slower phase compared to other developed nations. Here the country is already investing so much to develop vaccines to protect the human race against deadly diseases, besides which if the country has to spend on preserving these medicines, this will be an unbearable burden on the financial conditions of the country, which in turn will impact on the development process. To overcome these drawbacks, development of DNA vaccines will be more appropriate, which does not require any special storage conditions and is also cost-effective.

DNA vaccines • Use only the DNA

from infectious organisms.

• Avoid the risk of using actual infectious organisms.

• Provide both humoral & cell-mediated immunity.

• Refrigeration is not required.

Traditional • Use weakened

or killed form of infectious organism.

• Create possible risk of the vaccine being fatal.

• Provide primarily humoral immunity.

• Usually require refrigeration.

DNA vaccines vs Traditional vaccines:

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15. Mahoney, Richard T., Yu-Mei Wen, and Henry Wilde. “The Introduction of New DNA Vaccines into Developing Countries.” National Center for Biotechnology Information. http://www.ncbi.nlm.nih.gov/// cited [2013-06-06]See more at: http://triplehelixblog.com/2011/01/medical-

innovation-future-promise-of-dna-vaccines/#sthash.Pohh7Rnf.dpuf

16. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/prinvac.pdf cited [2013-06-06]

17. http://www.medscape.com/viewarticle/715527_6 cited [2013-06-06]

Srinivas Madhukar. R is pursuing Master in Pharmaceutical Regulatory Affairs from JSS University. He is undergoing training in Regulatory Affairs Department in Micro Labs Limited, Bangalore. He received the 2nd Best Poster Award for his presentation in 2nd International Regulatory Affairs Conference by

OMICS held in Hyderabad in November, 2012. He published an article titled “Cold Chain Management in Vaccines Logistics - A Review”. Email: [email protected]

Balamuralidhara V. is an Assistant Professor in Department of Pharmaceutics in JSS College of Pharmacy, Mysore. He has teaching experience of 10 years. He has authored 16 International and 11 National publications in reputed journals and a Book. He has attended various conferences and currently he is

working on Biosimilars.Email: [email protected]

Shilpi Khattri is currently pursuing full time Ph.D in Regulatory Affairs from JSS University, Mysore. She secured the highest marks in M. Pharma (Regulatory Affairs). She is graduated (B. Pharma) from Manipal University, Manipal. She published an article

titled Pharmacovigilance Regulations in India: A Step Forward in a reputed journal. Email: [email protected]

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

Email: [email protected]

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The United Federation or the Mafia?

In fact, there is a slight ‘cultural mismatch’ between ABC and CheckTrial. But it’s difficult to see. These things are often invisible, but they have an inexorable effect on relationships.

How Can We Explain Cultural Differences?This topic is wrapped in all sorts of sociological jargon. Let’s try to disperse this by making analogies that the theorists may be uncomfortable with, but we think make the point!

Since the dawn of time, our societies have been evolving ways to interact with each other. Humans since the Stone Age have built commonly understood principles of authority, exchange and what’s OK/what’s not OK, in order to survive and prosper. As new styles have developed we haven’t completely lost the older ones, and we can exhibit aspects of at least five different sets of behaviour in varying situations. But in general, most people will adopt the ways of doing things that they sense around them – it’s like a ‘cultural DNA’. We can classify these ways of thinking about the world into several key types, which are illustrated below. Each has ‘healthy’ and ‘unhealthy’ effects.

It’s natural to want to ‘fit’ people from different countries and ethnic groups into these categories and to an extent that can be done. But what is less well recognised is that organisations such as companies, government bodies, even sports teams, can have a prevailing cultural type. In some cases, even separate bits of large organisations can have different types. And it’s when there is a mismatch – when you fit naturally into one and a partner company is another – that you will almost always have problems.

In theory, CRO partnerships should work perfectly well. But many do not. One reason that there is so much debate about this topic is that it’s difficult to assess why they don’t. But there is some helpful thinking about this, which emphasises four key elements of a business partnership that need to be addressed in order to make it work really well – Strategic leadership,

effective cross-company teamwork, relationship skills on both sides, and perhaps the most difficult to measure – cultural compatibility. How can you tell if this is a problem? This article might help.

Christine is an outsourcing manager for ABC Pharmaceuticals. Three months ago they contracted CheckTrial to manage a Phase IIb and Phase III study in Europe. CheckTrial’s track record was perfect and the contract / deliverables were agreed happily by both parties, with open negotiations on both sides. Now there are signs that not everything is working well. Delays are creeping in; things that seem common-sense to Christine and her colleagues, such as when to escalate issues, and which minor decisions need to be taken quickly, seem not to be understood by CheckTrial’s staff. All through the negotiations, CheckTrial seemed almost a mirror of ABC; many of their staff had worked in the pharma business previously. They are open, keen and communicative. They are based in the same area of the country as ABC are. Have they prioritised work for other clients? Have they put lower-performing staff onto the ABC account? There is no evidence of that. It’s a mystery as to why it’s happening and despite promises from CheckTrial’s Account Manager, things don’t seem to be improving. There is only one thing that Christine can be certain of: ABC clinical managers are complaining to her and and asking why she recommended CheckTrial in the first place, and what she’s going to do about it now?

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The TribeOne of the earliest cultures to evolve, this emphasises loyalty and belonging. Protection and benefits for the tribe, family or clan, and enmity (sometimes violent) for those outside it. It’s strongly based on rituals, frequently racism, and respect for elders. Relationships are far more important than rules or laws. These tribes exist today in our society, but keep themselves anonymous and exclusive. Some highly exclusive societies do perform good works, but many do not. This is not a tenable attitude for organisations that interact with the general public, and in corporate life this way of doing things has largely been eradicated by modern needs.

The EmpireWe still refer today to ‘empire-building’ as a negative trait in companies. Influential individuals compete for power – personal control of as many people, resources and territory as possible. Rules and processes are there, but are interpreted by each player for their own benefits. It’s necessary to ‘court’ the powerful leaders, who may at one time be generous and at another be capricious and unpredictable. In corporate life we may see this culture represented in the stereotyped fiefdoms of hospital consultants, and of course in party politics. We may also see it in entrepreneurially-driven businesses. It can be enormously dynamic, and tends to work well at the start, but runs into trouble eventually.

The BureaucracyThis was the triumph of developments in the 17th and 18th centuries, in overcoming the organisations’ reliance on the favour of monarchs. Absolute power is not allowed. Obedience to rules is vital, processes must be followed. In particular, the rules exist separately from those in charge. Rules evolve and change slowly and methodically. You always know where you are, and how you progress, because there is a hierarchical organisation chart. The higher you are on this chart, the more authority you have. You have a clearly defined job and you don’t step outside of it. Who and where you are is more important than how expert you are.The military has run this way for a century and still does well with it today. Nearly every corporation has a hierarchical model at its core. At its best it’s fair, careful and protective. At its worst it can be risk-averse, stifle creativity and block essential change.But we must not overlook that fact that a trust in this way of doing things still beats in the hearts of millions of people worldwide.

The MarketScientific and technological progress, and the inexorable rise of bank-led economies, go hand-in-hand with a culture that values achievement over anything else. Law and rules are important, but not so important that they get in the way of keeping the customer satisfied. Fascination is with leaders rather than managers – people who can break the rules to achieve great things, yet take people along with them. Youth or class is no impediment to progression. You are paid for your performance – what you do not how much time you’ve served.

‘Process re-engineering’ – removing elements from a business that don’t add value, sits in this culture. The benefits of this culture are clear – agility, profit and removal of all sorts of nonsense. The downsides are the excesses of capitalism and a lack of care for vulnerable individuals.In our lifetime, mismatches between this market-oriented philosophy and the earlier, bureaucratic one have generated endless conflict, which still rages today. Even within an organisation we may find a senior management cadre driven by the values of strategy, goals, economic realities and customer benefit, mixed with a workforce that is largely more comfortable with hierarchy, fairness, order and certainty.

The CommuneThis culture has grown along with the market-oriented one. It is often not a complete description of how an organisation would work, but represents a very strong pocket within it. It is often found where types of jobs are seen as vocations and deeply caring, but not always.The noblest action in a commune is self-sacrifice for the benefit of others. To reward this, this type of culture avoids any form of discrimination between its members. Hence, performance-related pay is resisted doggedly; firing someone is only possible after protracted processes, and then frequently avoided at the last. This culture is difficult to distinguish from the bureaucracy, but perhaps it is in its absence of class and prejudice, which marks traditional bureaucracies’ manager selection processes.

The NetworkOne of the features of the above ways of thinking and behaving is that within them they feel legitimate and all of the others are assumed to be ‘wrong’. But this culture is the first that acknowledges their differences and tries to integrate them, or at least facilitate them working together. It has been discussed for many years, and people have worked tirelessly to make it a reality, with some success, but a lot of pain on the way. The most obvious example is ‘matrix management’ – which blends goal-oriented (‘market’) thinking into command-oriented (‘bureaucratic’) structures, with project managers to guide everything along. The difficulties are caused time and time again by the most natural of human behaviours: people just don’t do what they are told. They revert to the ways of doing things that seem natural for their cultural heritage.Yet this way of working is gradually assuming its place in organisations that are really serious about it.

Extreme Example - The Mafia

Extreme Example - The Tudors

Extreme Example - The Civil Service

Extreme Example - 1980’s

Government

Extreme Example - Schools

Extreme Example - The Federation

What cultures might organisations adopt?

Volume 5 Issue 6 Journal for Clinical Studies 47

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Volume 5 Issue 6 48 Journal for Clinical Studies

Sometimes just looking at the extreme models above is enough to let people like Christine, in our earlier example, sense the differences between the two organisations that are causing problems.

But often there won’t be so marked a difference and more subtle measures are needed. These can be subtle indicators and perhaps too easy to dismiss by impatient managers keen to conclude negotiations. Or of course rejected as ‘psychobabble’.

But there is a lot of money, time and quality at stake in CRO partnerships, and it would be sensible to make sure it’s likely to be spent wisely. The best approach is not to use words like ‘culture’, ‘bureaucracy’ and so on. It may be fun to have a

conversation within your trusted team where you describe another organisation as ‘the Mafia’, but you may not want to do this within the company at large! Instead look at ‘ways that they do things compared to the way that we work’. It sounds more practical and it is.

Of course, if there is a mismatch, and there is nothing you can do about it, what is the point? Should we reject deals with companies that don’t match our culture? Not at all. These differences can cause problems but they are usually slight. The simple act of raising peoples’ understanding of likely pitfalls is enough for the various players to adapt accordingly. These are simple, cheap strategies that can prevent huge problems down the line.

Diagnosing Which Culture You’re Dealing WithAs we have said, the subtle difference between players means that some expert help is usually required to diagnose them. But with some interviews, some quick questionnaires or other tools, or perhaps observation of some meetings, a useful assessment can be produced, and a ‘risk assessment’ for the partnership. Often, one team session with appropriate facilitation is enough to flag up what to be careful of. What you may hear is some of the cultural ‘buzz words’. This is what they mean in the context of our example of ABC Pharma and CheckTrial:

References1. Geert Hofstede – Cultures and Organisations2. Don Beck and Christopher Cowans – Spiral Dynamics3. Ken Wilber – The Theory of everything4. Fons Trompenaars – Riding the waves of culture

‘Group vs. Individual’Do people express exactly what they think? Or do they tend to espouse the views of the company, whatever the situation? If ABC is fairly individually-oriented, their staff may feel that CheckTrial’s people are covering up any problems that arise and not being honest. For CheckTrial it feels simply like being loyal.

‘Power distance’To what extent do people accept that senior people have much more authority? ABC may well be experimenting with pushing decisions down to the lowest level (as many companies are) but CheckTrial may have a more rigid hierarchy, and most everything needs to go ‘up the line’ – decisions will be slower.

‘Affective vs. Neutral’When something really works well, why don’t they seem pleased? For some, expressing emotions at work is a natural thing, and for others it doesn’t feel right. CheckTrial peoples’ reticence may be assumed to be doubt, lack of agreement or enthusiasm. For CheckTrial, it’s just being businesslike.

‘Rules vs. Relationships’How much do people stick to processes? We know many that can’t be deviated from, but where there is room for manoeuvre, how do people operate? For example, many people in ABC may feel that decisions are made before a decision-making meeting even starts. In CheckTrial perhaps it’s more formal, but the ABC way of working may seem haphazard and unpredictable.

‘Uncertainty avoidance’How comfortable are people with risk-taking? CheckTrial may well think that ABC are ‘winging it’ with a brand new strategy, and retreat into even more of a cautious style – making it seem that they are delaying things even more. Yet ABC may well be on course for FDA ‘breakthrough’ status.

‘Achieved vs. Ascribed’ How much do we trust someone’s track record? In ABC, it may seem that people that fit into certain stereotypes get the promotions, irrespective of their performance. Sometimes to get on, you have to move out. But in CheckTrial there may be more of a genuine meritocracy.

Should you pay attention to all this?

John Faulkes began his career as a scientist in the pharma industry, then in HR as an L&D Business Partner, before founding a training /consulting business, and a learning-related IT firm. John has helped cross-functional and international teams to raise

awareness of cultural differences within them and adopt better ways to manage / overcome them in day-to-day working. Also between partnered companies.Email: [email protected]

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


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The Importance of Communication in Life Sciences – Openness and Cultural Considerations

Full and open communication between companies working in partnership is important in all business sectors. An awareness of cultural differences can be just as important. I would argue that these are absolutely crucial in life sciences, and can indeed make or break projects.

Let me explain. I previously worked for a UK CRO that was awarded a project from a European biotech company. The project required us to add known amounts of viruses to a downscaled, laboratory version of the biotech company’s product purification process. We then measured the amount of virus that appeared after each purification step. The aim was to demonstrate complete viral clearance, thus indicating that even if there was a catastrophic introduction of virus derived from human or animal starting materials (eg. blood) then all of the virus would be removed by the processing steps – thus adding confidence in the purity of the final product.

If no virus is observed in the final product, we can further maximise the viral clearance figures, and thus the scope of confidence, by looking at ever greater volumes of product (obviously if we find no virus after looking at 100ml of product this is better than finding none after only looking at 1ml of product). Of course, this approach of looking at greater volumes of product is more expensive.

The biotech company had asked for the least expensive option, and made it clear that price was the deciding factor in placing the business. Although we discussed the larger-volume option verbally with the client, we did not think it wise to quote for it and only quoted for the basic approach. We also asked for a face-to-face meeting with the biotech but, due to their belief that their English was not good, they said that they preferred to plan the study by email only.

The study went ahead and demonstrated complete viral clearance. However, as we did not examine larger volumes of product, we could not show the high levels of viral clearance that the biotech wanted. This meant that the biotech was unhappy with our conclusions and needless to say it was resolved in court! Ultimately the judge determined that both sides had made assumptions that they should not have, and decided that the biotech should still pay for the study but that they should only pay 50% of the agreed price.

Both sides lost. The biotech did not get the results they could have, and we lost money and the short-term goodwill of the biotech company. Lessons were learned. As a CRO, from that point onwards, we ensured that we always discussed and quoted on all options, even if this might mean we lost business through our proposal being seen as too expensive. We would also always

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push for a physical meeting, and if verbal communication was seen as a barrier then we would offer face-to-face interpreters. The above became standard policy.

Life science projects are complex and expensive, and both teams need to know exactly what is expected of them! Thorough and full communication is fundamental to this. Once we address open and full communication, there are also challenges associated with language and culture.

Again, let me explain. Ever since being a boy, I have been fascinated by the planet Mars. At first, after reading HG Wells’ ‘War of the Worlds’, my imagination was filled with terrifying and threatening aliens waiting to launch another invasion of Earth. Later, as I became interested in science, I found it exciting to think about a planet, like ours, with polar ice-caps and water under its surface. More recently, fossilised bacteria may have been discovered and some scientists believe that such bacteria may have ‘seeded’ Earth by travelling through space on rock flung up as a result of Mars suffering an explosive impact – making us all originally Martians!

Many unmanned probes have been sent to Mars over the years. One of these was the Mars Climate Orbiter launched by NASA in December 1998. This spacecraft cost $700,000,000 and took almost a year to make its lonely way to the Red Planet. We can only imagine the excitement at Mission Control as, at last, the probe approached its destination. As the spacecraft started to position itself to begin its orbit of Mars, all communication was lost! Frantic hours went by before the mission was declared void. And now the investigations began. Incredibly, the resulting report detailed that the spacecraft was destroyed as it tried to enter its orbit due to ground-based computer software which produced output in imperial units (of pound-seconds), instead of the metric units (of newton-seconds) which had been specified in the contract between NASA and Lockheed. Instead of entering a successful orbit, the spacecraft orbited Mars at an incorrectly low altitude, causing it to enter the upper atmosphere and disintegrate.

I can remember reading this story with incredulity! But it does illustrate one point – the scientific culture of the USA was, and still is, defined by imperial measurement. The software experts involved were oblivious of any potential conflict as they were unaware of the use of the metric system – it was, and is, not a part of their culture! If only the cultural component of the project had been considered!

When we do consider cultural components in communications between scientists, such communication does become easier and more accurate. However, if the scientists speak different languages then we have another barrier to cross.

English is now almost exclusively the language of science - by learning a single language, scientists around the world gain access to humanity’s vast scientific literature and culture, and can communicate with other scientists anywhere in the world. However, for non-native speakers, there are obviously challenges! Just 5% of the world’s population are native English speakers. So, for scientists whose first language is not

English, writing grants and academic papers, preparing oral presentations, and communicating directly with other scientists in English is much more difficult than it is for native speakers of English. It may appear obvious, but those of us lucky enough to be native speakers should adopt an attitude of patient understanding. We can assist by helping with the preparation of text or presentations. If there are language errors, we should only offer constructive criticism, use actual examples that are unclear and suggest improvements. It is also fine to suggest seeking the assistance of expert English speakers or professional editing and/or translation services in preparing revised versions of manuscripts.

English, currently, is the global language of science. Optimising communication among members of the international community of scientists depends on elimination of obstacles – we should be open, clear, aware of cultural differences and cognisant of the global requirement to use English. This ideal can best be achieved when all of us, as members of the scientific community, work together. This is a key to scientific progress.

Dr Kevin Duff has spent 32 years working as a scientist in the life sciences industry. He has worked for several CROs, organising both preclinical and clinical studies, managed cell culture and viral vaccine production and has worked extensively in the project management of multinational clinical trials. Kevin is keen to

make Global Voices the first choice in Europe as the Language Service Provider for life science companies.Email: [email protected]

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As budgets become tighter and tighter, many pharmaceutical, biotechnology and device companies are having to continually re-assess the way that they are supporting research & development activities to ensure a cost-effective approach whilst maintaining quality.

Some companies have moved towards a full-service strategic approach utilising either an exclusive or dual-vendor strategy, others have moved towards a more functional approach utilising different strategic vendors for different service areas, and others still have continued with a more ad-hoc preferred vendor approach where competitive bidding continues. In addition, the role and cost associated with the use of in-house staff, contractors and the locations of those staff continue to be key decision points in regard to the most optimal strategy.

As a niche vendor with global capabilities, we are seeing a wide range of scenarios, and this paper assesses the different strategies that we are finding together with some considerations when assessing each type of strategy.

In-house SupportIf measuring the cost of staff at a salary level only, there would be a good case for maintaining a large in-house capability across functions with minimal outsourcing. FTE salary costs are lower than the rates provided by both contractors and CROs. There is also the added benefit of keeping knowledge in-house and maintaining control in terms of who is doing what and where. However, when measuring overall cost, it is also important to take into account the many overheads that every staff member has. Costs associated with buildings, utilities, benefits, management, attrition, technologies and training all need to be added to the cost per head. The location of offices can also impact overall cost since the offices could be based in higher cost locations.

In addition, flexibility can be compromised as the FTEs are located in fixed locations and work either needs to be allocated according to spare resources or people need to have some idle time built into their work. The peaks and troughs of work according to the pipelines of work and the limited visibility can make this all the more challenging. The efficiency and effectiveness of those working in-house also need to be taken into account. There needs to be a wide range of productivity metrics being collected and reviewed, and the technologies and tools available to enable day-to-day work may also impact productivity positively or negatively.

Since contractors and CROs are working across multiple clients and many of these overheads can be removed or diluted, there is a strong case for outsourcing aspects of clinical development where possible. What initially can look like higher hourly rates compared to internal salaries can quickly become comparative or even more competitive when compared to the total cost of a person working full-time within a pharmaceutical company.

Contingent Workforce Utilising ContractorsThe amount of flexibility during peaks and troughs can determine the efficiency of a solution. The use of contractors has become an option to many companies to ensure resource availability without the commitment and overheads of a FTE. Many people are attracted to becoming a contractor due to independence and higher hourly rate which makes up for the insecurity of not having contracts 100% of the time. Hourly costs are higher than an FTE within a company but are often lower than a CRO cost. Much like the FTE costs though, there are hidden costs associated with a contractor and also negative aspects, in addition to the positives of increased flexibility and reduced commitment.

This approach was, until recently, a preferred way of working with many pharmaceutical companies choosing to work primarily through a mixed in-house / contractor model with the use of CROs as required to fill any specific needs. However, recent changes in employment regulations, higher hourly rates than FTEs, and the ability for these staff to quickly move to other companies resulting in loss of knowledge and increased cost of replacement, means that this approach has become less attractive. This has resulted in many pharmaceutical companies moving towards the use of CROs.

The management and oversight of a large number of contractors also adds further to the costs, and higher turnover means that having a consistent, high-quality team can become more challenging. Overseeing the overall quality, training and tracking of the team and ensuring tools and technologies are optimal can also become a large task for pharmaceutical companies that choose this approach. Many contractors are also required to be on-site which then adds all the overheads seen by an FTE. A number of pharmaceutical companies that have historically used this method are now moving towards an outsourced approach to a CRO using one of the below methods to improve flexibility, assure quality, minimise oversight and reduce overall costs.

Competitive Bidding OutsourcingFor many years, the competitive bidding process using preferred vendors was the primary approach utilised to contract work to a CRO for many pharmaceutical companies. It is still the case in some companies. In a lot of cases, a preferred list of vendors would be used, and in others, a qualified list would be available. Whilst many companies managed the process via outsourcing teams, the actual selection was often decided primarily within the operational teams. With each study team having their preferred companies to work with in different service areas, the ‘preferred’ list could be huge. Managing and overseeing the quality of these vendors could be a massive task, and the competitive nature would mean that strategic approaches and initiatives to improve partnerships could be difficult to instil. However, the competitive nature did mean that if managed very closely and negotiated smartly, then individual study costs

A Review of Sourcing Approaches Within Clinical Development

could be reduced which would lead to savings. This model also fits well with a model that utilises in-house staff / contractors and uses CROs to meet specific needs.

Under this approach, and other approaches that utilise a CRO, companies need to determine what the benefits (and negatives) are of moving towards the outsourcing of work compared to in-house / contractor approaches. Speaking on behalf of a CRO, the obvious benefits include enhanced flexibility, ability to utilise efficiencies often seen within a CRO due to their cross-company support, ability to use lower cost locations and because it is a service industry, there is often a high focus on productivity, metrics and cost optimisation. Investment in tools and technologies also continues at a high pace, and a CRO is well placed to invest in these technologies since it is focused only in these areas and any investment can benefit multiple customers.

However, there are also perceived negatives when determining whether to outsource to a CRO, in particular the sense of a loss of control, the loss of in-house expertise, and the perception that costs are higher compared to FTE costs. Processes also need to be put into place to oversee the CROs to ensure quality, optimise communication, track key performance indicators and minimise issues. If the list of preferred vendors is big, then the investment in time to assure these can also be big.

Functional Service Provision (FSP)Whilst having a massive list of approved vendors that competitively bid has positives in terms of diversity and access to specific expertise, there are also challenges around the management of such large numbers of vendors as discussed above. In addition, if lots of vendors are receiving small pieces of work, then partnerships between a customer and the CRO can be difficult to build up and time to invest in building such partnerships is very limited. There will not be as much allegiance or focus on improving relationships. By selecting strategic partnerships with higher volumes, there will be a much higher focus on ensuring an optimal partnership as the revenues will become more important.

Functional partnerships usually consist of a small number of CROs with expertise in specific areas taking on responsibility for specific functions. For example, companies will often have functional providers for clinical operations (monitoring etc), data management, statistical programming, biostatistics, medical writing and pharmacovigilance. A company could decide to split functions further or have a single provider across multiple functions. It is usual though for 2-5 vendors to be selected per function. The idea is that the smaller the number of vendors, the more focus on partnership development can be given by the pharmaceutical company, and the higher the volume of work that ensures a priority focus by the CRO on the partnership. Whilst a small number of companies have formed exclusive partnerships, having more than one vendor enables some degree of competitiveness and prevents reliance on a single company.

Functional partnerships are often preferable because it allows the use of vendor companies that have focused expertise

in specific functions. There can also be competitive benefits to having multiple CROs involved in a single study or programme, rather than a single CRO across all functions, and there is also an element of risk mitigation by having multiple partners.. Having functional partners also should result in efficiencies across studies that can then help to reduce the overall cost of the work if programs are outsourced intelligently. This, coupled with less oversight, optimal overheads, reduced contractual development and improved communication pathways can enable the total cost to be lower that utilizing in-house or contractor approaches. From an operational efficiency perspective, a CRO with specific functional expertise will have invested its development of tools, technologies, processes, training and staff in those specific functional areas and so can provide added benefits.

The key disadvantages of using functional partnerships compared to competitive bidding outsourcing is that the overall number of vendors will be limited and individual study team preferences may not be available. A functional approach may also lose some efficiencies that can be gained across certain tasks that fall across multiple functions. For example, statistics and medical writing functions can be synergistic if supported by the same company for certain tasks.

Centralised Service Provision (CSP)Supporting at a functional level does have the potential to have partners supporting different service areas working in silos. There are efficiencies when looking at the task level to have the same company supporting specific tasks across functions. For instance, having the same company providing project management and monitoring services and another offering data centralization, statistics and programming can be beneficial particularly if a technology solution can help to bring it all together to enable a pharmaceutical company to get more out of its data or make trials more cost effective and efficient. A centralized service provision approach therefore has the benefits of a traditional FSP approach coupled with the added efficiencies seen in a full service approach, but with minimized risk and greater access to expertise and flexibility.

The disadvantages are similar to that seen within a functional partnership, although the cross-function efficiency loss can be mitigated.

Full-Service Cross Functional Strategic SupportA number of larger pharmaceutical look to large full service CROs to provide all services. In some cases, this has progressed to the point where a product is handed to the CRO and the pharmaceutical company has a completely hands-off approach to its development. The objective of such an approach is that efficiencies can be seen across the development which can then ensure that the development is efficient and cost effective. The introduction of various penalties and bonuses can also be used to ensure timelines and key milestones are met since the CRO has full control of all aspects. A risk-based approach can also make CROs more accountable for the resulting data and to ensuring that decisions are more effective. There are also benefits related to minimized oversight and the amount of time available by both companies to ensure an effective and optimal partnership.


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The challenge to utilizing such an approach is primarily the reliance on a very small number of CROs (sometimes only one) and that the expertise and capabilities in specific service areas may not be as consistently strong across the CRO. Since over 90% of the time and budget relates to the clinical operations aspect, the primary selection of a full-service CRO is based around capabilities in clinical operations and a functional or centralized approach may therefore be preferred to provide greater flexibility and to minimize risk.

As a data-focused CRO, we are often seeing gaps in certain service areas such as statistics and programming, and we find that we are being contracted to support the full-service CRO behind the scenes. Whilst this minimises the interactions that a pharmaceutical company has with its primary CRO, it does mean that the pharmaceutical company may not be seeing all the benefits of forming a functional partnership and they are more removed from decisions and opportunities to improve and expand the partnership.

Utilisation of Locations that Optimise CostIn addition to the sourcing strategy employed, costs can be

significantly saved if lower-cost locations are utilised. There has been much discussion in regard to the use of lower-cost locations, particularly in Asia, South America, Africa and Eastern Europe. There are clear cost advantages from FTE salary and officer overhead perspectives. Whether the use of lower cost regions happens in-house or via a CRO depends to a certain degree on size, investment availability, knowledge of the local regions, experience of utilising lower-cost locations, and whether there is an inclination to oversee and put in place processes to use these regions. Some companies have decided to open large captive centres in locations such as India to provide not just resources involved in tasks such as data management, programming and pharmacovigilance, but also those involved in functions such as finance.

In terms of clinical development, the determination of location of where staff are based is also something that different companies have differing views on, but the utilisation of staff based in locations such as India, Poland, Russia and China does enable a reduction of cost using staff that have the experience to undertake specific tasks. Most larger CROs and all BPO-type companies now have capabilities in lower-cost regions, and there is an attraction for pharmaceutical companies deciding to reduce costs by moving to lower-cost regions to utilise the longer-term expertise of CROs and BPO companies.

Having the right levels of quality control and oversight, whilst ensuring quality, timeliness and effective communications are all key to ensuring that the cost benefit of lower-cost staff is not outweighed by oversight in higher-cost locations at both the vendor and sponsor companies. As this model has progressed and quality has been demonstrated, the use of lower-cost locations has become more popular. The key longer-term issue is whether the cost differential will remain, as inflation in many of these lower-cost locations is rising much faster than in more developed locations. It is therefore important to put in place a sustainable approach and a forward-thinking strategy.

ConclusionIn conclusion, there are a number of ways to ensure that a cost-efficient approach is put into place to provide an optimal solution to support clinical development. As a data-focused CRO, Quanticate believes that there are a lot of advantages to the functional (FSP) and centralised (CSP) service provision approaches. These approaches offer a cost-effective solution that remains flexible and enables access to expertise. Additionally, CROs are well placed to maximise the use of lower-cost locations and can spread the growth across customers. This minimises risk and enables a longer-term and more sustained approach to continually evolving the model.

The role of a CRO is continually evolving, but we believe that close integration between CROs and pharmaceutical companies offers many advantages. This can result in reduced overall cost and increased flexibility through greater access to global locations, efficient technologies and expertise. The key is to select a group of CROs that have the experience and culture to develop strong and focused partnerships that enables the development of an optimal solution that best meets the needs of all involved.

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Daniel Chapple is Executive VP and Chief Commercial Officer for Quanticate (www.quanticate.com). He has over 15 years experience within the drug development field, with the last 11 years spent within the CRO and BPO sector. Prior to joining Quanticate in 2011, Daniel was European General Manager at Cognizant Technology Solutions.

Daniel holds a doctorate in biochemistry, microbiology & immunology. Email: [email protected]

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In recent years we have seen industry sponsored global clinical trials moving more and more to include emerging markets. Aside from countries such as Russia and India that have been prominent for some time, other countries in the Latin Americas and Asia are gaining in importance. The focus on China, in particular, appears to be rapidly intensifying. With this shift we see new challenges facing the diverse group of stakeholders involved in the planning and execution of a trial. Although clinical trial supply sourcing is a small part of the overall clinical trial supply chain, inclusion of it at an early stage in the trial planning and infrastructure can have a overall beneficial impact on both the efficiency and cost of a trial.

Determining the complexity and strategy of sourcing clinical trial supplies, be it comparator agents or non-investigational medicinal products (NIMPs), is arguably one of the biggest initial hurdles for any planning team. Procurement should be an integrated process within the overall clinical trial strategic plan. Whilst some sponsoring organisations opt to source internally through either onsite resources or local trial sites others prefer to outsource to a specialised provider. Important for any strategy, however, is early access to market intelligence as well as commercial and logistical expertise in the required markets to ensure product availability, transparency and above all product safety.

This article aims to highlight some of the current challenges teams are confronted with during global clinical trial supply sourcing and to look at some of the recommendations when sourcing on this scale. Procurement considerations, particularly in emerging markets, will be highlighted.

The Planning Stage The ultimate goal of sourcing clinical trial supplies is simple: to ensure that authentic material can be secured for the duration of the trial. Teams typically approach the topic of clinical trial sourcing by assessing the complexity of the trial. Determining commercial product availability is one major component of this process. This market intelligence may dictate your choice of sourcing strategy for a trial at an early stage. In order to tackle the challenges of clinical trial sourcing on a global scale the following should also be considered:

• reliable procurement in all regions• appropriate local warehousing• proactive inventory management• suitable distribution strategies

The growing geographical spread of clinical trials has impacted on the choice of strategy for sourcing of clinical trial supplies. One aspect that applies to a region such as Europe as much as it does to an emerging market such as India is what strategy to go for when sourcing products such as NIMPs. Many sponsors continue to choose to handle these products as investigational medicinal products (IMPs) in their trials. Some parties have voiced concern that ambiguity remains over NIMP regulations. Where as other companies may still be unaware of this topic and forego possible scenarios that are both safe and efficient, whilst meeting the economic constraints of a trial budget.

Sourcing for clinical trials can be carried out internally by the sponsors themselves, outsourced, or done through a

Industry Trends on Sourcing Clinical Trial Supplies Globally

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combination of the two. If teams decide to have clinical supplies sourced externally thorough research should be conducted to confirm capabilities of an external provider. Furthermore, it is recommended that in-place quality systems are audited and it may be advantageous to request to review case-study examples. This way it should be possible to find an organisation that best matches the needs of the clinical trial. Traditional wholesalers are usually able to source large quantities and have robust quality systems in place, but they can be limited in their capabilities by not being able to source globally. It is worth bearing in mind that working with a sourcing partner, who has a presence in prevalent markets as well as an emerging markets footprint, may be advantageous.

When working with a sourcing specialist the following benefits should be considered:

• transparency• access to local market intelligence including product

availability, documentation availability, information on product presentation

• access to products direct from manufacturers or their authorised distributors, ensuring authenticity

• presentation of flexible procurement options via a global network

• support for local storage and distribution solutions

Early consideration for the sourcing of clinical supplies is also important as the time needed to prepare the comparators or NIMPs for the trial may vary for different regions. In some cases this can be up to three months making product expiry an important factor. Furthermore, if choosing to source NIMPs locally you must establish whether the products are marketed and available in all the countries you plan to carry out the trial in. At times it may be necessary to negotiate more challenging sourcing projects with manufacturers to ensure supplies are coming from the most reliable source. In such cases it is advisable to calculate in a sufficient product lead-time, as otherwise trial timelines could be significantly affected. It should be noted that when planning to source NIMPs locally documentation is not required for purposes of release or import. Nevertheless, in many cases there is still access to documentation such as certificates of analysis (CoA).

Emerging MarketsIn expanding nations such as India and China, to name a couple, the demand for clinical trial supply sourcing is ever increasing. This is in line with the increasing number of clinical trials being carried out in these countries. As a result teams have been forced at times to become knowledgeable in unfamiliar regional territories or to look to sourcing partners with long-standing experience in these countries.

Along with evolving regulatory requirements in different regions that a clinical supply sourcing team needs to be aware of, there are also other factors to consider when sourcing for a global clinical trial. It is worth considering:

• pharmaceutical market authorisation variation• multiple languages • various time zones• local cultural aspects

The above factors can influence whether to source locally or centrally for globally conducted clinical trials. Specifically in regions where a team may as of yet be inexperienced it can be advisable to work with an experienced partner that can assist in laying the foundations and managing complex relationships with external providers of different cultural backgrounds.

There are several types of suppliers and each option has its advantages and disadvantages. A point to consider is that if sourcing is not being managed within the sponsor organisation, some degree of control and disclosure of trial information will have to be handed over in order to take full advantage of a specialised provider. This is why it is advisable to have an NDA or CDA in place. Whether the sourcing is carried out internally or outsourced, clinical trial supplies should be secured through the most authentic and direct route, whether this is through the innovator company, an authorised wholesaler or distributor, a speciality pharmacy, or the services of a sourcing specialist.

Many teams consider sourcing NIMPs through local trial sites the most opportune scenario for the sponsor organisation in terms of both risk and cost. Keep in mind, however, that the sponsor has limited control over budget and less control over stock and accountability in this instance. Moreover, sourcing through an innovator is preferable as it gives opportunity for steady supply of authentic product in large quantities and usually in single lots. Another advantage is that pricing can be more stable and predictable. Furthermore, this option gives the best access to global inventory and documentation. Depending on restrictions on the material supply, sourcing through the innovator company can entail disclosure of trial information and supply provision negotiations. For a global clinical trial, a team might find that they benefit from a partners local experience



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and can consult on matters such as safety stock in the various regions. This factor tends to be dependent on the risk level in a particular country. For example, typically for the German market safety stock may be in the region of approximately three months worth where as for the Philippines this increases to around six months worth of stock.

Reliable Supply ChainIrrelevant of location of sourcing and trial execution, as you know, all participants in the supply chain have a responsibility in ensuring that material is handled in the most compliant manor in accordance with all regulations. Why mention something so obvious in this article? Well, by moving to a global setting for clinical trials the quality aspects become considerably more complex, also on the sourcing front. Furthermore, each clinical trial should have its own distribution network that has been tried and tested for the proper and safe delivery of the clinical supplies. This includes testing various import/ export clearance points without incident. Prevention of falsified medicines entering the supply chain needs to be high at all times, specifically in markets that are still developing reliable and consistent regulatory systems.

The sponsor organisation is arguably further away at times when trials are globally spread and thus the risks can increase. Any partners should be appropriately licensed and audited by the necessary regulatory agencies, as well as the sponsor’s quality assurance department. It may also be a consideration to use the services of experienced partners who often already have a global network of qualified partners in place in various regions. This way a sponsor organisation can benefit from access to third party providers, such as logistics companies or depot providers that are already subject to a rolling system of audits.

The details surrounding the logistics and distribution of clinical trial supplies are often ignored. Because of this, unnecessary distress can be added to the execution of the study’s strategic plan if the supply cannot be delivered to the destination point as expected. Despite the investment in proper planning and preparation, if supplies cannot move seamlessly from A to B, then all of the pre-planning has been in vain. Adequate depot management of inventory and reliable distribution lanes should be tested and verified. With teams ensuring all regulations are complied with for the storage and distribution of supplies. Traceable point-to-point and just-in-time distribution is preferred to limit the probability of exposure of the clinical trial supplies to environments outside their storage conditions.

When evaluating the supply chain of clinical trial supplies, it is advisable to make it a requirement that reliable procurement policies and procedures are in place and are being followed in all regions of the trial.

ConclusionThe clinical trial environment is quite time-sensitive and ever changing. The process of securing clinical trial supplies has become increasingly difficult and more complex worldwide. There is increased demand globally, regardless of market

restrictions. Specifications are more stringent. Lead times are longer. Availability of supply and documentation are uncertain. Quality and supply chain expectations are increasing. As such it is important to monitor the regulations across all applicable markets or have access to such information through communication with third-party providers. This is particularly significant for markets where regulations are regularly changing, often without advanced notice. A recommendation is to take advantage of working with companies that have in house experts who are actively joining working groups on topics such as comparators and NIMPs. Thus, also capturing the current situation amongst industry members at first hand. In the particular case of NIMPs, it seems more companies are beginning to recognise and handle them with reduced complexity rather than treating them as IMPs. It is too early, however, to tell whether we will see solidification of the current trends in clinical trial supply sourcing. This is an area that is by all accounts still maturing.

Lekishia White, Vice President and Managing Director of Multipharma, Inc., manages the United States operations. She obtained her Bachelor of Science degree in Biology from Spelman College and her Master of Business Administration degree from Pepperdine University. Her industry experience includes laboratory research and drug

development along with having worked in many capacities and in several departments for Amgen, Inc. She has expertise and proficiency in the areas of GMP operations, warehousing and logistics, quality and regulatory compliance, supply chain management and strategic sourcing. Email: [email protected]

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

Email:[email protected]

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SC forces Centre to stop clinical trials of 162 drugsThe Supreme Court on Monday forced the Centre to stop clinical trials of 162 new drugs or chemical entities which had been cleared by the expert committee for testing on human beings in India.

A bench of Justices R M Lodha and Shiva Kirti Singh was about to pass an order restraining the Centre from going ahead with these clinical trials when additional solicitor general Sidharth Luthrapre-empted the order by giving an undertaking that no clinical trial would take place. Luthra sought two weeks time from the bench and said he would be able to satisfy the court that adequate safety and damage prevention mechanisms had been put in place by the Union government to commence clinical trials of the new drugs to test whether they were fit to be permitted for release in the market.

The law officer also informed the court that after receiving suggestions on clinical trials from various stakeholders, including National Human Rights Commission and NGOs, the health ministry had constituted an expert committee under the chairmanship of Prof Ranjit Roy Chaudhury to prepare guidelines for approval of clinical trials in the country. He said the Chaudhury committee had submitted its report and it was being considered by the government. Moreover, the Drugs and Cosmetics (Amendment) Bill, 2013, which has a separate chapter containing penal provisions for violation and non-compliance of provisions relating to conduct of clinical trials, was introduced in Parliament on August 29. The government said it had inspected 577 clinical trials and had issued notices to investigators, sponsors and ethics committees seeking clarifications in 235 cases. Of the 1,122 applications for approval of clinical trials, 331 related to approval of global clinical trials. New Drug Advisory Committees (NDACs) have recommended approval of 285 applications, which include testing of drugs relating to AIDS, oncology, cardiology, neurology, psychiatry, metabolism and endocrinology.

Clinical trials in India to get stringentIn an attempt to bring about reforms in drug regulation and clinical trials, a six-member expert panel constituted by the ministry of health and family welfare has said that in future, these trials can only be carried out in accredited centres. Also, the principal investigator and ethics committee of the institute where the trial is being done should also be accredited. Only then will trials be approved. These recommendations, already up on the website of the Central Drugs Standard Control Organization (CDSCO), are part of the Professor Ranjit Roy Chaudhury Expert Committee onNew Drugs and Clinical Trials Approvals and attempt to weed out fly-by-night operators who collude with drug companies and doctors to approve drugs whose trials have never taken place.

“While some of the recommendations can be implemented within two months after consultations, others will require an amendment of rules,” says a senior health ministry official. “The government will ensure that clinical trials are done legally and the safety of participants is adhered to.”

Dr Roy Chaudhury, adviser, department of health and family welfare, says the lack of regulation in clinical trials has seen India lose out to China, Malaysia and Singapore. “But this is set to change; we want India to once again be the centre for clinical trials.”

First topical pharmacologic therapy to enter clinical trials for “double chin”Topokine Therapeutics has initiated dosing in a Phase 2, randomized controlled clinical trial of XAF5 Gel for reduction of excess submental fat, commonly known as “double chin.” XAF5 Gel is a proprietary skin formulation of a compound already known to reduce fat around the human eye. Study participants are applying XAF5 Gel or placebo once a night to skin under the chin.

“Patients are increasingly interested in non-invasive therapies to rejuvenate the face,” said Jeffrey S. Dover, MD, FRCPC, a nationally recognized dermatologist and member of the Topokine’s Scientific Board of Advisors. “If approved, XAF5 Gel would provide a convenient topical medication that reduces submental fat.”

XAF5 is a small molecule that induces a G protein-coupled cascade in adipocytes to reduce cellular lipid content and differentiation. Daily administration of XAF5 reduces fat around the human eye and in five laboratory models. The technology was first conceived by ophthalmologists at the Massachusetts Eye and Ear Infirmary / Harvard Medical School Department of Ophthalmology.

The Phase 2 study follows positive data from a 6-week Phase 1 clinical trial completed in April 2013. In that randomized, double-blind, placebo-controlled study, 32 healthy men and women applied XAF5 Gel or placebo once a night to a 100 cm2 area of abdominal skin. The study met its pre-specified primary safety and tolerability endpoint at all doses. The only side effects were mild, temporary skin redness or itch, which occurred at similar rates with placebo. Exploratory CT scans showed a dose-dependent reduction in fat volume under treated skin as compared to contralateral untreated skin.

Antibiotic resistance breaker’ set for phase III trialsScientists have announced what they say is a “major breakthrough” in the fight against antibiotic resistance, after a new compound combined with an existing antibiotic has proven successful in phase II trials.

Antibiotic resistance is defined as an infection that does not respond to a particular drug, as a result of bacteria changes that make the infection immune to the drug.

Drug-resistant bacteria is a global concern. Earlier this year, in a statement from Chief Medical Officer for England, Dame Sally Davies, says that within the next 20 years, individuals undergoing simple operations may die because there will be no antibiotics left to effectively deal with routine infections.

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Scientists say a compound called HT61 has proven successful in phase II trials at boosting the effectiveness of old antibiotics

against drug resistance.

But small UK drug company, Helperby Therapeutics, has announced it has found a new series of “potent, fast acting drugs” that could boost the effectiveness of older antibiotics. - HT61 ‘rejuvenates existing antibiotics’ Investigators at Helperby Therapeutics have been investigating ways to combat antibiotic resistance for the past 12 years. These new drugs were tested specifically on non-multiplying dormant bacteria - something that had never been done before, according to the researchers. The investigators focused on one compound in particular, called HT61. In a phase II trial, this drug was successful in improving the effect of an old antibiotic.

Quintiles, ASTT agreement to enhance Vietnam clinical researchQuintiles has signed a two-year agreement with the Vietnam Ministry of Health’s Administration of Science, Technology and Training (ASTT), aimed at improving the country’s clinical-research environment. Together, ASTT and Quintiles will set up a working group to address various topics relating to clinical research in Vietnam, including enhanced processes for trial management; development of streamlined processes to improve trial efficiency and quality; and training for investigators and ethics committees.The US-based provider of biopharmaceutical development and commercial outsourcing services has been working with the Ministry of Health to provide investigator training and site development in Vietnam since it first established a local presence in 2005.

This agreement deepens our commitment to developing medicines here to fight tropical and infection diseases and other conditions that afflict populations in Vietnam and Southeast Asia,” noted Dr Ross Horsburgh, who leads Quintiles’ operations in Southeast Asia, Taiwan, South Korea, Australia and New Zealand.

ASTT director Professor Dr Nguyen Cong Khan said Quintiles “knows how to conduct clinical research to global standards and its experts understand Asia and Vietnam”.“By sharing its knowledge and insights, the company can “help us

develop and execute a long-term plan for improving the quality, scope and breadth of clinical research in Vietnam”, Khan added.

Videorecording of consent for clinical trials mandatoryThe Union Health Ministry has made audio-visual recording of the informed consent of each subject mandatory in a clinical trial. This is in addition to obtaining his/her written consent.This decision comes in the wake of the Supreme Court pulling up the Ministry for lack of transparency in clinical trials. In its October 21, 2013, order on a writ petition filed by an NGO, the Swasthya Adhikar Manch, Indore, the court said with respect to five global clinical trials, which was approved by the Drugs Controller-General of India (DCGI) office from January 1, 2013, to August 31, 2013, an appropriate provision should be made or administrative direction issued, ensuring that audio-visual recording of the informed consent process was done and the documentation preserved, adhering to confidentiality principles. In his order, DCGI G.N. Singh said all sponsors/investigators/institutes/organisations and other stakeholders involved in clinical trials should adhere to this requirement with immediate effect. Reacting to this, the Indian Society for Clinical Research — an association of professionals involved in clinical trials — said lack of guidance and direction on operational and logistical issues of managing the audio-visual recording process like the kind of equipment to be used, and where and how information should be stored could leave room for ambiguity and inconsistencies in execution. More clarity was required on how confidentiality of patients should be protected and maintained in an ‘audio-visual’ context and what processes needed to be followed in instances where, for religious and socio-cultural reasons, patients might not want to be videographed, the association said.

Sanofi and Regeneron Report Positive Results with SarilumabSanofi and Regeneron Report Positive Results with Sarilumab in First Phase 3 Rheumatoid Arthritis Registration Trial. Sarilumab, Given Subcutaneously Every Other Week, Met All Three Co-Primary Endpoints. Sarilumab is the First Fully-Human Monoclonal Antibody Directed Against the Interleukin-6 Receptor (IL-6R)

Sanofi (EURONEXT: SAN and NYSE: SNY) and Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) today announced that in the SARIL-RA-MOBILITY Phase 3 clinical trial in adult patients with active rheumatoid arthritis (RA) who were inadequate responders to methotrexate (MTX) therapy, sarilumab (the first fully-human anti-IL-6R monoclonal antibody) treatment in combination with MTX improved disease signs and symptoms as well as physical function, and inhibited progression of joint damage.

“IL-6 blockade is emerging as an important therapeutic approach for rheumatoid arthritis,” said Neil Graham, M.B.B.S., M.D., M.P.H., Vice President, Program Direction, Immunology and Inflammation, Regeneron Pharmaceuticals. “We are encouraged with these Phase 3 results, which demonstrated efficacy at both doses of sarilumab, each administered every other week.”


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