1. Do I Need FDA Approval Before I Start My Device Study? The ABCs of IDEs
Andrew Farb, MD and Dorothy Abel, BSBME
Division of Cardiovascular Devices
Center for Devices and Radiological Health (CDRH)
Food and Drug Administration
Monday, February 20, 2017
10:40 AM – 10:50 AM
Room: Congressional AB
Essentials of Clinical Research
CRT 2017
Washington, DC
February 20, 2017

2. Conflict of Interest
No conflicts of interest to report

3. The Investigational Device Exemptions (IDE) Regulations
The IDE regulations are intended to encourage development of useful devices while providing protection of public health and safety.
Clinical device studies (i.e., a standardized, systematic collections of safety and/or effectiveness data) performed in the US are subject to the IDE regulations
Regardless of whether the data would be used to support a marketing application.

4. IDE Basics
An IDE approval is issued by the FDA to allow the use of significant risk investigational devices in humans.
An approved IDE:
Provides protection to human subjects (e.g., informed consent), requires study monitoring, and allows shipping of devices.
Exempts sponsors from certain provisions of the FD&C Act.
Clinical study data collected under an IDE can be used to support a marketing application for a device [PMA or 510(k)].
IDE submissions have a 30-calendar day FDA review period.

5. Definitions
Sponsor: A person or other entity that initiates, but does not actually conduct the investigation
Investigator: An individual who actually conducts the clinical investigation, i.e., under whose immediate direction the investigational device is administered, dispensed, or used
Sponsor-Investigator: Individual who both initiates and conducts, alone or with others, a clinical investigation

6. IDE Application
The information to be included in an IDE application is listed in the regulations.
The IDE package:
Sufficient information in reports of prior investigations to justify the proposed study;
An appropriate investigational plan;
Adequate patient protection measures; and
Other required elements that address records and reports, study monitoring, and manufacturing information.

7. Staged approval (can apply to approval or approval with conditions):
IDE Decisions by FDA
IDE approval: No outstanding issues that must be addressed before initiating the clinical study
IDE approval with conditions: FDA has identified issues, but these issues do not raise concerns that preclude study initiation
Issues must be addressed within 45 days from the date of FDA’s decision letter
IDE disapproval
Outstanding issues that may lead to approval with conditions include:
Issues related to data analysis methods and handling if the corrections will occur prior to the gathering of important study data;
Issues related to late stage follow-up procedures and assessments, if the corrections are made prior to beginning any late-stage procedures or assessments;
Minor divergences from what FDA considers appropriate study endpoints, design assumptions, or key definitions;
Issues related to the informed consent document that must be corrected before enrolling subjects but can be reviewed by FDA after study initiation;
Requests for additional information or data involving non-clinical testing issues that do not need to be resolved prior to study initiation;
Other minor clarifications, corrections, or modifications that do not need to be resolved prior to review completion
Staged approval (can apply to approval or approval with conditions):
Approval of a limited subject cohort with enrollment expanded after review of selected nonclinical testing and/or initial patient safety data

8. IDE Decision-Making IDE disapproval is appropriate when:
Probable risks to subjects are not outweighed by the anticipated benefits and the importance of the knowledge to be gained
Safety concerns related to the device/procedure
Often that nonclinical testing does not provide adequate safety information
Unacceptable risks to subjects in the proposed study
Inadequate potential for benefit OR
The study does not pose a reasonable scientific question and/or is not designed to collect data related to that scientific question
Example – device intended to reduce brain damage in stroke patients but the protocol includes neither neuro exams nor neuroimaging

9. FDA Guidance Issued January 13, 2017
Clinical condition and available treatment or diagnostic options
Risk characterization and mitigation
Benefits to subjects and/or benefits to others
Patient preference information (if available)
Assessment of uncertainty and why the level of uncertainty is acceptable for the study

10. FDASIA: The FDA Safety and Innovation Act Section 601
Amends Section 520(g)(4)(C) of the FD&C Act
FDA shall not disapprove an IDE because:
the investigation may not support a substantial equivalence or de novo classification determination or approval of a device;
the investigation may not meet a requirement, including a data requirement, relating to the approval or clearance of a device; or
an additional or different investigation may be necessary to support clearance or approval of the device.
Don’t read slide, just summarize what FDASIA means: that the study cannot be disapproved by FDA even if we believe that the study will not be adequate to support a clearance or approval
Example: Sponsor proposes a single arm study for a new coronary stent, but FDA believes that a RCT is needed to support PMA approval. FDA cannot disapprove the IDE for that reason (as long as there are no major patient safety concerns)

11. Study Design Considerations (SDCs)
Concerns unrelated to subject safety which the FDA believes should be addressed for the study to support its goals, such as a future marketing application or a future study, for example:
Primary and secondary endpoints
Study success criteria
Randomization
Blinding
Follow-up duration and assessments
Statistical analysis plan issues
Sponsors are encouraged but not required to address SDCs

12. Clinical Studies vs. Practice of Medicine
The FDA approves a device for marketing for a specific use or uses, often based on data from clinical studies.
Off-label is a term applied to the use of an approved device under the practice of medicine, outside of the instructions for use.
Off-label use of an approved device is not necessarily inappropriate or unstudied, but is typically supported by less information than with on-label use.
FDA does not regulate the practice of medicine.
Well-designed and conducted clinical studies of off-label use conducted under an IDE can generate definitive data to guide informed treatment decisions.
Clinical studies do not fall under the
definition of practice of medicine.

13. Applicability of the IDE Regulations
A clinical study of a significant risk device that is subject to the IDE regulations requires prior FDA approval through the submission of an IDE application to FDA, and IRB approval, before initiating study subject enrollment.
Some clinical studies are exempted from the IDE regulations, for example:
The study of approved devices that are being used on-label
The testing of a modification of an approved device if the testing does not put subjects at risk and is not for the purpose of determining safety or effectiveness
A clinical study of a non-significant risk device must follow abbreviated IDE requirements
SR device studies must follow all the IDE regulations at 21 CFR 812.
• SR device studies must have an IDE application approved by FDA before they may proceed. 2. Nonsignificant Risk (NSR) Device Studies
NSR device studies must follow the abbreviated requirements at 21 CFR 812.2(b).
• These abbreviated requirements address labeling, IRB approval, informed consent, monitoring, records, reports, and prohibition against promotion. However, there is no need to make progress reports or final reports to FDA.
• NSR device studies do not have to have an IDE application approved by FDA.
• Sponsors and IRBs do not have to report the IRB approval of an NSR device study to FDA. This means that an IRB may approve an NSR device study and an investigator may conduct the study without FDA knowing about it.
• An IRB’s NSR determination is important because the IRB serves as the FDA’s surrogate for review, approval, and continuing review of the NSR device studies. An NSR device study may start at the institution as soon as the IRB reviews and approves the study and without prior approval by FDA.

14. What’s a Significant Risk Device?
Significant risk devices are those that present the potential for serious risk to the health, safety, or welfare of a subject.
A significant risk device may be:
an implant;
a life supporting or life sustaining device; or
a device of substantial importance in diagnosing curing, mitigating, or treating disease, or in otherwise preventing impairment of human health.

15. Do I need an IDE? Examples for Sponsor Investigators

16. Is an IDE Required? Example 1
A CABG patient has myocardial ischemia associated with a high-grade stenosis in the SVG to the RCA.
The clinician plans to perform SVG PCI with implantation of a DES that is approved for native coronary arteries.
The clinician plans to collect SVG PCI information required by the institution as part of a quality assurance plan.

17. Determining the Need for an IDE Submission
Question to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
If NO, then an FDA approved IDE is not required.
  
An IDE is Not Needed
Although the device is being used off-label, the clinician does not plan to systematically collect safety and effectiveness data. This use would fall under practice of medicine (although clinical studies for this indication are encouraged).

18. Is an IDE Required? Example 2
Investigator-initiated research will study a covered stent to treat stenosis at the venous anastomosis of 2 different A-V access grafts to determine whether patency of the covered stent is affected by the access graft type.
The covered stent and the two AV access grafts are FDA-approved/cleared and are being used in accordance with their labeling.
The covered stent labeling does not specify the brand of A-V access graft with which it can be used.
The investigator intends to publish the results.

19. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.

20. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.
  
The research constitutes a clinical study because the investigator plans to systematically collect safety and effectiveness data

21. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.
  
Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?
If NO, then the study is exempted from the IDE regulations and an FDA approved IDE is not required.

22. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.
  
Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?
If NO, then the study is exempted from the IDE regulations and an FDA approved IDE is not required.  

23. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?
If YES, proceed to next question.
If NO, then the study is exempted from the IDE regulations and an FDA approved IDE is not required.  
All devices are being used in accordance with their labels, so the study is exempted, and no IDE submission is required.

24. Is an IDE Required? Example 3
The investigator intends to compare the performance of two approved coronary DES to treat of stenotic SVGs.
The stents are FDA-approved for the treatment of native coronary artery lesions.
The investigator intends to publish the results.

25. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.
  
Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?

26. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.
  
Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?

27. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Is the Investigational Device a Significant Risk (SR) Device (per 21 CFR 812.3(m) and (a)(1)?
(a) Is the investigational device intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a subject?
(b) Is the investigational device 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?
(c) Is the investigational device 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?
(d) Does the investigational device otherwise present a potential for serious risk to the health, safety, or welfare of a subject?
If YES to any of questions (a) - (d), the study utilizes a Significant Risk Device and therefore requires IDE approval prior to study initiation.
  
N/A

28. An IDE is Needed
The research constitutes a clinical study because the investigator plans to systematically collect safety and effectiveness data.
Although the devices are commonly used off-label for the treatment of stenotic SVGs, the proposed prospective clinical study of these significant risk devices requires IDE and IRB approval prior to initiation.

29. Is an IDE Required? Example 4
An investigator is treating patients with suprarenal AAA’s using an aortic endovascular graft that he modifies by creating fenestrations to allow blood flow into branch vessels.
The endovascular graft is FDA-approved for the treatment of an infrarenal AAAs.
The investigator plans to present his case series at a professional society meeting and publish the results.

30. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
It should: proceed to next question.
N/A
Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.

31. Determining the Need for an IDE Submission
Questions to Address
Determining the Need for an IDE Submission
YES NO
Does the research constitute a clinical study?
It should: proceed to next question.
N/A
Does the study involve: a) an off-label use of a medical device that has been approved/cleared by the FDA; or b) an Investigational Device?
If YES, proceed to next question.
If NO, then an FDA approved IDE is not required.
  

32. An IDE is Needed
Once the physician modifies the endograft by making fenestrations in the marketed device, it becomes an investigational device.
And the new device also has a different intended use as compared to the marketed device.
The only mechanism for using an investigational device is through application of the IDE regulations.
Safety and effectiveness data should be systematically collected.
The clinical study of the significant risk investigational device requires IDE and IRB approval prior to initiation.

33. Parting Thoughts
IDE approval is needed for some clinical research studies, depending on:
the device’s approval status;
the intended clinical use; and
whether it is a significant risk or non-significant risk device.
Contact FDA if you are not sure whether an IDE is needed.
Early interaction with the appropriate branch in the Division of Cardiovascular Devices is recommended to discuss the entire IDE process.
Helps sponsor-investigators determine what’s needed to meet IDE requirements.

35. Back-ups

36. Outline Investigational Device Exemptions (IDE) regulations
IDE basics and decision-making
IDE applicability to clinical studies
Practice of medicine and off-label use
Exempted investigations
Significant risk studies
Case studies for sponsor-investigators
Is an IDE required?

37. Early Feasibility Study (EFS) Program Contact: andrew.farb@fda.hhs.gov
Intent - CDRH priority program intended to facilitate the clinical evaluation of medical devices in the US under the IDE regulations
Definition of an EFS - Small number of subjects for a device that may be early in development, typically before the design has been finalized
Key Guidance Principle - Approval of an EFS IDE may be based on less nonclinical data than would be needed to support the initiation of a larger clinical study
Guidance Provisions – A regulatory toolkit that enables sponsors and regulators to think in new ways about:
Device development
Appling benefit-risk principles and risk mitigation strategies
Justifying the appropriate data needed to move from bench to clinical study
The implementation of timely device and clinical protocol modifications
Contact:

38. CDRH’s Expedited Access Pathway
For devices with the potential to address unmet needs for life threatening or irreversibly debilitating diseases or conditions
More FDA interaction and assignment of a case manager
Senior CDRH management involvement
Priority PMA review
Potential for FDA to accept greater uncertainty for approval if available data demonstrate a reasonable assurance of safety and effectiveness
Use of a Data Development Plan to appropriately balance pre- and post-market data requirements

39. Practice of Medicine
Section 1006 of the Food, Drug and Cosmetic Act specifically states that: Nothing in this Act shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship.
Practice of medicine is not doing a study
Clinical studies do not fall under the
definition of practice of medicine.