The Product Development Process: Pre-Submission for De Novo Applications

The Product Development Process: Pre-Submission for De Novo Applications

Srilekha Deka, 24Jan.2024

Introduction

Development of molecular diagnostic products begins with an innovative concept. Developing that concept into a diagnostic product involves multiple coordinated steps. Regulatory agencies like the Food and Drug Administration (FDA) that govern the development of in vitro diagnostic (IVD) products have set up guidelines that need to be followed by assay developers.

Classification of devices are based on the criteria laid out in section 513(a)(1) of the FD&C Act. Devices of a new type that FDA has not previously classified based on these criteria are “automatically” or “statutorily” classified into class III by operation of section 513(f)(1) of the FD&C Act. This is because a new type of device:

  • would not be classified into class I or class II.
  • would not have been on the market prior to implementation of the 1976 Medical Device Amendments.
  • there would be no available predicate device.

Therefore, regardless of the level of risk they pose or the ability of general and special controls to assure safety and effectiveness, these devices are automatically classified into class III.

This scenario was targeted when Congress enacted section 513(f)(2) of the FD&C Act as part of the Food and Drug Administration Modernization Act of 1997 (FDAMA) and is referred to as the “De Novo classification process”. Manufacturers were now allowed to submit a De Novo request to FDA for devices “automatically” classified into Class III if they fulfilled the following conditions:

  • a device was found not substantially equivalent (NSE) to legally marketed predicate devices through a premarket notification (510(k)).
  • manufacturer believes their device is appropriate for classification into Class I or Class II and there is no legally marketed predicate device, a De Novo request without a preceding 510(k) and NSE may be submitted. This is referred to as a “Direct De Novo”.

A final rule was added on October 5, 2021 that describe the procedures and criteria FDA will use for assessing requests for an evaluation of De Novo classification requests to determine if it contains the information necessary to permit a substantive review.

Submitting a Pre-Submission for a De Novo Request

A Pre-Submission (Pre-Sub) is not mandatory for FDA review of a De Novo request but is definitely a useful way for the manufacturers to obtain feedback from the Agency. Therefore, it is strongly recommended that the manufacturers take advantage of this opportunity to obtain early feedback from the FDA. This becomes more important in the case of a Direct De Novo since the Agency has not previously reviewed this device under a 510(k) application.  

The Pre-Sub allows the FDA to provide feedback on whether:

  • a device may be eligible for the De Novo classification process.
  • a potential predicate device exists.
  • advise you on the documentation needed in a subsequent De Novo request.

A major advantage is that it provides the manufacturer with an opportunity to get the Agency’s preliminary perspective and feedback on

  • the regulatory controls that would be necessary for providing a reasonable assurance of safety and effectiveness
  • non-clinical evidence and data that will be required to support the De Novo request.
  • clinical evidence and data that will be required to support the De Novo request.

What is the right time for a Pre-Submission?

A Pre-Sub may be submitted at any point during the development process for the device. However, in order for it to provide the most value to the manufacturer, it is most useful after the proposed intended use has been clearly identified and key aspects of the device design have been sufficiently developed. This allows for a meaningful discussion during the meeting with the Agency experts.

Content of a De Novo Pre-Sub

The Pre-Sub for an anticipated De Novo request should contain sufficient information regarding the test methods and study designs/protocols to be used for the collection of non-clinical and clinical data. This will allow the FDA expert(s) to provide meaningful guidance and feedback on the proposed strategy for collection of relevant non-clinical and clinical data.

De Novo Pre-Subs are handled in accordance with the normal pre-submission process as given in the FDA guidance document entitled “Requests for Feedback on Medical Device Submissions: The Q-Submission Program and Meetings with Food and Drug Administration Staff” (Q-Sub Guidance)].

A Pre-Sub prior to the submission of a De Novo request should contain all the recommended content for all Pre-Subs (device description, proposed intended use, summary of previous communications, etc.). In addition, it is suggested that the Pre-Sub prior to a De Novo application also includes the following:

  • Proposed class (I or II). Why does the manufacturer believe that general or general and special controls are adequate to provide reasonable assurance of safety and effectiveness.
  • The searches of FDA public databases and other resources, including search terms that were used to establish that no legally marketed device and no classification regulation for the same device type exists. It is also helpful to provide a list of regulations, 510(k)s, PMAs, and/or product codes that may be relevant to the subject device. The manufacturer should also provide a rationale for why the subject device does not fit within and/or is different from any identified classification regulations, 510(k)s, PMAs, and/or product codes, based on available information.
  • Specific questions regarding review issues that are relevant to the planned De Novo request. In order to allow the reviewer to consider the specific questions, the Pre-Sub should also include the following:
    • Each identified risk to health associated with the device and the reason for each risk (tracing back to risk analysis, clinical testing, etc.). Information on any ongoing and/or planned protocols/studies that will be completed in order to collect the necessary data and evidence for establishing the device’s risk profile.
    • Information regarding the safety and effectiveness of the device. References to the types of valid scientific evidence that the manufacturer will provide/anticipate providing in the De Novo request. The Pre-Sub should also include types of data/studies relating to the device’s safety and effectiveness that have been performed or are planned. A brief description of ongoing and/or planned protocols/studies that will be completed to collect the data to demonstrate necessary safety and effectiveness of the device.
    • Study designs and protocols for non-clinical and clinical studies (if applicable). The manufacturer should also describe how these planned studies will address the anticipated risks. Targeted performance levels that will show that general controls or general and special controls are sufficient to provide reasonable assurance of safety and effectiveness should also be included.
    • The Pre-Sub should also include the proposed mitigation measure(s)/control(s) for each risk, based on the best available information at the time of submission. Also, mitigations that are general controls and those that are special controls should be highlighted. Details should also be provided regarding each recommended mitigation measure (e.g., specific testing required, labeling, etc.).

Another advantage of a Pre-Sub is the ability to pose questions to the FDA and receive their feedback regarding the proposed strategy that is being presented. Questions regarding regulatory strategy, risk assessment, controls strategy and study designs for non-clinical and clinical studies proposed are some of the topics that may be addressed.

Following submission of the Pre-Sub, the FDA may ask the manufacturer to provide additional clarification or provide additional information on specific topics. In-person or teleconference meetings provide an additional opportunity to obtain clarification on relevant topics, both for the manufacturer and for the FDA reviewers.

Summary

The Pre-Submission process was established under MDUFA III and further refined under MDUFA IV and the Q-Submission Program guidance. It is important to mention that Pre-Submissions and their associated response from the FDA are strictly voluntary. The recommendations made by the agency following review of the study designs and protocols during these meetings are merely recommendations and are not binding on the manufacturer or the FDA. An FDA review of a pre-submission does not guarantee approval or clearance of a medical device through a future premarket application. However, being able to arrive at an alignment of the requirements and using these as a guide during the product development process could streamline the review process for a future submission.

References