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International Clinical Trials

Priority PASS

Regulatory agencies worldwide are increasing the pressure on pharmaceutical companies and other marketing authorisation holders for post-approval commitments focused on safety, with potentially large penalties for noncompliance. The European Union (EU) is a case in point. Recent changes in pharmacovigilance legislation in the EU promote more proactive approaches to measuring the efficacy and safety of medicinal products in the postauthorisation environment. In light of this development, pharma companies are seeing – and will continue to see – more obligations to conduct Post-Authorisation Safety Studies (PASS).

Legislative Overview

EU Regulation No. 1235/2010 and Directive 2010/84 were approved by the European Parliamentary system in December 2010. All pharma companies, regulatory agencies and other stakeholders had 18 months to implement the new requirements, with a deadline of July 2012. The Regulation and Directive were supported by Commission Implementing Regulation No. 520/2012, published in June 2012, which provides additional information and includes transitional timeframes for some elements of the new legislation.

The final layer of documentation that supports the legislation is the Good Pharmacovigilance Practices (GVP). This is a new concept in the EU and describes the expected operational application of the Regulation, Directive and Implementing Regulation. The GVP is being presented in 16 modules, which began to be published last year (see Table 1).


The content of Module VIII of the GVP is largely aligned with the requirements of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) and the International Society of Pharmacoepidemiology (ISPE). It is not mandatory for an organisation to be registered with ENCePP to comply with GVP, although use of ENCePP-registered organisations will provide a level of reassurance to regulatory agencies.

A post-authorisation safety study is defi ned in the EU’s Directive 2010/84 as: ‘Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confi rming the safety profi le of the medicinal product, or of measuring the effectiveness of risk management measures.’

This is a change from previous definitions, with the addition of the measurement of the effectiveness of risk management measures. The revised pharmacovigilance legislation reinforces the expectation that risk minimisation activities will be monitored for their effectiveness. It is anticipated that PASS will be a common tool utilised in this activity.

PASS may be interventional or non-interventional (observational). Interventional studies must follow the requirements outlined in the existing European Clinical Trial Directive (2001/20). The requirements described in GVP largely apply to non-interventional studies only. Studies are considered to be non-interventional when the product is used within the terms of the marketing authorisation, there is no assignment of patients to a particular therapeutic strategy, and there are no additional diagnostic or monitoring procedures.

A common area of discussion is the use of interviews, questionnaires, and/or blood tests. In GVP these are not considered interventional, but practical experience shows that some European agencies continue to consider them to be so. The result: the same study may be interventional in some countries, but not in others. This presents challenges for the study sponsor in identifying which regulatory requirements to adhere to and how to manage conflicts that may arise.

EU PAS Register The recommendation is to include information regarding both interventional and non-interventional studies in the EU PAS Register, the electronic register for PASS. This is currently under development by the European Medicines Agency, and will be an evolution of the current ENCePP register. Also recommended is to include the study protocol, any substantial protocol amendments, progress reports and the final study report.

A common concern of the pharma industry is the protection of intellectual property; GVP does allow for redaction within protocols. Redaction should be justified and kept to the minimum necessary. Another concern is understanding whether the addition of studies to the EU Register will be considered mandatory by the regulatory agencies in practice. This requirement is mentioned in GVP Module VIII as guidance for the implementation of legal requirements, but not as a legal requirement in itself.

PASS Conduct

GVP Module VIII also provides guidance on the conduct of PASS, including research contracts with investigators, the development of the protocol, management of substantial amendments to the protocol, requirements for progress reports, and preparation of the final study report. Suggested formats and contents for these documents and the use of ENCePP checklists and additional guidance are described and recommended.

Furthermore, GVP emphasises the importance of continuous pharmacovigilance activities throughout the conduct of PASS. Study sponsors are expected to monitor the data being generated at frequent intervals to identify any change to the current knowledge of the benefi t-risk profi le of the product. This is typically performed at monthly or quarterly intervals by a cross-functional group involving physicians, clinical research staff and pharmacovigilance personnel.

Adverse Events

A key impact of the revised pharmacovigilance legislation is the management of adverse events. While adverse events occurring in interventional clinical studies continue to follow traditional processes, the adverse event management within observational studies has become increasingly complex. Adverse events observed in studies based on retrospective record review do not require submission to regulatory agencies outside of the final study report. However, studies based on primary data collection now need to collect all adverse events (related and unrelated to study drug, serious and non-serious). All serious related adverse events need to be submitted to regulatory agencies within 15 days, including events that are both expected and unexpected.

Of more impact, however, is the new requirement to submit non-serious adverse events to regulatory agencies on an expedited basis. This does not affect non-serious adverse events occurring in a site outside the EU, but those non-serious adverse events occurring in a site within the EU require expedited submission within 90 days. Consequently, these events need to be made available to the responsible pharmacovigilance department promptly to enable the submission process. The requirement to submit non-serious adverse events within 90 days is currently in a transition phase. Six countries in the EU required this as of July 2012, but it will be required for all EU countries by 2016.

Consideration needs to be given to management of these requirements across studies that have sites both in and outside the EU. One strategy is to apply the same adverse event collection processes across the study, collecting non-serious adverse events across all sites to forward to the relevant pharmacovigilance group. However, this may cause a significant resource burden for the investigator, the clinical research personnel and the pharmacovigilance personnel. Another strategy is to customise the adverse event collection process across the sites, only collecting non-serious adverse events from the EU sites. This process has logistical issues with differing requirements for different sites.

Once these hurdles have been overcome, the study completed and the study report submitted to the relevant regulatory agencies, there is one final requirement: GVP recommends that final manuscripts are forwarded to regulatory agencies within two weeks of first acceptance for publication. This has caused concern in the pharma industry about potential infringement of legal agreements with journals and the potential for accidental distribution of an article before publication.

The implementation of GVP in the EU has a significant impact on both European and global PASS. Consideration to GVP requirements should be given to both ongoing PASS studies and those currently in the planning stage.

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Miranda Dollen is a Director of pharmacovigilance at Optum. She joined the company in June 2004 as a consultant specialising in European pharmacovigilance and providing the services of the EEA Qualified Person for Pharmacovigilance for a number of organisations. Prior to working at Optum, Miranda had eight years’ experience in the pharmaceutical industry, with roles in the UK at Roche Products Ltd and Pharmacia Ltd. She started her career with a one-year position in pharmacovigilance at the UK Medicines and Healthcare Products Regulatory Agency.

Kosta Cvijovic is a Director of pharmacovigilance and medical information and has been with Optum since February 2010, providing pharmacovigilance and medical information services to clients in Canada, the US and Europe. Previously, Kosta had three years’ experience in the pharmaceutical industry in Europe and two years’ in Canada. He also spent three years working with Health Canada and one year practising as a pharmacist. He has held positions at Apotex Inc, where he worked in medical affairs, as well as at a start-up biotech company, where he specialised in business development.

Miranda Dollen
Kosta Cvijovic
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