Clinical trials play a crucial role in the development of new medicines and medical devices, but conducting clinical trials involves ethical, legal, and regulatory challenges. As reported in our latest article, Prevent a Clinical Trial from Turning into a Criminal Trial, the United States has recently seen a surge in clinical trial fraud investigations and enforcement actions, highlighting the need to ensure that appropriate compliance measures are in place to mitigate enforcement risks.
Meanwhile, across the pond, the European Union adopted the Clinical Trials Regulation (CTR or “Regulation”) in 2022, which will apply to all newly submitted clinical trials from January 31, 2023. One of the aims of the CTR is to increase public transparency in the way clinical trials are conducted in Europe. This means that sponsors will have to follow a strict regime of publication rules, allowing for greater scrutiny of the trial data by regulators, researchers, and the general public.
In this article, we give an overview of the transparency requirements that sponsors face under the CTR, and we summarize other key aspects of the new EU clinical trial regime that sponsors should be aware of when developing compliance strategies for clinical trials conducted in the EU and the European Economic Area (EEA).
Background
The CTR applies to interventional and low-interventional clinical trials with medicinal products for human use.[1] It replaces the Clinical Trials Directive (CTD) and national implementing legislation in the EU Member States. Since January 31, 2023, all clinical trial applications have been subject to the CTR. However, trials approved under the CTD before January 31, 2023, can continue to be regulated under the CTD until January 31, 2025.
The CTR aims to simplify and accelerate the authorizing process of clinical trials, as well as harmonize administrative procedures across the EU and the EEA. It is directly applicable in the EU Member States without the need for transposition into national law. Other regulatory aspects, such as authorization and monitoring procedures, are governed by the Directive 2001/83/EC and Regulation (EC) 726/2004.
Increased transparency requirements
Among other things, the CTR focuses on increasing public transparency of clinical trial data. In the past, there have been concerns about selective reporting of trial results, where only positive results are published and negative or inconclusive results are not. This can lead to a biased view of the safety and efficacy of a particular treatment.
The CTR requires the sponsor to make all clinical trial information available in the recently launched Clinical Trial Information System (CTIS) for access by the competent authority of the Member State(s) where the trial is being conducted. This includes information such as the trial protocol, clinical trial results, and adverse events. After a review process, the information is made publicly available on the CTIS website. The information must be updated throughout the trial, and once the trial is completed, the sponsor must publish a summary of the results, including a layperson summary, within one year of the end of the trial.
Sponsors may request a delay in the publication or redaction of certain information if the disclosure of such information would jeopardize the protection of personal data, trade secrets, or the sponsor’s legitimate commercial interests. However, it should be noted that certain information, such as essential characteristics of a clinical trial or reasons for the temporary halt and early termination of a clinical trial, is generally not considered confidential. Furthermore, a delay of publication of confidential information in results of the clinical trial may be granted only for a limited time.
In summary, more information needs to be made available to national competent authorities and the public, including data that was not previously made available. This increases transparency and enables patients and healthcare professionals to make informed treatment decisions. For the sponsor, however, there is a risk that potentially confidential information may be inadvertently disclosed to the public, which could, for example, be detrimental to the sponsor’s ability to secure patent protection for inventions that are the subject of, or made during, the clinical trial.
Consent requirements
When conducting a clinical trial, the sponsor must also be aware of different consent requirements.
The CTR simplifies the informed consent process by laying out procedures to obtain effective consent of patients participating in the clinical trial, which in principle apply in all EU and EEA countries. This also includes more detailed guidelines for vulnerable subjects like minors or incapacitated people and pregnant or breastfeeding women. It also allows for a simplified consent process for low-risk trials, which could reduce the burden on trial participants and investigators.
Data protection considerations for consent
Sponsors should clearly distinguish between informed consent for purposes of conducting the trial, and consent obtained for purposes of data protection. The General Data Protection Regulation (GDPR) requires a legal basis whenever personal data are processed. Where explicit consent is relied upon as a legal basis under GDPR, in particular to process health and genetic data, this should be obtained separately from the informed consent under the CTR.
However, in the EU there is no clear consensus on whether explicit consent is always appropriate in a privacy context for the processing of personal data for research activities. In its opinion concerning the Q&A on the interplay between the CTR and the GDPR, the European Data Protection Board (EDPB), a consortium of national EU data protection authorities, concluded that consent may not be the appropriate legal basis in some cases. Legal bases other than consent, such as public interests in the area of health or scientific research, should preferably be relied upon. However, these other legal bases require a corresponding implementation in national Member State law, which not all Member States may have arranged for at this time.
Other key considerations
Other notable changes under the CTR regime that are relevant to sponsors of clinical trials are the following:
1. Simplified application process: The CTR harmonizes the procedures for obtaining authorization and conducting clinical trials across the EU and in EEA countries, by introducing a single application process through the CTIS. This allows sponsors to submit a single application for authorization to conduct a clinical trial in several European countries, making the conduct of such multinational trials more efficient. The CTIS also allows national regulators to collaboratively process clinical trial applications, request information, authorize or refuse a trial, and oversee an authorized trial. This aims to stimulate innovation and research in the EU by facilitating the conduct of larger clinical trials in several EU/EEA countries.
2. Shorter authorization and response times: The timeline to authorize clinical trials is set at 60 days. If no decision is made within this period, the trial may go ahead (“tacit approval”). Decisions on applications for substantial modifications of clinical trials must be made within 49 days. Where no decision is issued, the authorization is considered to have been given. However, the other side of the coin is that response times for sponsors have also drastically shortened. Sponsors now have a maximum of 12 days to respond to application queries or requests for information. Otherwise, applications will lapse by default.
3. Simplified safety reporting:The CTR strengthens safety monitoring by requiring the sponsor to submit safety reports on unexpected adverse reactions to regulatory authorities within strict timelines between 7 and 15 days. However, whereas the CTD required multiple safety submissions to national competent authorities and ethics committees, the CTR requires all safety reporting via EudraVigilance and allows for submission of a single report for all trials involving more than one investigational medicinal product.
4. Harmonization of ethical review: The CTR aims to harmonize the ethical review process. Although the ethical review must be performed by an ethics committee in accordance with the law of the respective EU or EEA country concerned, the procedures and the timelines for the ethical review must be compatible with the authorization procedure stipulated by the Regulation.
Conclusion
Given that all future clinical trial applications in the EU will be subject to the CTR rules, it is high time for sponsors to develop and adopt appropriate compliance measures for their upcoming clinical trials. Sponsors would be well advised to consider the shortened response times and increased transparency and reporting requirements. They should put in place rapid response teams and processes to ensure that the relevant information is made available to the national competent authorities in a timely manner. Sponsors should also be aware that the burden of requesting a deferral of publication or a redaction of confidential information or personal data rests with the sponsor. Therefore, mechanisms should be put in place to ensure that such deferral and redaction requests are made for all documents containing such information. If such information is relevant to patent protection, the filing strategy and timing should be considered as well. Watch our blog for further news on clinical trials.
[1] There is a simpler framework at the European level for clinical investigations of medical devices and in vitro diagnostic medical devices. The Medical Devices Regulation (MDR) and In Vitro Diagnostic Medical Devices Regulation (IVDR) form the core legal framework (read more about the MDR and IVDR on our MoFo Life Sciences Blog).