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You should submit comments and suggestions regarding this draft document within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit e lectronic comments to http://www.regulations.gov. Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this document, contact Andrew Farb, 301-769-6343, Andrew.Farb@fda.hhs.gov or Dorothy Abel, 301-796-6366, Dorothy.Abel@fda.hhs.gov.

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U.S. Department of Health and Human Services

Food and Drug Administration

Center for Devices and Radiological Health

Preface

The following is a hypothetical scenario that illustrates the concepts described in Section 7 regarding device iteration during an early feasibility study.

A sponsor approaches FDA with a proposal to evaluate an innovative device in an early feasibility study to treat a disease common in the elderly. The device is unique in that delivery of the treatment will be through a novel catheter design, rather than through the standard procedure which involves open surgery. The sponsor proposes to enroll up to 10 subjects at up to 3 investigational sites. The sponsor will evaluate the device performance and clinical outcomes after each subject is treated, and prior to enrolling the next subject. Based on these assessments, they will consider device and clinical protocol modifications.

In their original IDE application the sponsor seeks contingent approval for several types of changes. They propose the following specific iterative changes that they would like FDA approval for implementing as they complete their pre-specified device evaluation plan:

  • improvements in maneuverability, including:
    • modifying the shape of the nose cone of the introducer (e.g., make sharper or more blunt); and
    • making the sheath stiffer or more flexible;
  • changing the length of the catheter to allow for the use of alternative access sites;
  • modifying the hemostatic valve by changing material properties or device dimensions to improve hemostasis or reduce friction;
  • implementing ergonomic changes in the handle that do not affect the overall function of the device (e.g., changing texture of knobs or handle);
  • adding, moving, or changing the radiopaque bands on the catheter to improve visibility; and
  • modifying the operator interface console.

The sponsor and FDA reach concurrence on the test plan to evaluate the proposed changes through informal discussions that are subsequently documented in the original IDE submission. Although some of these changes may have been appropriate for 5-day notices, obtaining prospective, contingent approval provides the sponsor with more predictability in the regulatory process for their device modification plans.

With help from their principal investigator, the sponsor identified other types of changes that may be needed for their device and clinical protocol during the conduct of their early feasibility study and discussed these with FDA under a pre-IDE. The sponsor includes the following table in their original IDE to describe their plan.

Table: Regulatory Process for anticipated modifications

Changes that may be appropriate for 5-day notificationChanges that may be appropriate for contingent approvalChanges that may be appropriate for 30-day interactive IDE supplement
Addition of surface coating to catheter if lubricity is needed to improve access*If a surface coating is added, need to modify the distribution, thickness or area covered by the coatingExpand the subject selection criteria (e.g., inclusion of younger subjects than defined in the original protocol)
Change specific features of the device to be consistent with device approved for use under another IDE for a similar indication*Modification to improve catheter resistance to kinking, with the type of modification and appropriate testing to be identified prior to supplement submissionChanges identified as necessary during the early feasibility study 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
Changes in the device preparation for useChanging the device to accommodate a broader range of subject anatomies (i.e., type of modification and therefore type of appropriate testing not identified in the original IDE)Change from percutaneous access to an open cutdown or to use of a vascular conduit
Addition of use of approved ancillary device intended to improve the safety of the procedure*Other device modifications identified during the clinical study for which an appropriate testing plan and acceptance criteria can be identified 
Use of off the shelf tools (i.e., that were not identified in the original IDE) to perform bailout procedures  
Modification to subject selection to limit, rather than expand, the criteria*  
Modify procedural imaging modalities*  
Reducing follow-up assessments if early data support change (i.e., show that the change would not affect the safety of the subjects)*  
Change case report forms to capture additional information  

* These types of changes would not generally be appropriate for 5-day notification in a pivotal study due to their possible effect on the scientific soundness of the investigational plan and/or data validity.

Many of the types of changes that might be appropriate for 5-day notification during this early feasibility study would not normally be acceptable for studies enrolling a larger number of subjects or in a study intended to collect data to independently support a marketing application. However, for this early feasibility study, the changes proposed to the device and clinical protocol would not adversely alter the risks for the study subjects. The developmental device changes would be appropriate for 5-day notification because they:

  • are reasonably defined such that appropriate testing and expected outcomes are known;
  • do not constitute significant changes in the basic principles of operation; and
  • are not considered significant because they would not adversely affect the interpretability of the results of an early feasibility study, and would not be expected to adversely affect device performance or to be associated with additional risk to the study subjects.

Similarly, the clinical protocol changes would be appropriate for 5-day notification because the changes do not affect:

  • subject safety, rights, or welfare, because enhanced subject protection measures are in place for the early feasibility study;
  • the validity of the data or information resulting from the completion of the approved protocol because the such data or information will not be pooled;
  • the relationship of likely patient risk to benefit relied upon to approve the protocol; or
  • the scientific soundness of the study because there are no statistical hypotheses to be tested in the early feasibility study.

During the course of the sponsor’s early feasibility study, the sponsor made some of the anticipated changes, but also identified an additional modification that had not been predicted in the original IDE submission which the sponsor described to FDA informally. The sponsor requested contingent approval of a change in a material used in the construction of the device based on obtaining acceptable results for this material using same types of testing used to evaluate the original device design. To formally request this change, the sponsor submitted an IDE supplement that described the change and evaluation plan. FDA and the sponsor reached a consensus regarding the proposal during the 30-day review time for the supplement, and FDA granted approval of the modification contingent on the sponsor’s successful completion of the proposal and reporting of the change and supporting information to FDA within 10 days of implementing the change. The sponsor evaluated the modified device according to the test plan, obtained acceptable results, implemented the change and submitted their test report to FDA 7 days after making the change.


1 Significant risk device is defined at 21 CFR 812.3(m) as an investigational device that:

(1) Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject;

(2) Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a subject;

(3) Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a subject; or

(4) Otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.

2 Additional testing could be completed concurrent with conducting the early feasibility study if needed to support the conduct of a traditional feasibility or pivotal study.

3 Note that this guidance does not recommend that sponsors prematurely initiate clinical testing when further useful and appropriate nonclinical testing can be performed for the particular device the sponsor is developing.

4 21 CFR 812.20(a).

5 21 CFR 812.27(a).

6 Characterization tests (i.e., testing conducted to describe the device) may not have specified acceptance criteria.

7 At the early feasibility stage, a descriptive risk analysis may be more informative than a formal failure modes and effect analysis (FMEA), which provides a quantitative ranking of risks.

8 See 21 CFR 812.25 and 812.30(b)(4).

9 21 CFR 812.25(a).

10 21 CFR 812.25(b).

11 21 CFR 812.25(b).

12 See 21 CFR Parts 50 and 56.

13 21 CFR 50.25(a)(1). For more information on Informed Consent see, "A Guide to Informed Consent - Information Sheet."

14 See 21 CFR 50.25(b)(1).

15 21 CFR 56.111(a)(1) and (2).

16 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM269919.pdf

17 http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf

18 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm082145.htm

19 See 21 CFR 812.35(a)(4).

20 21 CFR 812.35(a)(3).

21 21 CFR 812.35(a)(3)(i) and (ii). These changes must be supported by credible information as defined at 21 CFR 812.35(a)(3)(iii).

22 See 21 CFR 812.35(a)(3)(ii).

23 812.35(a)(3)(ii)(A) and (B).

24 See 21 CFR 812.35(a)(1).

SOURCE

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