The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of medical devices, has issued a guidance document dedicated to the procedures for handling post-approval studies imposed by premarket approval application orders. The document constitutes a draft version of the guidance and has been published by the authority to initiate public consultations and obtain feedback from industry representatives and other parties involved.
Table of Contents
Once finalized, the document will provide additional clarifications and recommendations on the matter. Due to their legal nature, FDA guidance documents do not introduce additional regulatory requirements themselves but describe how compliance with such requirements could be achieved. An alternative approach could also be applied, providing such an approach complies with current legislation and has been approved by the authority in advance. The Agency will accept comments and suggestions within 60 calendar days from the date the draft guidance was published.
In particular, the present draft FDA guidance highlights:
- The most important aspects related to the applicable procedures,
- Key requirements regarding the information to be included in PAS-related submissions, and also the particular way such information should be provided,
- Main points to be considered by the interested parties in terms of study timelines and other aspects.
Regulatory Background
In the course of evaluating a premarket approval application (PMA), the regulating authority assesses the sufficiency of the information provided by an interested party (a sponsor) to demonstrate that the medical device in question complies with the applicable regulatory requirements in terms of safety and effectiveness. In certain cases, the Agency is entitled to request a post-approval study (PAS), which will be a condition for further approval of the application. According to the document, a PAS is a clinical or non-clinical study, as specified in the PMA approval order, and is typically intended to gather specific data to address questions about the postmarket performance of or experience with an approved medical device. Hence, under certain conditions, the regulating authority may find it acceptable to collect additional data in the course of postmarket activities instead of requesting such data to be provided prior to granting approval. The Agency could apply this approach if the uncertainty associated with the information regarding the medical device subject to review still exists, but the information available at the moment of making a decision on approval is sufficient.
The FDA states that it conducts track recording for all PAS procedures starting from 2006. For this purpose, the special Post-Approval Studies Program Database has already been established. The information kept in this database regarding each particular case includes the following details:
- General information,
- General and detailed PAS protocol parameters,
- Interim or final data summary,
- The sponsor’s progress or “study status”, and
- Reporting information.
It is also important to mention that a sponsor may be asked to provide preliminary updates in the course of public meetings of a Medical Device Advisory Committee Panel.
The primary purpose of the regulatory requirements associated with the PAS Program is to ensure that:
- A party responsible for PAS employs the appropriate approach and methodologies,
- The approach is the least burdensome from a regulatory perspective,
- The updates regarding PAS, including the results, are provided in accordance with the timing requirements,
- The Agency provides all necessary notifications to the parties involved,
- The information regarding PAS is publicly available.
Post-Approval Study Requirements in PMA Approval Orders
If the FDA indicates a PAS as a mandatory condition of premarket application approval, the appropriate order issued by the Agency will contain details about the particular requirements to be applied. Such requirements could include the requirements on the initial purpose of the procedure, the number of study subjects to be involved, as well as the reports to be provided upon completion. In each case, the Agency will provide the requirements related to the main aspects of the study, namely:
- Study design,
- Objectives,
- Population,
- Endpoints to be collected,
- The length of follow-up and frequency of assessments,
- A high-level description of the data analysis plan for the primary endpoints.
Additionally, the regulating authority will specify the exact timelines for all the process’s main steps, including enrollment, completion, and reporting.
The Agency expects the sponsor to collaborate actively in order to facilitate and streamline the process. For instance, input from the sponsor is important for ensuring the initial objectives of a study are determined correctly and the results achieved are accurate and reliable. In most cases, the following timelines will apply:
- First subject enrolled within 6 months of the study protocol approval date,
- 20% of subjects enrolled within 12 months of the study protocol approval date,
- 50% of subjects enrolled within 18 months of the study protocol approval date,
- 100% of subjects enrolled within 24 months of the study protocol approval date.
Post-Approval Study Requirements in PMA Approval Orders
If the FDA indicates a PAS as a mandatory condition of premarket application approval, the appropriate order issued by the Agency will contain details about the particular requirements to be applied. Such requirements could include the requirements on the initial purpose of the procedure, the number of study subjects to be involved, as well as the reports to be provided upon completion. In each case, the Agency will provide the requirements related to the main aspects of the study, namely:
- Study design,
- Objectives,Population,
- Endpoints to be collected,
- The length of follow-up and frequency of assessments,
- A high-level description of the data analysis plan for the primary endpoints.
Additionally, the regulating authority will specify the exact timelines for all the process’s main steps, including enrollment, completion, and reporting.
The Agency expects the sponsor to collaborate actively in order to facilitate and streamline the process. For instance, input from the sponsor is important for ensuring the initial objectives of a study are determined correctly and the results achieved are accurate and reliable. In most cases, the following timelines will apply:
- First subject enrolled within 6 months of the study protocol approval date,
- 20% of subjects enrolled within 12 months of the study protocol approval date,
- 50% of subjects enrolled within 18 months of the study protocol approval date,
- 100% of subjects enrolled within 24 months of the study protocol approval date.
Post-Approval Study Protocols
Apart from the general information regarding the post-approval studies, the present FDA draft guidance also describes the regulatory requirements for study protocols, which are required in all cases when the Agency requests a PAS to be conducted. Such protocols will be subject to review by the regulating authority together with the initial premarket application. Once the initial PMA application has been approved, any changes to PAS protocols should be subject to additional approval.
According to the guidance, a PAS study protocol shall cover the following aspects:
- Background (e.g., device’s regulatory history, brief description of device, indications for use),
- Purpose of study, study objectives,
- Study design,
- Study population (including subject inclusion and exclusion criteria and definition and source of comparator group),
- Enrolment and recruitment plan (including enrolment milestones),
- 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 follow-up rate targets,
- Description of baseline and follow-up assessments,
- Description of data collection procedures (including data management and quality control),
- Data analyses and statistical tests planned (such as a statistical analysis plan including interim data release plan, when appropriate, and final data analysis),
- Data collection forms, informed consent forms, and Institutional Review Board (IRB) approval forms,
- Study timelines.
In summary, the draft guidance on post-approval studies published by the FDA describes the recommended approach for sponsors to take when carrying out such studies, including the principles to follow and information to provide. The document also outlines the primary requirements the PAS protocols should meet in order to be admissible.
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