The German Bundestag adopts Fourth Act on the Amendment of the German Drug Act and Other Provisions
Author: Mark Heinemann, Princpal Regulatory Consultant, RWE and Insights, inVentiv Health
The 4th law on the amendment of the German Drug Act came into force on December 24, 2016 (G. v. 20.12.2016 BGBl. I S. 3048 (Nr. 63)).
The new law specifically amends the existing clinical trial rules to establish compliance of German law with the EU Regulation No 536/2014. The amendments particularly affect the approval procedure for new studies and the competencies of the ethics committees and regulatory authorities. While currently two full stand-alone approvals for a study are required (i.e., from the ethics committee and the competent authority), under the new law, certain parts of the ethics committee’s opinion may be overruled by the authority. In addition, a new federal ethics committee can be established by the regulatory authorities that would additionally lead to significant changes in the procedure.
With the new act, several other amendments will be enacted in other areas of the German pharmaceutical rules that go beyond clinical trials. These include, among other things, amendments to the formal requirements for notifications about non-interventional studies.
The majority of changes to the law do not have any impact on the conduct of non-interventional studies in Germany. Per Article 4 (23) AMG, non-interventional studies are not considered as clinical trials. Consequently the modifications described above and that relate to section 6 of the AMG (Protection of the Human Being in Clinical Trials) do not apply to non-interventional studies as defined by the law.
Changes related to non-interventional studies were made in Articles 63 f and 67 (6) AMG:

  • Art. 67 (6) describes the notification conditions for “Anwendungsbeobachtungen” (also called AWB) – English: ‘drug use observation studies’.
  • As a result of the amendment, the German health insurance head organizations KBV, PKV, GKV must create uniform conditions for the notification of such studies Art. 67 (6) Sentence 13. A further change made to this section is a clarification of information to transmit to these organizations compared to the previous version of the law.
  • Art. 63 f that defines the principles for voluntary post-authorization safety studies, was amended in the same sense as Art. 67 (6) AMG, referring to above-mentioned sentence 13 of Art. 67 (6) concerning the notification conditions to the German health insurance head organizations.

As of February 2017 neither the KBV nor PKV or GKV have introduced any changes to the notification process that would create the uniform conditions demanded by the law.
‘AWB’ and voluntary post-authorization safety studies are to be notified separately to the three German health insurance head organizations: KBV and GKV provide a notification system online similar to BfArM or PEI, whereas the PKV offers reporting by e-mail only.
To the general notification obligations for the sponsor of a non-interventional study with marketed medicinal products outlined above add the participating doctor’s obligation to seek ethical advice.
Usually the ethics committee is located at the doctor’s state’s chamber of physicians (Landesärztekammer).
Doctor’s ethical consultation duties associated with non-interventional studies are not an obligation in relation to section 6 of the AMG – non-interventional studies are not clinical trials!
Despite this differentiation, German physician’s professional bylaws demand that a doctor seeks ethical advice prior to participating in non-interventional research projects.
Moreover, the German pharmaceutical industry’s association ‘FSA’ (Freiwillige Selbstkontrolle für die Arzneimittelindustrie e.V.) also recommends that sponsors carry out an ethical consultation prior to the implementation of a non-interventional research project.
These ethical considerations aim at the professional ethics and professional questions associated with the project. In general, when involving the mental or physical integrity of a human being, the use of body materials or data that can be assigned to a particular human being, the  ‘ethical approval’ of the research project must be available prior to the inclusion of the first patient in the study at the doctor’s site.
Documents to submit to the ethics committees consist among others of a EC-specific application, study protocol (in Germany called ‘observational plan’) and summary in German language, CRF and patient facing documents like diaries or PROs and a contract template including the financial aspects. In this context also note that specific consideration must be given to Fair Market Value and remuneration in relation to the actual services provided.
The timelines to start a non-interventional study in German depend mainly on the timeframe required to finalize the ethical advice provided by the state medical ethics committees and on the execution of study contracts. The observed approval timeframe in 2016 was between 16 to 24 weeks.
<<Learn more in our NIS Considerations – Germany Report, published in February 2017>>