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International Clinical Trials
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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).
GVP Module VIII
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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Points to Consider When Developing a TMF (Trial Master File) Strategy
Phlexglobal Ltd
Many organizations are currently outsourcing clinical trial activities to one or more contract research organizations (CROs). This strategy enables companies to leverage specialized expertise and take advantage of flexible resourcing throughout the conduct of a clinical trial. Outsourcing minimizes the costs of recruiting experts, building a team and maintaining an infrastructure. However, it can also add complexity as the organization looks to meets its compliance obligations regarding clinical trial documentation.
The documentation referred to in Article 15(5) of Directive 2001/20/EC as the trial master file shall consist of essential documents, which enable both the conduct of a clinical trial and the quality of the data produced to be evaluated.1 This essential study specific documentation is also known as the TMF. As organizations try to minimize their reliance on paper files, the electronic TMF (eTMF) has emerged. A current industry initiative to standardize the organization of this content is known as the TMF Reference Model. This model is helping standardization efforts across paper and electronic systems.
As companies implement outsourcing strategies, CROs and sponsor organizations look for a common foundation on which to build their TMF capabilities. The following paper outlines some of the challenges organizations face when outsourcing clinical trial activities to multiple contract research organizations and a strategy to facilitate partnering and management of trial information between sponsors and CROs.
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