On April 2, the European Parliament voted overwhelmingly to repeal the current EU Directive on clinical trials of medicinal products for human use and replace it with a new Regulation. The primary goals of the new Regulation are to:
- Streamline the approval process for studies conducted across multiple Member states;
- Harmonize the regulation of clinical trials throughout the Member states; and
- Increase transparency of Clinical Trial results.
It was the European Parliament’s hope that accomplishing the first two goals would increase the number of clinical trials being conducted in the EU. The Regulation has streamlined the review and approval process by permitting sponsors to submit only one application using a central portal. That one application will then undergo a two phase review, the first is the assessment of the clinical trial with respect to those aspects that have been harmonized, and is cooperatively reviewed by all Member States in which the study will be conducted. (Part I of the Assessment Report). Once authorization is granted in Part I of the Assessment Report, the second phase of the review, which is the assessment of the aspects of the clinical trial that are “intrinsically national in nature,” begins. This assessment is performed by each Member State separately, and includes the review and assessment by the Ethics Committee in the Member State (Part II of the Assessment Report).
In addition to this fully streamlined process, Article 11 of the Regulation establishes what I will call a split review process. Under this process a sponsor can request a limited review of the application under Part I of the Assessment Report. Then the sponsor has up to two years to request an assessment under Phase II of the Assessment Report in each of the countries in which the study will be conducted.
With one exception, in my opinion, the EU Parliament struck the right balance between harmonizing the regulation of aspects of the study that are appropriately standardized across the EU, and allowing Member States to retain control of those aspects of a study that are “intrinsically national in nature.” However, it is this one exception, the lack of harmonization of the informed consent process, that may cause a significant number of sponsors to opt for the split review process under Article 11 as opposed to the fully streamlined pathway. Specifically, the assessment of a sponsor’s proposed informed consent process is left to each Member State during Part II of the assessment. Although the Regulation establishes specific information that must be provided to potential subjects during the informed consent process and requires the information to be “comprehensive, concise, clear, relevant and understandable to a lay person” it leaves the Member States free to establish different requirements for how the required information is presented.
I recently assisted a client navigate the ethical review process for several Phase III clinical trials in the EU and some of the biggest challenges we faced were caused by the variability in each Member State’s requirements for how the required informed consent information should be presented to the subject (e.g., imposing page limits for consent forms, requiring certain information to be in an Annex attached to the consent form). Responding to these divergent assessments can be a very time consuming process, especially if the sponsor does not have any internal local resources. However, companies are generally able to respond to these assessments in a timely manner because, unless they hit the unlucky lottery, the assessments are not all provided at one time or within a few days of each other. However, if a sponsor were to take advantage of the fully streamlined process, these assessments could all come within days of each other and the sponsor would have, at most, 12 days to respond or risk having the application deemed lapsed.
The European Parliament could have reduced this risk if it had done more to harmonize the assessment of the informed consent process. I am not saying that it should have fully harmonized the informed consent requirements, as I agree that certain aspects of the informed consent process are “intrinsically national in nature,” such as consent requirements for incapacitated subjects or minor subjects. However, I at least partially agree with the European Parliament’s Committee on the Environment, Public Health and Food Safety that:
Currently, the ethical review procedure varies greatly between Member States, often with various bodies at national, regional and local levels, and multiple procedures leading to divergent assessments. This is a source of delays and fragmentation. In the interests of European patients and public health, the procedures and principles of ethical review should be better harmonised [sic] through the sharing of best practices between ethics committees. To this end the Commission should facilitate the cooperation of ethics committees. [Proposed Amendment 27]
Alternatively, I may have pushed for more harmonization, with the sections of a sponsor’s proposed informed consent form template that do not relate to those aspects of the clinical trial that are “intrinsically national in nature,” being assessed during Part I. Then, during Part II, each Member State would be responsible for assessing those sections that relate to aspects of the study that are “intrinsically national in nature” that the sponsor proposes for each Member State.
In light of the European Parliament’s decision not to further harmonize the assessment of the informed consent process, sponsors may want to consider taking advantage of the split review process under Article 11 as a way of mitigating the risk of having their applications deemed lapsed. This would allow the sponsor to first obtain approval of the harmonized aspects of the Study under Part I of the assessment, and then stagger its submissions to the various Member States for an assessment under Part II. Although this approach does not avoid the challenge of the divergent assessment from different member states, the split review process offers some of the benefits of the streamlined process while allowing the sponsor to better align the timing of their obligations to respond to member states’ requirements for revision with their available bandwidth.
The Regulation also includes new requirements for transparency of clinical trial data that have been the source of much debate. Please stay tuned for my analysis of how different these new requirements actually are.