Zinserling_-_WMA_DoH_Revision

Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Selected ethical aspects
of international clinical trials
Dr. Jörg Zinserling
Federal Institute for Drugs and Medical Devices,
Germany
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Regulatory perspective on clinical trials
• Clinical trials should provide sound
scientific evidence for benefit/risk
assessment for medicinal products
• Requirements for clinical trials are defined
– by ethical principles (WMA DoH, WHO/CIOMS,…)
– in Guidelines (ICH, EMA/CHMP,…)
– by EU Regulations and Directives, national law
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Regulatory perspective on clinical trials
outside EU
• EU legal requirement: Directive 2001/83/EC, Paragraph 8 of
the Preamble of Annex 1
Clinical trials conducted in third countries and used in
Marketing Authorisation Applications in the EEA or in
applications for a Scientific Opinion under article 58 of the
Regulation (EC) No. 726/2004, must be conducted on the
basis of principles equivalent to the ethical principles and
principles of good clinical practice applied to clinical trials
in the EEA.
• EMA guidance: “Reflection paper on ethical and GCP aspects
of clinical trials of medicinal products for human use
conducted outside EU/EEA and submitted in marketing
authorisation applications to the EU Regulatory Authorities”
(EMA/121340/2012)
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Regulatory perspective: Selected topics
• EMA guidance defines framework, procedures and proposed
regulatory actions
• Reflection paper provides consensus position
• From Table of contents:
4. Clarification of the practical application of ethical standards for
clinical trials on medicinal products for human use in the context
of the European Medicines Agency activities
4.1. Ethics committee and national regulatory authority oversight
4.2. Information/Consent procedure
4.3. Confidentiality
4.4. Fair compensation
4.5. Vulnerable populations
4.6. Placebo and active comparator
4.7. Access to treatment post trial
4.8. Applicability of data to EEA population
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Ethics committees
• Local or national ethics committee should review the trial.
Ethics committees have to
– be independent
– be pluralist, multidisciplinary and representative of stakeholders
– include expertise in vulnerable populations (paediatric, mental
disorders, …)
• In many countries a trial application has to be made to a
regulatory authority
– In Germany trial application must be approved by BfArM
• Review by additional ethics committees is optional
– in multicentre studies a central ethics committee could review
the study in addition to local or national ethics committees
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Ethics committees: Regulatory action
• Failure to submit a protocol to an independent EC is a serious
violation of ethical standards. EU regulatory authorities
should disregard data obtained in a such unethical manner
when submitted in support of a MAA.
• Approval by ethics committee and national regulatory
authority must be provided. Description of adherence to
ethical standards should be provided in study report and
assessed by regulatory authorities.
• EU Regulatory Authorities should identify studies that may
give rise to special ethical concern (e.g. design, vulnerability
of study subjects) and where applicable seek additional
assurance that the trial have been ethically conducted.
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Biobanks and confidentiality
• Confidentiality must be maintained.
• Participants are entitled to know any information collected on
their health. Participants may choose not to receive or not
receive information about their health.
• Biological sample retention and consent procedure for
analysis and re-analysis should be according to the protocol.
• Samples cannot be used for purposes different of the ones
described in the protocol without a new written informed
consent.
– In exceptions, where consent is impossible, impractical or where
validity of research would be compromised, ethics committee
approval is necessary.
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Biobanks: Regulatory action
• EU regulatory authorities should disregard reports which fail
to properly protect the confidentiality of the trial subjects,
when submitted in support of a MAA.
• EU regulatory authorities should identify studies that may
give rise to special concern regarding confidentiality (e.g.
arising from the use of genetic information or bio-banked
samples).
• From a scientific and public interest perspective use and re-
use of biological samples is highly appreciated to capture
important information for optimization of therapies
– Biobank use in European Network of Paediatric Research (Enpr-
EMA).
– Steps toward mechanism-based and individualized medicine
(EMA Patients’, consumers’ and healthcare professionals’
expectations survey, Doc ref. EMEA/40926/2009).
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Vulnerable groups
• Inclusion of participants from vulnerable populations should
be fully justified and research in vulnerable groups should be
only undertaken when there is a reasonable likelihood for
direct benefit to the subject or group concerned.
• Vulnerability due to poverty, lack of adequate health care
systems or lack of access to medicines and exploitation of a
vulnerable group for benefit of EU patients is of main
concern.
• Category of vulnerability and therefore justification may vary
(e.g. impoverished persons, patients with incurable diseases,
those incapable of giving consent,…).
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Vulnerable groups: Regulatory action
• The inclusion of vulnerable subjects in a clinical trial without the
approval of the ethics committee and without implementation of the
appropriate consent processes is a serious violation of ethical
standards. EU regulatory authorities should disregard data obtained
in such an unethical manner when submitted in support of a MAA.
• Justification of inclusion and specific measures implemented to
protect rights and welfare of vulnerable groups should be described
in the protocol, the clinical study report and made public in the
European Public Assessment Report.
• EU regulatory authorities should identify studies that may give rise
to special ethical concern regarding the inclusion of vulnerable
populations and where applicable seek additional assurance that the
inclusion of such populations was justified and their rights and
welfare protected.
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Post-study arrangements
• Differences in patients‘ access to medicinal products needs to
be considered by sponsor, ethics committees and regulatory
authorities.
• For patients who participated in a trial continued access to
beneficial product is crucial.
• Post-trial access to treatment or care provided by the
sponsor cannot substitute for shortcomings of national or
regional health care systems.
• Transparency on post-trial access is paramount. Ethics
committees, national regulatory authorities and participating
patients need to be fully informed about post-trial
arrangements and benefits.
Federal Institute for Drugs
and Medical Devices
The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health
Post-study arrangements: Regulatory action
• EU regulatory authorities should identify studies that may
give rise to special ethical concern regarding access to
treatment post trial and where applicable to seek additional
assurance that the solution was appropriate and ethically
acceptable.
• Information on post-trial access will be summarized in the
European Public Assessment Report.