Through new guidance published this month, the US Food and Drug Administration has clarified its review and approval process for its Investigational Device Exemption (IDE) regulations, and has also proposed steps to allow clinical investigations of high-risk medical devices in some instances where IDE approvals have not been finalized.

Approval of an IDE submission must occur before a manufacturer can begin clinical investigations of its device. The guidance explains four outcomes of its IDE review process: approval, approval with conditions, staged approval with or without conditions, and disapproval.

IDE Approval

If a manufacturer’s IDE application obtains FDA approval without conditions, the firm may begin clinical investigation efforts according to the terms set forth in the agency’s approval letter.

IDE Approval with Conditions

In instances where the FDA approves an IDE application with conditions, manufacturers may begin clinical investigations provided that they submit data to address outstanding issues within 45 days. If the agency takes issue with sponsors’ informed consent documents, however, those issues must be resolved before clinical investigations begin.

Issues often garnering approvals with conditions by the FDA include proposed study data analysis methods; late-stage follow-up procedures and assessments; divergences from appropriate study endpoints; and requests for additional information related to non-clinical testing issues.

Failure to submit supplements to the FDA within the 45-day timeframe will result in disapproval of an IDE application.

Staged Approval with or without Conditions

The new FDA guidance introduces staged approval and staged approval with conditions to the IDE approval process. Under these scenarios, manufacturers may begin limited subject enrollments for their investigations while simultaneously addressing issues raised by the regulatory about their IDE applications.  (Once outstanding questions have been resolved, sponsors could then expand their study enrollments.)

Staged clinical investigations are warranted, according to the guidance, in instances where obtaining clinical data of a device’s safety characteristics is deemed necessary, requiring review of data from subjects in early stages of a clinical investigation before allowing a wider pool of subjects to be added to the investigation.

Staged investigations are also valuable when existing data supports enrolling a limited number of subjects in a clinical investigation while also conducting long-term non-clinical testing. The FDA would require validation of non-clinical testing results before allowing full enrollment in the sponsor’s clinical investigation.

IDE Disapproval

If the FDA disapproves an IDE application, the sponsor must submit an amendment to its IDE to address deficiencies; only following subsequent approval or approval with conditions by the agency may that sponsor proceed with its clinical investigation.

The guidance identifies five common factors for IDE disapproval:

• Failure to comply with any relevant FDA requirement
• IDE application contains false information or omits required information
• Request for additional information is not addressed within required timeframe
• Device’s health benefits do not outweigh the risk its use poses to patients, or it is ineffective
• Inadequacies in the sponsor’s report of prior investigations, manufacturing processes or monitoring process of its investigation

Key Factors for Consideration

The FDA’s guidance also lists some of the major factors its reviewers evaluate in order to determine approval status of IDE applications. These include:

• Non-clinical testing data, reviewed to see whether it supports a device’s safety and performance
• Category of clinical investigation—feasibility or pivotal—can affect which elements of an IDE application FDA reviewers will examine most carefully
• Risk assessment—are the expected risks of a clinical investigation acceptable?
• Sudy design elements such as subject safety, enrollment criteria and clinical methodology for feasibility studies, and primary safety and effectiveness endpoints, assessment methodologies and statistical analysis plans for pivotal studies
• Informed consent documents must meet requirements of 21 CFR Part 50
• Least burdensome approaches to address premarket regulatory issues to ensure appropriate timeframes, efforts and cost-effectiveness for industry participants and FDA personnel