1. What is an IDE? Is Clinical Data Conducted Outside the U.S. Acceptable?
Carole C. Carey, BSEE, M.Engineering
Director, International Staff
US Food and Drug Administration (USFDA)
Center for Devices and Radiological Health (CDRH)

2. Learning Objectives
To gain an understanding of the Investigational Device Exemption (IDE) regulations.
The purpose of the IDE regulation
The major regulatory elements that constitute medical device Good Clinical Practices
Significant Risk and Non-Significant Risk Studies
FDA review criteria
Clinical trials outside U.S. and FDA jurisdiction
2009 Sep 29 Edmonton

3. statutory authority, FDCA, Section 520(g) 21 CFR Part 812
What is an IDE?
Investigational Device Exemption
To encourage discovery and development of useful medical devices for human use,
to the extent consistent with the protection of the public health and safety and with ethical standards,
while maintaining optimum freedom for scientific investigators in their pursuit of that purpose.
Allows the use of unapproved devices.
statutory authority, FDCA, Section 520(g) 21 CFR Part 812
2009 Sep 29 Edmonton

4. Definitions a PREMARKET device Investigational Device
Is still in the developmental stage
Is not considered to be in commercial distribution
The object of a clinical investigation is to determine safety and effectiveness
a MARKETED device
Investigational Use
Clinical evaluation of an already legally marketed device for a new intended use
2009 Sep 29 Edmonton

5. Applicable Regulations (Medical Device Good Clinical Practices)
21 CFR Part 812: Investigational Device Exemptions covers the procedures for the conduct of clinical studies with medical devices including application, responsibilities of sponsors and investigators, labeling, records, and reports.
21 CFR Part 50: Informed Consent, Human Subject Protections
Section elements of IC
Section IC waiver (emergency)
Section IC waiver (emergency research)
21 CFR Part 56: Institutional Review Boards covers the procedures and responsibilities for institutional review boards (IRBs) that approve clinical investigations protocols
2009 Sep 29 Edmonton

6. Applicable Regulations- cont’d (Medical Device Good Clinical Practices)
21 CFR 54, Financial Disclosure by Clinical Investigators, covers the disclosure of financial compensation to clinical investigators which is part of FDA’s assessment of the reliability of the clinical data.
21 CFR 820 Subpart C, Design Controls of the Quality System Regulation, provides the requirement for procedures to control the design of the device in order to ensure that the specified design requirements are met.
IDEs are exempt from GMP/QSR (except Design Controls)
2009 Sep 29 Edmonton

7. When is an IDE application required?
Research in human subjects conducted in the United States:
To support device marketing application: PMA, HDE or 510(k)
To collect safety and effectiveness information (e.g., for a new intended use of a legally marketed device)
Unapproved devices or new intended use of approved device (even if no marketing application planned) by sponsor-investigator.
2009 Sep 29 Edmonton

8. The Regulatory Path IDE PMA 510k !!! MARKET !!! 8 October 7, 2009
2009 Sep 29 Edmonton
October 7, 2009 8

9. Valid Scientific Evidence
Comes from…
Well-controlled investigations
Partially-controlled investigations
Studies & objective trials without matched controls
Well-documented case histories conducted by qualified experts
Reports of significant human experience with a marketed device
Valid scientific evidence is NOT…
Isolated case reports
Random experience
Unsubstantiated opinions (e.g., testimonials)
2009 Sep 29 Edmonton

10. Required Elements of an IDE
U.S. Sponsor (manufacturer or investigator)
Prior Investigations
Investigational Plan
Manufacturing Information
Investigator and IRB Information
Labeling
Informed Consent
Sales Information
“CAUTION - Investigational device.
Limited by Federal
(or United States) Law
to investigational use.”
2009 Sep 29 Edmonton

11. Investigational Plan Purpose Written Protocol & Analysis
Name and intended use of device
Objectives and duration of study
Written Protocol & Analysis
Methodology and an analysis demonstrating scientific soundness
Number of patients and sites
Inclusion and exclusion criteria
Statistical methods
Case Report Forms
2009 Sep 29 Edmonton

12. Investigational Plan (cont’d)
Risk Analysis
Description of all risks
Justification for investigation
Description of the Device
Each important component
Principle of operation
Copies of all labeling
Monitoring Procedures
Monitor to oversee progress of investigtion
2009 Sep 29 Edmonton

13. Endpoints: Outcome Variables
Parameters that determine study success:
Primary Effectiveness: The most clinically relevant parameters addressed by the clinical trial question
Safety Assessment: What are the expected & unexpected unfavorable outcomes & how can they be avoided?
Secondary effectiveness endpoints: Other parameters that support study success
2009 Sep 29 Edmonton

14. Strategies: Clinical Considerations
For CDRH:
US studies must be conducted in compliance with the IDE regulations (21 CFR Part 812)
Proper Informed Consent (21 CFR Part 50)
IRB Regulations (21 CFR Part 56)
Adequate monitoring
Dependent upon the data present & device characteristics, feasibility study often necessary prior to pivotal study
Support proof of concept
Assist with refining inclusion/exclusion criteria
Refine surgical technique
Recommendation of pilot study with control group
2009 Sep 29 Edmonton

15. Significant Risk Study is…
a study that presents a potential serious risk to the health, safety, or welfare of a subject
An implant
for use in supporting or sustaining human life
for a use of substantial importance in diagnosing, curing, mitigating, or treating disease or otherwise preventing impairment of human health
FDA and IRB Approval is required
Cardiac catheters
Surgical tissue adhesives
Vascular and arterial graft protheses
Dental endosseous implants
Cochlear implants
Implantable infusion pumps
Implantable pacemaker
2009 Sep 29 Edmonton

16. Non-significant Risk Study
Do not pose significant risk to research subjects
Sponsor presents protocol to IRB and a statement why investigation does not pose significant risk
If IRB approves the investigation as NSR, it can begin.
No IDE submission requirement to the FDA
Abbreviated IDE
Daily wear contact lenses
Glucose monitor
Magnetic resonance imaging (MRI)
Pulse oximeter
Ob/Gyn diagnostic ultrasound
2009 Sep 29 Edmonton

17. Abbreviated IDE No formal FDA approval is needed
IRB is required to meet all aspects of:
21 CFR Part 50 (protection of human subjects)
21 CFR Part 56 (IRB)
Labeling requirements
2009 Sep 29 Edmonton

18. Studies Exempt from Part 812
Preamendments (pre-1976) devices
510(k)-cleared and HDE- or PMA-approved devices, If used in accordance with approved label
In vitro diagnostic devices (most)
Consumer preference testing of marketed devices
Combinations of legally marketed devices
Custom devices (are narrowly defined)
Studies outside the US: Declaration of Helsinki
2009 Sep 29 Edmonton

19. Approved IDEs are Exempt from…
Registration
Performance Standards
510(k) regs
PMA regs
Misbranding regs
GMPs (except Design Controls)
Color Additive requirements
Banned Devices regs
Restricted Device requirements
2009 Sep 29 Edmonton

20. Approved IDEs are NOT Exempt from…
Adulteration regs
Labeling regs
Prohibition on: promotion/marketing, commercialization, prolonging the investigation, representing the device as safe and effective
Import/Export Regs
2009 Sep 29 Edmonton

21. Bioresearch Monitoring (BIMO) Program
To ensure the quality and integrity of data and information submitted in support of research and marketing permits that include  IDE, PMA, and 510(k) submissions, and
To ensure that human subjects taking part in investigations are protected from undue hazard or risk.
2009 Sep 29 Edmonton

22. Differing levels of regulatory control depending on the level of risk
2009 Sep 29 Edmonton

23. FDA Review Criteria Scientifically sound
Reasonably believed to be able to provide the desired results
Data from non-clinical studies support the proposed human research
Research conducted by qualified investigators
2009 Sep 29 Edmonton

24. FDA Review Criteria (cont’d)
Expected benefit outweigh any expected risks
Research subjects fully informed to the risks involved in the research, understand these risks and freely volunteer to participate
IRB approval of the research
2009 Sep 29 Edmonton

25. FDA Review Times and Decision
FDA review time for IDE is 30 days.
Within 30 days, FDA will approve, approve with conditions, or disapprove an IDE application.
For disapproved IDE, the sponsor can respond to the deficiencies and/or request hearing.
2009 Sep 29 Edmonton

26. Clinical Trials Outside U.S. (OUS)
“Acceptance of Foreign Clinical Studies: Guidance for Industry - Acceptance of Foreign Clinical Studies”, March 2001
FDA will accept a foreign clinical device study only if the study conforms to the ethical principles of the Declaration or with the laws and regulations of the country, whichever provides greater protection of the human subjects.
Subject to Human Subject Research Protections laws applicable in that country
Studies performed by clinical investigators of recognized competence
2009 Sep 29 Edmonton

27. Same scientific and data integrity standards
FDA does not have legal authority/jurisdiction outside of the United States
But FDA has authority to set conditions for accepting non-U.S. data that is used to support marketing (PMA, 510(k), HDE, etc.) in the U.S.
Once accepted for review, the same scientific and data integrity standards are applied as for studies conducted in the U.S.
2009 Sep 29 Edmonton

28. Early Consultation with FDA
If intended to support eventual marketing application in US, should:
Reflect US medical practice patterns
Reflect US patient population
Ensure adequate documentation of good study conduct, availability of raw data
Therefore: It is beneficial to consult with FDA (e.g., Pre-IDE) on clinical protocol beforehand if intended to support US marketing application
2009 Sep 29 Edmonton

29. FDA Jurisdiction
FDA has jurisdiction over the export of unapproved devices exported for use in foreign studies.
FDA does not have jurisdiction over the manner in which the investigational study is conducted outside the U.S.
An IDE is not necessary for a study conducted entirely at foreign sites.
FDA has authority to accept or deny data that has been collected during a study at a foreign site that is submitted to support a research or marketing application.
2009 Sep 29 Edmonton

30. Summary
All clinical investigations subject to the regulation must be approved before they can begin.
All subjects in the investigation must give informed consent – human subject protection.
The basics of good clinical studies and good clinical practices are the same worldwide.
2009 Sep 29 Edmonton