www.jforcs.com Journal For Clinical Studies Your resource for Multisite Studies & Emerging Markets Volume 7 - Issue 3 Parkinson’s Disease Functional Imaging of theDopamine Pathway Common Pitfalls of RECIST 1.1 Application In Clinical Trials. Orphan Drug Designations Are the EMA and FDA Looking for the Same Information? Raising Clinical Trial Standards Through Competency-Based Training www.jforcs.com PEER REVIEWED JOURNAL FOR Your Resource for Multisite Studies & Emerging Markets CLINICAL STUDIES U Volume 7 - Issue 3
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Volume 7 Issue 3I Journal for Clinical Studies
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w.jforcs.com
Journal For Clinical Studies Your resource for M
ultisite Studies & Em
erging Markets
Volum
e 7 - Issue 3
Parkinson’s Disease Functional Imaging of theDopamine Pathway
Common Pitfalls of RECIST 1.1 Application In Clinical Trials.
Orphan Drug Designations Are the EMA and FDA Looking for the Same Information?
Raising Clinical Trial Standards Through Competency-Based Training
www.jforcs.com
PEER REVIEWED
JOURNAL FOR
Your Resource for Multisite Studies & Emerging MarketsCLINICAL STUDIESU
Volume 7 - Issue 3
For 25 years, for clients around the globe, Myoderm has made sourcing comparators simple. We’re obsessed with making sure that no matter what challenges may arise, your trial runs effectively. Efficiently. Without worry. Talk to us. And learn how Myoderm can simplify your world.
08 Device Integration in Clinical Research – A Fad or the Future?
Nowhere is the advance of technology felt more acutely than in the field of healthcare and clinical research. The very future of the industry relies on ever-more intelligent solutions to increase the cost-effectiveness of clinical trials through ensuring on-time and highly-accurate recording of patient outcomes. Within this white paper, Chris Watson, Product Manager at Exco InTouch, focuses on device integration in clinical research.
10 Biomarker-based Decision-making in Early Stage Oncology Drug Development:
Finding a Balance Between Tradition and Rational Considerations
Until 10 to 15 years ago, oncology drug development was mainly conducted with compounds that were either genotoxic or cytotoxic. Determining the dose level that would provide the best ratio between efficacy and tolerability was mostly straightforward. As there is a clear justification for chemotherapeutics to destroy more cancer cells with an increasing dose, the highest tolerated dose level would also be the optimal dose to be taken forward. Rob Berg, MD, Ph.D., Senior Medical Director Oncology from INC Research, provides a medical oversight on oncology drug development.
12 The Future of the Drug Label FDA’s Proposed Rule on Electronic Distribution of Prescribing Information
Prescription labelling is currently distributed in paper form on or within the package of a prescription drug or biological product when it is dispensed. In a proposed rule, announced in the Federal Register on December 18, 2014, the US Food and Drug Administration (FDA) states its intention to require electronic distribution of the prescribing information for healthcare professionals. When the proposed rule is finalised, the paper form will no longer be permitted. As with many regulatory actions, however, any exceptions would be listed. Regina Ballinger, Senior Manager of Regulatory Intelligence with Thomson Reuters, gives us an insight into the future of drug label.
14 The Impact of Exercise on the ArteriesEverywhere we turn we are continuously reminded of the benefits of exercising: it promotes weight loss, lowers blood pressure, improves how we feel, is good for the heart, relieves stress … the list goes on. Of course, these are all important aspects of a happy and healthy life. Dr Dean Winter and Bobby Stutz of AtCor Medical, Inc discuss one of the less-touted effects that regular exercise can have on the health of your arteries.
16 Logistics Challenges in Sub-Saharan AfricaAfrica is the second largest of the earth’s seven continents and makes up approximately 22% of the earth’s total land area. In the last decade private capital flows to Sub-Saharan Africa
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Volume 7 Issue 32 Journal for Clinical Studies
Contents
have begun to exceed official development assistance. Six of the world’s ten fastest-growing economies over the previous decade were situated below the Sahara, with the remaining four in East and Central Asia. Economies are thriving; political stability is at an unprecedented level. Sue Lee of World Courier highlights some of the problems in delivering healthcare both in big cities and out in the bush, whilst balancing responses from the WHO, MSF etc. with government policies and actions.
18 Beware the Financial Cost of Human Clinical Trials Compensation Claims
Research subjects, both healthy and sick, are clearly giving something to society by making sure that drugs and devices are safe before going into open circulation. They may have consented to being tested on and absolved investigators of blame for injuries, but generally society agrees that in the event that an injury occurs the research subject should get compensation for injury. Alex Forrest of Chubb Insurance discusses why sponsors need to be aware of the potential different coverage options, be it a negligence-only-based policy or something containing some no-fault compensation provisions, and be ready to select the correct one according to their needs, or one containing both.
REGULATORY
20 Supplier Qualification: A Review It is a GMP requirement to certify the vendor to deliver high-quality and safe medicines, and to prevent recalls, deaths, adverse events, and serious illness due to substandard quality of manufactured medicines. The main aim of business is to get profit. To achieve good profits, sometimes pressure will be increased to get raw materials of low cost, which sometimes leads to procurement of substandard material. This can be avoided by using supplier qualification as a tool. Bhushan Dinesh Belgaonkar, Balamuralidhara V., Lokesh M S, and
Kotha Arun Kumar submit a review on supplier qualification.
26 Common Pitfalls of RECIST 1.1 Application in Clinical TrialsRevised Response Evaluation Criteria in Solid Tumours came into effect in 2009. While RECIST 1.1 has addressed many challenges with the previous version, some drawbacks still remain. More than five years of clinical trials monitoring, across numerous international sites, has revealed that investigators across all countries encounter many and similar difficulties in interpreting RECIST 1.1, and tend to make the same mistakes. These errors, if not identified and corrected in good time, lead to increased variability of data across the trial sites and may affect efficacy endpoints. In our opinion, proactive training, focused on typical questions/mistakes, may help to increase the accuracy of the RECIST data extraction at the trial sites. Iryna Teslenko, MD, Ukraine, Maxim Belotserkovsky, MD, Germany, Akhil Kumar, MD, USA, PSI CRO AG, Switzerland share their thoughts on common pitfalls of RECIST 1.1 application in clinical trials.
34 Orphan Drug Designations – Are the EMA and FDA Looking for the Same Information?
Whilst working on a recent European application for an orphan drug designation (ODD) for a rare neurological condition that was being made to the EMA, I noticed that there was a markedly lower number of ODD application approvals for that particular indication in the EU than in the US. I then looked at some other rare diseases, in case this was a peculiarity of this specific rare neurological condition but, no, for other indications there were also fewer registrations for ODDs in the EU than in the US. Susan McGoldrick from QCTR reflects on orphan drug designations.
MARKET REPORT
38 From Clinical Trial to Real-world OutcomesThe need for costly clinical trials in order to bring a drug successfully to market is undoubtable. However, outside of this carefully controlled, highly supportive environment, the real-world actualities are very different. In today’s healthcare environment, where competitive products are coming to market within months of each other, there is limited differentiation in clinical efficacy, and pricing strategies are very similar, payers are increasingly expecting the industry to differentiate their products by delivering services beyond the pill. Paul Tanner, Chairman of 90TEN Healthcare invites us to take a journey from clinical trial to real-world outcomes.
Journal for Clinical Studies 3www.jforcs.com
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42 Raising Clinical Trial Standards through Competency-Based Training
Ensuring Organisational Excellence in the new EU Regulation on Clinical Trials of Medicinal Products for Human Use
The Clinical Trial Directive – 2001/20/EC – has been in place for about a decade. In that time the number of drug trials conducted in the EU has fallen by about 25%. Opinion has been divided about the benefits of the directives and various stakeholders in the clinical research community have expressed concerns about the rise in bureaucracy, the increase in costs of running trials, and the continuing lack of uniformity in the EU. The call has been for more streamlining, which includes taking a proportionate risk-based approach to the conduct of trials, with more public openness about each trial and the results they produce. Dr Martin Robinson, Executive VP & IAOCR Ambassador, focuses on clinical trial standards.
THERAPEUTICS
46 Parkinson’s Disease Functional Imaging of the Dopamine Pathway
The diagnosis of movement disorders and neurodegenerative diseases can be problematic for clinicians and radiologists alike. There is considerable overlap in the early presentation of these diseases, especially when tremor is absent or atypical in character. Routine anatomic imaging is insensitive and early imaging findings are typically absent or non-specific. Dr Barry Menick from Intrinsic Imaging deals with Parkinson`s disease, by mentioning the Dopamine as well.
48 Methodological Issues in the Design and Conduct of Opioid Use Disorders Studies
Opioid use disorders have significantly increased over the past two decades, affecting between 26 and 36 million people worldwide. There are several unique methodological challenges in the design and conduct of studies assessing the efficacy of various opioid use disorder treatments. Nonetheless, with careful planning these can all be effectively managed. Barry J. Dussault, Jr. and Henry J. Riordan of World Wide Clinical Trials explain that, given the currently available treatment options and increasing global prevalence, more clinical trials of drugs to treat opioid use disorders with eventual subsequent approvals of new and improved treatments for this growing epidemic are essential.
TECHNOLOGY
54 Unlocking the Potential of Social Media in Drug SafetyDrug safety and pharmacovigilance (PV) have evolved and grown significantly more complex over the past decade due to higher data volumes, evolving regulations, increased influence of emerging markets and the emergence of social media and innovative technological advances. The phenomenal reach of the internet has led to a revolutionary shift in how people are communicating with one another, with digital platforms and applications quickly becoming the go-to form of communication in the era of Web 2.0. Supriya Desai MD, PGDBM, Director of Medical Safety Operations at Sciformix Corporation, explains the relevancy of social media in drug safety.
58 Clinical Trial Retention Meta-analysis How Patient Recruitment Methods Directly Rate to the Retention of Subjects
Patient recruitment methods can have a significant effect on the retention of subjects in clinical trials; these effects can result in considerable cost implications. Subjects that actively sought clinical trial involvement through an online pre-screener showed 38% lower relative risk of dropout across four studies compared to those who were recruited by sites, with divergence across visits in all four studies. Clare Jackson, Strategic Program Manager, Utku Ozdemir, Director of Business Analytics, and Liz Moench, President at MediciGlobal, deal with clinical trial retention meta-analysis and patient recruitment methods.
Journal for Clinical Studies 5www.jforcs.com
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Volume 7 Issue 36 Journal for Clinical Studies
Foreword
Editorial Advisory Board
Art Gertel, VP, Clinical Services, Regulatory & Medical writing, Beardsworth Consulting Group Inc.
Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA
Bakhyt Sarymsakova - Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan
Catherine Lund, Vice Chairman, OnQ Consulting
Cellia K. Habita, President & CEO, Arianne Corporation
Chris Tierney, Business Development Manager, EMEA Business Development, DHL Exel Supply Chain, DHL Global
Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe
Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters
Elizabeth Moench, President and CEO of MediciGlobal
Eileen Harvey, Senior VP/General Partner, PRA International
Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet Development Group
Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics
Georg Mathis, Founder and Managing Director, Appletree AG
Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research
Hermann Schulz, MD, CEO, INTERLAB central lab services – worldwide GmbH
Janet Jones, Senior Director, ICON Clinical Research
Jerry Boxall, Managing Director, ACM Global Central Laboratory
Jeffrey Litwin, MD, F.A.C.C. Executive Vice President and Chief Medical Officer of ERT
Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma.
Jim James DeSantihas, Chief Executive Officer, PharmaVigilant
Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation
Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP
Nermeen Varawala, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation
Patrice Hugo, Chief Scientific Officer,
Clearstone Central Laboratories
Rabinder Buttar – President & Chief Executive Officer of ClinTec International
Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy
Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group
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
There is a lot that we don’t know about people and their health. Scientists spend a lot of time studying models of disease in animals and even single cells, but sometimes there is nothing better than studying actual people. After an idea has been demonstrated to be safe, a hospital or university’s medical ethics board will approve a scientist to study patients.
Like every release, the current edition is also rich in science, developments and research, and both our regular and newly-welcomed authors have submitted new and exciting features in this issue.
Our current edition focuses on clinical trial standards, drug designations and common diseases in the elderly.
Parkinson’s disease (PD) is now the second most common neurodegenerative disease after Alzheimer’s disease (AD), affecting approximately 1 million Americans and 4 million people worldwide. It affects 0.5-1.0% of the population between 65 and 69 years old and older than 80. In 1-3% of idiopathic PD, the cause is the degeneration of neurons which connect the subtantia nigra to the striatum, the so called nigrostriatal pathway. 2015`s third edition gives us an insight into Parkinson`s disease from a different point of view with the assistance of Dr Barry Menick from Intrinsic Imaging.
We are happy to introduce Dr Martin Robinson, Executive VP from IAOCR who has published an article on Clinical Trial Standards, Ensuring Organisational Excellence in the new EU Regulation on Clinical Trials of Medicinal Products for Human Use. The Clinical Trial Directive – 2001/20/EC – has been in place for about a decade. In that time the number of drug trials conducted in the EU has fallen by about 25%. Opinion has been divided about the benefits of the directives and various stakeholders in the clinical research community have expressed concerns about the rise in bureaucracy, the increase in costs of running trials and the continuing lack of uniformity in the EU. The call has been for more streamlining, which includes taking a proportionate risk-based approach to the conduct of trials with more public openness about each trial and the results they produce.
The central nervous system is always an issue in healthcare. Susan McGoldrick from QCTR answers the question on orphan drug designations – are the EMA and FDA looking for the same information? Both the EU and US publish their orphan or rare disease designations in publicly available websites. The US gives a list of the generic name of the drug, and the indication that has been granted the orphan drug designation; by clicking on the generic drug name you can find the drug’s trade name, the name of the sponsor, and whether the drug has gained FDA marketing approval. We also get explanations on the differences between FDA and EMA, and answers on the advantages of orphan drug designation.
Since the global requirement for randomised and controlled clinical trials over the past four decades for new drug approvals in oncology, there has been a challenge to uniformly apply imaging-based tumour-specific response criteria with the purpose of objectively assessing treatment response in cancer trials. Iryna Teslenko from Medical Monitoring & Consulting at PSI CRO AG, Maxim Belotserkovskiy, and Akhil Kumar, a board certified haematologist and oncologist, submit a feature on common pitfalls of RECIST 1.1 applications in clinical trials.
Journal for Clinical Studies wishes you a successful and pleasant summer, and we are hoping we receive positive feedback again on the many informative features.
Orsolya BaloghEditor
Journal for Clinical Studies 7www.jforcs.com
Volume 7 Issue 38 Journal for Clinical Studies
Watch Pages
Device Integration in Clinical Research – A Fad or the Future?
Nowhere is the advance of technology felt more acutely than in the field of healthcare and clinical research. The very future of the industry relies on ever-more intelligent solutions to increase the cost-effectiveness of clinical trials through ensuring on-time and highly accurate recording of patient outcomes.
These steps forward have manifested themselves in the increased popularity of Bluetooth® integrated devices in the clinical arena over the past 18 months. However, this was not always the case. Traditionally, data collection was conducted using paper diaries due to the associated hardware costs of implementing electronic solutions. Collecting and consolidating data this way can be resource-intensive and a burden on both timescales and budget, though. Additionally, retrospective data interrogation is near impossible due to the difficulty of re-engaging with patients and the timeframes elapsed between recording and review. This is where Bluetooth®-enabled device integration comes into its own.
Medical device readings are an important endpoint in patient-reported outcome (PRO) data. The cost, specificity and expertise required to collect readings from medical devices and transfer them to clinical databases have traditionally restricted this data collection to clinical trials site only. However, the move towards electronic
patient-reported outcome (ePRO) data collection and the addition of Bluetooth® technology to many devices now enables integration of medical device readings into regular ePRO collection performed by the patient, whether it be as part of a clinical trial or in a real-world setting.
What’s more, as device integration is not simply limited to medical devices, the industry has seen a growing trend towards the utilisation of consumer technology to collect secondary outcomes data (often called consumer technology integration), such as activity trackers (e.g. the Fitbit, or the Microsoft Band), weighing-scales and thermometers, which are also becoming increasingly popular tools in clinical research.
How Does Device Integration Work?Data is received automatically from diagnostic monitoring devices such as spirometers, ECGs, weighing-scales and blood-pressure monitors via Bluetooth®, which negates transcription errors and maintains data integrity, with a full audit trail (date and time stamps). Assessment responses and medical device measurements are then transmitted automatically to the central database by the software application installed on a mobile phone or tablet using the device’s mobile connectivity. This takes place immediately on completion of the assessment (or
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if there is limited network availability, when network connection is resumed).
The Benefits of Device IntegrationDevice integration has multiple benefits. This includes time- and cost-saving in large projects as well as ease of use for patients where real-time data review reduces the need for a visit to their HCPs or clinical sites. In addition, device integration resolves the problem of patients reporting incorrect or subjective information on their wellbeing, which can often be an issue in real-world evidence collection in healthcare and clinical research.
Device integration allows for more holistic, objective data to be collected via different instruments or medical devices – especially when compared with anecdotal evidence from a patient, who may not always be honest when reporting their results in person. Healthcare providers and sponsors can now have access to real-time result reporting, whilst patients are able to complete assessments using devices that are an integrated part of their lifestyle, via a simple, easily-recognisable interface.
The technological advances that device integration brings also mean that healthcare professionals are no longer reliant on collecting patient data at a clinical site – real-time data review has now been opened up across the sphere. This is brought into particular focus when it comes to large-scale, global trials, which can be costly and time-consuming.
The device inclusive approach to clinical trials allows the integration of medical devices or consumer technology with any connected device (including mobile phones, tablets, laptops, PCs and medical devices). This approach offers the flexibility to capture outcomes from devices that fit into the everyday lives of the patients, taking into account patients’ preferences and familiarity with them.
Objective Patient Measurement Solutions – Meeting Regulatory GuidelinesDevice integration brings with it regulatory challenges. Regulatory authorities recognise different classes of medical devices based on their design complexity, their characteristics when in use, and their potential for harm to the patient if misused.
It is worth remembering that the use of devices for the collection of primary endpoints in Phase IIIa studies requires the devices themselves to be fully validated and checked, and it must be ensured that they guarantee acceptable measuring tolerances which can be reproduced. In the EU, this means that, as a minimum, the device must be registered as a Class I measuring device and in the US, for a device to meet regulatory guidelines, it must have 510(K) registration awarded by the FDA.Devices that fall under both of these subsets are known as ‘objective patient measurement solutions’.
There are other medical devices and consumer technologies which provide valuable insight during clinical trials, adding value typically only as secondary outcomes in Phase II, Phase IIIb and Phase IV studies due to them not being validated or controlled to produce variable readings.
What Does the Future Hold for Device Integration?The ultimate aim of device integration is to be fully-compatible with a range of home monitoring devices, which can be integrated into an eDiary via Bluetooth® or near field communication to ensure on-time, accurate outcome recording, thus simplifying the clinical trial process for all users; from sponsor research teams, to sites, through to the patients themselves. Device integration has proved highly beneficial, in part because it creates a simple interface for medical device readings which are a fundamental part of electronic clinical outcomes assessment (eCOA) data. Additionally, there is a clear market trend to design solutions fully compatible with a multitude of wearable and home monitoring devices, all of which are capable of being integrated into eDiaries, via Bluetooth® or near field communication, ensuring on-time and highly accurate recording of outcomes. As a consequence, demand for device integration will be rising fast.
Watch Pages
Dr Chris Watson, Product Manager, Exco InTouch. Chris has a PhD in Behavioural Neuropharmacology and is an experienced product strategist with over 16 years’ experience in the delivery of business and consumer based solutions, the last 6 of which have been focused in the clinical
technology industry. He has an extensive knowledge of product and software development processes and is responsible for implementing mobile product strategy at Exco InTouch.Email: [email protected]
Volume 7 Issue 310 Journal for Clinical Studies
Watch Pages
Biomarker-based Decision-making in Early-stage Oncology Drug Development: Finding a Balance Between Tradition and Rational Considerations
Until 10 to 15 years ago, oncology drug development was mainly conducted with compounds that were either genotoxic or cytotoxic. Determining the dose level that would provide the best ratio between efficacy and tolerability was mostly straightforward. As there is a clear justification for chemotherapeutics to destroy more cancer cells with an increasing dose, the highest tolerated dose level would also be the optimal dose to be taken forward. Consequently, the traditional setup of early stage development programmes in oncology has been a Phase I study to determine the maximum tolerated dose (MTD), which was then taken forward as the recommended Phase II dose (RP2D). As studies with genotoxic or cytotoxic agents cannot be conducted in healthy volunteers, the resultant characteristic aspect of oncology drug development is the need to commence clinical studies in cancer patients that have exhausted traditional treatment options.
The appearance on the scene of non-cytotoxic anticancer therapeutics, often targeted at specific components of signal transduction routes, has led to
a situation in which the main rationale behind the traditional early-stage development paradigm has evaporated. In particular, tyrosine kinase inhibitors provide an opportunity for dose-setting based on in vivo assessment of full target inhibition, a dose level that would provide the optimum biological dose and that may be reached below the MTD. However, in many clinical development programmes the designs of Phase I studies have not changed. At the recent 13th International Congress on Targeted Anticancer Therapies (TAT, Paris, 2-4 March 2015), an overview was presented on study designs and objectives of Phase I trials with cytotoxic versus non-cytotoxic anticancer agents published in 2012 and 2013. The classic 3+3 design or the accelerated design has been used in the majority of studies with cytotoxic as well as with non-cytotoxic agents (84 per cent and 63 per cent respectively). As one would expect, the use of pharmacodynamics (PD) endpoints was more prominent with non-cytotoxic agents than with cytotoxic agents (63 per cent versus 23 per cent). However, such PD endpoints were almost exclusively used as an exploratory secondary endpoint (Bosch et al., poster at TAT 2015).
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The preference of many companies to use traditional early-stage development approaches with tolerability as the primary endpoint and PD as the secondary endpoint may be due to the complications around biomarker-based primary endpoints. Employing PD biomarkers in an exploratory fashion may serve to provide additional confidence for a decision to proceed with clinical development after Phase I. However, the issue arises in interpreting negative outcomes. In such cases it is hardly possible to distinguish between different potential explanations, such as failure of the target, failure of the compound or the administration regimen, or failure of the biomarker itself (incorrect marker, assay or tissue). Theoretically, biomarker-based endpoints in Phase I studies could serve to answer the pivotal question whether or not there is full in vivo target engagement at tolerable dose levels. As such, biomarker-driven decision-making has a solid scientific foundation, but also requires a lot of development work in order to have the biomarker fit for purpose.
The minimum pre-work for enabling a biomarker to be suitable for decision-making comprises at least three critical steps: Firstly, the analytical parameters of the assay should be established (detection limit, technical variability and others). The second challenge is to determine a surrogate tissue easily amenable to frequent sampling and with similar in vivo exposure to the study drug as to the tumour to be treated. Also, the technical and biological variability in the clinical sample format should be ascertained. This may require separate in-human studies to assess the within-subject and between-subject variability in the tissue of choice under real-life conditions. Thirdly, based on the established variability the patient number should be calculated in a way that would allow reaching a methodically sound conclusion. The latter is particularly painful when it involves much larger patient numbers than would be expected under the classic 3+3 design, which only aims to establish maximum tolerability. The supporting argument in favour of using decision-making biomarkers is that there is no compelling argument for conducting such work in end-stage cancer patients. As such, low dose levels could be administered to healthy volunteers, which comes with the big advantage of a homogeneous patient population without co-morbidities or co-medication. At higher dose levels, a switch to end-stage cancer patients may need to be made to permit a reliable read-out of tolerability in the targeted population.
Hypothesis-driven Phase I studies with decision-making biomarkers may be a science-grounded approach to verify if an investigational compound has the required pharmacological characteristics in humans. However, the need to rapidly achieve development milestones will force many biotech companies into the “MTD equals RP2D” paradigm. The latter approach bears the risk of overshooting on the RP2D if the optimum biological dose could have been reached below the MTD.
Watch Pages
Gijsbert Veerman, Executive Director, Early Phase Oncology, provides strategic and operational oversight in the European Early Phase Oncology Specialty Team at INC Research. His background includes seven years’ pre-clinical oncology research and 18 years’ clinical development in CRO
environment with a focus on oncology both in solid tumours and haematological malignancies.
C. Meghann Howland, Executive Director, Global Early Phase Oncology, provides strategic and operational oversight to INC Research’s global Early Phase Oncology Specialty Team. Her background includes 20+ years of clinical and research experience in both the tertiary care and the CRO setting, with a primary focus
on haematology/oncology as well as Rare and Orphan Indications.
Rob Berg, MD, Ph.D., Senior Medical Director Oncology, provides medical oversight for many of INC Research’s Oncology and Haematology-Oncology studies in Europe. His background includes academic research in oncology and carcinogenesis, medical
practice, and 14 years in oncology clinical development in both a pharmaceutical industry and a CRO environment. Email: [email protected]. Website: www.incresearch.com
Volume 7 Issue 312 Journal for Clinical Studies
Watch Pages
Prescription labelling is currently distributed in paper form on or within the package of a prescription drug or biological product when it is dispensed. In a proposed rule, announced in the Federal Register on December 18, 2014, the US Food and Drug Administration (FDA) states its intention to require electronic distribution of the prescribing information for healthcare professionals. When the proposed rule is finalised, the paper form will no longer be permitted. As with many regulatory actions, however, any exceptions would be listed.
This regulatory move is no surprise, given the advent of virtual communications among healthcare providers, upcoming regulations requiring electronic submission of more and more information related to product applications, and expanding use of the electronic health record (EHR). The proposed rule impacts regulations found in 21 CFR 201.100, 201.306, 201.310, 606.121, 606.122, 610.60, and 610.61 for human prescription drugs and biological products, and blood and blood components intended for transfusion. The FDA believes that electronic distribution of the prescribing information
would increase its ability to enforce the misbranding provisions in sections 502(a) and (f) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as well as the safety and effectiveness provisions of section 505 of the FD&C Act.
The electronic distribution requirements of this proposed rule would not apply to patient labelling (including patient package inserts and medication guides), or to prescribing information accompanying promotional labelling, which would continue to be provided in paper form. These exclusions are explained in more detail in a section below and in full depth on the Federal Register announcing the proposed rule.
Summary of the Major Provisions of the Regulatory Action
• Manufacturers would be required to submit prescribing information to the FDA for posting on FDA’s publicly available labelling repository website (labels.fda.gov) every time there is a change in the labelling.
The Future of the Drug Label: FDA’s Proposed Rule on Electronic Distribution of Prescribing Information
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• Manufacturers would also be required to review the labelling posted at FDA’s website to verify that the correct version of the labelling appears in the repository, and to promptly notify the FDA if the correct version is not posted.
• A product’s immediate container label and outside package would bear a statement directing healthcare professionals to FDA’s labelling repository to view the electronic version of prescribing information. The statement would also provide a toll-free telephone number, to be maintained by the manufacturer, for handling requests to the manufacturer for an emailed, faxed, or mailed paper copy of the prescribing information.
• Manufacturers would be required to ensure the toll-free number service was in operation 24 hours a day, seven days a week. This would ensure that the prescribing information is accessible in most situations when internet access is not available to the healthcare professional.
In addition, the proposed rule provides that the FDA may grant an exemption from the electronic distribution of labelling requirements when compliance is not technologically feasible, could adversely affect the safety, effectiveness, purity, or potency of the drug, or is otherwise inappropriate. Manufacturers of exempted products would distribute prescribing information in paper form on or within the package from which the product is dispensed. Products intended for use in an emergency room or emergency stockpiles are examples of products that could be granted an exemption.
Prescription drug labelling includes prescribing information; patient labelling; the product’s immediate container label; outer container; the outside package; and other written, printed, or graphic information that accompanies the product. Section 201 of the FD&C Act provides a complete definition of labelling. 21 CFR 601 details the general labelling provisions for biologic products. Recommendations on labelling content and format from 21 CFR 201.56 and 201.57 are outlined in the FDA Guidance for Industry: Labeling for Human Prescription Drug and Biological Products—Implementing the PLR Content and Format Requirements. All components of labelling are submitted to the FDA as part of an applicant’s new drug application (NDA), abbreviated NDA (ANDA), biologics license application (BLA), supplement, annual report, or in other submissions, such as establishment registration and drug listing.
Exclusions to the Proposed RuleCurrent labelling regulations state that prescribing information must also accompany “promotional” labelling, as described in 21 CFR 202.1(l). This proposed rule would not apply to prescribing information that accompanies promotional labelling. This type of information would continue to be distributed in paper form. The FDA is proposing a new section 201.100(d)(4) to make clear that prescribing information accompanying promotional labelling must be distributed in paper form.
“Patient labelling,” another component of labelling for some prescription drugs, is FDA-approved information that is intended for patient use and includes patient package inserts and medication guides. Patient labelling must be reprinted in the prescribing information or must accompany the prescribing information. Because the FDA is examining methods to improve the content and distribution of patient labelling in a separate initiative, patient labelling is not affected by this proposed rule and will continue to be provided in paper form, as required by applicable regulations, and be electronically submitted to the FDA with the prescribing information.
Regina Ballinger is a Senior Manager with Thomson Reuters. She currently manages US regulatory content for Cortellis, and is the executive editor of the AdComm Bulletin. Ms Ballinger has specialised experience in public health, pharmaceutical regulatory affairs, and health communications. She
has had numerous articles published on topics related to new drug approvals and drug regulatory issues. Ms Ballinger was educated at the University of Maryland in law and nursing. She holds an MS degree in healthcare systems management.Email: [email protected]
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Volume 7 Issue 314 Journal for Clinical Studies
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The Impact of Exercise on the Arteries
Everywhere we turn we are continuously reminded of the benefits of exercising: it promotes weight loss, lowers blood pressure, improves how we feel, is good for the heart, relieves stress … the list goes on. Of course, these are all important aspects to a happy and healthy life, but one of the less touted, and just as important, benefits is the effect that regular exercise can have on the health of your arteries. In order to understand these benefits it is important to first understand why arterial health is important.
It’s fairly obvious that one critical role of the arteries is to transport oxygenated blood to all the major organs and tissues throughout the body, i.e. they act as a conduit. Their second, less obvious, vital function is to absorb the pulsatile flow generated by left ventricular ejection by expanding to accommodate the increased blood volume and transform it into a steady, continuous supply to the downstream vessels and tissues by gradually recoiling. In this same capacity they also dampen the transmission of the pulsatile pressure waves as they propagate distally, acting as a buffer for the major organs and protecting them from potentially damaging pulsatile energy.1
In the healthy young, the arteries are highly efficient at dampening the pulsatile pressure and flow waves. As age, disease, and certain lifestyle choices introduce themselves, the large elastic arteries such as the aorta become stiffer and their buffering ability is diminished.2
This is especially critical in the brain and kidney, high volume flow organs in which increased arterial stiffness can lead to increased pressure pulsations in the microcirculation and damage to both organs.1 It is well established that increased arterial stiffness also increases the risk of coronary heart disease, stroke, cardiovascular disease events, and all-cause mortality.3,4 So what role can exercise play in this pathophysiological process?
First consider how the physically active measure up to untrained and less active individuals. In a cross-sectional examination, Laurent et al. compared aortic pulse wave velocity (PWV), a direct measure of aortic stiffness, in athletes who completed four 60-minute endurance training sessions per week to sedentary men who performed less than one hour of physical activity per week. Despite being matched for blood pressure and age, the sedentary group had a significantly higher PWV, signifying a much stiffer aorta than the endurance-trained athletes.5 Similarly, regular exercise has been shown to blunt the age-associated increase in aortic stiffness in women, which may partly explain why there is a lower incidence of cardiovascular disease in those who are physically active post-menopause.6 Additional data supports that regular physical activity and higher aerobic capacity mitigates the normal arterial stiffening found with advancing age.7 However it’s possible that excessive training may negate these beneficial effects and actually be detrimental.8
To prevent the development of arterial stiffness would be preferred, but what about the ability to reverse or reduce it? The answer to this question is less clear and seems to be dependent on a number of factors. Most of the data indicates that aerobic training will promote arterial destiffening, specifically regimens lasting at least 12 weeks,9 and that these benefits even extend to those individuals with coronary artery disease and the metabolic syndrome.10,11 The effects of resistance training, however, don’t look as promising. Studies have shown that although there isn’t any improvement in arterial stiffness with resistance training, in most instances there isn’t a negative impact either.12
In summary, increased arterial stiffness is a strong predictor of future cardiovascular risk. With advancing age the large elastic arteries progressively stiffen, but this process can be mitigated, and somewhat prevented, through habitual aerobic exercise. This form of exercise can also reduce or reverse arterial stiffness, while the effects of resistance training don’t appear to be as beneficial. Regular, moderate aerobic exercise has been repeatedly shown to improve health. It now appears that one part of that health improvement is in the health of our arteries.
References1. O’Rourke MF and Safar ME (2005, July). Relationship
between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension, 46 (1), 200-4.
2. Boutouyrie P et al. (2010, Oct). Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values.’ Eur Hrt J, 31(19), 2338–2350.
3. Ben-Shlomo Y et al. (2014, Feb 25). Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol, 63 (7), 636-46.
4. Vlachopoulos C et al. (2010, Mar 30). Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol, 55(13), 1318-27.
5. Laurent S et al. (2011, Mar-Apr). Differences in central systolic blood pressure and aortic stiffness between aerobically trained and sedentary individuals. J Am Soc Hypertens, 5(2), 85-93.
6. Tanaka H et al. (1998, Jan). Absence of age-related increase in central arterial stiffness in physically active women. Arterioscler Thromb Vasc Biol, 18(1), 127-32.
7. Vaitkevicius PV et al. (1993, Oct). Effects of age and aerobic capacity on arterial stiffness in healthy adults. Circulation, 88(4 Pt 1), 1456-62.
8. Vlachopoulos C et al. (2010, Sept). Arterial stiffness
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and wave reflections in marathon runners. Am J Hypertens, 23(9), 974-9.
9. Montero D et al. (2014, May 15). The impact of aerobic exercise training on arterial stiffness in pre- and hypertensive subjects: a systematic review and meta-analysis. Int J Cardiol, 173(3), 361-8.
10. Edwards D et al. (2004, Jun). Effect of exercise training on central aortic pressure wave reflection in coronary artery disease. Am J Hypertens, 17(6), 540-3.
11. Donley DA et al. (2014, Jun 1). Aerobic exercise training reduces arterial stiffness in metabolic syndrome. J Appl Physiol (1985), 116(11), 1396-404.
12. Ashor AW et al. (2014, Oct 15). Effects of exercise modalities on arterial stiffness and wave reflection: a systematic review and meta-analysis of randomized controlled trials. PLoS One, 9(10), e110034.
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Bobby Stutz is currently the Senior Research Engineer for AtCor Medical, Inc. He has spent the last eight years in the medical device industry after earning his Masters and undergraduate degrees in biomedical engineering at The Catholic University of America in Washington, D.C.
Dr Dean Winter is currently Senior Consultant - Scientific and Clinical Affairs for AtCor Medical, Inc. Prior to joining AtCor, he was Director of Bioengineering at Southwest Research Institute, where he developed the first commercial blood pressure monitor based on arterial
tonometry. He is an internationally recognised expert in physiological fluid mechanics, biomechanics and medical device development. Dr Winter may be contacted at: [email protected]
Volume 7 Issue 316 Journal for Clinical Studies
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Logistic Challenges in Sub-Saharan Africa
Africa is the second largest of the earth’s seven continents and makes up approximately 22% of the earth’s total land area. In 1974, the skeleton of “Lucy”, a hominid who lived approximately 3.2 million years ago, was discovered in Hadar, Ethiopia. In 1979, a 165-foot trail of the earliest hominid footprints was discovered in the Kibish region of Tanzania. Africa was the birthplace of humanity.
The population in around 50 countries (the number changes depending on who is defining it) covers all extremes: nomadic herders, village dwellers, city folk, well educated business professionals, subsistence farmers, miners, oil workers, fishermen – a whole diversity of communities and people. The population are generally young due to rapid population growth in the last few decades, and because of the effect of AIDS on recent generations.
Sub-Saharan Africa displays the most linguistic diversity of any region in the world. This is apparent from the number of languages spoken. There are several European languages – English, French, German, Portuguese, and Afrikaans, which is derived from Dutch – but whilst these are spoken and are often still the official languages of countries, the region contains over 1000 languages, which is around 1/6 of the world’s total.
In the last decade private capital flow to Sub-Saharan Africa has begun to exceed official development assistance. Six of the world’s ten fastest-growing economies over the previous decade were situated below the Sahara, with the remaining four in East and Central Asia. Economies are thriving; political stability is at an unprecedented level.
However it is not all rosy. There are still significant problems getting healthcare out to everyone, due to lack of infrastructure in rural areas, despite the efforts of governments and NGOs like the Gates Foundation. Ebola has highlighted some of the problems in delivering healthcare both in big cities and out in the bush, whilst balancing responses from the WHO, MSF etc. with government policies and actions. Many governments have been guilty in the past of trying to downplay disease situations in order not to scare off foreign investment and to maintain order.
There are some amazing initiatives to deliver vaccines, including drones which can travel 100K into the bush and parachute them in. Energize the Chain is an initiative between the University of Pennsylvania’s Wharton School and Econet Wireless, a global telecoms leader. Together they have started a programme in Zimbabwe to place vaccine fridges into mobile phone tower compounds,
which are in place all over Africa. The electricity grid in rural Zimbabwe might not be able to ensure continuous, reliable power supply, especially in remote parts of the country. In such regions, vaccines may be stored at a central point and moved over large distances by road for each vaccination session, greatly increasing transportation time, logistical hurdles, and operational costs. Their solution shifts the last point of storage significantly closer to the point of vaccine delivery by deploying highly energy-efficient vaccine-storage refrigerators to rural clinics and/or co-locating such refrigerators with Econet’s tower sites. This simple but revolutionary approach reduces vaccine transportation time and increases health system efficiency. It’s a fantastic solution to a continent-wide problem.
The regulations vary across such a wide region for import and export, but universally we should expect clearances to take days rather than hours, and so packaging should be chosen with that in mind. Some of the best examples can be found on page 17.
Clinical sites are available mainly in the larger cities, and really the next big area for clinical studies has to be Sub-Saharan Africa. There’s actually nowhere else left to go. There are already about 4500 studies underway, but it should be borne in mind that almost half of those are in South Africa. There are currently at least 905 million people in the region and the UN predicts this will rise to around 1.5 billion by 2050. That will create a potentially huge market for commercial drug, which is very hard to ignore. There are many countries with less than a hundred studies underway and we need to work together with governments and NGOs to deal with the logistical issues and make the most of this region.
Journal for Clinical Studies 17www.jforcs.com
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Sub-Saharan Africa
Africa is the second largest of the earth’s seven continents and makes up approximately 22% of the earth’s total land area. In 1974, the skeleton of “Lucy”, a hominid who lived approximately 3.2 million years ago, was discovered in Hadar, Ethiopia. In 1979, a 165-foot trail of the earliest hominid footprints was discovered in the Kibish region of Tanzania. Africa was the birthplace of humanity.
to take days rather than hours, and so packaging should be chosen with that in mind. Here are some of the best examples:
Kenya Tanzania Uganda Paperwork for importing pharmaceuticals
Import permit issued by the Ministry of Heath
Shipments with a value exceeding 70USD require formal customs entry and special import documentation by the consignee.
Small quantities of medicines for personal use are no problem, provided that the medicines have not expired.
Medicines shipped for commercial purposes can only be imported provided that the consignee is registered with the National Pharmacy Board or has obtained an approval from the National Pharmacy board to import a particular shipment containing medicines. Details of shipments must always be submitted to the National Pharmacy Board for prior importation approval.
All pharmaceutical and biological samples require an import permit; most hospitals have a permanent authorisation. All pharmaceutical and biological samples require a certificate from the NDA (National Drug Authority) in Kampala. Consignee must apply for it, and it takes 2-4 weeks to obtain.
Expected clearance time 72 Hours 4 hours 2 hours Storage at the airport Only one handler
(Swissport) has storage in Nairobi airport; this should be taken into account when choosing the airline
Refrigerator +2 to +8C: 375 m3
No freezer or controlled ambient areas
Dar Es Salaam
Refrigerator +2 to +8C: 80 m3
Freezer -20C: 18 m3
Controlled ambient area: not available
Entebbe Airport
Refrigerator +2 to +8C: 600 m3 (extra charges apply)
Freezer -20C: 600 m3
Controlled ambient area: not available
Replenishment during clearance
Is possible Not possible Must be requested, not always possible
Exporting biological samples
Invoice & certificate of origin: export permit
Invoice, pro-forma: no export permit required
Invoice. An export permit is required for all biological samples, but most hospitals have a permanent authorisation
Extra information No clearance after hours for normal shipments. Only perishables, temperature-controlled, limited-lifespan materials require a 24 hrs pre-alert advice
Shipments with a value over USD 300 are subject to special inspection; the inspection fee is 1.2% of the FOB value and Customs duties & VAT (20%) apply
As required by the Uganda Revenue Authority (URA) all importers/exporters must appoint their (clearing) agents online. Selection is done on a per shipment basis
Clinical sites are available mainly in the larger cities, and really the next big area for clinical studies has to be Sub-SaharanAfrica. There’s actually nowhere else left to go. There are already about 4500 studies underway, but it should be borne in mind
Sue Lee has worked for World Courier for 25 years. During this time she has experienced a variety of customer service and operational functions, including the setting up of numerous, multi national, clinical sites for the transportation of biological samples in her capacity as Head of the Major Clinical
Trial Unit. Sue has orchestrated the shipping thousands of shipments with very specific temperature requirements to a host of challenging locations, and each presenting their own obstacles and dilemmas. More recently in her role as Regional Quality Manager, Sue has been auditing and developing procedures and systems for regulatory compliance, package and vehicle testing, as well as temperature control and mapping. Email: [email protected]
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Beware the Financial Cost of Human Clinical Trials Compensation Claims
Human clinical trials obviously vary significantly in scale, location and complexity. Compensation claims that arise from such trials can be complex to manage. But the financial impact can be mitigated through smart insurance planning. Alex Forrest of Chubb Insurance, considers the current compensation claim environment.
There are a number of different ways in which people who are injured from medical products globally can access compensation. The three most common legal systems in operation are:
• A tort based legal system – where some form of negligence must be proved to have happened. This is used in most of the English speaking world.
• A defined benefits based compensation system for medical injuries.
• A no-fault compensation system.
Each of these systems has applicability when looking at injury caused by approved and sold medical products. There are merits in each system, and they have been designed to work with the underlying legal framework and regulatory choices of the respective country.
Why we compensate research subjects for injury?Research subjects, both healthy and sick, are clearly
contributing to society by helping to ensure that drugs and devices are safe before going into open circulation. It is likely that they have consented to being tested on and absolved investigators or sponsors of blame for injuries from those experimental products. “Society” agree that should an injury occur the research subject should receive some form of compensation but the mechanism can vary greatly.
So what are the coverage options?Insurance cover for clinical trials can be based on any of the above systems. When we look at compensation connected with clinical trials and consent, however, it is far more complicated and issues can arise when a negligence based tort system is used. Medicinal products undergoing trials are, by their very nature, experimental. They will always carry some risk that there could be an unforeseen negative outcome for patients. Indeed some clinical trials, such as dose-escalating studies, are specifically designed to find the point at which negative outcomes for patients occur and to find optimum concentrations of a drug or therapeutic delivery from a
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device. So, how does a negligence based legal system fit with this scenario when the clinical trial investigators are just doing their jobs? How do compensation claims get treated? How can insurance help avoid potential issues caused by such claims and protect sponsors adequately?
This is where no-fault compensation insurance cover plays a key role. It provides a framework for when some element of causality can be proven and there is a structured way in which the research subject can get compensation for their injury - without trying to find some form of negligence, whether it existed or not.
Before a human clinical trial study commences a research subject will always sign a consent form in which they agree that the research is experimental. The form effectively absolves the sponsor company from blame for injury. To most, this would seem to prevent a research subject pursuing any future compensation, should they be injured legitimately. There may well be elements of negligence involving the investigators but this is only likely to be for a small percentage of cases. The tort based system therefore creates a very high barrier to any injured patients from claiming compensation – as negligence has to be proven.
How can sponsor companies help protect themselves through insurance?Not all insurance policies are the same, and when it comes to clinical trials insurance there is still a great variety of stances across the countries where clinical trials are conducted. Even in Europe, clinical trial insurance harmonisation has been highly elusive. Sponsors need to understand the different types of cover available or required in each country, as choosing an inadequate or inappropriate insurance policy could be a very costly mistake.
Some territories, such as Germany, are highly prescriptive and a defined benefits system operates: compensation is calculated purely according to the physical injury but would not include any pain and suffering or consequential financial loss. Others, such as the UK and Sweden, have little codified law and leave it in the hands of the medical industry and insurance industry to find their own path. This is where the sponsor must carefully consider whether a negligence only based policy or one containing some no-fault compensation provisions is more suitable, and which gives greater peace of mind.
There are many other additional insurance cover needs to consider, such as:
• Does the policy extend to the investigator’s negligence or just the inherent defects of the investigational product?
• Additional cover for research subjects travelling to and from the clinical sites. This is a specific nuance available in Germany.
• Does the policy extend to all screened patients or just the research subject admitted to the trial?
• What Limit of Insurance should be purchased?
Given all these different variables, it is difficult to expect a sponsor to keep up with both the buying choices and the requirements of various laws, regulators and Ethics Committees. Insurance brokers who specialise in this very niche field of life science insurance add invaluable help in dealing with these issues. They can make sure that the cover you buy fits your own risk appetite, meets all the compliance requirements across all applicable jurisdictions and ensure the correct service from your insurers to prevent delays.
Alex Forrest studied Biochemistry at Nottingham University. He joined Chubb Insurance, a leading global insurer of life science companies, as an assistant underwriter into the Technology Specialty in 2003. He has led the Life Science Practice in the UK and Ireland since 2012.
Abstract:It is a GMP requirement to certify the vendor to deliver high quality and safe medicines, and to prevent recalls, deaths, adverse events, and serious illness due to substandard quality of manufactured medicines. The main aim of business is to generate profit. To achieve good profits, sometimes pressure will be increased to get raw materials of low cost, which sometimes leads to procurement of substandard material. This can be avoided by using supplier qualification as a tool.Key words: GMP, vendor, quality assessment.
Introduction:Relationship between quality and increasing risk of raw materials is as follows:
The manufacturer has the ultimate responsibility to qualify the vendor. Internally, the vendor should also have an efficient vendor certification programme for qualifying the supplier from whom he will procure the raw materials. All the documents of manufacturer and vendor will be verified during audit.
Supplier qualification prerequisite:1. Sample evaluation2. Evaluation of supplier’s quality system to assure
quality and safety of procured materials by checking manufacturing controls.
Steps of Supplier Qualification:1. Supplier selection2. Due diligence3. Quality assessment of all suppliers4. Change control and production assessment5. Supply chain security6. Ongoing monitoring and evaluation
1. Supplier Selection:The purpose of this step is to define a set of criteria that can be taken into consideration in the selection process of a supplier. The supplier selection process starts with
the definition of the user requirements for the material within scope. The user requirement specifications provided to purchasing should contain as a minimum the information: Name of the product (including formulae and CAS number when available), material specifications, quantity required. To select the supplier, the criteria of materials to be procured are determined and the user requirement specification form is developed, stating:
i. Name of the productii. Material specificationsiii. Quantity required
Information to be requested from the supplier for selection should contain:
i. Specificationsii. Manufacturing, packaging and labelling detailsiii. Material safety data sheetsiv. Analytical test methods to examine the sample
against the specified criteria.
Supplier Assessment Dimensions:Dimension Parameters checked forAssurance of supply It is an essential element to assure the supply in specified time
Quality and regulatory compliance The supplier should be checked for
i. cGMP compliance – regulatory track recordii. recall – complaintsiii. change controliv. material management controlv. quality management systemvi. production facilities and equipmentvii. process validationviii. documentation standards.
Procurement cost i. cost managementii. presence in low-cost countriesiii. ability to achieve target price
Technical aspects i. plant capabilitiesii. laboratory capabilitiesiii. business programme resolving capabilitiesiv. staff qualificationv. control systemsvi. development capabilitiesvii. process development expertiseviii. project managementix. willingness to innovatex. intellectual property
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Responsiveness and communication i. rapidity project assessmentii. resource availabilityiii. flexibility in attitudeiv. opennessv. ease of communicationvi. proactiveness
A multi-disciplinary team is appointed by buyer to assess all the above characteristics of the vendor. The multi-disciplinary team, after thorough review, shortlists a number of vendors of appropriate competence.1
2. Due Diligence:Purpose:
• This step is not applicable for non-critical raw materials.
• For critical raw materials, including API starting materials, the necessity to perform due diligence can be based on a risk assessment according to ICH Q9.
• Documented evidence will be assembled to support the go/no-go decision process.
• The possibility of establishing a long-term business relationship with the supplier will be evaluated.
• The implemented systems and existing facility will be assessed and challenged in order to evaluate the capability of the supplier to comply with the customer’s requirements.
Due diligence is a legally binding process during which the buyer evaluates the assessments and liability of the vendor. It is essential to assure that the appropriate due diligence is conducted prior to contracting with a supplier, and that documented evidence is created to take decisions such as go/no-go processes. The possibility of establishing a long-term business relationship with the supplier is evaluated during due diligence.
The various supplier challenges that have to be assessed are:i. Process containmentii. Process equipmentiii. Quality of utilitiesiv. Analytical equipment availability and method
developmentv. Performance of preparing for regulatory submission.
Selection of Cross-functional Team:Depending upon the criticality to be evaluated, a cross-functional team is established, consisting of representatives fromi. Engineeringii. Regulatoryiii. Environmental / health / safetyiv. Technical expertsv. Procurement department
The cross-functional team will evaluate the vendor for qualification, and recommendations will be sent to the
senior management to take go/no-go decisions.
All the above areas are assured and challenged to evaluate capacity of vendor, to take appropriate decision on go/no-go situations.2
3. Quality Assessment:The supplier must assure that supplies are of quality and can be used at any stage of manufacture, and should assure that the material being produced complies with “Note for guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal product” – EME/410/01 (TSE guidelines). The material which is delivered by tanker is assured for its quality. The tanker should be specific for a particular product,
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and if not, necessary cleaning is assured by cleaning validation. The quality unit is responsible for evaluating the quality of the vendor. If needed an audit team must be established with appropriately qualified personnel to audit the vendor. The audit questionnaires must be tailored to the raw material being purchased, its mode of manufacture, API delivered from plant sources, sterile liquids, and biotechnological processes.
i. The audit must aim to find whether the manufacturer being audited has the potential to supply to a different regulatory standard, if it is required in the future?
ii. Does this supplier have the potential to be a long-term partner?
The auditor should also decide to what extent the audit must be conducted; if needed, a re-audit must be done with appropriate remediation. The audit finding should address the capability of the vendor, and should assist in taking go/no-go decisions.
Operation of a Quality Assessment:
*(if available), √ - required, **√ - Dependent on risk assessment performed on material being purchased
Establishing Supply Agreement / Contract:The agreement should address the raw materials and quantities required, and it should also focus on the expected quality of raw materials.
It should address the need for:i. Notification of any potential changes that may
impact the quality of the productii. No changes to be made without prior approval.3
4. Change Control and Production Assessment:All the changes that impact the quality of product must be evaluated and agreed by both supplier and firm. The change can be initialised at any stage, by any department. To track the change a change control form is issued.Contents of change control form are:
i. Tracking numberii. Detailed description of changeiii. Specification for material based on requirementsiv. Defined number of batches being affectedv. Products impactedvi. Reason for changevii. Acceptance criteriaviii. Supporting documentation:
• Outline of changes to master formula record• Financial impact• Impact on current testing• Validation impact
The change control form is evaluated by the cross-functional team, after the approval of the change is implemented. After successful implementation of change, a closure memo is prepared by the assigned coordinating function that verifies and shows evidence that all requirements of the temporary change request have been met.5
Change Control and Assessment Process:The change control and production assessment process follows five main steps: initiation of change, execution of change, evaluation of change, closure of the temporary change control package and preparation for ongoing monitoring as follows.
Initiation of Change The execution of changes to the process are managed by a cross-functional team according to the following principles: • The system for change control is overseen by the
quality organisation, but may be managed by another function
• All changes are assessed from a technical, quality, regulatory, stability, safety, environmental and business standpoint, with the appropriate personnel involved in the review.
• The impact of the change on the affected areas, processes and systems is evaluated and communicated
• All changes requiring a change to the filed process will be communicated to the appropriate agencies
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• For non-critical raw materials, the process may be streamlined to assess the change as there is no regulatory impact, and the impact may be minor to the process.
Mechanism for Review of Change:For Critical Raw Materials and API Intermediates
The mechanism for review is as follows. • Tracking number • Detailed description of change • Specification for the material based on user
requirements • Defined number of batch that will be impacted • Products impacted (name and identification code) • The reason for the change • Acceptance criteria • Supporting documentation
• Outline of changes to master batch records • Financial impact • Impact on current testing • Validation impact • Results of use test of material and the follow-on
product evaluation
Execution of Change: Following approval of the temporary change request by the appropriate functions and the completion of all actions required for the change, the process is executed using the new material.
Evaluation of Change: The evaluation of the change is performed at a number of levels as follows:
• The resulting material produced as part of the temporary change is then evaluated by
• Routine testing of the material for all materials • Use tests to produce the final product for critical
materials and API intermediates • Extra testing to evaluate the material produced
and ensure that it is within expectations for critical materials and API intermediates
• The validation completion report is drafted and approved as per the normal site procedure
• All prior-to-release and prior-to-implementation requirements are assessed and tracked to closure as per the site systems.
5. Supply Chain Security:Along with supplier and manufacturer, other firms such as agents, brokers, distributors, re-packers, re-labellers and transport companies are involved in contributing to the supply chain. The shorter the supply chain, the more secure it will be.
The entire supply chain from the manufacturer of an API, registered intermediates or critical raw material to the customer should be assessed and qualified from
a quality perspective, mainly related to quality system, transportation, storage and related conditions, as well as traceability of the material.5
Apart from the supplier qualification and management activities, the following measures related to packaging can be considered and may increase the supply chain security for APIs:
• Use of tamper-resistant packaging closure by the manufacturer
• Evaluation of the label by the customer: the label on the material matches the reference label provided by the manufacturer.
• 6. Ongoing Monitoring and Evaluation:After approval, the vendor has to be checked periodically for compliance. The quality unit is responsible for the evaluation and re-approval of the vendor.
Responsibilities The evaluation should be under the control of the quality unit, but completed as part of a multi-displinary team evaluating all aspects of supply.
i. Ongoing Monitoring:At least the following aspects should be taken into consideration:
• Specification (results on certificate of analysis and own results)
• Statistical evaluation of quality control data for critical parameters (if applicable) to identify any adverse trends
• Packaging, sealing • Labelling • Delivery dates and quantities • Certificates and other documents
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All deviations should be monitored and managed according to the company’s complaints procedure.
ii. Periodic Evaluation:Regularly, typically on an annual basis, the supplier’s performance should be assessed. Depending on the type of material, the following data should be evaluated:
• Periodic full testing of material • Quality – for example number of not right-first-time
Conclusion:The main aim of any firm is to produce the medicinal products which are safe and of good quality. To maintain the quality, the raw material should be purchased from a competent supplier, identified and evaluated for his competence. Proper vendor certification will ensure the quality of incoming raw materials and reduce the cost involved in retesting. The supplier qualification will increase the confidence of the firm to produce the product of good quality.
References1. ACTIVE PHARMACEUTICAL INGREDIENTS
COMMITTEE (APIC) guidelines on supplier qualification & management guideline, December 2009.
2. ICH harmonized tripartite guidelines, Q7: good manufacturing practice guide for active pharmaceutical ingredients, 10th November, 2000.
3. Note for guidance in minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal product, EMEA/410/01 (TSE guidelines).
Lokesh M S Quality Assurance Group,Department of Pharmaceutics,JSS College of Pharmacy,JSS University,Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India
Balamuralidhara V. Assistant ProfessorRegulatory Affairs Group,Department of Pharmaceutics,JSS College of Pharmacy,JSS University,Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India
Bhushan Dinesh Belgaonkar Quality Assurance Group,Department of Pharmaceutics,JSS College of Pharmacy,JSS University,Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India
Abstract: Revised Response Evaluation Criteria in Solid Tumours (RECIST 1.1) came into effect in 2009 in order to address the issues and limitations of RECIST 1.0. While RECIST 1.1 has addressed many challenges with the previous version, some drawbacks still remain. More than five years of clinical trials monitoring across numerous international sites has revealed that investigators across all countries encounter many and similar difficulties in interpreting RECIST 1.1, and tend to make the same mistakes. These errors, if not timeously identified and corrected, lead to increased variability of data across the trial sites and may affect efficacy endpoints. In our opinion, proactive training, focused on typical questions/mistakes, may help to increase the accuracy of the RECIST data extraction at the trial sites.
BackgroundSince the global requirement of randomised and controlled clinical trials, over the past four decades, for new drug approvals in oncology, there has been a challenge to uniformly apply imaging-based tumour-specific response criteria with the purpose of objectively assessing treatment response in cancer trials. In 2009 a revised RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) was developed to address the drawbacks of previously applied response systems such as the WHO or the initial version of RECIST (1.0). The major changes, from RECIST 1.0 to RECIST 1.1, included the number of lesions to be assessed (reduced from a maximum of 10 to a maximum of five in total (and from five to two per organ, at maximum)). In RECIST 1.1, target lesions (TL) must be at least 10 mm in the longest diameter. Furthermore, assessment of pathological lymph nodes (LN) was incorporated with a short axis of 15mm or more, and these could also be considered assessable as target lesions. The key features of RECIST 1.1 versus RECIST 1.0 are summarised in Table 1.
As seen in Table 1, RECIST 1.1 also clarified progressive disease (PD) in several aspects. In addition to the RECIST 1.0 PD definition of an increase in sum by 20%, a 5 mm absolute increase was further added to guard against over-calling PD (progressive disease) when the increase in total sum is very small. Finally, interpretation of the new FDG-PET CT scan in the detection of new lesions was included. While RECIST 1.1 provides a standardised post-treatment monitoring with clearly defined outcome, it could be applied incorrectly. Thereby, a false radiological interpretation may occur, resulting in negative implications not only for clinical trial results but also for patient care.
Findings and Procedure DetailsHaving maintained a database of frequently asked questions on RECIST 1.1 applications received from
clinical trial sites since the revised RECIST criteria were implemented in 2009, we have identified the most frequent mistakes in RECIST 1.1 interpretation and grouped them into five major categories (Table 2). Our database contains questions collected from more than fifty clinical trials in several malignancies, namely: lung, colorectal, breast, prostate, pancreatic, gastrointestinal and ovarian cancer.
We have identified that the most common mistakes are related to selection of inappropriate lesions at baseline, inaccurate reassessment of both target lesions and non-target lesions, difficulty in assessment of small new lesions, evaluating lymph nodes both at baseline and at follow-up, and substantial deviation from scanning schedules.
Despite a clear definition, in RECIST 1.1, of target lesion number and size, we could subsume that almost half of all the mistakes occur under the first category pertaining to an incorrect number or identification of target lesions selected at baseline. The most common mistake was to select more than two target lesions per organ in cases when only one or two organs were involved in the malignant process. Another mistake was to select all suitable target lesions but less than five, and then at a follow-up timepoint to add additional target lesions in
Common Pitfalls of RECIST 1.1 Application in Clinical Trials
Table 1 Highlights of revised RECIST 1.1, summary of major changes RECIST 1.0 to RECIST 1.1:
RECIST 1.0 RECIST 1.1
Number of target lesions 10 lesions, 5 per organ 5 lesions, 2 per organ
Assessment of pathological lymph nodes
Not mentioned Nodes with a short axis of ≥ 15 mm are considered measurable and assessable as target lesions.
The short axis measurement should be included in the sum of lesions in calculation of tumor response.
Nodes that shrink to <10 mm short axis are considered normal.
Definition of disease progression
20% increase in target lesions sum
20% increase in target lesions sum plus 5 mm absolute increase
Detection of new lesions Not specified Section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included
Definition of unequivocal progression of non-target lesions
Unequivocal progression considered as PD
More detailed description of unequivocal progression to indicate that it should not normally trump target disease status. It must be representative of overall disease status change, not a single lesion increase
Imaging guidance Not included Includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions
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case non-target lesions grew or new lesions appeared. For example, in one case we discovered that all the five target lesions assigned were liver metastases even though RECIST 1.1 clearly states: “When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline.” Thus RECIST 1.1 is clear that when patients have only one or two organ sites involved, a maximum of two and four lesions respectively could be recorded.
An additional common error discovered is that while all suitable target lesions, but with a total numbering less than five, were identified at baseline, at a follow-up timepoint new target lesions were added if non-target lesions grew or new lesions appeared.
One extra issue identified is that of lesions in paired organs like lungs or adrenals. While RECIST 1.1 is silent on this issue, a commonly accepted approach is to select not more than two target lesions in paired organs, i.e. not more than two in lungs, and not more than two in adrenals, etc. The same common approach is relevant to lymph node lesions, i.e. not more than two target lesions in lymph nodes5.
See Table 3 Case 1.Another mistake found was declaring lesions with non-reproducible measurements, most often a lesion in a hollow movable, distensible organ, e.g. a bowel wall lesion, as target lesions. This error mostly occurred in
gastrointestinal cancer trials. According to RECIST 1.1 guidelines, “Target lesions should be selected on the basis of their size (lesions with the longest diameter); be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements.” Measurements of a lesion located in a distensible or hollow organ are not expected to be reliably reproduced and thus, even though gastrointestinal lesions are not truly non-measurable, many of them should not be described as target lesions as their longest diameter can hardly be defined on single plane images. The assessment of lesions in hollow organs may demonstrate a marked variability in size depending on the filling status of the organ making the lesion non-measurable.
One more issue relates to selecting a pseudolesion as target. These lesions are not part of the malignant clone. Examples of such pseudolesions are incidental adrenal masses, hemangiomas, benign ovarian tumours and cysts. Assignment of non-malignant lesions as target at baseline results in incorrect follow-up evaluation of an imaging-based endpoint and outcome of response assessment. It is, however, NOT recommended that a wrongfully included pseudolesion at the baseline sum is simply later excluded from follow-up sums since this biases in favour of therapy response. In such situations when a pseudolesion has been identified in follow-up, a new baseline must be created after the lesion is proved to be non-malignant.
Assignment of lymph node lesions as target merits particular attention. This is because RECIST 1.1 introduced rules for lymph nodes to be considered pathological for the first time: “…pathological nodes which are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥ 15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum.” Since lymph nodes are normal anatomical structures, which could be seen on CT scans even if they are normal and not involved by cancer, RECIST 1.1 discriminated between normal and pathologic nodes by size. Lymph nodes sized ≥ 1 cm in the short axis diameter are considered malignant, according to RECIST 1.1, and if they are smaller than 15 mm in the short axis they cannot be considered as target lesions. Benign nodes are more likely to be ovoid and malignant infiltration makes them more rounded. Thus, if the ratio of the long axis to short axis diameter is less than two the lymph node, there is a higher probability that the lymph node is malignant. The reason that the short axis diameter of a lymph node should be measured for deeming them as pathological or for determination of target lesion size is because it has been demonstrated that that the lymph nodes are more likely to become rounder (i.e. increase in the short axis) in case of malignant infiltration. The short axis diameter is measured perpendicular to the longest diameter of the lymph node.
Table 2 Five major categories of typical RECIST 1.1 pitfalls
(1) selecting target lesions at baseline a) wrong number of the target lesions selected at baseline or change of the number of target lesions at a follow-up timepoint
b) selecting a target lesion with non-reproducible measurements, most often a lesion in a hollow movable, distensible organ, e.g. a bowel wall lesion
c) selecting of a target lesion that is not clearly a metastasis
d) selecting a lymph node lesion smaller than 15 mm in short axis as a target or using long axis measurement for lymph nodes
(2) reassessing target lesions a) premature declaration of progressive disease based on 20% increase in total sum non-metering the 5 mm absolute increase rule or based on 20% increase in a single lesion instead of total sum
b) assessment of a timepoint response with reference to the previous timepoint rather than to baseline and nadir
c) trouble assessing target lesions response in situations where one of the lesions could not be visualized or resolved
(3) reassessing non-target lesions a) premature declaration of progressive disease based on change in size of non-target lesions by analogy with the target lesions assessment rules
b) trouble interpreting changes in volume or reappearance of a pleural effusion or ascites that was present at baseline
(4) assessing for new lesions a) new lesion is not acknowledged as progressive disease if its size is smaller than the measurable lesion threshold
(5) substantial deviations from the scanning schedule
a) critical deviations from the tumor assessment visit window outlined in the study protocol
b) failure to perform end of treatment RECIST 1.1 assessment in case of symptomatic deterioration
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In spite of the RECIST 1.1 guidelines for pathological lymph nodes, in the presence of non-nodal lesions suitable to be target, it is advisable to register malignant lymph nodes as non-target as there are more challenges and controversies in assessment of the nodal lesions response. Unfortunately, and despite the agreed upon guidelines by the experts, 10-20% of normal-sized locoregional nodes contain tumour deposits and up to 30% of enlarged nodes demonstrate only inflammatory hyperplasia. Also, in some tumours, the incidence of metastatic disease within normal-sized nodes is greater than others. For example, in patients with colorectal cancer, 90% of nodal metastases occur in nodes less than 10mm.
An additional issue pertains to bony lesions. RECIST 1.1 suggests that lytic or mixed lytic-blastic bone lesions with identifiable soft tissue components can be considered as measurable target lesions. However, pure bone lesions, which are much more common, usually do not show any change in size under therapy and thus do not qualify as target lesions.
See Table 3 Case 2.The second most common category of errors we found is re-assessment of target lesions in follow-up. This included premature declaration of progressive disease based on 20% increase in total sum but not triggering the required 5 mm absolute increase rule. Additional mistakes in this category included declaring PD based on 20% increase in a single lesion instead of total sum, assessment of a timepoint response with reference to the immediately previous timepoint rather than to the guidelines recommended comparison with baseline or the nadir, whichever is smaller. Also, some clinical sites wrongfully understand stable disease category as no change comparing to baseline, rather than a calculated category which numerical value shows neither sufficient increase to constitute progressive disease nor sufficient shrinkage to represent partial response. A genuine issue with RECIST 1.1 also
occurs occasionally. Since tumour therapy may induce tumour necrosis, at times tumour size could be maintained or even increased even though the living tumour mass may be lesser. In such situations, the actively perfused part of the tumour may actually be lower even though necrotic and edematous areas may show increase. Evaluation criteria like Choi which include tumour density following contrast media application have been proposed as the criterion of choice for the determination of tumour response in such situations.2, 3
See Table 3 Case 3.Besides, investigators had trouble assessing target lesions’ response in situations where only one of the lesions could not be visualised. At that, the approach is different in situations when a target lesion is not visible on the scan at a timepoint because of some technical reason or being shadowed by another pathological
Table 3 Сase reports
Case 1: A patient had two lymph node lesions at baseline that corresponded to a measurable nodal lesions definition. The radiologist selected both lesions as target. At the re-assessment time point on week 32, two more lymph node lesions appeared. Instead of declaring progressive disease the radiologist added these new lesions as target thus violating several RECIST 1.1 rules at once. As a result of the mistake new lesions were not considered progressive disease, number of target lesions was changed at a post baseline assessment and more than 2 target lesions in one organ (lymph node) were selected. Case 2 Radiologist described groups of slightly enlarged inguinal lymph nodes suspicious of metastatic involvement in a colorectal cancer patient. The lesions were smaller than 10 mm in their short axis, yet by their round shape they were most likely malignant. According to RECIST 1.1 these lesions could not be included as pathological and should have been considered normal because of the size criterion even though the radiologist, in the radiological summary, indicated the lymph nodes were suspicious of metastases. At follow up, at week 16, the lesions started to grow and became more than 10 mm in their short axis. According to RECIST 1.1 the patient had to be discontinued from the study due to new lesions appearance even though target lesions showed no progression and the lymph nodes in question were suspected to be malignant by the radiologist. Case 3 In a patient with colorectal cancer and multiple metastases in liver and lungs the radiologist described all present lesions in great details including accurate measurements of all the target and non-target lesions at every visit. The investigator performing RECIST 1.1 assessments at each visit tried to calculate response of both target and non-target lesions based on their measurements. In follow up, at week 32, the investigator erroneously determined PD because of one initially non-target lesion which increased in size by 20 % and showed more than 5 mm absolute increase. She made decision to discontinue the patient from the study based on an increase in a single non-target lesion that should have been assessed qualitatively only and never to be measured as per the criterion meant by the RECIST 1.1 for target lesions only. Case 4 Patient with SCLC had two target lesions selected in the right lung. At week 16 he developed collapsed lung segment that shadowed one of the target lesions on CT. In such a situation the case should have been considered non-evaluable and the patient followed for progressive disease only. However the investigator mistakenly decided to replace the target lesion that could not be anymore visualized with a different lesion in different location and continued response assessment. In general it is not recommended to select target lesions in anatomical areas that could potentially become non-evaluable, like this lesion in a collapsed lung. Case 5 A patient with breast cancer had five target lesions at baseline. In the course of the treatment one of the lesions resolved and the rest four lesions significantly decreased in size showing partial response. The investigator stopped documenting the resolved lesion among the target ones and added another lesion suitable to be target instead thus affecting response assessment.
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process such as a collapsed lung versus only one target lesion resolved because of a good response to treatment. The first situation makes the case inevaluable at this timepoint. This is clearly described in the RECIST 1.1 guidelines under paragraph 4.4.2. 1 Missing assessments and inevaluable designation: “When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at that time point. If only a subset of lesion measurements are made at an assessment, usually the case is also considered NE at that time point, unless a convincing argument can be made that the contribution of the individual missing lesion(s) would not change the assigned time point response. This would be most likely to happen in the case of PD. For example, if a patient had a baseline sum of 50mm with three measured lesions and at follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have achieved PD status, regardless of the contribution of the missing lesion.” However, if one of the target lesions resolved, the case is evaluable at the timepoint with the default value of 0 mm recordered for the resolved lesion and response assessed based on the total sum of diameters of the target lesions that are still visible.
See Table 3 Cases 4 and 5.Errors in re-assessment of non-target lesions are the third category. These errors, in our database, were most often due to premature declaration of progressive disease based on change in size of non-target lesions by analogy with the target lesions assessment rules. This error comes from misunderstanding of the basic RECIST 1.1 concept that lies in division of all the lesions detected in the patient`s body by target, to be measured and assessed quantitatively throughout the course of treatment, and non-target, which are to be assessed qualitatively only and are never measured independently of whether they are measurable or not. In cases when investigators perform assessment based on radiological summary containing non-target lesions measurements, they should disregard the measurements for the purpose of RECIST 1.1 assessment.
Another common difficulty in this category pertains to interpretation of changes in volume or reappearance of a pleural effusion or ascites that was present at baseline. Reappearance or increase in volume of an effusion or ascites present at baseline does not represent progressive disease. Change in volume of pre-existing exudate may be due to several reasons, including reaction to the anti-cancer therapy itself.
The fourth category in our classification is perception of a new lesion by the reader. This, in our experience, is the most common reason of inter-reader variability in RECIST 1.1 assessment. Some readers do not acknowledge a new lesion if its size is smaller than the measurable lesion threshold. This contradicts the RECIST 1.1 definition of a new lesion: “A lesion identified on a follow-up study in an anatomical location that was not
scanned at baseline is considered a new lesion and will indicate disease progression…While there are no specific criteria for the identification of new radiographic lesions, the finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor.” In other words, any, even very small, unequivocal new lesion, independently of its size or location, indicates progressive disease.
The last error category we found and describe in this article relates to substantial deviations from the scanning schedule. Overall, strict compliance to the scanning schedule is critical if one wants to obtain accurate study results. Critical deviations from the tumour assessment visit window outlined in the study protocol are considered as major protocol deviations because they may exclude the patient from the final statistical analysis and thus compromise the trial results. In situations when treatment cycle is delayed, for example due to toxicity, and treatment visits are re-scheduled, tumour assessment visits should continue in strict compliance with the initial schedule. The investigators often wrongfully ignored the requirement and delayed the scanning visit in order to conduct it at the same time as the delayed treatment visit to avoid additional patient visits to clinic. However, a gradual shift in scanning schedule to bring it in compliance with the treatment schedule threatens the clinical trial results. From our point of view, the investigators often make this error simply because there was not enough emphasis placed in the study protocol on the importance of sticking to the scanning schedule that should be taken into account at the time of the protocol writing.
Finally, very often, the investigators fail to perform end of treatment RECIST 1.1 assessment in case of symptomatic deterioration. Symptomatic deterioration even being the reason for stopping therapy is not a descriptor of an objective tumour response, and every effort should be made to document objective progression even after discontinuation of treatment.
ConclusionIn clinical trials with the imaging-based primary endpoints, investigators, CRAs, and radiologists should be aware that even minor mistakes contradicting RECIST 1.1 guidelines can dramatically influence both the treatment decision and the clinical trial results. We found a substantially high number of common errors across numerous international clinical sites. Proper training of all the study stakeholders about the correct application of the current RECIST 1.1 criteria can avoid possible pitfalls and limitations, thereby lowering the negative implications for patient management and the clinical trials results.
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L.H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., Rubinstein, L., Shankar,
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L., Dodd, L., Kaplan, R., Lacombe, D., Verweij J. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer. 45, 228–247 (2009).
2. Choi, H. et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 25(13), 1753-9 (2007).
3. Van der Veldt, A. A., et al. Choi response criteria for early prediction of clinical outcome in patients with metastatic renal cell cancer treated with sunitinib. Br J Cancer. 102(5), 803-9 (2010).
4. Sharma, M. R., Maitland, M. L., Ratain, M. J. RECIST: No Longer the Sharpest Tool in the Oncology Clinical Trials Toolbox. Cancer Research. 72 (20), October 15, 2012.
5. Darkeh, M. H. S. E, Suzuki, C., Torkzad, M. R. The minimum number of target lesions that need to be measured to be representative of the total number of target lesions (according to RECIST). The British Journal of Radiology. 82, 681–686 (2009).
6. Moskowitz, C. S., Jia, X., Schwartz, L. H., Gönen, M. A simulation study to evaluate the impact of the number of lesions measured on response assessment. European Journal of Cancer 45, 300–310 (2009).
7. Verweij, J., Therasse, P., Eisenhauer, E. on behalf of the RECIST working group Cancer clinical trial outcomes: Any progress in tumour-size assessment? European Journal of Cancer. 45, 225 –227 (2009)
8. Kekelidze, M., Lodise, P., Tozakidou, M., Seitel, M., Bongartz, G. M., Basel, C.H., Rome, I.T., Heidelberg, D.E. 10 most frequently made mistakes with RECIST 1.1: how Radiologist can fail - and how to avoid them. European Society of Radiology. (2014).
9. Schwartz, L. H., Bogaerts, J., Ford, R., Shankar, L., Therasse, P., Gwyther, S., Eisenhauer, E. A. Evaluation of lymph nodes with RECIST 1.1. European Journal Of Cancer. 45, 261 –267 (2009).
10. Bogaerts, J., Ford, R., Sargent, D., Schwartz, L. H., Rubinstein, L., Lacombe, D., Eisenhauer, E., Verweij, J., Therasse, P., for the RECIST Working Party Individual patient data analysis to assess modifications to the RECIST criteria. European Journal of Cancer. 45, 248–260 (2009).
11. Ford, R., Schwartz, L., Dancey, J., Dodd, L. E., Eisenhauer, E. A., Gwyther, S., Rubinstein, L., Sargent, D., Shankar, L., Therasse, P., Verweij, J. Lessons learned from independent central review. European Journal Of Cancer. 45, 268–274 (2009)
13. Ratain, M. J., Sargent D. J. Optimising the design of phase II oncology trials: The importance of randomization. European Journal of Cancer. 45, 275–280 (2009).
14. Dancey, J. E., Dodd, L.E., Ford, R., Kaplan, R., Mooney, M., Rubinstein, L., Schwartz, L. H., Shankar, L., Therasse, P. Recommendations for the assessment of
progression in randomised cancer treatment trials. European Journal Of Cancer. 45, 281–289 (2009).
15. Sargent, D. J., Rubinstein, L., Schwartz, L., Dancey, J. E., Gatsonis, C., Dodd, L. E., Shankar, L. K. Recommendations for the assessment of progression in randomised cancer treatment trials. European Journal of Cancer. 45, 290–299 (2009).
16. Forrest, J. V., Friedman, P. J. Radiologic Errors in Patients With Lung Cancer. The Western Journal of Medicine. 13, (485-490) 1981.
Akhil Kumar, MD (USA), is a board-certified haematologist and oncologist in the USA. He currently works as an independent consultant and has been a medical director at the PSI CRO AG, MGI Pharma, and GlaxoSmithKline. Prior to joining the pharmaceutical industry in 2005, PSI,
he was an assistant professor of medicine and medical oncology at the Rutgers Cancer Institute of New Jersey (CINJ). He is an author of 11 publications.Email: [email protected]
Maxim Belotserkovskiy, M.D., Ph.D., MBA is Head of Medical Affairs at PSI CRO AG, and has board certifications in internal medicine, rheumatology, anaesthesiology and intensive care, and haemodialysis, Certified Associate Professor of Pathological Physiology. He has more than 25 years of
experience in clinical research as an investigator and clinical research professional. He is also the author/co-author of more than 140 publications.E-mail: [email protected]
Iryna Teslenko, M.D., MSc, MBA is Director of Medical Monitoring & Consulting at PSI CRO AG. She is a board-certified physician and holds a Master of Science degree in radiology diagnostics. She has more than 11 years of experience in clinical research as a clinical research professional. She is
also the author/co-author of more than 20 publications.E-mail: [email protected]
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Orphan Drug Designations – Are the EMA and FDA Looking for the Same Information?Whilst working on a recent European application for an orphan drug designation (ODD) for a rare neurological condition that was being made to the EMA, I noticed that there was a markedly lower number of ODD application approvals for that particular indication in the EU than in the US. I then looked at some other rare diseases, in case this was a peculiarity of this specific rare neurological condition but, no, for other indications there were also fewer registrations for ODDs in the EU than in the US. Now I was getting quite obsessed with this so decided to look in more depth at the total number of ODD applications approved in the US and EU.
Both the EU and US publish their orphan or rare disease designations in publicly available websites. The US gives a list of the generic name of the drug, the indication that has been granted the orphan drug designation; by clicking on the generic drug name you can find the drug’s trade name, the name of the sponsor and whether the drug has gained FDA marketing approval. Whilst on first look, the EU publishes a similar public listing (showing the name of the active substance and the name of the condition), if you click on the active substance then much more information is revealed, including:
• A summary description of the condition, including an explanation of how this condition is serious or life-threatening.
• The estimated prevalence of the condition in the EU. This summary does not give details of the references the applicant has made to justify this, but does summarise the conclusions made on the number of patients affected in the EU.
• Details of what treatments are available in the EU at the time of the application. A very useful source of information for anyone submitting an ODD application for a condition that already has achieved ODD designation.
• How is this medicine expected to work? This section contains a summary of the mechanism of action of the drug in the condition.
• The stage of development at the time of the submission of the application becomes public knowledge in this section. This can be whether the drug has been evaluated in experimental models or if clinical trials have been conducted or are ongoing.
• The name, address and contact details of the sponsor. Note the sponsor needs to be an EU resident so it may be an agent holding this on behalf of a non-EU entity.
Given this apparent greater transparency then you could perhaps assume that there would be more drugs for rare diseases granted orphan drug designation in Europe; after all, companies have access to the main pieces of prior knowledge that previous successful applicants have made.
But the EU ODD regulations are considerably ‘younger’
than their US counterparts, coming into force in 2000, compared to the US regulations that came into force in 1983. So could that be the reason? However, when you strip out the older designations and factor in the globalisation of the pharma industry in terms of drug development and the harmonisation efforts of the EU and FDA, are the numbers still lower? Let’s take a look.
As at the end of March 2015, there are 3387 ODD applications that have been approved by the FDA, since the regulations were introduced in 19831. However if this is limited just to ODD applications approved since 2000, the date the EU legislation came into force, this has a total of 2400 ODD applications approved.
In contrast, since the EU regulations were passed in 2000, to 31 March 2015, there are 1464 ODD applications recorded, including those applications withdrawn or with an negative opinion. If this is restricted to ODD applications approved, this number is 11682, a hefty 51% lower than the US. So why is this? On the face of it, the two sets of regulations are the same – or are they? Indeed, when you are dealing with both US and EU applications for the same ODD some important differences come to light that are crucial to ensuring you have a successful outcome in both jurisdictions.
What is an Orphan Drug Designation?Firstly let’s recap briefly on what an orphan drug is. Well, firstly, it is not a rare drug but it is in fact a rare disease, and you are seeking to develop either a treatment, a diagnosis or a prevention for this. The drug could be an old drug or a new drug. Indeed there are a number of ‘old’ drugs that have no patent protection, that have then been found to be of use in these rare conditions that are then afforded marketing exclusivity – a key benefit of getting an orphan drug designation. In the US the terminology is orphan drugs; in the EU the terminology is rare disease designations.
What is a Rare Disease?Now this is different depending on whether you are applying to the FDA or the EMA. In the US it is an absolute number and to be ‘rare’ then the condition must affect fewer than 200,000 people in the US3. In the EU it is an odds ratio of 5 in 10,0004. This can then accommodate the changing population and number of member states in the EU.
How do you Know if a Condition is ‘Rare’?Evidence must be produced for applications to both jurisdictions that justify your claim that the condition is rare. The fact that someone else has obtained ODD approval for that same condition does set a precedent that will help your case, so a search of the ODD registers in the EU and US is always a good starting point. If there are no other approvals to act as a precedent, then you need to make the case from the literature or, if there are no published epidemiological studies,
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then a case review could provide your evidence. You must provide evidence, however. What both the FDA and EMA are very wary about is slicing a common indication to make it rare by use of subsets. These subsets of larger conditions must be medically plausible. An example where an application in the EU was rejected on these grounds was an application based on a subset of breast cancer – Tariquidar for the treatment of P-gp positive breast cancer. This was judged by the EMA not to be a valid subset of breast cancer. The sponsor had claimed 25% of P-gp positive breast cancers as this is the proportion they expect to be multidrug resistant. However, the COMP noted that P-gp may be found in close to 100% of breast cancer patients, and that their drug could therefore have an effect in a much larger population group than the subset proposed by the sponsor5. Both the EU and the FDA give careful scrutiny of sub-sets of patient populations, so in this respect they are on the same page.
What are the Differences Between the FDA and EMA?One area where there is an important difference is that in the EU, the disease has to be not only rare, but also life-threatening or chronically debilitating. In the US, the condition needs to be rare and the reason why the treatment is needed must be explained.
Another reason for rejection of an ODD application by the EMA is that there is no data to support the use of your drug in the disease. It is not enough to have a hypothesis for the effect, data, preclinical or clinical needs to be provided. The EMA’s latest revision to the format and content of the application for designation for orphan medicinal product states:
‘It should be noted that for the purpose of designation and to support the rationale for the development of the product in the proposed condition some preliminary preclinical or clinical data are generally required.’6
The data to justify the use of the drug in the rare condition can be from preclinical or clinical sources. If it is preclinical data, then the EU will look for the applicant to substantiate the relevance of the animal model to the rare disease. This is another important point when drafting an application. The EMA will also critically evaluate the applicant’s data from the preclinical model to see that it supports the drug’s method of treatment, prevention or diagnosis being claimed.
This contrasts with the FDA, where the regulation remains that the sponsor must append a discussion on the rationale for the use of the medicinal product for the rare disease or condition, and whilst all relevant supporting information from non-clinical or clinical studies must be submitted, they are not necessarily required.
Another key difference between the EMA and FDA, is that the EMA require details of whether there are other methods for treatment available in the EU or not. So you need to search for all the possible approved treatments in your ODD indication and be aware there may be an old approved drug in some EU member states. This means searching each EU
member state’s national approved drug register, and to help with this challenge, the EU have recently issued the following guidance7. If there is already a drug approved for your orphan disease then it will be deemed to be ‘satisfactory’, no matter how effective it is and you will have to make the case that your drug will offer a significant benefit to those affected by the condition. Note this can be that made on the basis of improved safety profile, or as improved efficacy or a major contribution to patient care (such as easier method of administration, oral vs IV). In all cases, the significant benefit argument needs to be justified by data. An illustration of this criterion serving as a basis for rejection of an ODD application by the EMA is for nabilone as a treatment of amyotrophic lateral sclerosis (ALS). The negative opinion was based on the fact that the sponsor had not provided any data on the effect of nabilone on ALS, and without data it was not possible to establish a potential significant benefit over current treatments8.
The data to justify significant benefit can be from preclinical or clinical sources. Although companies may perform preclinical models with their drug, they do not always include the approved drug to provide comparative data. If there is already published data on the approved drug in your animal model then that could be used to support your position of significant benefit, however if the approved drug did not perform particularly well in the preclinical model then it is unlikely to have been published. As that data would be particularly useful, it is something to consider early in the development plan for the product.
It is important to note that the EMA publishes the reasons for negative opinions for the ODD applications, for those applications that proceed to a full vote by the Committee for Orphan Medicinal Products (COMP). It is possible for the applicant to withdraw an application if the trend of voting at the COMP is negative. If the applicant withdraws at this stage (prior to the formal vote) then it does not appear as public information. In contrast, the FDA publishes a limited amount of information only on those applications granted ODD.
What are the Advantages of Orphan Drug Designation?So there seems to be a lot of work, and although there is an illusion of ‘harmonisation’, there still seems to be more work on the EU side. So what are the advantages for pursuing ODD approval in the EU and US?
Firstly there are important advantages which the ODD affords for both EU and FDA, and some important differences. In fact, I would be as bold as to say that if you get through the ODD approval process and engage with the EMA, through protocol assistance there is more opportunity for you to get approval in the EU than in the US. In both countries, marketing exclusivity is a big prize for an orphan drug, offering 10 years of marketing exclusivity in the EU and 7 years in the US; particularly attractive for an older drug off-patent. Both sides offer assistance with the protocols for pivotal studies, but whilst in the EU this is through protocol assistance, a special type of scientific advice specifically for orphan medicines that often involves the same people that reviewed the ODD application, in the US this is through the same process for all drugs. In
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the FDA, once the ODD is approved for drug development aspects, then the drug company needs to engage with the division that will consider their IND and ultimately NDA; there is no link back to the Office of Orphan Products Development and no special orphan drug pathway to approval. In the EU there are two additional types of marketing approval that are available to companies with ODD. These are conditional approval9 and approval under exceptional circumstances10. These additional approvals, whilst being by no means easy to obtain, at least offer an alternative route for companies working in rare diseases.
Finally the statistics: the EMA quote that of the 82 medicines approved in 2014, 17 were in rare diseases and special regulatory pathways were used for three of these medicines (two obtained conditional marketing authorisation and one obtained approval under exceptional circumstances11.
In the US, the FDA granted approval to 44 new drugs in 2014, with 11%5 in rare diseases12.
So in conclusion, obtaining orphan drug designation approval in the EU may prove to be more challenging than the US; however, once you have made it through the doorway it can offer additional paths and specific guidance on your journey to approval, which should make it all worthwhile.
Susan McGoldrick is an experienced pharmaceutical executive, having worked in various roles within the pharma industry, including a small pharma company developing a treatment for Huntington’s disease and founding and running a CRO specialising in CNS disorders. Susan
now advises The CNS Company on clinical trial issues, particularly in rare disorders. Email: [email protected]
Regulatory
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Market Report
From Clinical Trial to Real World Outcomes
The need for costly clinical trials in order to bring a drug successfully to market is undoubtable. However, outside of this carefully controlled, highly supportive environment, the real-world actualities are very different. In today’s healthcare environment, where competitive products are coming to market within months of each other; there is limited differentiation in clinical efficacy; and pricing strategies are very similar, payers are increasingly expecting the industry to differentiate their products by delivering services beyond the pill.
Historically, drug manufacturers have brought products to market and then focussed on the acquisition of new patients, with the marketing budgets directed at growing the market. Patient retention strategies have been poor cousins and yet in other markets the model of keeping customers loyal – particularly evident in the retail sector – is highly advanced. After all, the average cost of acquiring a new customer is 5-10 times the cost of retaining an existing customer. However in health, a Gap Gemini study showed average medication adherence levels drop over the course of the patient treatment journey from 69 per cent of patients filling their first prescription to 43 per cent continuing their treatment as prescribed after six months, leading to a potential 59 per cent revenue loss as a result of non-adherence. If you were a retail brand manager, this would be unacceptable.
Services beyond the pill provide a continuum of care that delivers real value to stakeholders (payers, regulators, physicians, and patients). This model is still based around product, but focuses on establishing new customer partnerships to address prevention, diagnosis and treatment. This new way of working requires new tools and capabilities, along with real-world data to justify the economic and clinical value of prescription products.
To provide these services, drug manufacturers need to build truly patient-centric services that improve health outcomes and support the healthcare professional to more effectively manage their patients. This is no small task and it involves the creation of new business models, the implementation of new company cultures and the establishment of service-based structures.
One-Size-No-Longer-Fits-AllOver the last few years there has been a paradigm shift in the belief that a patient adherence or support programme is an expensive ‘nice to have’, with drug manufacturers believing that it’s good enough to provide a one-size-fits-all range of interventions. Those predominantly focus on educating the patient about their condition and treatment, and providing medication reminders (timing and dosage) – usually through pill boxes, websites, mobile apps, sms, or printed materials.
Today, it is widely acknowledged that simple reminders and education are not the solution. Behavioural scientists have clarified that non-adherence to medication is a ‘normal’ human behaviour. It is the outcome of a range of psycho-social factors which differ from patient to patient, and change over time, based on their experience of the illness and as their social circumstances alter.
Some of the facts around non-adherence are well documented: 1
• An estimated 20-30 per cent of prescriptions aren’t filled,
• Only 16 per cent of patients who are prescribed a new medicine are taking it in line with their healthcare professional’s advice, experiencing no problems and receiving as much information as they need,
• Research shows that 10 days after starting a medicine, almost 33 per cent of patients are already non-adherent,
• 50 per cent of patients discontinue their treatment within 12 months.
Adherence programmes are only effective if they utilise sophisticated clinical psychology techniques to support long-term behavioural change among those patients who are at the highest risk of non-adherence and to support long-term adherence to medication. Evidence-based behavioural change interventions are used to screen patients to identify not only their risk of discontinuation, but also their beliefs and attitudes towards their treatment and condition. Adherence programmes with measurable real-world data and improved health outcomes, need to focus on providing personalised communications that utilise evidence-based behavioural change models to address unhelpful beliefs and sustain long-term behavioural change.
Why is this necessary? Correctly adhering to a medication (or indeed any health-based lifestyle change) is an intentional behaviour. How often have you promised yourself you’ll start a new fitness plan, go on a diet or stop smoking only to procrastinate or quit after a few months? Patients with asymptomatic conditions, such as osteoporosis, Type 2 diabetes, hypertension and high cholesterol often don’t see an effect or outcome from their treatment. If they feel well and the medicine makes them feel worse or restricts their lifestyle, why should they continue to take it? The three most commonly cited reasons for primary non-adherence are general concerns about taking the medication (63 per cent), a decision to try lifestyle modifications (63 per cent), and fear of side-effects (53 per cent). 2
One clinician recently told me that during his consultation with an elderly patient, she had spent two minutes
listening to his advice about the new treatment he prescribed and five minutes trying to negotiate with him as to why she shouldn’t take the prescribed treatment in the dosage and timing he had recommended. Like you and I, patients have their own views, beliefs and attitudes regarding their disease and treatment, and, because of this, require personalised support to adopt new behaviours and habits.
To make long-term changes in behaviour you need to understand and address how someone feels and thinks about adopting the new behaviour, along with ensuring that they can turn these thoughts and feelings into action.
There is no doubt that delivery interventions do have an impact on adherence, but these are limited and do not address long-term behaviour change. Consider your own personal use of a new health app – when did you last use it? A recent Walgreens report said that soon-to-be-published adherence data, from their balance rewards programme, indicates that:3
• Email and text message reminders can create a two per cent boost in medication adherence,
• Hypertensive and diabetic patients who use a wearable device and walk one mile a day are seven per cent more adherent to their medication than
those that don’t do either of those things,• Hypertension patients who used a connected device
to track their blood pressure were 3.9 per cent more adherent to treatments,
• Patients with diabetes who used a connected glucose meter were 10.9 per cent more adherent to their medications.
In comparison, a personalised adherence programme for patients prescribed a serotonin-norepinephrine reuptake inhibitor, utilised a mixture of interventions, motivational interviewing and cognitive behavioural therapy techniques, driven by personalised contact through nurses. The outcome was a reduction in the average discontinuation rate after six months on treatment from 74 per cent to 31 per cent.
Earlier Stakeholder InvolvementTo improve market access, drug manufacturers should be considering placing a different weighting on evaluating a drug earlier in the development cycle. This evaluation should consider the potential strengths and weaknesses of the treatment, from the point of view of adherence and outcomes outside of the clinical trial environment, when it launches.
Adopting the best practice of retail brand managers, conducting ethnographic research amongst potential
Journal for Clinical Studies 41www.jforcs.com
patient populations, and engaging with a steering committee of payers at this stage, would ensure that issues with current medications, packaging, dosage, delivery and support interventions are identified and addressed, where feasible, before the new treatment comes to market.
But R&D can’t do this alone; senior level internal stakeholder engagement is essential to elevate the importance of adherence at the formulation stage of drug development. Drug manufacturers’ traditional organisational silos mean that real-world evidence, whilst being the core of the brand, is not aligned to one department. Instead of silo working, market access teams, medical affairs, health economics and R&D teams need to be aligned at an earlier stage to support the multi-faceted approach to adherence outside of the clinical setting and in order to secure win-win partnerships with payers and to develop long-term relationships that continue to evolve.
Delivering OutcomesWith healthcare budgets under extreme pressure, real-world data is key to demonstrating the clinical and economical effectiveness of a drug. Payers are broadly looking for two types of partnership. The first is where a drug manufacturer proposes a pre-formed project to improve health outcomes. This often takes the format of providing medication adherence programmes, homecare or nurse-driven interventions. These types of programmes can support market access and demonstrate a commitment from the drug manufacturer to go beyond the pill. The second type is a co-creation project, which has longer lead times, but is bespoke and addresses a locally defined problem. This opens up interesting opportunities for drug manufacturers to gather and demonstrate real-world evidence outcomes, through local healthcare partnerships.
Payers have also expressed their interest in working with consortia of drug manufacturers to address local challenges and support patient adherence across a specific condition, rather than each manufacturer providing an individualised adherence programme for their treatment. As one payer told me recently, “We need to partner with pharma to buy eyesight, not one specific product.”
With payers focussing on cost, the move to generics has strong financial benefits. In the USA, generics make up approximately 85 per cent of all human prescription drugs prescribed. However, different generics made by different manufacturers vary substantially from each other in their physical appearance (colour, shape, size) and pharmacists regularly switch generic drug suppliers to take advantage of pricing discounts. Patients who refill their generic prescriptions can often experience changes in the appearance of their medication, which, according to the FDA, can result in non-adherence: “Studies indicate that patients are more likely to stop taking their generic
medications when they experience a change in their drugs’ physical characteristics, leading to harmful clinical and public health consequences, as well as increased health care costs.”4
The traditional one-size-fits-all patient support tools that focus on education and reminders relied on ROI being demonstrated through patient-reported outcomes. However, the benefit of investing in a personalised adherence programme that demonstrates real-world outcomes, that are comparable to clinical trial results, is significant. For example, an adherence programme that we are currently delivering has been written into multiple hospital protocols in one market with patients prescribed the treatment automatically being enrolled onto the supporting programme.
The importance of aligning scientific opportunity with commercial insight cannot be underestimated. If drug manufacturers invest in earlier stakeholder engagement, offer payers valuable services beyond the pill that build true partnerships and optimise health outcomes, they have the opportunity to address the potential 59 per cent revenue loss through non-adherence.
Without real-world data on medication adherence and clearly differentiated health outcomes, payers will continue to select either the cheapest treatment option or the treatment that truly does go beyond the pill.
References1. Lars Osterberg, M.D., and Terrence Blaschke, M.D., N
Preference and Adherence. 6, 643–651 (2012)3. www.mobihealthnews.com/42326/walgreens-shares-
digital-adoption-data-announces-unitedhealthcare-partnership/ visited on 14 April 2015
4. w w w . f e d e r a l r e g i s t e r . g o v /a r t i c l e s / 2 0 1 4 / 1 0 / 1 5 / 2 0 1 4 - 2 4 3 6 5 / a g e n c y -i n f o r m a t i o n - c o l l e c t i o n - a c t i v i t i e s - p r o p o s e d -c o l l e c t i o n - c o m m e n t - r e q u e s t - s u r v e y - o f -pharmacists#h-8 visited on 14 April 2015
Paul Tanner is Chairman of 90TEN Healthcare, a healthcare communications agency that operates internationally to optimise brand outcomes through sustained behavioural change. He has over 12 years’ experience delivering programmes that improve health outcomes by empowering patients to change their health beliefs and
behaviours, and support HCPs in their management of those patients.Email: [email protected]
Market Report
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Market Report
Raising Clinical Trial Standards through Competency-Based TrainingThe Clinical Trial Directive – 2001/20/EC – has been in place for about a decade. In that time the number of drug trials conducted in the EU has fallen by about 25%.1 Opinion has been divided about the benefits of the directives and various stakeholders in the clinical research community have expressed concerns about the rise in bureaucracy, the increase in costs of running trials and the continuing lack of uniformity in the EU. The call has been for more streamlining, which includes taking a proportionate risk-based approach to the conduct of trials with more public openness about each trial and the results they produce.
The European Commission has responded by introducing legislation, the EU Clinical Trial Regulation 536/201. This regulation will replace Directive 2001/20/EC, which will be repealed. The regulation was approved by the European Parliament in April last year and has now been published in the Official Journal of the European Union, with an implementation date planned for 28th
May 2016. The Regulation sets out the requirements for a single clinical trial approval portal and the content of clinical trial applications to be standardised.2 It also deals with making information about trials more transparent and the results more accessible to the lay person. This will be achieved through an EU portal which will allow the EU database on clinical trials to be publicly accessible, with the data presented in an easily searchable format.
A Welcome RegulationThe Regulation will ensure that the rules for conducting clinical trials are identical throughout the EU. It also allows the EU Commission to conduct controls in member states and other countries to make sure the rules are being properly supervised and enforced. One of the problems of directives is that they allow national authorities to draw up their own legislation, which has resulted in varying degrees of interpretation of the directives and has not achieved the harmonisation initially hoped for, particularly with respect to competent authority approvals.
The EU Regulation has been brought in to remedy some of the difficulties caused by the current situation, one of which requires submission of separate applications for each of the countries involved in a trial. This has caused delays in the start of clinical trials and a disproportionate administrative burden, despite the use of the Voluntary Harmonisation Procedure which took a more centralised approach to Competent Authority approvals. The new Regulation provides specific timelines for the different steps in the authorisation process and confirms the concept of tacit authorisation to ensure that timelines are adhered to. Furthermore, it provides a mechanism to extend the clinical trial to one or more additional
member states, without requiring the reassessment of the application by all member states involved in the initial authorisation.3 It will also clarify when modifications to an already approved trial should be subject to a new authorisation procedure.
In summary, the main features of the new Regulation include:• A single approval portal• Standardised content of clinical trial applications• Greater transparency about clinical trials• Information about subject protection and informed
consent, including some details about specific groups of patients such as pregnant women
• More stringent requirements for reporting trial progress
• Safety reporting is to be via one EU database, using a standard form
• Reporting of serious breaches of the protocol or the Regulation
• Reporting of urgent safety measures taken to avoid hazards to study subjects
• Archiving of essential documents for 25 years
One area which the new Regulation neglects is in ensuring the competence of people working in clinical research. Under the heading “Suitability of individuals involved in conducting the clinical trial” (Article 49) the Regulation restates the directive it was designed to repeal (2001/20/EC) when it reaffirms that “…individuals involved in conducting a clinical trial shall be suitably qualified by education, training and experience to perform their tasks.”
Clinical research is becoming ever more complex and demanding and it is unfortunate that the Regulation has not been used as an opportunity to define more precisely how these demands are going to be met by the skills and abilities of the individuals working in the sector.
The Increased Need for Industry CompetenceMost people working in the clinical research industry are highly qualified, with many of them having degrees in medicine or biological sciences, or a nursing qualification. However, none of these qualifications is related specifically to conducting clinical trials competently. Nowhere in the Regulation is there a mention of competence in terms of the ability of individuals to conduct clinical trials. Having internationally recognised and accredited professionals whose competence has been independently assessed would give both the industry and the general public further reassurance that those in clinical research are competent to fulfil their roles.
Unfortunately, neither education, training nor experience
Journal for Clinical Studies 43www.jforcs.com
can guarantee competence. Clinical research staff need to have the skills and abilities that reflect the contemporary setting in which they work to ensure that out-of-date and substandard practice is eliminated.
Training and CompetenceAs the clinical research environment grows increasingly pressured and complex, there is a need for consistent standards in training. Currently there is no requirement for the type of training that should be conducted, who delivers it and, most important, the learning outcomes that each training intervention should accomplish. Having a competence-centred approach based on defined learning outcomes would enable organisations to ‘recognise’ each other’s training programmes and avoid unnecessary repetitive training.
An initiative to recognise training courses has been developed by an organisation called TransCelerate. This body is a collaboration between biopharmaceutical companies to design and facilitate the implementation of solutions to drive efficiency and effectiveness in the development of new medicines.4 Founded in 2012, the organisation has eleven initiatives at the time of writing this.
One of the TransCelerate initiatives (initiative 2) is centred on minimum criteria for GCP training content that will enable member companies to mutually recognise one another’s training, including the use of a common “TransCelerate GCP Training Certificate”. The focus is on the content of the training rather than the learning outcomes. While this is a welcome step, the initiative does not go far enough, focusing only on inputs rather than the all-important outputs – the learning outcomes.
It is common practice in the clinical research sector for individuals to document the training they receive, but what is truly being recorded? What was accomplished in the training session? The piece of paper that says an individual has attended a course is not a meaningful record of the new skills acquired during the session. The answer is to have training sessions with pre-defined learning outcomes which are measurable and competence-based. The term competence is sometimes misunderstood and it can be defined as an observable demonstration of knowledge, skills and behaviours. Rather than maintaining just a training file, individuals should be encouraged to keep a competence file which is a record of knowledge, skills and behaviours they have acquired through learning interventions including on-the-job training.
Training programmes can be designed for specific job roles by having competency frameworks for each role. These frameworks can be used as performance standards by setting out the required role-specific competencies.5 A benefit of using this approach is that it would also cut out redundant and unnecessarily repetitive training – particularly with respect to good clinical practice (GCP),
just like the mutual recognition of training courses discussed earlier.
Experience and CompetenceThere is no doubt that having experience is extremely valuable and certainly increases the chances of an individual being competent. However it is no guarantee and it can be easy to be deceived into thinking that experience equates to competence. Pharma companies and CROs understandably return to known and well-used investigators’ sites each time a study is set up, as they are considered experienced researchers having participated in numerous previous studies. The true competence of the investigator and/or the site is unknown. There are no standard methods of assessing competence except for
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internal metrics that are not shared between commercial organisations. (These metrics can include patient recruitment targets met, number of screen failures, number of protocol/GCP deviations etc.) The result is that there is over-use of some investigator sites that are substandard in terms of delivery and quality, and under-utilisation of new sites that may lack experience and which are an unknown factor in terms of competence.
The other area where experience currently counts for more than competence is in staff recruitment. From the pharmaceutical companies’ perspective, the search is often for people with at least two years’ experience. This occurs both for permanent hires and when selecting contract staff from a CRO’s team. Staff may appear to have the relevant experience but not necessarily the benefit of good relevant experience of the right quality. Bad habits may have been learned and embedded over a number of years. The solution could be to have internationally recognised and accredited professionals whose competence has been independently assessed, which would give both the industry and the general public further reassurance that those in clinical research are competent to fulfil their roles.
In organisations that do not use competence-based assessments, individuals can be promoted or hired based solely on a number of years of experience. Undoubtedly experience is very important in acquiring and perfecting skills, but it is also an opportunity to acquire bad habits, to stagnate and allow competence to become outdated.
Using competency frameworks to manage performance is a far more reliable and objective measure, which allows clarity for both the manager and their reports in highlighting when someone’s performance is satisfactory, below par or when that person exceeds expectations. Work-based examples that demonstrate competence can be used by both parties, and this allows a discussion based on objective criteria. Developmental strategies to overcome underperformance can be devised to address any shortcomings. These plans should be reviewed regularly to check progress on how the individual is moving in the right direction to be able to acquire the desired competence.
ConclusionsThe new EU Clinical Trial Regulation may need further detail and clarification in some areas in order to be able to implement the new requirements. There may well be some guidance documents already in preparation by the European Commission. Perhaps the solution to the problem of a lack of competence standards in the sector is to have a guidance document which sets out the requirements for training and experience centred on a competence-based approach.
The need for quality, competent and well-trained staff is more important than ever. The danger is that, unless a competence-based approach is used, potentially
incompetent people can still be hired, employed or promoted with the resulting risk to the safety and wellbeing of patients and the integrity of clinical trial data. The benefit for clinical research as a whole would be better qualified and more competent people who are able to conduct clinical trials more quickly, efficiently and intelligently.
This represents a great opportunity for the clinical research sector to make a major step forward in developing a talented, flexible and global workforce that is equipped to meet the challenges of conducting top-quality clinical trials internationally.
References1. Richard Bergström, 2012. European Federation
of Pharmaceutical Industries and Associations (Internet) http://www.efpia.eu/mediaroom/63/70/quot-Reform-of-EU-Clinical-Trials-Rules-Europe-can-t-afford-to-fai l -33-quot-says-Richard-Bergstroem [Accessed 26/05/2015]
2. Michael Mezher, 2015. EMA Seeks Feedback on Clinical Trial Database (Internet) http://www.raps.org/Regulatory-Focus/News/2015/01/22/21138/EMA-Seeks-Feedback-on-Cl inical -Tr ia l -Database/ [Accessed 26/05/2015]
3. NHS European Office, 2014. The new EU Clinical Trials Regulation How NHS research and patients will benefit (Internet)http://www.nhsconfed.org/~/media/Confederation/Files/Publications/Documents/eu-clinical-trials-regulation-2014.pdf [Accessed 26/05/2015]
4. Moe Alsumidaie, 2015. TransCelerate Vs. ACRES: Site Accreditation Initiatives (Internet) http://www.appliedclinicaltrialsonline.com/transcelerate-vs-acres-site-accreditation-initiatives [Accessed 26/05/2015]
5. Peter Schueler, Brendan Buckley, 2014. Re-Engineering Clinical Trials: Best practices for streamlining the development process. Academic Press, London
To learn more about IAOCR please visit http://iaocr.com/, or call us at +44 (0)1628 784906.
Martin Robinson PhD is Executive VP & IAOCR Ambassador, where he leads a team providing independently accredited training courses for clinical research professionals, including project management, CRA and GCP training. He has over 15 years of international experience in training and
education in clinical research. Martin’s CV includes work in organisational development for Dovetail and in training and development for the Institute of Clinical Research. He has also worked for Covance where he had a number of roles in training and development and project management.Email: [email protected]
The diagnosis of movement disorders and neurodegenerative diseases can be problematic for clinicians and radiologists alike. There is considerable overlap in the early presentation of these diseases, especially when tremor is absent or atypical in character. Routine anatomic imaging is insensitive and early imaging findings are typically absent or non-specific. Functional nuclear medicine imaging of the dopamine pathway using I-123 Ioflupane (DaTSCAN) SPECT and F-18 Dopamine (DOPA) PET offers renewed hope in categorising these diseases as Parkinsonian (degenerative) or non-Parkinsonian (non-degenerative) in etiology.
Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease (AD) affecting approximately 1 million Americans and 4 million people worldwide. It affects 0.5-1.0% of the population between 65 and 69 years old, and 1-3% of the population older than 80. The cause of idiopathic PD is the degeneration of neurons which connect the subtantia nigra to the corpus striatum, the so called nigrostriatal pathway. These neurons control the release of the neurotransmitter dopamine to receptor cells which affect motor function. Pre-synaptic dopamine transporter proteins are located on the cell membranes of these terminal neurons, which continuously reuptake dopamine from synaptic clefts after the completion of interaction with dopamine receptors on the post-synaptic neuron. Non-degenerative Parkinsonian syndromes may be drug-induced or vascular as a result of ischemic insults to the pathway.
DaTSCAN SPECT and F-18 DOPA PET image different points along the dopamine pathway. The I-123 isotope of iodine bound to fluoropropyl-carboxymethyl-iodophenyl nortropane or FP-CIT, sold under the trade name DaTSCAN, binds reversibly to human recombinant dopamine transporters and is blocked by dopamine reuptake inhibitors. The dopamine transporter is thus a surrogate marker for dopaminergic nigrostriatal neurons. Fluoro-DOPA is an analog of levo-DOPA (L-DOPA). Dopamine in circulation does not cross the blood-brain barrier of the central nervous system. L-DOPA is carried across by the neutral amino acid transport system. L-DOPA is then converted to dopamine in the brain by L-aromatic amino acid decarboxylase. Dopamine is stored in pre-synaptic intraneuronal vesicles and released when the nerve cell fires. Flourine-18 bound to dopamine is the PET imaging analog.
Both DaTSCAN SPECT and F-DOPA PET assess the pre-synaptic dopaminergic system. DaTSCAN images correlate with dopamine transporter density in the corpus striatum. F-DOPA images correlate with the activity of the decarboxylating enzyme and the storage capacity of dopamine in these same structures. Early in PD, dopamine
transport is downregulated to preserve pre-synaptic dopamine, making DaTSCAN SPECT more sensitive in detection. Conversely, the decarboxylating enzyme can be upregulated as a compensatory mechanism and F-DOPA PET imaging may be falsely negative early in PD. Both tests are highly effective in differentiating PD and the atypical Parkinsonian syndromes (APD) multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and dementia with Lewy bodies from non-degenerative essential tremor (ET) and drug-induced Parkinsonism.
While F-DOPA PET has certain imaging advantages over DaTSCAN SPECT, its use is limited mostly to academic centres with on-site or near-site cyclotrons. The isotope fluorine-18 has a half-life of less than two hours and its binding to L-DOPA is a rigorous process. Incubation time between injection and imaging is less than one hour and the spatial resolution of PET is superior to that of SPECT. The isotope iodine-123 has a half-life of 13 hours and is readily available via commercial distribution. The thyroid gland is blocked with Lugol’s solution or potassium iodide prior to radioactive iodine administration. Imaging requires incubation of the I-123 DaTSCAN agent between three and four hours. The gamma photon energy of 159 keV is standard and SPECT images are reconstructed for viewing in the transverse plane.
It is generally accepted that the motor symptoms of PD occur after 60-80% of dopamine-producing neurons are lost and that loss proceeds at a rate of 6-13% per annum. Degeneration occurs in dopaminergic cells which originate in the substantia nigra and terminate in the corpus striatum. The disease process produces loss of striatal dopamine and the dopamine transporters that collect spent dopamine from the synaptic cleft. The loss of neurons in the striatal terminals proceeds from lateral to medial, thereby affecting the posterior putamen before the caudate head. PD and APS typically produce asymmetric motor symptoms. The imaging abnormalities are correspondingly variable and can be unilateral, bilateral or bilaterally asymmetric. In essential tremor and drug-induced Parkinsonism there is no nigrostriatal dopaminergic cell loss, therefore imaging by either modality is normal.
DaTSCAN SPECT provides an in vivo marker of dopaminergic neuronal degeneration which helps differentiate PD and APS from ET, drug-induced Parkinsonism and other non-Parkinsonian syndromes. There is no clinical biomarker for the pathologic substrate of PD, the intraneuronal inclusion of Lewy bodies in the substantia nigra compacta. Clinical history, physical examination and a positive response to L-dopamine remain the standards for diagnosis. PD is generally characterised by an asymmetric rest tremor, slow movements (bradykinesia), stiffness (cogwheel rigidity)
Parkinson’s Disease: Functional Imaging of the Dopamine Pathway
Journal for Clinical Studies 47www.jforcs.com
and problems with walking or balance (postural instability). A positive clinical diagnosis is established by bradykinesia and one additional cardinal feature plus a positive response to dopamine therapy. In ET, tremor is the primary symptom, typically symmetrical and produced with action or upon standing.
Sometimes PD patients have no tremor or a postural tremor that mimics ET. Occasionally ET patients have an asymmetric tremor, rest tremor or cogwheeling rigidity that mimics PD. The overtreatment of non-PD patients with anti-Parkinsonian medications is estimated at 15-47%. Post-mortem confirmation of a non-PD diagnosis in a hospital study of patients treated for PD has been reported as 10-24%. The DaTSCAN can be a valuable tool in reducing the overdiagnosis of PD. A negative DaTSCAN
in the presence of tremor has a negative predictive value of 87.5%. Conversely, an abnormal DaTSCAN has a positive predictive value for PD or APS of virtually 100%.
As the imaging of movement disorders plays a larger role in the aging demographic of our clinical practices and as disease documentation prior to deep brain stimulation becomes a medical requirement, it is helpful to become familiar with the newer functional molecular imaging tools at our disposal. In addition, since both Parkinson disease and atypical Parkinsonian syndromes can produce cognitive decline, the functional modalities FDG-PET and DaTSCAN SPECT will become increasingly beneficial to avoid unnecessary and occasionally harmful therapies.
References1. Broski S, Hunt C, Johnson G, Lowe V, Peller P. Structural
and Functional Imaging in Parkinsonian Syndromes. Radiographics 2014; 34: 1273-1292.
2. Marshall V, Reininger C, Marquardt M, Patterson J, Hadley D, Oertel W, Benamer H, Kemp P, Burn D, Tolosa E, Kulisevsky J, Cunha L, Costa D, Booij J, Tatsch K, Chaudhuri K, Ulm G, Pogarell O, Hoffken H, Gerstner A, Grosset D. Parkinson’s Disease is Overdiagnosed Clinically at Baseline in Diagnostically Uncertain Cases: A 3-Year European Multicenter Study with Repeat [123I]FP-CIT SPECT. Movement Disorders 2009; 24(4): 500-508.
3. Booij J, de Bruin K, van Royen E, Speelman J, Horstink M, Sips H, Dierckx A, Versijpt J, Decoo D, Van Der Linden C, Hadley D. Doder M, Lees A, Costa D, Gacinovic S, Oertel W, Pogarell O, Hoeffken H, Joseph K, Tatsch K, Schwarz J, Ries V. Accurate Differentiation of Parkinsonism and Essential Tremor Using Visual Assessment of [I123]-FP-CIT SPECT Imaging: The [I123]-FP-CIT Study Group. Movement Disorders 2000; 15(3): 503-510.
4. Nanni et al. 18F-DOPA PET and PET/CT. Journal of Nuclear Medicine 2007; 48(10): 1577-1579.
5. Hauser R, Grosset D. [I123]FP-CIT (DaTscan) SPECT Brain Imaging in Patients with Suspected Parkinsonian Syndromes. Journal of Neuroimaging 2012; 22(3): 225-230.
Therapeutics
Dr Barry Menick is a board-certified radiologist at Intrinsic Imaging with fellowship training in diagnostic neuroradiology. He received undergraduate and medical degrees from Duke University in Durham, North Carolina. He completed his radiology residency and two-year
neuroradiology fellowship at the Hospital of the University of Pennsylvania in Philadelphia. Dr Menick has been a Senior Member of the American Society of Neuroradiology since 1991. A member of the American Society of Functional Neuroradiology, he has special interests in quantitative imaging for neurodegenerative disorders and functional imaging of tumours.
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Therapeutics
Opioid use disorders have significantly increased over the past decade, affecting between 26 and 36 million people worldwide. It is estimated that approximately 2 million people in the United States alone have substance use disorders related to prescription opioid pain relievers, with an additional 467,000 people having heroin use disorders1. Furthermore, there is accumulating evidence to suggest a link between the medically supervised use of prescription analgesics and heroin abuse. Efforts to make abuse deterrent formulas have not helped and to the contrary, an increase in heroin use was noted following the introduction of abuse deterrent formulations of prescription opioids such as OxyContin, with data suggesting that up to 70% of those who stopped taking abuse deterrent formulation of OxyContin started to use heroin instead; very recent literature suggests a correlation between increasing heroin overdoses and a decreasing number of prescriptions for abuse-deterrent opioids and overdoses of same2. Of those who continued to abuse the abuse deterrent formulation, 43% reported simply changing their preferred route of administration to the oral route, while 34% reported being able to defeat the abuse deterrent mechanism and continued to inject or inhale the drug3.
The large increase in the number of prescription opioid- and heroin-related overdoses and deaths has caused government agencies around the globe to launch various initiatives to stem the tide of growing opioid abuse. For example, the US Health and Human Services department has introduced several initiatives, including: increased education, guidance, updated prescriber guidelines to assist health professionals in making informed prescribing decisions, increased use of naloxone, and support of various programmes designed to expand the use of medication-assisted treatment (MAT) by combining medication and behavioural therapy4. The pharmaceutical industry has also responded to this growing epidemic by increasing its efforts to develop drugs to treat opioid use disorder. However, there is relatively little direction on the appropriate design and conduct of such studies. This short feature is an attempt to highlight important methodological and operational challenges that can arise in the conduct of such trials.
Typically, studies seeking to enroll subjects with opioid use disorders will permit male and female subjects 18 to 65 years of age who have a diagnosis of moderate to severe opioid use disorder according to DSM-5 criteria in the past 12 months, and who, importantly, are willing to switch to opioid substitution therapy. This motivation is a crucial feature, as adherence to medication, compliance with protocol procedures and the risk for diversion are all characteristic hallmarks of these subjects who often present with varying and unreliable social/medical histories. Therefore, diagnostic misclassification must be minimised. To this end, a full diagnostic interview or a DSM-5
checklist (at a minimum) should be required for study entry.
It is important to note that the DSM-5 does not separate the diagnoses of substance abuse and dependence as in DSM-IV TR. Rather, current criteria are provided for substance use disorder, accompanied by criteria for intoxication, withdrawal, substance/medication-induced disorders, and unspecified substance-induced disorders, where relevant. Otherwise the DSM-5 substance use disorder criteria are nearly identical to the DSM-IV TR substance abuse and dependence criteria, combined into a single list, with two exceptions: DSM-IV TR recurrent legal problems criterion for substance abuse has been deleted from DSM-5, and a new criterion for craving or a strong desire or urge to use a substance, has been added. The DSM-IV TR specifier for a physiological subtype has been eliminated in DSM-5, as has the DSM-IV TR diagnosis of poly-substance dependence.
Furthermore, the threshold for substance use disorder diagnosis in DSM-5 is set at two or more criteria, in contrast to a threshold of one or more criteria for a diagnosis of DSM-IV TR substance abuse and three or more for DSM-IV TR substance dependence. Finally, the severity of the DSM-5 substance use disorders is based on the number of criteria endorsed, with 2 to 3 criteria indicating a mild disorder; endorsement of 4 to 5 criteria indicating a moderate disorder; and 6 or more criteria indicating a severe disorder. Importantly, DSM-5 now defines early remission from a substance use disorder as at least three but less than 12 months without substance use disorder criteria (except craving), and sustained remission is defined as at least 12 months without criteria (except craving). Therefore, any outcome measures related to early and sustained remission should follow these criteria. Additional new DSM-5 specifiers include “in a controlled environment” and “on maintenance therapy” as the situation warrants.
There are two general types of study designs which can be done separately or combined when attempting to investigate drugs designed to treat opioid use disorders, classified as “induction” and “maintenance” designs. The goal of induction is to safely suppress opioid withdrawal as rapidly as possible with adequate doses of approved drugs such as Suboxone® (buprenorphine HCl/naloxone HCI dihydrate) or Subutex®
(buprenorphine HCl), while the goal of maintenance is to prevent the emergence of withdrawal symptoms, suppress cravings, and attenuate the effect of self-administered opioids in subjects who continue to episodically use opioids.
When designing maintenance studies it is important to ensure that subjects be currently taking a stable, daily dose of an approved medication such as 8/2 to 32/8 mg buprenorphine/naloxone or Suboxone® tablets or films for at least 30 days prior to baseline and have positive buprenorphine and norbuprenorphine upon screening.
Methodological Issues in Design and Conduct of Opioid Use Disorders Studies
Journal for Clinical Studies 49www.jforcs.com
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Subjects should not have received any medication such as methadone or buprenorphine for opioid dependence in the last 30-90 days and should have negative urine drug screening for these before randomisation. As such, subjects should demonstrate at least mild withdrawal symptoms as defined on a scale such as the clinical opioid withdrawal scale (COWS), with a score ≥ 9.
If induction is the main objective, or at least a formal part of the study, then subjects should have successfully undergone induction in the first three days and also be free from significant withdrawal symptoms and cravings for opioids, typically operationalised as ≤ 12 on the COWS at baseline, while also having a score of ≤ 20 mm on the 100-mm opioid craving visual analog scale (VAS) at baseline, in order to properly evaluate the maintenance response. The number of subjects who successfully complete induction, which can typically take between two and four days (with retention in treatment at day three serving as a primary outcome measure), serves as the key outcome measure for studies looking at induction. Other useful outcome measures for longer maintenance studies have included the following: craving VAS, SOWS/COWS, self-report of substance use, the addiction severity index – lite (ASI-Lite), a pain assessment NRS, the SF-36 v2, the work productivity and activity questionnaire – specific health problems (WPAI:SHP) and the clinician and patient global impression of change (C/PGI). Regardless of the nature of the study, it is essential that all reported medical history should be confirmed with urine/blood tests.
When conducting studies designed to assess the effectiveness of drugs designed to treat opioid use disorders, there are a number of unique operational challenges which need to be considered and resolved in order to help guarantee successful study outcome. The first concerns the qualifications of the investigator and staff to work in this indication. Although appropriate subjects can be recruited at most qualified sites with a psychiatry specialisation, it is imperative to ensure that the investigator is qualified to work with subjects suffering from opioid addiction specifically. The simplest way to do this is to require at least one member of the study staff (preferably the principal investigator) to be board certified in addiction medicine, and in the United States to have a Center for Substance Abuse Training (CSAT) waiver in place. This qualification signifies that the investigator is credentialled to work with opioid-addicted subjects, has previous experience with this subject population, and has likely undergone a minimum of eight hours of training by an accredited professional society (e.g., ASAM, AAAP, and AMA). Preferably, the investigator is in possession of this qualification prior to study start, however obtaining this certification could be made a condition of participation in the study.
The second challenge relates to the fact that many currently approved treatments for opioid addiction, can (at least partially) agonise the µ-opioid receptor and therefore have addictive properties of their own. Therefore study drug may be subject to abuse and/or diversion as well, which is defined as any use of study drug other than that for which
it is intended. There are anecdotal reports of the “street” resale value for addiction treatments of $50 per tablet or more, making the easy availability of these treatments very attractive for those with access to resale channels.
There are a number of measures designed to help manage the potential for diversion by subjects and staff. Initially, this is through employment of a meticulous, tablet-by-tablet, drug accountability regimen at each site. It is only when the study drug is carefully tracked that it can be identified as missing in the first place. The second suggestion is to implement a study-wide drug diversion policy. The purpose of such a policy is multi-faceted. First, it should outline the minimum requirements at the site level for the storage, security and accountability of the study drug. Additionally, it should provide guidance as to potential signs of study-drug diversion (in subjects and in staff), including changes in appearance and/or behaviour, excessive absenteeism (from work and/or study visits) and a decrease in an individual’s reliability. Finally, this policy should guide the sites as to the steps to be taken in case of suspected or confirmed study drug diversion, including, in the worst cases, reporting of the event to the authorities. All members of the site staff that come in contact with study drug should be required to read and acknowledge the policy by wet-ink signature, with the original filed in the study trial master file. In addition, and separate from the study, sites that handle such compounds as a matter of course should be encouraged to institute a zero-tolerance policy regarding theft of study drug or failure to report same.
A third operational challenge revolves around the recruitment of appropriate subjects for opioid use disorder studies. There are primarily two sub-groups of subjects in this indication; those who have become addicted to illicit opioids (heroin being the most prominent example) and those who have become addicted due to continued (prescription) use of opioid analgesics (e.g., opioids were originally prescribed for chronic or post-surgical pain). However, as noted earlier, many of these latter subjects often convert to illicit heroin use as well. From a clinical trials perspective, these two sub-groups represent very different populations; the former is easy to recruit, but less likely to comply with protocol procedures (and therefore more likely to miss critical urine testing procedures or drop out of the study) and importantly more likely to divert study drug. These subjects are more likely to be poly-substance abusers, with alcohol and sedative use disorder being common, and it is imperative that subjects do not meet criteria for other use disorders, with the exception of nicotine, prior to study participation. These subjects should not have any pending legal action that could affect compliance, such as house arrest or incarceration. The latter population are relatively more difficult to recruit, but typically are more motivated to quit their addiction and therefore comply with the protocol, remain in-study and follow study procedures. Significantly, in this latter population, subjects should have had an original diagnosis of chronic pain as the basis for them requiring prescription opioids for treatment initially, but should not currently have chronic pain requiring treatment. A mixture of urban/non-urban sites helps to ensure that subjects representing both sub-groups will be represented.
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Regardless of the type of subjects, it is important to ensure that all subjects recruited to participate in the study are doing so with the correct motives, which should be thoroughly questioned prior to study participation. A first pass at assessing these motives, in addition to identifying those who may be prone to convert to illicit heroin use, can be attained through the use of a risk-assessment tool such as the screener and opioid assessment for patients with pain (SOAPP)® or the opioid risk tool (ORT). Subjects identified as being susceptible to such risks can be steered to avenues of treatment other than clinical research5,6. For similar reasons, advertising for the purposes of recruitment should be kept to a minimum. Ideally, the subjects recruited to participate (from either group noted above) should already be known to the investigator or staff, and be motivated to quit their dependency. Finally, it should be noted that in many CNS indications, the primary concern regarding subject recruitment is that it is variable, hard to predict, laborious and slow. However, due to the growing global prevalence of opioid dependence, a new concern regarding recruitment is that it occurs so quickly that it outpaces a site’s and sponsor’s/CRO’s ability to manage it. Although it may sound enticing, swift recruitment that is ahead of projections can present numerous problems, including: a lag in the entry of data into the electronic data capture (EDC) system in use for the study, the accumulation of unmonitored data at the site, and the concern that the proper patients are not enrolled. In order to manage anticipated brisk enrolment at the study level, it may be necessary to impose controls on recruitment. One effective method is to mandate that each site “pause” enrolment activities at a preset ceiling (e.g., after five or six subjects), thereby giving sites the time to enter data, the monitors time to evaluate it, and the sponsor/CRO time to ensure that the optimal subjects are enrolled. Only when these have been confirmed, with no issues identified, should a site continue enrolment. In such an instance, there must be a commitment at the site to rapid data entry (i.e., within 48 hours) and by the monitor to be at the site as soon as possible after the “ceiling” subject is reached.
In summary, there are several unique methodological challenges in the design and conduct of studies assessing the efficacy of various opioid use disorder treatments. Nonetheless, with careful planning these can all be effectively managed. Trials and approvals of new and improved treatments for this growing epidemic are essential given the currently available treatment options and increasing global prevalence.
References1. Substance Abuse and Mental Health Services
Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration (2013).
2. Marc R Larochelle, MD, MPH; Fang Zhang, PhD; Dennis Ross-Degnan, ScD; J Frank Wharam, MBBCh, BAO, MPH, Rates of Opioid Dispensing and Overdose After Introduction of Abuse-Deterrent Extended-Release Oxycodone and Withdrawal of Propoxyphene, JAMA
Intern Med, published online April 20, 2015.3. Cicero, T, Ellis M Abuse-Deterrent Formulations and the
Prescription Opioid Abuse Epidemic in the United States: Lessons Learned From OxyContin. JAMA Psychiatry. Mar 11 (2015).
4. HHS Press. HHS takes strong steps to address opioid-drug related overdose, death and dependence. Evidence-based, bipartisan efforts focus on prescribing practices and treatment to reduce prescription opioid and heroin use disorders. HHS Press Release, March 26 (2015). http://www.hhs.gov/news/press/2015pres/03/20150326a.html
5. Akbik H, et al. Validation and clinical application of the Screener and Opioid Assessment for Patients with Pain (SOAPP). J Pain Symptom Manage. 2006;32(3):287-293.
6. Webster LR. Predicting aberrant behaviors in opioid-treated patients: Preliminary validation of the opioid risk tool. Pain Medicine. 2005;6(6):432-442
Henry J. Riordan, Ph.D. is Executive Vice President of Medical and Scientific Affairs and Global Lead for Neuroscience at Worldwide Clinical Trials. Dr Riordan has been involved in the assessment, treatment and investigation of various CNS drugs and disorders in both industry and academia for the past 20 years. Dr Riordan specialises in clinical trials methodology and has advanced training in biostatistics, experimental design, neurophysiology, neuroimaging and clinical neuropsychology. He has over 90 publications, including co-authoring two books focusing on innovative CNS clinical trials methodology. Email: [email protected]
Barry J. Dussault, Jr., MBA is Director of Project Management, Neuroscience at Worldwide Clinical Trials (WCT). Mr Dussault has worked in all phases of drug development over the course of his 18-year career, with a recent focus upon clinical project management in roles on both the sponsor and CRO side. Since joining WCT, he has specialised in trials of addiction and opioid dependency. Email: [email protected]
Volume 7 Issue 354 Journal for Clinical Studies
Unlocking the Potential of Social Media in Drug Safety
Drug safety and pharmacovigilance (PV) have evolved and grown significantly more complex over the past decade due to higher data volumes, evolving regulations, increased influence of emerging markets and the emergence of social media and innovative technological advances. The phenomenal reach of the internet has led to a revolutionary shift in how people are communicating with one another, with digital platforms and applications quickly becoming the go-to form of communication in the era of Web 2.0.
However, unlike other areas such as clinical medicine, the use of the internet and social media has progressed slower in product safety and PV. This presents the biopharmaceutical industry with exciting opportunities, and challenges, for the appropriate and effective use of social media for the detection, assessment, understanding and prevention of adverse effects and other drug-related issues. Within the last decade, social platforms have become powerful sources for news updates, viral marketing, online networking and entertainment, and hold the promise to drive consequential and valuable changes in PV.
Social media presents new channels and methods for companies to move away from traditional PV systems and safety reporting methods towards more patient-centric models for reporting, analysing and monitoring of safety data. These channels have the capability to allow swift and open communication between drug companies and their consumers, patients and healthcare providers, thereby helping foster transparency and build public trust. With this said, careful evaluation and assessment of employing social media as a PV tool needs to be conducted; in terms of its meaningfulness and impact on outcomes, validity of the use of data obtained via social media channels, adherence to regulations and laws and overall cost-benefit analysis.This article examines how the influence and reach of the internet and social media can be harnessed to drive valuable outcomes for the PV industry. It details the industry’s current state and future considerations for use of social media in PV, possible areas of influence, expected challenges, potential solutions and next steps.
Social Media in Pharmacovigilance - Current Regulations and ImpactToday, biopharmaceutical companies operating in the social media space have a responsibility to document and follow-up on any potential adverse outcomes communicated through these forums. Companies must comply with all applicable legislations including the European legislations (Regulation 726/2004 (as amended by Regulation 1235/2010) and Directive 2001/83/EC (as amended by Directive 2010/84/EU)1,2 and the US Food and Drug Administration (FDA) guidance for product promotion on social media and the internet by biopharmaceutical and medical device companies3, 4, 5, 6. The FDA draft guidance documents address different aspects including how pharmaceutical and device companies should respond to off-label inquiries, including inquiries from digital platforms3, how to provide benefit and risk information on internet and
social media platforms with character space limitations (e.g. Twitter)4, how to address misinformation about company products on the internet and social media websites5 and how to fulfill company post-marketing regulatory requirements for submission of “interactive promotional media” for their FDA-approved products6.
These regulatory guidelines have helped clarify, to a certain extent, the thinking and approach of regulatory authorities towards evaluating content shared on internet and social media platforms, and serve as an important first step towards providing guidance for companies to develop and implement their social media strategies for PV.
Today, biopharmaceutical companies are actively engaged in identifying and understanding the value drivers for adopting a comprehensive PV social media strategy including proactively creating social media platforms that solicit, capture, monitor and report AE activities, and also examining the successes and challenges of the of the social media platforms being used. For example, there are now multiple sites and applications for safety reporting, such as MedWatcher, a free tool that allows patients and physicians to submit “adverse event” reports to the FDA via smartphone or tablet. The primary purpose of such tools is to provide patients or healthcare professionals (HCPs) information on drugs, devices, interactions and other pharmaceutical information, while some also allow reporting of adverse events (AEs).
Companies provide their employees with social media guidance and best practices to facilitate effective safety reporting via social media7. By employing appropriate and sufficient controls over social media sites, organisations can avoid potential gaps/risks in the areas of reporting, identification and monitoring of AE data, thereby developing a cohesive and effective social media ecosystem.
Social Media for Safety Data Reporting and Follow-upSocial data offers some advantages over traditionally reported safety data or data mined from health and reimbursement records. Social reports are rapid, closer to real-time data and potentially richer sources than reports filtered through HCPs. Social media channels have the potential to act as a significant source of AEs, data on off-label use and impact of treatments on quality of life. One of the key areas of influence is, therefore, to establish social media as a safety reporting channel by expanding its existing use and unlocking its potential as a value-add for companies’ PV strategies.
Social media platforms, by design, can work to increase connections between companies and healthcare consumers. This gives companies an opportunity to directly connect, engage and encourage patients and consumers to report more, helping address the concern of adverse events going unreported.
Per the applicable FDA draft guidance for AE reporting and good pharmacovigilance practices (GVP) Module VI2, only valid
Technology
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individual case safety reports (ICSRs); consisting of four criteria; identifiable patient, identifiable reporter, suspect product and adverse event/reaction, qualify for reporting. Further, GVP module VI (Section VI.B.2, page 12) states: “When collecting reports of suspected adverse reactions via the internet or digital media, the term “identifiable” refers to the possibility of verification of the existence of a reporter and a patient (see VI.B.1.1.4).”
In a social media setting, patients are likely to be reporters themselves, without any confirmation of data from healthcare professionals (HCPs). Credibility and origin of these self-generated reports are key issues. Also, there is concern that social media with no appropriate checks on provenance can open the avenue to unscrupulous attacks from “pseudo-reporters”. Further, the absence of oversight of the social media means that data may be inadequate and inconsistent, and require additional follow-up. Another concern is around the fact that PV data obtained via social media would contain personal data related to the patient (subject of the case) and the reporter (patient’s healthcare provider, family member or the patient themselves). Overcoming these hurdles for confirmation of “identifiability” of both patient and reporter, and thereby validation of incoming safety data obtained via social media, becomes critical.
Companies need to prioritise and focus on company-managed social media websites to help decrease the chances of receiving incomplete and/or duplicate adverse event reports from different online reporting channels and help maintain the reliability of incoming data.
Validation of the reported information in a credible and identifiable way is possible by allowing posts/shares on company-monitored websites only after the user has registered and recorded basic user information. This can help PV teams verify the reported data with respect to the four minimal criteria to confirm case validity, confirm that a patient exists within each potential reporting scenario, and follow up with any additional questions on the report.
This processing of personal data for PV by companies needs to be in compliance with the applicable data protection laws, along with transparent and robust processes to ensure personal data protection. A data protection notice should be given on company-sponsored sites, that user-generated information deemed to be an adverse event (AE) or product complaint (PC) will be collected by the company in order to meet legal obligations, with explanation on why such information is beneficial for the protection of public health. It should also be noted that the company may follow up directly with the individual who generated the AE/PC information in order to gain more information. Regular training in data protection requirements is recommended for all company staff involved in PV activities8.
Social Media and Big Data ChallengesSocial media is a promising source for new safety data and potential emergent safety signals. However, this data is unstructured, without governing data quality standards and specific business area orientation. In addition, the sheer size of the information and its rapidly changing nature, makes it a
big data problem. Consequently, companies may struggle to integrate adverse event reports received through social media with reports received from more standard sources like email correspondence or physician hotlines. In addition, the retrieval and analysis of safety data, obtained via social media channels entails extra workload and additional resources, given the size and success of social media.
Another concern is the potential bias introduced by the “reporter population” and thereby accurate representation of the reported safety data. Of the large number of social media users, only a small percentage (1%) are actually commenting and reporting AEs, while most others are only occasional contributors or simply observers/readers. Also, many elderly individuals do not use social media and this is important because it creates a strong user bias for PV as this demographic is a large user of prescription medications.
There are a number of additional technical challenges to be addressed here, including:
1. Duplicate safety information i.e. same adverse drug reaction (ADR) reported by the same, or a different, user, on multiple digital media platforms
2. Multiple languages and how data collected in different languages maps to standard ADR
3. Data privacy and personal data protection4. Data curation and cleaning to mitigate the risk of spreading
rumours/false safety concerns
On top of all this, are the global diversity challenges, not just confined to linguistic issues and translation, but relating to social structures, practices and intangibles9. Overcoming these social media hurdles for validation and consolidation of incoming data is problematic and requires intensive efforts of the PV teams.
Social Media and Global InitiativesBoth biopharmaceutical and life sciences companies, along with regulators, now recognise the benefit of adapting automated tools for big data analytics to help manage and differentiate between signals received from social media platforms and any accompanying noise.
Google Insights for Search is a tool that allows one to look at any public concerns, as measured by web traffic, which can include drugs and disease terms and browsing possible associations. Although an interesting tool, it currently lacks precision, has limited use in deriving possible associations between adverse events and a companies’ products, and does not help companies prioritise amongst an influx of incoming social media signals9. The FDA is currently actively exploring a number of such social media-based tools and strategies, including Google-based search tools towards optimising safety data gathering from social media sites.
The WEBAE project (Web Adverse Events) aims to form a specialist public-private consortium between the EFPIA (European Federation of Pharmaceutical Industries and Associations) and the Applicant Consortium to undertake research for the development of policy and technology solutions in pharmacovigilance to strengthen the protection of public
Volume 7 Issue 356 Journal for Clinical Studies
health10. This will enable mining of publicly available web and social media content and help adopt methodologies and data-mining algorithms applicable to social media content in order to find emerging, self-reported medical insights such as adverse events associated with medicines and medical devices. This programme also intends to enable direct reporting of suspected ADRs to national competent authorities via EudraVigilance, with required applications available to all users of tablets, smartphones, and mobiles for all major platforms as well as social networking sites.
Employing Social Media as a Transformational Asset for Risk CommunicationThere are multiple ways for industry to positively engage consumers and healthcare providers while adhering to the regulatory guidance1, 2, 3, 4, 5. The first step is switching to a proactive company mindset that focuses on listening, educating, building trust, increasing safety awareness, and improving health outcomes. Some ways that PV teams can use social media to engage and improve awareness about the safety of a product, and provide more value to patients and healthcare professionals, can be seen in Figure 1.
Figure 1: Using social media to engage and improve awareness about product safety
SummaryThe use of social media forums and channels focusing on various health-related topics, including diseases and associated treatments, has increased rapidly in recent years. However, unlike many other areas in the healthcare industry, social media do not yet play a major role in drug safety and PV. Appropriate engagement of consumers and healthcare providers through social media by PV teams, certainly holds the promise of better outcomes (Figure 2).
Figure 2: Social media promises better outcomes
There are many questions that need to be addressed before the industry can be comfortable with the use of social data for drug safety surveillance.
Though traditional PV methods will certainly prevail, social media has the potential to become an added new-age tool to cull data in real time, making it an early indicator of potential safety issues for further investigation. Further, companies can generate more robust product safety profiles by leveraging the additional social media information. Overall, the benefits of social media engagement for PV seem to significantly outweigh perceived risks. The time is now right to elevate the PV role to a more strategic level through appropriate and effective use of social media to drive better PV outcomes.
References1. European Medicines Agency 2013. The EU
pharmacovigilance system. Available at: http://ec.europa.eu/health/humanuse/pharmacovigilance/index_en.htm
2. European Medicines Agency 2013. Good pharmacovigilance practices Module VI, Section VI.B.1.1.4.
3. Guidance for Industry Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices (FDA Draft Guidance) (FDA Draft Guidance December 2011).
4. Guidance for Industry Internet/Social Media Platforms with Character Space Limitations—Presenting Risk and Benefit Information for Prescription Drugs and Medical Devices (FDA Draft Guidance June 2014).
5. Guidance for Industry Internet/Social Media Platforms: Correcting Independent Third-Party Misinformation About Prescription Drugs and Medical Devices (FDA Draft Guidance June 2014).
6. Guidance for Industry Fulfilling Regulatory Requirements for Post-marketing Submissions of Interactive Promotional Media for Prescription Human and Animal Drugs and Biologics (FDA Draft Guidance Jan 2014).
7. Roche, 2013. Roche Social Media Principles. (Internet) www.roche.com/social_media_guidelines.pdf [Accessed 20/04/2015]
8. Guidance on UK data protection in post-marketing pharmacovigilance (ABPI Guidance, 2013).
9. Ralph Edwards and Marie Lindquist, 2011. Social Media and Networks in Pharmacovigilance: Boon or Bane? I. Uppsala Monitoring Centre, Uppsala, Sweden.
Supriya Desai MD, PGDBM is a Clinical Research and Pharmacovigilance (PV) Executive with over 16 years of experience in clinical practice and in various leadership roles in the healthcare industry including clinical research, drug safety and PV. In her current role as Medical Director and Practice Head at Sciformix, she provides scientific and operational leadership to a global
medical team (across India, Philippines and US); involved in medical review activities across pharmacovigilance, safety writing, signal management and allied safety surveillance activities, spanning diverse therapeutic areas.
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Volume 7 Issue 358 Journal for Clinical Studies
Clinical Trial Retention Meta-analysisHow Patient Recruitment Methods Directly Relate to the Retention of Subjects
Patient recruitment methods can have a significant effect on the retention of subjects in clinical trials; these effects can result in considerable cost implications. Subjects that actively sought clinical trial involvement through an online pre-screener (in response to online clinical trial advertising) using the MediciGlobal model, showed 38% lower relative risk of dropout across four studies compared to those who were recruited by sites [95% confidence interval (CI) 19%–53%], with divergence across visits in all four studies. Since increasing sample size is typically associated with an increase in the statistical power of the study, the loss of subjects over the course of a trial can result in missed endpoints, and negatively impact the outcome of the study. Engaging subjects that actively seek clinical trial participation results in a reduction of study withdrawals or patient dropout rates; the effect of which eliminates the need for over-enrolment of patients to offset expected retention loss. Increased retention rates accelerate enrolment timelines and result in saving time and money.
Rationale: Enrolling subjects into clinical trials is, needless to say, crucial to the development of new medicines and new treatment indications. But keeping subjects enrolled is also critical to ensure that the statistical power of the study is achieved, particularly for ‘intent to treat’ analyses. Overlooking patient retention issues at the beginning of a study can lead to costly implications later, either in failing to achieve endpoints, or the potential for re-opening recruitment to offset higher-than-expected attrition rates.
Recruitment for clinical trials is performed in various ways; site databases, insurance claims data, pharmacy databases, digital and social media marketing, targeted mailings, traditional media, patient advocacy and other methods. Digital techniques such as web-based screening have been documented to increase recruitment efficiency rates in several studies.1–4 However, it is not well understood what effect, if any, these different routes to enrolment have on retention rates amongst subjects. A 2009 study by Raynor et al. evaluating recruitment methods across two paediatric obesity trials reported higher retention rates amongst subjects that had initiated their own enrolment, by responding to advertising when compared to those that had been reached out to by the site.5
To further investigate this question, a meta-analysis of four studies has been performed comparing attrition rates for subjects that took an active role in their recruitment to those that were passively approached. The aim of the analysis is to determine whether the route of entry has an effect on the probability of dropout.
During the course of the recruitment process, many factors vary
which could alter the attrition rates of subjects, including method of first contact – whether the subject is approached for trial inclusion, or whether they sought out inclusion in the trial independently. In addition, the length and methodology of pre-screening procedures vary. For example, some subjects may undergo automated phone-based screening, compared to others that undergo a two-step process of online pre-screening combined with nurse follow-up — a ‘second level’ of pre-screening before the patient is referred to a research site for an initial screening visit.
Hypothesis, Objective and Outcome MeasuresIt is arguable that a passively approached patient (not actively seeking a clinical trial and invited by a medical professional to participate) may differ in their motivation to join a trial compared to a patient that proactively seeks trial inclusion. Proactive versus passive methods to clinical trial enrolment may impact subject retention. The objective of this meta-analysis is to quantify the end of study difference in attrition levels between randomised subjects that actively sought out clinical trial participation versus those that were approached passively.
The primary outcome measure was retention rates of subjects that enter trials by actively seeking them out, compared to subjects that enter by being approached by a medical professional. A secondary outcome was retention rates across all study visits, to determine divergence patterns between the two groups. Patients not actively seeking clinical trial participation may differ in their motivation to join a clinical trial compared to a patient that proactively seeks trial inclusion.
The study populations were subjects of randomised controlled clinical trials, which showed two clearly identifiable and distinct subject groups. Group A entered tahe trials through MediciGlobal’s recruitment model of advertising coupled with intensive online pre-screening for study inclusion/exclusion criteria, with further phone follow-up by a nurse for secondary pre-screening prior to being referred to a study site. Group B were recruited by medical professionals at study sites, with many subjects being offered study participation through referral by their healthcare professional, or contacted as a result of a database review. In such cases, patients played no active role in initiating the recruitment process. However, it should be noted that a small portion of group B played an active part in their recruitment by responding to site advertising. In total, early termination data from 2849 subjects was assessed for a minimum of seven months across four studies.
Search StrategyUsing PRISMA guidelines, systematic searches of MEDLINE, the Cochrane Library and the Educational Resources information centre were performed. These included studies from the past five years and produced 714 results, of which two compared the role of active and passive recruitment strategies to retention rates, underlining the lack of information and need for further research in this area.
Search terms included clinical trial retention, recruitment strategies, and attrition. See Table 1 for the full list of search terms. In order to be included, studies were required to have at least six months of retention data, specifying which subjects terminated early from the study, from the point of first randomisation. Neither of the two studies identified as relevant were found to have sufficient dropout data to be included in the analysis. The MediciGlobal database of past studies since 2009 was also searched for suitable studies, with four studies meeting the inclusion criteria.
In three out of four of the studies, data were available to show dropout rates at every study visit until the final visit. The fourth longer-term study is ongoing with final visit data yet to be collected.
Technology
Journal for Clinical Studies 59www.jforcs.com
MethodologyFor all four studies conducted by MediciGlobal, study visit attendance data was counted from the point of randomisation, through to the final visit (or in the case of the ongoing study, to visit 9 out of 10). The number and percentage of dropouts at each visit were calculated for each group, as shown in Table 2. The data included interim patients who had neither dropped from nor finished the study. These subjects had their visit attendance counted, but did not appear in the dropout counts, therefore the percentage dropout rate at each study visit only included discontinued patients.
The end of study retention percentages were calculated by applying the observed dropout percentages for each group at each visit, as shown in Table 3. This accounted for the interim nature of the data by assuming that a percentage of subjects that neither discontinued nor completed the study would drop out in line with
the historical data. P values were calculated using the Poisson test for individual studies, and 95% confidence intervals were calculated.
Relative risk was calculated to show the difference in risk of dropout between group A and B, and then data sets were combined to give overall relative risk of dropout across all studies. Heterogeneity or “non-combinability” was tested for using chi square statistic of Cochran’s Q (defined as the weighted sum of squared differences between individual study effects and the pooled effect across studies, with the weights being the number of subjects in each group of each study, as used in the pooling method).
Results and DiscussionWhen plotting actual early terminations from groups A and B and disregarding subjects that are yet to complete the study, all four studies display a lower relative risk of dropout by the end of data collection for subjects that played an active role in seeking out trial
Technology
Methodology For all four studies conducted by MediciGlobal, study visit attendance data was counted from the point of randomisation, through to the
final visit (or in the case of the ongoing study, to visit 9 out of 10). The number and percentage of dropouts at each visit were calculated
for each group, as shown in Table 2. The data included interim patients who had neither dropped from nor finished the study. These
subjects had their visit attendance counted, but did not appear in the dropout counts, therefore the percentage dropout rate at each
study visit only included discontinued patients.
Study 4 Baseline Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Total ET
week 2 week 6 week 13 week 26 week 39 Week 52
Number of dropouts (last visit 3 2 4 5 4 2 0 20
attended) - Group A
Number of dropouts (last visit 24 29 47 58 20 9 4 191
attended) - Group B
Group A randomisations that 112 109 107 92 89 78 60
attended visit
Group B randomisations that 777 753 724 677 502 301 173
attended visit
Group A dropout rate 3% 2% 4% 5% 4% 3% 0%
Group B dropout rate 3% 4% 6.5% 9% 4% 3% 2%
Table 2 Visit attendance and early dropout counts for study 4 The end of study retention percentages were calculated by applying the observed dropout percentages for each group at each visit, as
shown in Table 3. This accounted for the interim nature of the data by assuming that a percentage of subjects that neither discontinued
nor completed the study would drop out in line with the historical data. P values were calculated using the Poisson test for individual
studies, and 95% confidence intervals were calculated.
100 Group A 100 97.3 95.5 92.0 87.0 83.1 80.9 80.9 19.1 31% u=28,
Randomisations x=19
Group B 3% 4% 6.5% 9% 4% 3% 2%
Dropout rate
100 Group B 100 96.9 93.2 87.1 79.7 76.5 74.2 72.5 27.5 0.02
Randomisations
Table 3 Comparing attrition rates for study 4 Relative risk was calculated to show the difference in risk of dropout between group A and B, and then data sets were combined to give
overall relative risk of dropout across all studies. Heterogeneity or “non-combinability” was tested for using chi square statistic of
Cochran’s Q (defined as the weighted sum of squared differences between individual study effects and the pooled effect across
studies, with the weights being the number of subjects in each group of each study, as used in the pooling method).
mediciglobal.com 3
Methodology For all four studies conducted by MediciGlobal, study visit attendance data was counted from the point of randomisation, through to the
final visit (or in the case of the ongoing study, to visit 9 out of 10). The number and percentage of dropouts at each visit were calculated
for each group, as shown in Table 2. The data included interim patients who had neither dropped from nor finished the study. These
subjects had their visit attendance counted, but did not appear in the dropout counts, therefore the percentage dropout rate at each
study visit only included discontinued patients.
Study 4 Baseline Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Total ET
week 2 week 6 week 13 week 26 week 39 Week 52
Number of dropouts (last visit 3 2 4 5 4 2 0 20
attended) - Group A
Number of dropouts (last visit 24 29 47 58 20 9 4 191
attended) - Group B
Group A randomisations that 112 109 107 92 89 78 60
attended visit
Group B randomisations that 777 753 724 677 502 301 173
attended visit
Group A dropout rate 3% 2% 4% 5% 4% 3% 0%
Group B dropout rate 3% 4% 6.5% 9% 4% 3% 2%
Table 2 Visit attendance and early dropout counts for study 4 The end of study retention percentages were calculated by applying the observed dropout percentages for each group at each visit, as
shown in Table 3. This accounted for the interim nature of the data by assuming that a percentage of subjects that neither discontinued
nor completed the study would drop out in line with the historical data. P values were calculated using the Poisson test for individual
studies, and 95% confidence intervals were calculated.
100 Group A 100 97.3 95.5 92.0 87.0 83.1 80.9 80.9 19.1 31% u=28,
Randomisations x=19
Group B 3% 4% 6.5% 9% 4% 3% 2%
Dropout rate
100 Group B 100 96.9 93.2 87.1 79.7 76.5 74.2 72.5 27.5 0.02
Randomisations
Table 3 Comparing attrition rates for study 4 Relative risk was calculated to show the difference in risk of dropout between group A and B, and then data sets were combined to give
overall relative risk of dropout across all studies. Heterogeneity or “non-combinability” was tested for using chi square statistic of
Cochran’s Q (defined as the weighted sum of squared differences between individual study effects and the pooled effect across
studies, with the weights being the number of subjects in each group of each study, as used in the pooling method).
mediciglobal.com 3
Table 2 Visit attendance and early dropout counts for study 4
Table 3 Comparing attrition rates for study 4
Volume 7 Issue 360 Journal for Clinical Studies
Technology
inclusion compared with passive recruitment. This ranged from a relative risk of 0.72 (28% less likely to drop out) to a relative risk of 0.52 (48% less likely to drop out). One was found to be statistically significant when the studies are considered alone, as shown in Figure 1, in which three out of four of the studies have 95% confidence intervals which cross the “no-effect” line. However, combining the data from all four studies shows a statistically significant reduction in risk of dropout of 38% for the active group overall. It is also 95% certain that the true reduction in risk lies between 19% and 53%.
Despite the clear improvement in retention rates for actively seeking subjects, there was found to be an 89% chance of heterogeneity, meaning it is highly likely that recruitment method A or B is not the only factor affecting the retention levels within these studies. This limits the combinability of the results and brings into question what other factors may be at play. Compounding factors include trial design, intervention and therapy area. Future studies could improve on this analysis by controlling for these factors where possible, for example, combining the results from studies within the same therapeutic area.
The retention differences between groups A and B increase with time across all four studies, as shown in Figure 2. Group A — those taking an active role in their own recruitment through a MediciGlobal recruitment model showed superior retention rates in each case compared to those subjects recruited by sites. Interim study visits are accounted for by applying the actual dropout percentage at each visit to the whole group. The difference in retention rates between groups A and B by the end of study vary from 31%, as shown in study 4, to 41%, as shown in study 2. When counted across studies, group A shows lower dropout percentages than group B at 16 out of 26 visits (62%), equal dropout levels at five visits (19%) and greater dropout levels at five visits (19%).
There may be multiple factors resulting in the retention differences, such as the motivation of the subjects in each group, or study-specific reasons. Factors could include the process of vetting candidates, differences in access to healthcare between the two groups, personalities of people proactively researching their options or financial motivations. Further research in this area is needed to better understand the motivations of subjects entering research through various channels.
Firstly, in all of the studies included, the process of vetting
candidates from the proactive group was sufficiently thorough that only high-quality, motivated candidates make it through to
randomisation. Such methods include a comprehensive online or telephone pre-screener (or both) during which the inclusion/exclusion criteria are applied, before the candidate is passed on to the site as a referral. In the mainly passive group, the candidate usually starts off being reached out to directly by the study site or healthcare professional.
As previously mentioned, Raynor et al. (2009) found that enrolled subjects responding to advertising, such as newspapers, internet and television ads) dropped out at a lower rate in comparison to those contacted by sites directly.5
Secondly, people come from a variety of backgrounds and have different levels of access to healthcare. One 2014 study on recruitment strategies by Maghera et al. published in the journal of BMC Medical Research Methodology found that recruitment strategy has an effect on the demographic profile of applications such as family income, university attendance and race.6
Those that were contacted passively, through their healthcare professional or other databases, have all had access to medical treatment at some point, and may be more likely than those who are seeking inclusion in clinical trials to still have access to healthcare. People who are unable to access healthcare may seek out clinical trials and be more committed to completing a study, and therefore drop out at a lower rate.
Thirdly, people vary in their behaviours when facing medical problems. Some proactively seek out information and options, whilst others take no action. It can be argued that those actively seeking inclusion in trials may contain a larger proportion of the proactive part of the behavioural spectrum than those who were approached. A 2002 study on cancer prevention programmes by Linnan et al. published in the Annals of Behavioural Medicine found that subjects who responded to recruitment advertising as opposed to being approached offered significantly higher “reach” within the study (such as giving permission to be called at home) than those who were approached (74.5% vs. 24.4%).7 In addition, those who are proactively researching their options are seeking to reach their own conclusion regarding whether to participate in a trial or not. This may also lead to firmer decisions being made, and lead to lower dropout levels.
In addition to the retention boost that an actively-initiated pre-screening process can produce, one 2012 study on cost efficiency in randomised trials by Yu et al. in the journal BMC Medical Research Methodology found that a two-stage screening procedure, including a pre-screening phase, significantly reduces costs.8
ConclusionThis analysis has shown that the method used for patient recruitment had a significant effect on patient retention rates in clinical trials. Subjects that actively sought out clinical trial involvement through MediciGlobal’s online recruitment model showed 38% lower relative risk of dropout across four studies compared to those who were recruited by sites — the majority of which played a passive role in initiating enrolment [95% CI 19%–53%]. The retention levels of the active and passive groups diverged across visits in all four studies. Higher retention levels of actively recruited subjects compared to those that were approached may be related to different motivations between the groups, and in part due to the comprehensive vetting procedures used on the active group. More research is needed to understand the cause of these differences.
Figure 1 Relative risk of dropout of patients who played an active role in their recruitment as opposed to passive. Subjects actively seeking enrolment show 38% lower risk of dropout than those approached for enrolment [95% CI 19%–53%]
Journal for Clinical Studies 61www.jforcs.com
Technology
From a business and data perspective, retaining subjects is the most important aspect of maintaining data integrity and sustaining the statistical power of a study. The loss of too many subjects over the course of a trial, particularly those with data that will undergo intention to treat analyses, could jeopardise the drug approval process. If necessary, re-opening a study for enrolment is hugely costly and results in lost time. Recruiting subjects that are actively seeking clinical trial enrolment minimises the risk of dropout, and could make the difference between re-opening enrolment or not, saving significant time and money in the process.
References1. Smith KS, Eubanks D, Petrik A, Stevens VJ. Using web-
based screening to enhance efficiency of HMO clinical trial recruitment in women aged forty and older. Clinical Trials 2007;4(1):102–5.
2. Thadani SR, Weng C, Bigger JT, Ennever JF, Wajngurt D. Electronic screening improves efficiency in clinical trial recruitment. Journal of the American Medical Informatics Association 2009;16(6):869–73.
3. Carmi L, Zohan J. A comparison between print vs. internet methods for a clinical trial recruitment—A pan European OCD study. European Neuropsychopharmacology 2014;24(6):874–878.
4. Web applications aid clinical trial recruitment. Cancer Discovery. January 12, 2012. http://cancerdiscovery.aacrjournals.org/content/2/2/OF2.long (accessed 2 Jul 2008).
5. Raynor HA, Osterholt KM, Hart CN, Jelalian E, Vivier P, Wing RR. Evaluation of active and passive recruitment methods used in randomized controlled trials targeting pediatric obesity. International Journal of Pediatric Obesity 2009;4(4):224–32.
6. Maghera A, Kahlke P, Lau A, Zeng Y, Hoskins C, Corbett T, Manca D, Lacaze-Masmonteil T, Hemmings D, Mandhane P. You are how you recruit: a cohort and randomized controlled trial of recruitment strategies. BMC Medical Research Methodology 2014 Sep 27;14:111.
7. Linnan LA, Emmons KM, Klar N, Fava JL, LaForge RG, Abrams DB. Challenges to improving the impact of worksite cancer prevention programs: comparing reach, enrollment, and attrition using active versus passive recruitment strategies. Annals of Behavioral Medicine 2002 Spring;24(2):157–66.
8. Yu M, Wu J, Burns DS, Carpenter JS. Designing cost-efficient randomized trials by using flexible recruitment strategies. BMC Medical Research Methodology 2012 Jul 24;12:106.
Clare Jackson has an MSc in Clinical Research, and a passion for research projects within the arena of clinical and healthcare research. Areas of research include patient recruitment and retention in clinical trials, key success factors in hospital-based research projects and barriers to the roll out of online health tools.
Liz Moench, President and CEO of MediciGroup® Inc, has implemented innovative programs that have changed the pharmaceutical industry twice in her 30 year career. Her achievements include launching the industry’s first direct-to-consumer advertising campaign (1983) for Boots-Ibuprofen, and pioneering the first direct-to-patient clinical trials recruitment for Taxotere (Rhone-Poulenc Rorer Pharmaceuticals, now Sanofi-Aventis)
in 1991. Today her pioneering initiatives involve optimising digital strategies and social media for patient recruitment and engagement, including development and management of some of the largest online patient communities globally like Team Epilepsy, Gout Study and Lupus Team to promote clinical research. Email: [email protected]
Figure 2 Retention percentages of studies by visit number
Utku Ozdemir is the Manager of Business Analytics and directs the Business Analytics team at Medici Global. With a strong statistical and business analytics background, Mr. Ozdemir specializes in performance measurement and benchmarking patient recruitment performance rates against Key Performance Indicators (KPIs).
Mr. Ozdemir has structured the Business Analytics team to work collaboratively within the Company to ensure that every project is managed by metrics. He has instilled the credo across all internal functional teams that “if you can measure it – then you can manage it”.
Mr. Ozdemir’s education and experience in data management intelligence bring a new level of excellence to patient recruitment and retention, enabling MediciGlobal to lead the industry in recruitment-retention performance analytics.”Email: [email protected]
Volume 7 Issue 362 Journal for Clinical Studies
Contamination scare at NIH leaves clinical trial subjects with tough choice
Some people enrolled in clinical trials with the U.S. National Institutes of Health (NIH) are continuing the use of experimental drugs despite the possibility the compounds have fungal contaminations.
NIH suspended operations yesterday at a facility that makes experimental drugs for the agency’s Clinical Center in the wake of an investigation by the Food and Drug Administration (FDA) that revealed multiple problems that could expose sterile drugs to contamination. Forty-six trials currently underway receive materials from the facility, and NIH is searching for alternate sources of products for about 250 patients involved in the studies. In some instances, however, finding those other sources won’t be possible, and some trials will have to be delayed, says Lawrence Tabak, principal deputy director of NIH. In addition, a few trial subjects, after being informed of the risks, have requested to continue with their experimental treatments made by the now-closed facility. NIH Director Francis S. Collins has granted exceptions to those whose conditions could be severely compromised if they failed to receive their next scheduled dose. They will be monitored for signs of infection.
Amgen releases phase III AMG 416 data for secondary hyperparathyroidism in CKD
Amgen has released pooled data from two pivotal phase III, global, randomized, placebo-controlled trials evaluating AMG 416, a novel calcimimetic, for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) receiving hemodialysis. Both studies met the primary endpoint, demonstrating that a greater proportion of patients in the AMG 416 groups achieved a greater than 30% reduction in parathyroid hormone (PTH) during the efficacy assessment phase compared with placebo. “Secondary hyperparathyroidism is a complex and challenging condition that can be difficult to manage, as it may require patients to take demanding drug regimens multiple times a day,” said John Cunningham, lead author of the studies, professor of nephrology at the University College London Medical School and consultant physician at The Royal Free Hospital, London. “Providing patients with CKD on haemodialysis with a calcimimetic that can be administered intravenously on the same schedule as dialysis has the potential to fulfil an unmet need in this patient population.” AMG 416 is a novel calcimimetic agent in clinical development for the treatment of SHPT in patients with CKD who are receiving haemodialysis. In the registration programs, AMG 416 is administered intravenously at the end of dialysis. AMG 416 acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in PTH. Sustained elevations in PTH are known to lead to significant clinical consequences for patients with CKD.
FDA approves Invega Trinza, only four-times-a-year treatment for schizophrenia
The FDA has approved under Priority Review Janssen Pharmaceuticals’ New Drug Application (NDA) for the three-
month long-acting atypical antipsychotic Invega Trinza. Invega Trinza, a three-month injection, is an atypical antipsychotic indicated to treat schizophrenia. Before starting Invega Trinza, patients must be adequately treated with Invega Sustenna (one-month paliperidone palmitate) for at least four months. Priority Review is a designation for drugs that, if approved, would offer significant improvement in the treatment of serious conditions.
In a long-term maintenance trial, 93% of patients treated with Invega Trinza did not experience a significant return of schizophrenia symptoms. Based on positive efficacy, Janssen concluded this study early following the recommendation of an Independent Data Monitoring Committee (IDMC).
“With a dosing interval that can be measured in seasons, not days, people living with schizophrenia and their treatment teams can focus on recovery goals beyond short-term symptom control,” said trial investigator Joseph Kwentus, M.D., Precise Research Centers. “Recovery looks different for everyone, and the long-term symptom control offered by Invega Trinza can help patients work toward their own personal goals.”
Schizophrenia is a complex and chronic brain disorder in which symptoms can be severe and disabling and can affect all aspects of a person’s daily life. With this new treatment option, healthcare providers can give patients greater independence by enabling them to focus less on taking their medication and more on other aspects of their treatment plan.
News
JCS News
Journal for Clinical Studies 63www.jforcs.com
Ligand Announces Favourable Results from Phase 1b Trial with LGD-6972 in Type 2 Diabetes
Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) announces results from a Phase 1b clinical trial with LGD-6972 that demonstrate favourable safety, tolerability and pharmacokinetics in normal healthy volunteers and in subjects with type 2 diabetes mellitus. The trial results also demonstrate a robust, dose-dependent reduction of fasting plasma glucose. LGD-6972 is Ligand’s novel glucagon receptor antagonist, and these results were presented at the American Diabetes Association’s 75th Scientific Sessions meeting underway in Boston. Glucagon receptor antagonists are the leading non-insulin mechanism in development for the treatment of type 2 diabetes. Based on earlier data and these latest results, Ligand believes LGD-6972 has best-in-class properties given its potency, preliminary effectiveness in lowering plasma glucose in patients with type 2 diabetes and its safety profile demonstrated in two Ligand-sponsored clinical trials.
In this randomized, double-blind, placebo-controlled trial, LGD-6972 was administered in sequential increasing oral doses daily over two weeks to both healthy subjects and subjects with type 2 diabetes. A total of 48 subjects were enrolled in the trial.
Clovis Oncology’s Phase 2 Studies of Rucaparib in Ovarian Cancer Demonstrate Highly Compelling Clinical Activity
Clovis Oncology (NASDAQ:CLVS) today announced updated Phase 2 results from two ongoing clinical studies with rucaparib: ARIEL2 and Study 10. Rucaparib is the Company’s investigational oral, potent, small molecule inhibitor of PARP1 and PARP2 being developed for the treatment of advanced ovarian cancer, specifically in patients with BRCA mutations and other DNA repair deficiencies beyond BRCA, commonly referred to as “BRCA-like.” Updated data from the ARIEL2 study in 204 patients with advanced ovarian cancer are being presented Monday in an oral presentation by Professor Iain McNeish at the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago. Additional data from Study 10, a Phase 2 study of 40 platinum sensitive ovarian cancer patients with germline BRCA mutations were also presented in a poster session today. “To see the encouraging progression-free survival rates mirror the impressive response rates in both the BRCA-mutant and BRCA-like populations represents a very exciting step forward in the treatment of advanced ovarian cancer,” said Robert L. Coleman, MD, Professor & Deputy Chairman, Vice Chair, Clinical Research, Ann Rife Cox Chair in Gynecology, Department of Gynecologic Oncology and Reproductive Medicine at University of Texas MD Anderson Cancer Center in Houston and one of the two principal investigators of the ARIEL3 study. “The opportunity to provide a very compelling targeted therapy in an ovarian cancer population in addition to those who carry germline or somatic BRCA mutation represents a potentially practice changing advance in the treatment of this terrible disease.”
Amplifying the Patient Voice
PatientsLikeMe’s centerpiece is its social network: a site where patients living with major chronic illnesses can find other people dealing with the same symptoms to share treatment experiences, ways of coping, and research opportunities. Facebook was just two years old when PatientsLikeMe launched its first “community” in 2006, for patients with amyotrophic lateral sclerosis (ALS), yet the organization’s founders already had an intuitive sense for the strengths of social media, which would quickly make the service a popular meeting space for patients.
Key to the website’s success is its search function. Members of PatientsLikeMe communities enrich their profiles by recording symptoms they’ve experienced, along with other information like their medications and side effects. They can then search the entire site for other members who have dealt with the same or similar symptoms. These matches are the beginning of the personal contacts members forge among themselves, the core of PatientsLikeMe’s mission. At the time PatientsLikeMe was building its platform, this kind of user-defined tagging of content was seen as a new feature of the social web, and a big departure from traditional search functions that relied on top-down data structures. Letting members enter their experiences with disease in their own words allowed PatientsLikeMe to build its entire data scheme on what the organization calls “the patient voice.”
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Volume 7 Issue 364 Journal for Clinical Studies
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