FDA’s new draft guidance on IDE Decisions and the New Pre-Decisional IDE Process offers sponsors more direction on opportunities for early collaboration and feedback on clinical protocols.

In June, 2013, the Food and Drug Administration (FDA) announced the availability of a new draft guidance document, “Draft Guidance for Industry, Clinical Investigators, Institutional Review Boards, and Food and Drug Administration Staff: FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations.”1 The new draft guidance retains many of the proposed changes from earlier draft guidance issued by FDA in 2011,2 and, in response to the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), introduces a new voluntary Pre-Decisional IDE process to provide sponsors with information regarding the design of studies intended to support market approval or clearance.3 The new process is intended to provide sponsors with timely feedback from FDA review staff on a near-final IDE application, with the opportunity for early interaction with the review team to promote a clearer understanding and quicker resolution of major safety and study design issues prior to submission of an IDE. FDA believes that this process could result in faster approval of IDE submissions that may support market approval or clearance, and help to address several commonly reported challenges in the initiation of clinical trials, such as delays in Institutional Review Board (IRB) approvals and reimbursement from third party payors. Ultimately, FDA intends for this process to lead to faster enrollment and completion of trials for selected devices, as well as to promote more efficient allocation of FDA and sponsor resources with the submission of higher quality IDE applications and higher quality study-generated data.

Background on FDASIA

FDA’s decision-making process for IDEs was modified with the passage of FDASIA in July 2012. Specifically, Section 601 of FDASIA amended Section 520(g) of the Federal Food, Drug, and Cosmetic Act (FDCA) to specify certain situations in which FDA cannot disapprove an IDE. Section 520(g)(4)(C) of the FDCA now states that FDA shall not disapprove an IDE because:

  • The investigation may not support a substantial equivalence or de novo classification determination or approval of the device
  • The investigation may not meet a requirement, including a data requirement, relating to the approval or clearance of a device
  • An additional or different investigation may be necessary to support clearance or approval of the device4

In the new draft guidance, FDA explains that the Agency recognizes that despite the above provisions, “some IDE sponsors may wish to determine whether [a] pivotal study design may support a marketing application if it is successfully executed and meets its stated endpoints without raising unforeseen safety concerns.” FDA states that in order to meet this interest, FDA is proposing a new, voluntary program intended to facilitate the development of trial designs that may support a marketing approval or clearance. FDA is careful to clarify that the program is unlikely to be suitable for all IDE sponsors, and that the program is not intended to become a “a routine step prior to submission of an IDE.” FDA also states that the program is not intended to replace or substitute for the existing Pre-Submission process5 — in contrast to the Pre-Submission process, Pre-Decisional IDEs should include data and full study protocols and reports where appropriate, and will be reviewed in a similar manner as an IDE, allowing for more complete and meaningful feedback from FDA review staff.

The Pre-Decisional IDE Review Process

The new Pre-Decisional IDE process is completely voluntary and can be utilized prior to a planned original IDE, IDE amendment (e.g., in response to a previous disapproval letter), or IDE supplement which requests approval to initiate a pivotal study. FDA has made clear that due to resource constraints, eligibility for this process will be limited to pivotal studies for which an IDE is required.

To participate in the program, a sponsor must submit an application clearly labeled as a Pre-Decisional IDE. The application should follow the format and contain all of the content required for an IDE, as well as a description of the Device Evaluation Strategy employed to address the risks of the investigational device identified in a risk assessment and the potential for benefit for the identified patient population.

Following submission of a Pre-Decisional IDE, the process will proceed as outlined below. The draft guidance provides several helpful examples of how the Agency envisions the conduct of this process once implemented, pursuant to the below procedures and timelines.

  • Application Screening: Within 5 calendar days of receipt of a Pre-Decisional IDE application, the lead reviewer will evaluate whether the application is eligible for the Pre-Decisional IDE process and sufficiently complete for substantive review, as defined by criteria set forth in the guidance.
  • Substantive Review: Once the Pre-Decisional IDE is accepted for review, a 30-day review clock will start. The lead reviewer will contact the sponsor to schedule a meeting or teleconference (as requested by the sponsor) to occur within 15 days after the close of the 30-day review period, or at a mutually agreeable date shortly thereafter. During the 30-day review period, the review team will conduct a full review of the information submitted and provide the sponsor with comments via e-mail reflecting any significant issues identified in the review. These comments will focus on concerns that, if the application were submitted as an actual IDE, would result in a disapproval decision, would be a condition of approval, and/or would constitute study design considerations that FDA believes would not support a market approval or clearance either independently or as a component of a larger clinical study program.
  • Mid-Cycle Interaction: The meeting or teleconference with the sponsor will be a maximum of 90 minutes in duration and the sponsor may recommend the topic(s) to be discussed based on the initial feedback provided by the review team.
  • FDA Response: Following the meeting, the sponsor will have the option to request that the Pre-Decisional IDE be converted into an actual IDE, in which case FDA will issue a decision letter within 15 days of the conversion request, which will include the deficiencies and recommendations provided in the initial feedback. If any new information, including a modified study protocol, is provided as part of the conversion request, a standard IDE review will commence. In the absence of a conversion request, FDA will provide comprehensive written feedback to the sponsor on the Pre-Decisional IDE within 15 days of the meeting or teleconference. This feedback will list the deficiencies and recommendations identified during the review, taking into account any clarifications from the meeting or teleconference with the sponsor. If information submitted in a subsequent IDE is consistent with that provided in the Pre-Decisional IDE and any new data submitted in the IDE application do not raise new issues materially affecting safety or effectiveness, FDA intends to adhere to the feedback and decisions reached during the Pre-Decisional IDE review.
  • Sponsor Response: Following receipt of FDA’s complete feedback on the Pre-Decisional IDE, the sponsor may choose to:
    • Submit a formal IDE application, identifying which parts of the application are identical to that submitted in the Pre-Decisional IDE and which parts address FDA’s feedback.
    • Submit a focused response to specific issues from the Pre-Decisional IDE for which a follow-up discussion would be useful. Such a response will be treated as a supplement to the original Pre-Decisional IDE and should be submitted within 30 days of FDA’s complete feedback. FDA will provide comments by e-mail within 30 days of receipt of the additional information.
    • Submit a focused response to FDA’s complete feedback and a request to repeat the Pre-Decisional IDE process as described above. FDA intends to grant these requests only once to avoid multiple Pre-Decisional IDE cycles.

IDE Decisions

This section of the draft guidance focuses on the topics addressed in the original 2011 draft guidance, and outlines the regulatory implications of FDA’s actions on IDE applications. The draft guidance explains that FDA regulations provide for three FDA actions on IDE applications: Approval, Approval with Conditions and Disapproval. The draft guidance elaborates on the meaning of each of these regulatory actions, and provides details on its decision-making criteria in each context.

  • IDE Approval: FDA will approve an IDE application without conditions when the IDE sponsor has submitted data and an adequate clinical investigation plan that support initiation of the study in humans. The sponsor may begin subject enrollment in accordance with FDA’s decision letter immediately upon receipt of IRB approval.
  • IDE Approval with Conditions: FDA will approve an IDE with conditions (previously known as “conditional approval”) if it has determined that, despite some outstanding issues, the information provided is sufficient to justify human clinical evaluation of the device and the proposed study design is acceptable with regard to protection of study subjects. The sponsor may begin subject enrollment upon receipt of IRB approval on the condition that, within 45 days from the date of FDA’s decision letter, the sponsor submits information addressing the issues identified in the letter.
  • Staged Approval or Staged Approval with Conditions: Under these processes, FDA will grant IDE approval or approval with conditions while certain outstanding questions are answered concurrently with enrollment of a limited number of subjects in the clinical investigation. The sponsor will be permitted to expand enrollment once an IDE supplement containing the necessary additional information is submitted to FDA and found acceptable.
  • IDE Disapproval: FDA may disapprove an IDE for various reasons as outlined in the FDCA and FDA regulations, as discussed further in the guidance. Consistent with FDASIA, FDA may not disapprove an IDE for reasons related to FDA’s determination that the investigation may not be sufficient to support marketing approval or clearance. If FDA disapproves an IDE application, the sponsor may not initiate the clinical investigation until the sponsor submits an amendment to the IDE to respond to the deficiencies identified in FDA’s letter and subsequently receives a new letter from FDA granting approval or approval with conditions.

In the draft guidance, FDA states that for studies which the sponsor intends to use in support of a marketing application or clearance, the sponsor and other stakeholders may benefit from awareness of the modifications that FDA believes are needed to achieve this objective. Accordingly, although FDA will not disapprove an IDE for these reasons, FDA states that it will convey such considerations to the sponsor to provide greater clarity and predictability. In addition, FDA will convey certain considerations that FDA believes will be important for future submissions related to the proposed investigation.

Comments and Industry Response

FDA’s new Pre-Decisional IDE process creates an opportunity for sponsors to receive a higher level of substantive communication from the FDA on IDE study designs, and the draft guidance discussion on regulatory decisions provides helpful information on FDA’s considerations in its IDE reviews, which FDA hopes will lead to higher quality IDE submissions and interactions. Though the Pre-Decisional IDE process may end up taking longer than the formal IDE process, the fact that the new process allows sponsors to enter a dialogue with the FDA earlier, and in more developmental stages of the application, may help avoid initial disapproval and a longer periods of revision and review. Industry should watch closely to monitor whether FDA’s new guidance will result in faster and higher rates of IDE approvals, especially clean approvals without conditions.

FDA has made the draft guidance available for public comment on Regulations.gov at Docket No. FDA-2011-D-0790 and has requested comments by September 12, 2013 in order for the Agency to consider them before beginning work on the final guidance. FDA also held a webinar on the draft guidance on July 2, 2013. Industry and other interested persons may access the webinar for helpful additional discussion on FDA’s website.6