Medical device companies developing a product that poses significant risks to patients must obtain an Investigational Device Exemption (IDE) from the FDA before they conduct clinical trials in humans to assess the feasibility of the device or to obtain data to support a Pre-Market Approval (PMA) application to the FDA to market the device in the U.S. On Nov. 10, 2011, the FDA issued two related draft guidance documents, one designed to foster early-stage development of medical devices and one to promote the initiation of clinical trials of medical devices by clarifying the FDA's approval process.

The first draft Guidance, titled "Investigational Device Exemptions for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies," seeks to promote early state development. The draft Guidance begins by distinguishing among several types of clinical trials, including "early feasibility," "first in human," "traditional feasibility," and "pivotal" studies. The draft Guidance is focused on early feasibility studies, which it defines as "a limited clinical investigation of a device early in development, typically before the device design has been finalized, for a specific indication (e.g., innovative device for a new or established intended use, marketed device for a novel clinical application)." According to the draft Guidance, an early feasibility study may "evaluate the device design concept with respect to basic safety and device functionality in a small number of subjects (generally fewer than 10 initial subjects) when this information cannot be readily provided through additional nonclinical assessments or appropriate nonclinical tests are unavailable." The draft Guidance relates to first in human studies only to the extent they also meet the definition of an early feasibility study.

Significantly, the draft Guidance describes new FDA policies concerning the application for and approval of IDEs for early feasibility studies. First, the new policy allows for FDA approval of IDEs for early feasibility studies with less nonclinical data than required for a traditional feasibility or pivotal study. Given that early feasibility studies, by definition, are only appropriate when additional nonclinical data are not available or are not adequate to advance development of the product, the new policy allows an IDE for such a study to be approved with less evidence. Second, the new policy allows for "timely device and clinical protocol modifications during an early feasibility study" through new approaches such as (1) allowing more types of modifications to be made under a five day notification to FDA and without actual prior FDA approval, (2) permitting changes without FDA approval contingent upon acceptable nonclinical test results, and (3) interactive review of IDE supplements.

The second draft Guidance, titled "FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations," summarizes the FDA's IDE approval process and describes the different types of decisions FDA makes and the common reasons behind them. As noted above, the goal is to clarify FDA's decision process and thereby promote the initiation of clinical trials for medical devices. Some of the decisions that FDA makes during the approval of an IDE for a particular product are designed to allow clinical investigations to begin, even though there may be issues with the IDE application, while still protecting the patients.

This Guidance identifies and describes several FDA responses to an IDE application: (1) Approval, (2) Approval with Conditions, (3) Staged Approval or Staged Approval with Conditions, and, (4) Future Considerations in Approval, Approval with Conditions, or Disapproval. Approval is just what it states and allows the IDE applicant (or sponsor) to "begin subject enrollment in accordance with the limits described in FDA's decision letter, including the maximum number of subjects and investigational centers." Approval is automatic if FDA does not respond to an IDE application within thirty days of its receipt. FDA will approve an IDE application when it contains adequate data and an appropriate plan for the clinical trial.

The draft Guidance states that upon Approval with Conditions, and upon approval by the relevant Institutional Review Board (IRB), the sponsor may begin enrolling subjects in the trial "on the condition that, within 45 days from the date of FDA's decision letter, the sponsor submits information addressing the issues identified in FDA's [conditional approval] letter." The common reason for this type of decision is that, although there may be some outstanding issues with the IDE application, "the information provided is sufficient to justify human clinical evaluation of the device, and that the proposed study design is generally acceptable."

The draft Guidance describes Staged Approval or Staged Approval with Conditions as a decision that allows enrollment in a clinical trial to begin, limited to a certain number of patients in the first stage, while certain outstanding questions are answered at the same time. The sponsor can expand enrollment after submitting an IDE supplement that answers the outstanding questions. The draft Guidance states that Staged Approval is used most often with pivotal studies, defined as "studies that are designed to provide the primary clinical evidence to support a marketing application" (PMA).

Finally, the draft Guidance notes that any type of FDA decision on an IDE application, including a disapproval, may refer to future considerations "intended to provide helpful advice to sponsors regarding important elements of the future application that the IDE may not specifically address." Several examples are given, including the FDA may remind the sponsor that in light of exclusion criteria from a clinical trial, the device may not be approved for certain patient populations. The FDA may alert the sponsor to certain analyses that it expects to see in a final PMA, such as "analyses demonstrating that [any] US and non-US data can be pooled." If the FDA wants to see additional non-clinical data as part of the final PMA, the decision letter (again of any type) may so advise the sponsor.          

As always, it is important to remember that "FDA's guidance documents ... do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited." Further, the documents described above are drafts, not final guidances.