The Food and Drug Administration (FDA or the Agency) has published a guidance document dedicated to the De Novo Process and requests associated thereto. The document provides an overview of the applicable regulatory requirements and is intended to assist medical device manufacturers in ensuring compliance thereto. As mentioned by the Agency, the provisions of the guidance are non-binding in their nature, while an alternative approach could be also applied, provided such an approach has been agreed with the authority in advance.
The present article addresses the aspects related to submissions medical device manufacturers may file in the context of the De Novo framework, including pre-submissions and the submissions themselves.
Pre-Submission for a De Novo Request
To begin with, the authority states that filing a Pre-Submission (hereinafter referred to as a “Pre-Sub”) is not mandatory. At the same time, the Agency encourages medical device manufacturers to file Pre-Subs as this could facilitate and simplify the process in general. In this way, an interested party may obtain feedback from the regulating authority before filing the main submission, hence, will be able to make necessary changes. This becomes especially important in the case of medical devices that haven’t been reviewed by the FDA previously under a 510(k) framework. According to the guidance, a Pre-Sub allows FDA to provide feedback on whether a device may be eligible for the De Novo classification process, including whether a potential predicate device exists, and/or to advise [the applicant] on the documentation needed in a subsequent De Novo request. For instance, in such a way the medical device manufacturer will be able to get additional clarifications regarding the particular aspects requiring the most attention, especially the ones related to the safety and effectiveness of a medical device in question. Such feedback will allow medical device manufacturers to focus on the most important matters and make changes (if necessary) to the De Novo request. Moreover, it will also make it easier for the FDA to review the request itself once it will be filed.
According to the guidance, a Pre-Sub should be filed as early, as possible, to reduce the time and efforts needed to make changes to a medical device, if this will be required. At the same time, the authority recommends submitting it after [the manufacturer] has identified the proposed intended use and key aspects of the device design sufficient to permit a meaningful discussion. In particular, the information contained in a Pre-Sub should be sufficient for the regulating authority to provide its recommendations regarding the particular approach to be applied when collecting non-clinical or clinical data.
The authority also mentions that a Pre-Sub would be subject to review under the general rules for pre-submissions addressed in detail in the appropriate guidance published earlier by the FDA. However, apart from the general requirements described therein, the authority also highlights some points that are specific for pre-submissions filed in the context of the De Novo framework. In particular, the Agency encourages medical device manufacturers to provide the following:
- Indication of the particular class to be applied under the risk-based classification, accompanied by a detailed justification describing the measures duly developed and implemented by the manufacturer to ensure the safety and effectiveness of a medical device in question when used for its intended purpose.
- Details regarding the searches conducted in the appropriate databases, confirming that there are no similar medical devices already placed on the market in the US. The manufacturer should also explain the reason the device in question falls outside the scope of classification applicable for existing medical devices.
- Submission-specific aspects, including the ones related to the risks associated with a medical device in question, its safety, and effectiveness, as well as additional control and measures intended to mitigate such risks. It is also stated that the manufacturer should explicitly indicate which mitigations are general controls and which are special controls.
The guidance further provides examples of questions the authority may ask concerning a Pre-Sub and medical device subject to review. These questions include, inter alia, the following ones:
- Whether the device is eligible for the framework described herein due to its intended use and characteristics;
- Whether there are any additional risks associated with the intended use of the device;
- Whether the controls implemented by the manufacturer are sufficient to mitigate the risks associated thereto;
- Whether the non-clinical study protocols address the important matters;
- Whether the clinical studies designed to collect additional information are relevant for the device in question and the nature of the risks associated thereto.
The authority also reserves the right to ask additional questions after Pre-Sub has been submitted by the manufacturer, while the latter may ask for a meeting to discuss the most important regulatory matters associated with a medical device subject to review.
Submitting a De Novo Request
Apart from the aspects related to a Pre-Sub, the guidance also provides additional clarifications and recommendations regarding the submission of a De Novo request itself. According to the guidance, a De Novo request may be submitted with or without a preceding 510(k) premarket notification. The authority additionally emphasizes the importance of a search to be conducted by the medical device manufacturer before filing a submission, as well as the sufficiency of information submitted in terms of risks and corresponding controls.
According to the guidance, the regulatory requirements for De Novo requests are prescribed by 21 CFR 860.220. In particular, the aforementioned regulation outlines the scope of information to be included in a request, such as a device’s regulatory history, indications for use, and device description. It is further stated that the submission should be filed together with an eCopy under the applicable procedure. Should the manufacturer fail to submit an eCopy in time, the review of the application would not commence unless a valid eCopy will be provided.
The authority also mentions that a De Novo request should be initially submitted to the relevant Center (CDRH or CVER) depending on the regulatory status of a medical device subject to review.
In summary, the present guidance describes in detail existing types of submissions available under the De Novo framework and highlights the most important aspects associated thereto. The document also provides additional recommendations regarding the contexts of the submissions to ensure completeness of the information to be provided by a medical device manufacturer.
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