The Food and Drug Administration (FDA) has published a guidance document dedicated to clinical investigations for prostate tissue ablation devices. The document constitutes a final version of the draft guidance initially published on June 29, 2019. The document has been published under the general procedure – thus, all industry representatives may submit their comments and suggestions that will be taken into consideration by the FDA when developing the new version of the guidance.
Prostate Tissue Ablation Devices: Regulatory Background
The present FDA guidance is dedicated to ultrasound systems for prostate tissue ablation, regulated under 21 CFR 876.4340(b)(8). In particular, the document describes information about clinical testing to be provided in the course of 510(k) premarket notification, and also about the way the clinical data should be collected. The medical devices covered by the scope of the FDA guidelines are designed to transmit high-intensity therapeutic ultrasound energy. Devices using other sources of energy fall within the scope of the guidance too. According to the document, the type of energy used by the device does not impact its admissibility for the purpose of the marketing authorization. The FDA also mentions that the present guidance does not cover specific aspects related to the treatment of particular diseases.
Due to its legal nature, the FDA guidance does not create any binding obligations. Rather, it is intended to provide medical device manufacturers and other parties involved in operations with useful information and recommendations in order to assist them in maintaining compliance with the applicable requirements.
According to the information provided by the FDA, a De Novo request was initially granted for a high-intensity ultrasound system earlier in 2015. The medical devices of such kind are regulated under 21 CFR 876.4340(b)(8) which sets forth the main requirements, namely:
- to document the adverse event profile,
- to provide evidence of prostatic ablation, and
- to demonstrate that the device performs as intended under anticipated conditions of use.
In particular, the document is intended to provide all parties that are going to submit an application related to the aforementioned devices, providing that the device in question has general indications for use and is not intended to treat a particular disease.
The FDA also highly recommends that the applicant commence the registration process by submitting a Pre-Submission. In this case, the FDA will provide the applicant with a detailed response that will be useful for the applicant when making certain changes and improvements to its application. This approach allows the medical device manufacturer or other entity acting as an applicant to obtain feedback regarding its planned application in advance.
Clinical Investigation Recommendations
The scope of the guidance only covers clinical investigations performed to collect additional information to be provided in the course of applying for marketing authorization for certain types of medical devices. The scope of the present FDA guidance also covers medical devices with the PLP product code assigned. These medical devices of a similar type that are intended to treat specific prostatic diseases happen to fall outside of the scope of the document. The FDA also mentions that the information and recommendations provided in the guidance do not cover such aspects as non-clinical testing or labeling.
According to the FDA guidance, clinical studies should be performed in order to:
- maintain compliance with the clinical testing special control, or
- support marketing submission for medical devices falling outside of the scope of the aforementioned regulation 21 CFR 876.4340.
The FDA also states that tissue ablation devices are associated with significant risk and thus should be treated accordingly. The scope of regulations the medical device manufacturer shall comply with includes, inter alia, the following ones:
- the Investigation Device Exemption (IDE) regulation 21 CFR 812,
- the regulation 21 CFR 56, establishing the rules on institutional review boards, and
- the regulation 21 CFR 50, that covers all aspects related to informed consent.
The FDA guidance also describes the rules to be applied if the clinical investigations have been performed abroad. In such a case, the medical device manufacturer shall submit such data in accordance with the regulation 21 CFR 812.28 which governs the provision of clinical data deriving from trials that took place in other countries.
According to the document, it is also allowed to use “real-world data” (RWD) when applying for changes to energy output characteristics. The FDA states that under certain conditions, the IDE would be necessary for making changes to the FDA-cleared device. However, if the medical device in question is being used for its intended purpose indicated by the manufacturer and in the appropriate clinical environment, under the general rule, the IDE is not necessary. The FDA emphasizes that the particular requirements to be applied for the application for making changes to an already approved device would be determined by the regulating authority on a case-by-case basis.
The FDA requires the entity applying for marketing authorization to provide a clinical investigation report describing the results achieved. In accordance with the recommendations, such a report shall contain:
- summary of the study,
- information about the site,
- information about the investigator,
- information about patients participating in the study,
- details about the treatment,
- information about any and all deviations from the study protocol that took place in the course of the investigation,
- rigorous analysis of the safety and effectiveness aspects,
- the protocol of the study,
Specific Clinical Study Recommendations
The FDA guidance also provides specific clinical study recommendations to be considered by the entity responsible for clinical investigations. These recommendations are based on the principle of the lowest regulatory burden admissible according to the risks associated with the use of the medical device in question. The FDA states that the uncertainty related to the benefit-risk determination should be identified and mitigated to the maximum extent possible.
The specific clinical study recommendations provided by the FDA cover, inter alia, the following key aspects:
- The purpose of the study is to confirm that the prostate tissue ablation device subject to review meets applicable safety and performance requirements when being used for the intended purpose. In particular, the medical device should not damage tissue outside of the targeted volume.
- The design of the study. The FDA states that clinical data accompanying the submission could derive from either internally or externally controlled investigations. Both these types have their own benefits based on their specific features. In accordance with the recommendations, the study should cover at least 100 patients for any results to be reliable.
- In accordance with the FDA recommendations, the follow-up duration should be at least one year.
- The patients’ enrollment should be based on the appropriate inclusion/exclusion criteria.
The guidance also describes specific requirements related to patient demographics, treatment parameters, study protocols, safety endpoints, and data analysis.
Summarizing the information provided hereabove, the FDA guidance on clinical investigations for prostate tissue ablation devices (ultrasound systems) describes the most important aspects related to the regulatory framework and also provides the parties involved in clinical trials with important recommendations to be considered when conducting a clinical investigation or submitting clinical data in the course of a marketing approval application.
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