FDA Guidance on Early Feasibility Studies, Including First-in-Human Andrew Farb, MD and Dorothy Abel Division of Cardiovascular Devices Center for Devices and Radiological Health (CDRH) andrew.farb@fda.hhs.gov FDA Town Hall II CRT 2012 Washington, DC February 7, 2012

Andrew Farb, MD I have no real or apparent conflicts of interest to report.

Why an Early Feasibility Study Guidance? The FDA has acknowledged a real or perceived problem Initial clinical testing of novel products has moved to non-US sites; Product innovation may follow overseas; and FDA’s requirements can be an impediment to early clinical testing of new devices Encouraging medical device innovation, enhancing regulatory science, and facilitating clinical studies in the US are CDRH priorities. The Agency recognizes the need for a cultural change to shift the focus from not only protecting public health to also promoting public health.

Early Feasibility Study (EFS) Clinical investigation of a small number of subjects (generally fewer than 10 initial subjects) 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 Does not necessarily involve the first clinical use of a device Intended to provide proof of principle and initial clinical safety data

Key Principles of the Guidance An EFS may be appropriate when: Nonclinical testing methods are not available or adequate to provide the information needed to advance the developmental process; and Clinical experience is necessary. An EFS must be justified by an appropriate risk-benefit analysis and adequate human subject protection measures FDA approval of an EFS IDE application may be based on less nonclinical data than would be expected for a traditional feasibility or a pivotal study. Thus, FDA approval of an EFS IDE application may be based on less nonclinical data than would be expected for a traditional feasibility or a pivotal study.

Scope of the EFS Guidance Not applicable to traditional feasibility studies, which involve near-final or final device designs in a relatively larger number of subjects Not applicable to pivotal studies, which are intended to capture definitive evidence of the safety and effectiveness of a device Not all novel devices or uses warrant an EFS An EFS may be appropriate even if a device or a prototype of the device has previously been used clinically for the intended indication

Targeting IDE Approval Questions to be Addressed in the IDE What is the clinical condition to be treated or assessed by the device? What is the standard of care for the clinical condition and expected clinical outcomes associated with the standard of care? Address the totality of the potential benefit/risk profile for the device, for example: Disease or condition (e.g., life-limiting, life-threatening) Limitations of, and risks associated with, currently available therapies

Targeting IDE Approval Questions to be Addressed in the IDE Does the information included in the Report of Prior Investigations support initiation of the study? Approval of an EFS IDE may be based on less nonclinical data (e.g., small sample sizes or short implant durations) For some new devices, exhaustive nonclinical testing would not likely provide the information needed to further device development It may be acceptable to complete additional tests concurrently with the EFS

Report of Prior Investigations Need information to: Support an expectation of acceptable clinical use and that the device will function as intended e.g., successful device placement using a benchtop model that simulates clinical conditions and/or a suitable animal model Address basic device safety, including, but not limited to, sterility, biocompatibility, electromagnetic compatibility, chemical compatibility (e.g., with concomitant drugs, chemicals, cleaners) Characterize catastrophic failure modes and risk mitigation approaches

In Vivo Animal Studies Short-term studies may be adequate for the initiation of an EFS Additional animal study data may be needed to support a larger clinical study with a near-final or final device design Generally required to follow GLP Non-GLP study data may be used to support an EFS IDE if the deviations from GLP are identified and justified and do not compromise the validity of the study results

Targeting IDE Approval Does the Investigational Plan include a thorough risk/benefit analysis, sufficient risk mitigation strategies, and adequate human subject protection measures? An EFS may carry greater unknown risk than traditional feasibility and pivotal studies Benefits from the knowledge to be gained may be substantial, particularly for innovative devices or intended uses during the early phase of device development Human subject protection measures, such as adequate informed consent and IRB review, are critically important

Human Subject Protection Measures Informed Consent Key elements: Statement that the proposed investigation is an EFS (small study of an innovative device or use for which there is less nonclinical data than would be required for a larger study) Language that the study may carry greater inherent risk, especially unknown risk, vs. a traditional feasibility or pivotal study A description of any benefits to the subject or to others which may reasonably be expected from the research Should not include language that could lead subjects to overestimate the chance of personal benefit

Targeting IDE Approval Does the Investigational Plan include an appropriate clinical study protocol? Studies should be scientifically sound, enrolling the right subjects and utilizing meaningful endpoints Some essential elements of larger studies, such as a definition of study success, prespecified SAP, sequential enrollment, & highly detailed CRFs are not necessary

New Regulatory Tools The guidance introduces new approaches to facilitate timely device and clinical protocol modifications during an EFS that comply with current IDE regulations in 21 CFR Part 812. Expanded application of 5-day Notices Contingent approval Interactive review This guidance introduces new approaches

Expanded Application of 5-Day Notification 5-day notices provide notification of non-significant changes to an investigational device or to the study protocol without requiring prior FDA approval Changes should be expected not to adversely affect device performance or pose additional risk to study subjects For an EFS, many changes will not affect the interpretation of the results, so more changes can be made through notification, rather than approval

Expanded Application of 5-Day Notification Sponsors should explain how enhanced risk mitigation strategies and patient protection measures provide additional support when considering appropriate 5-day notice changes Examples: Modify procedural imaging modalities Modify subject selection to limit, rather than expand, the criteria Reduce follow-up assessments if early data support change (i.e., show that the change would not affect the safety of the subjects)

New “Contingent Approval” Process Approval of anticipated device changes can be obtained contingent on the completion of an agreed-upon test plan and reporting of the test data i.e., the change is approved, but only if the sponsor successfully executes the plan After successful completion of testing, the sponsor can implement the change and will inform FDA within 10 days of making the change The sponsor can begin to study the modified device without additional FDA action Examples: Modify the distribution, thickness or area covered by a coating on a delivery catheter proposing the same testing and acceptance criteria as for the initial coating Improve catheter resistance to kinking proposing appropriate testing and acceptance criteria Comparable to the mechanism used to change shelf-life If the sponsor deviates from the plan, the contingent approval would no longer be valid, and the sponsor would need to renegotiate and obtain a new contingent approval or seek approval through the submission of a 30-day IDE supplement

New “Interactive Review” Process Intended to encourage communication between FDA and sponsor within the 30-day review cycle to address investigational plan deficiencies and allow submission of additional information leading to IDE approval Examples: Expand the subject selection criteria (e.g., inclusion of younger subjects than defined in the original protocol) Changes identified as necessary during the EFS for which the testing needed would be different from that previously used or where it is difficult to determine reasonable acceptance criteria for the testing Success of the interactive review process depends on the availability of FDA and sponsor resources and the acceptability of test results

Next Steps in Clinical Evaluation Subsequent clinical evaluation depends on the stability of the device design, the availability of data to justify the next study, and the purpose of the clinical study Expansion of the EFS e.g., further device iterations are expected Either a traditional feasibility or a pivotal study Device design is near-final or final, and EFS results support the initial safety of the device and proof of principle Communication with FDA is important to determine the most appropriate clinical evaluation plan

EFS Pilot Program Pilot program of up to 9 innovative device technology submissions is underway to implement and evaluate the draft EFS guidance Status of the Pilot Sponsors with accepted EFS nominations has been notified that their submission has been included in the Pilot A CDRH staff training program for the EFS Pilot has commenced Initial pre-IDE FDA/sponsor interactions have started

Conclusions Early feasibility studies provide: Early device safety data and clinical verification of the proof of principle An opportunity to obtain clinical experience with a new or modified device or new clinical use, while utilizing appropriate subject protection measures and good clinical study practices Information that may lead to device modifications and refinement of future nonclinical testing and clinical study protocols Interaction between FDA and sponsors, particularly via the pre-IDE process, will be instrumental in the successful implementation of this guidance and in re-invigorating early feasibility clinical investigations in the US.

EFS Draft Guidance Website http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm277670.htm