The new article highlights the aspects related to study protocols for post-approval studies.
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to post-approval studies (PAS). The document provides additional clarifications regarding the existing regulatory requirements, as well as recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance thereto. At the same time, provisions of the guidance are non-binding in their nature, nor are intended to introduce new rules or impose new obligations. Furthermore, the authority mentions that an alternative approach could be applied, provided such an approach is in line with the applicable regulatory requirements and has been agreed with the authority in advance.
According to the guidance, in certain cases, the authority may find it reasonable to request additional information regarding the safety and effectiveness of the product to be collected at a later stage, after making a regulatory decision. In such a case, the respective approval to be granted by the authority will be conditional to post-approval studies to be conducted in accordance with the applicable regulatory requirements and recommendations provided in the present guidance.
The scope of the guidance covers, inter alia, the aspects related to post-approval study protocols. Under the general rule, when a PAS is required as a condition of approval of the PMA, prior approval of the PAS protocol is included as part of the condition. Thus, study sponsors are encouraged to get in touch with the authority in order to discuss the details related to a study protocol. According to the guidance, the authority will review the study protocol in parallel with the review of the initial application for marketing approval (PMA). The present guidance highlights the key points to be considered with respect to the submission and review of post-approval study protocols, as well as changes thereto once the initial application is approved.
PAS Protocol: Key Elements
First of all, the authority outlines the key elements to be included in a PAS protocol. According to the document, they are:
- Background (e.g., device’s regulatory history, a brief description of device, indications for use);
- Purpose of study;
- Study objectives;
- Study design;
- Study population;
- Enrolment and recruitment plan;
- Sample size calculation that is statistically justified and based on study hypothesis, where applicable;
- Primary and secondary endpoints, when applicable, including definitions for study endpoints and list of adverse events/complications;
- Procedures for a determination of adverse events/complications relatedness with device and/or the procedure;
- Length of follow-up, follow-up schedule, plans to minimize losses to follow-up, and estimated follow-up rates;
- Description of baseline and follow-up assessment;
- Description of data collection procedures;
- Data analyses and statistical tests planned;
- Interim data release plan;
- Data collection forms;
- Informed consent forms;
- Institutional Review Board (IRB) approval documentation;
- Enrolment milestones and study timelines.
The document also provides additional clarifications with respect to each of the elements listed hereabove.
As explained by the authority, it will review the PAS protocol provided by the study sponsor interactively, i.e. providing feedback without additional delays. The purpose will be to make sure the review of the study protocol is completed together with the approval of the initial application. In order to streamline the process, the authority encourages the parties responsible for medical devices to provide a draft post-approval study protocol into the initial application for marketing approval. Should a sponsor determine that a post-approval study is not needed, the appropriate justification should be provided as well.
The authority also mentions that in the case a PAS protocol is not developed and provided within the timeframe described herein, it should be submitted by a sponsor as a PMA supplement within 30 calendar days from the date the initial application has been approved. The appropriate supplement should be labeled as a “PAS Protocol”. In case there are several protocols, they should be submitted as separate supplements. The authority will review the protocol submitted by study sponsors within 60 calendar days from the date the main application has been approved, while the initial response will be provided by the authority within 30 calendar days from the date the protocol has been received by the authority. In order to avoid undue delays, study sponsors should pay all the efforts necessary to ensure the responses to additional requests and questions raised by the authority are provided as soon, as possible, and stay in touch with the authority on all the matters pending.
Changes to a PAS Protocol
The authority also provides additional clarifications regarding the approach to be followed when making changes to a post-approval study protocol that has already been approved by the authority. According to the guidance, in such a case, a study sponsor should submit a PMA supplement to be reviewed and approved by the authority. Should it be needed to revise several protocols at once, each of them should be submitted for review as a separate PMA supplement.
It is further stated that it should not be a common practice to make changes to post-approval study protocols – such an approach should be applied on a case-by-case basis when it is reasonably necessary. For instance, such changes will be reasonable in case the changes to the study milestones are justified based on the new information a study sponsor became aware of.
In summary, the present FDA guidance describes in detail the approach to be applied with respect to protocols for post-approval studies. The document provides recommendations regarding the suggested structure of such protocols, and also explains the way they should be submitted by study sponsors and reviewed by the authority.
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