Process Intended to Facilitate Studies Likely to Support Marketing Approval

On Friday, June 14, 2013, the Food and Drug Administration’s (FDA or the Agency) Center for Devices and Radiological Health (CDRH) released draft guidance aimed at helping companies design studies that are more likely to support successful marketing applications in the future.

The guidance, titled Draft Guidance for Industry, Clinical Investigators, Institutional Review Boards, and Food and Drug Administration Staff: FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations, follows a 2011 draft that was ultimately withdrawn per the FDA Safety and Innovation Act of 2012 (FDASIA), in which Congress specifically objected to FDA attempts to refuse to approve IDE applications because a study may not support clearance or approval of the device. While the 2013 draft guidance explicitly notes that the agency will not refuse IDE approval on this basis, it also outlines a new, voluntary Pre-Decisional IDE Process that would allow companies to obtain key feedback prior to submitting an IDE application for a clinical study, including whether the study would be adequate to support marketing clearance or approval. It is noted that while the Center for Biologics Evaluation and Research (CBER) is an author on the guidance, the Pre-Decisional IDE Process only applies to applications reviewed by CDRH, and only to significant risk pivotal studies that will require an approved IDE application.

While the emphasis of this Alert is on the new Pre-Decisional IDE Process, the draft guidance also discusses more generally the types of decisions FDA can make on an IDE application, and the implications of those decisions. The draft guidance retains the clarification of the meaning of “approval with conditions” and the description of staged approval (or staged approval with conditions) outlined in the 2011 draft guidance. See FDA Issues New Draft Guidance Documents Outlining IDE Decision Pathways; New Policies and Pilot Program for Early Feasibility IDE Studies.

Pre-Decisional IDE contents

Under the new Pre-Decisional IDE Process, a study sponsor can submit a Pre-Decisional IDE, which would contain all of the content required in a traditional IDE application, including study protocols and reports of any initial data on the device. In this way, a Pre-Decisional IDE would differ from a Pre-Submission, in that FDA now discourages sponsors from providing data for review in Pre-Submissions. In addition, a Pre-Decisional IDE would not contain specific Questions for FDA, as a Pre-Submission does. Finally, a Pre-Decisional IDE would include an additional section to those included in IDE applications, called a Device Evaluation Strategy, which is essentially an analysis of risks and potential benefits of the device. The draft guidance provides a framework for how to prepare a Device Evaluation Strategy.

Review process

The review process (also shown in a flowchart included in the guidance document) would proceed as follows:

  • Screening review (five days): Within five days, FDA will conduct a screening review of the submission, in accordance with the checklist provided in the draft guidance. If there are significant deficiencies, the sponsor can convert the submission to a Pre-Submission (and submit Questions for FDA) or withdraw and re-submit the Pre-Decisional IDE.
  • Initial feedback (30 days): Within 30 days, FDA will conduct a full review of the submission, and provide high-level comments to the sponsor via e-mail regarding any significant issues identified that could lead to disapproval of the IDE, would be a condition of approval, or could adversely affect marketing clearance or approval.
  • Meeting to discuss initial feedback (15 days): FDA will schedule a meeting with the sponsor of up to 90 minutes within 15 days of the close of the review period to discuss the initial feedback. The sponsor should then provide draft meeting minutes within seven days.
  • Options after meeting: After the meeting, the sponsor can elect either of the following options:
    • Convert to IDE (seven days): Request that the Pre-Decisional IDE submission be converted to an IDE. FDA will then issue a decision on the IDE within 15 days, unless new information is submitted, in which case the standard 30 day review period for IDEs will apply.
    • Wait for full written feedback (15 days): If the sponsor does not request conversion to an IDE, FDA will provide comprehensive written feedback on the submission within 15 days of the meeting, taking into account information the sponsor provided at the meeting. FDA has indicated the agency generally intends to follow its Pre-Decisional IDE advice in reviewing an eventual IDE application, as long as new issues affecting safety or effectiveness do not arise.
  • Next steps: After receipt of FDA’s full written feedback, the sponsor may submit a formal IDE, submit a response to the feedback (which will either be considered as a Pre-Decisional IDE or Pre-Submission depending on the timing of the response) to obtain additional FDA feedback, or submit a response to the feedback and request to repeat the Pre-Decisional IDE Process a second time.

Conclusions

The Pre-Decisional IDE process appears to be an attempt by the agency to provide useful feedback interactively to sponsors that may speed IDE approvals and provide information regarding whether a study would be adequate to support marketing clearance or approval. A helpful feature for industry may be that sponsors can choose to convert the Pre-Decisional IDE to an IDE (presumably if FDA’s initial feedback is positive), and obtain a decision on the IDE within 15 days. However, in such cases, the total Pre-Decisional IDE review time would be longer (65 days) than if the sponsor had proceeded directly to submitting an IDE in the first place (30 days).

In addition, the review process for the Pre-Decisional IDE is highly complex, and includes a number of opportunities for feedback from FDA with varying levels of detail, as well as a number of different decision points for the company, including opportunities to route the submission into either the IDE or Pre-Submission processes. The proposed process also includes extremely tight deadlines, such as seven day deadlines for the sponsor to provide meeting minutes or to request conversion to an IDE, and a 15 day deadline for FDA to incorporate the sponsor’s feedback from the meeting and provide comprehensive comments on the Pre-Decisional IDE. Given that a Pre-Decisional IDE will be a significantly more comprehensive submission than a Pre-Submission (for which the agency recently extended the review clock from 60 to 90 days), and will involve review of study reports and data by the agency, the timeframes specified in the guidance would likely be very challenging, if not impossible, to meet. In addition, while the agency indicates it intends to follow its own advice in later IDE submissions, the guidance includes the standard caveats that such advice might change.

In sum, it remains to be seen whether and how this process will be implemented following the comment period, which could generate significant discussion, and whether it will indeed be helpful to industry, or be hampered by complexity and unrealistic timelines.

Comments

At this time, the draft guidance is being circulated for public comment. As described in the associated June 14, 2013, Federal Register notice1, comments will be accepted until September 12, 2013, and can be submitted electronically at www.regulations.gov, referencing Docket No. FDA-2011-D-0790.