20/21 November 2019
As reported under "New Definition for Auxiliary Medicinal Products (AMPs)" the EU Commission (EC) launched four public consultations on recommendations related to clinical trials:
The public consultations took place from 1 June 2016 to 31 August 2016. Summaries of the comments as well as the replies are now available on the commission´s website.
The EC’s draft guideline on Ethical Considerations for Clinical Trials with Minors proposes a number of new requirements, i.e. relating to the development and testing of information materials for the informed consent process. The guideline’s aim is to align the recommendations on ethical aspects of clinical trials with minors with the requirements of the upcoming EU Clinical Trials Regulation (No 536/2014) and with the latest scientific insights on research with children. The nearly fifty-page guideline drew 30 responses from stakeholders. "The guideline goes well beyond ethical considerations, and touches on many general study and good clinical practice topics" the EFPIA (European Federation of Pharmaceutical Industries and Associations) said in its detailed feedback to the draft guideline. In addition, the Swedish Medical Products Agency (MPA) recommended that the commission should not finalize the guideline until the International Council for Harmonization’s (ICH) addendum to its revised E11 guidance on "Clinical Investigation of Medicinal Products in the Paediatric Population" is finalized (to ensure there is no conflicting wording between the documents).
The eight-page consultation document titled Definition of Investigational Medicinal Products (IMPs) and use of Auxiliary Medicinal Products (AMPs) intends to "clarify and provide additional guidance on the definition of IMPs and to provide recommendations about the use of auxiliary medicinal products (AMPs)". It stated that medicinal products with a marketing authorization can be IMPs if they are used as a test product or reference product, including as a placebo. In addition, it defined AMPs as non-investigational products that are used for the needs of a clinical trial as described in the protocol. The proposal drew 26 responses from stakeholders. Overall, it seems that more clarification is needed on the proposal that offers a revised definition for investigational medicinal products and deals with the use of auxiliary medicinal products in clinical trials. In detail, the EFPIA has demanded clarity on the section explaining good manufacturing practice (GMP) requirements for AMPs. It wants to know how deviations from “full GMP” should be justified, and suggested that such justifications should reside in the local pharmaceutical quality system, and should not be required as part of the protocol or be in any way subject to regulatory pre-approval. Furthermore, EFPIA emphasized that the document should state explicitly that AMPs do not require a certification from QPs (qualified persons).
Regarding the draft guideline (14 pages) on using a Risk-proportionate Approaches in Clinical Trials, to which 40 stakeholders responded, questions arise on how it will be implemented in practice. In detail, clarity has been requested on several topics, especially on the new requirements such as preparing a risk assessment and mitigation plan as part of a trial protocol. According to the EFPIA the guideline "could benefit from a clearer definition of what constitutes a low-intervention clinical trial, along with examples of how the guideline would be implemented in practice". Furthermore, EFPIA has requested for more clarity on what a risk assessment and mitigation plan should include (a template for such a document would be helpful for sponsors). In addition, the guideline should also be clear to inspectors. There should be a “clear commitment” that a proposed risk identification and mitigation approach – once endorsed following the assessment of the clinical trial application – would not be questioned at the time of any regulatory inspection, unless there is a change in the benefit-risk assessment of the trial. “We understand that the accepted “risk identification and mitigation approach from the CTA (clinical trial application) review will be carried through for any regulatory inspection,” the association states.
Beyond that, stakeholders pointed out that the commission’s guideline should not only take into account the risks to the subjects participating in research, but also the risks related to the reliability of trial results. The US-based Association of Clinical Research Organizations (ACRO) said it was surprised to note that the importance of a risk-proportionate approach to ensuring data integrity and the quality of the clinical trial was not “equally stressed” in the draft guideline, and urged the commission to adequately address this “significant omission”. Finally, several stakeholders recommended that the commission’s guideline should be aligned with the revised ICH GCP guideline (ICH E6(R2) Integrated Addendum), especially on trial monitoring.
46 responses were received regarding the twenty-eight-page draft document Summary of Clinical Trial Results for Laypersons, which provides recommendations and templates for the production of summaries of clinical trial results for laypersons by sponsors and investigators. In its twenty-five-page response the EFPIA emphasizes, amongst others, that "the EU should collaborate with regulators worldwide to create a lay summary template that is readily understandable for audiences in all countries where the trial was performed. Today, clinical research is fully globalized and internet access will make published information accessible globally. The value of this new document will be jeopardized if it is written with an EU vs non-EU focus and it is not a good use of resources for clinical trial sponsors to write multiple versions of the lay summary for a global clinical trial". Therefore, the EFPIA strongly recommends this guidance be geographically agnostic to the extent possible.
Furthermore the EFPIA adresses the need for lay-friendly language of headings: Sponsors should have the flexibility to modify the listed headings to provide consistency within each lay summary. Appropriate language for the headings in the template could be determined through user testing.