The US Food and Drug Administration (FDA or the Agency) issued draft guidance on June 18 about assessing the benefits and risks for Investigational Device Exemption (IDE) applications.[1] The draft guidance provides a benefit-risk framework for evaluating IDE applications and is intended to facilitate understanding of the factors that influence the FDA’s decisionmaking when reviewing IDE applications.[2]

Background

Prior to initiating a clinical study, both the sponsor and the FDA are required to make risk determinations for clinical studies, although different considerations apply to these determinations. A sponsor conducting a clinical study of an investigational medical device must first determine whether the study presents a “nonsignificant” or “significant risk,”[3] because an IDE application is required to be submitted to the FDA only for a significant risk study.[4] This determination continues to be a difficult one, as demonstrated by Warning Letters that the FDA has issued to sponsors.

The FDA’s draft guidance addresses the factors that the Agency uses to assess risk in deciding whether to approve an IDE application that has been submitted. Prior to enacting the Food and Drug Administration Safety and Innovation Act (FDASIA), industry expressed concern to the FDA and Congress that IDE applications were being disapproved on the basis that the investigation may not support approval or clearance of a device or a de novo classification determination. Because clinical studies are conducted for many reasons and not always to support a marketing application, industry sought and obtained a provision in FDASIA that specifically states that FDA may not disapprove an IDE application on the basis that the study described in the IDE submission may not support market clearance or approval. This provision was included in FDASIA as enacted.

In the subject draft guidance, the FDA clarifies that the Agency can disapprove an IDE application for other reasons. In particular, the focus of the draft guidance is the FDA’s authority to disapprove an IDE application when “[t]here is reason to believe that the risks to the subjects are not outweighed by the anticipated benefits to the subjects and the importance of the knowledge to be gained, or informed consent is inadequate, or the investigation is scientifically unsound, or there is reason to believe that the device as used is ineffective.”5 The draft guidance describes the FDA’s approach to applying this benefit-risk assessment when reviewing IDE applications.

Benefit-Risk Assessment for IDE Applications

In addition to considering various benefit-risk factors, the FDA considers the context of the device development pathway when considering an IDE application. Specifically, the FDA considers (1) the development stage of the device (e.g., first in human, early feasibility, pivotal); (2) the maturity of the proposed technology; and (3) the availability of nonclinical testing to supplement or replace clinical testing. Concerning the development stage, the FDA recognizes that there is greater uncertainty with devices in earlier stages of development than devices entering pivotal studies.

Other benefit-risk factors outlined in the FDA’s draft guidance include

  • patient preferences; subject tolerance for risk and perspective on benefit,
  • the type of risks (e.g., device-related serious adverse events, procedure-related risks) to study subjects,
  • the likelihood of risks,
  • risk control measures (including risk mitigation efforts),
  • risk communication,
  • benefit of knowledge to be gained,
  • risk to others (e.g., health care practitioner),
  • type and magnitude of benefit to the study subject,
  • probability of study subject experiencing a benefit,
  • societal benefit,
  • disease characterization,
  • availability of alternatives,
  • uncertainty, and
  • quality of prior nonclinical and clinical data and its predictive capability.

FDA Recommendations for IDE Applications

The FDA’s draft guidance recommends that IDE sponsors include a section in their applications that summarizes the primary or most important considerations in the IDE benefit-risk assessment. The Agency states that the summary should not be a comprehensive review, but rather, should focus on those factors likely to significantly affect the FDA’s decision. The draft guidance recommends that the following information be included:

  • The context for the proposed study (e.g., the disease/condition to be treated/diagnosed, a description of the device, and introduction to the study)
  • A summary of the key risk elements, as listed above (e.g., type and likelihood of risks)
  • A summary of the study’s key benefits
  • A summary of any patient preference information
  • A summary of key sources of uncertainty in the evidence and in the study
  • Conclusions—a summary of how the factors discussed justify the decision to proceed with the study

The FDA provides hypothetical examples of how it would apply these benefit-risk factors in Appendix 2. It includes examples that look at a pivotal study of a device intended to treat a life-threatening condition, a feasibility study for a device to treat a life-limiting condition with some alternative treatments, and an early feasibility study for a device to treat a life-threatening condition without an alternative treatment option.

The FDA requests that comments on the draft guidance be submitted by September 16 to ensure that they will be considered before it prepares the final guidance.