What is an IDE? Is Clinical Data Conducted Outside the U.S. Acceptable?

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What is an IDE? Is Clinical Data Conducted
Outside the U.S. Acceptable?

• Carole C. Carey, BSEE, M.Engineering
• carole.carey_at_fda.hhs.gov
• Director, International Staff
• US Food and Drug Administration (USFDA)
• Center for Devices and Radiological Health (CDRH)

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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

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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
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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

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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 50.25 -- elements of IC
• Section 50.23 -- IC waiver (emergency)
• Section 50.24 -- 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

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Applicable Regulations- contd (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 FDAs 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)

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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.

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The Regulatory Path
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October 7, 2009
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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)

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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.
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Investigational Plan

• Purpose
• 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

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Investigational Plan (contd)

• 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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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Differing levels of regulatory control
depending on the level of risk
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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

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FDA Review Criteria (contd)

• 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

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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.

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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

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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.

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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

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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.

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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.