Investigational Device Exemptions 21 CFR Part 812 A Review for OCRA US RAC Study Group September 2005 Ginger Clasby, MS Promedica International gclasby@promedica-intl.com 714-799-1617 x 25

IDE About the Regulation Provides procedures for conduct of clinical studies for unapproved devices Exempts products from 510(k) or PMA approval requirements: Registration, listing, interstate distribution Labeling GMPs Applies to most studies to determine device safety & effectiveness

When IDE Application Not Required Clinical Study Situations Device legally marketed for indicated use Marketing preference studies Market seeding studies Device is substantially equivalent to pre 1976 commercially distributed device Device is non-significant risk & IRB has approved study Many diagnostic devices Veterinary devices Custom device

Defining Device Types Significant or Non-Significant Risk? Significant Risk: device has potential for serious risk to patient health, safety or welfare Implants Products supporting/sustaining life Products with substantial role in diagnosing, curing mitigating or treating disease (or preventing impairment of human health) Non-Significant Risk: all other devices

Defining Device Types Significant or Non-significant Risk? How to decide? Sponsor makes initial determination; IRB makes final call

Regulatory Differences Significant vs. Non-significant Risk Significant Risk Devices require FDA (IDE) & IRB approval prior to clinical study initiation Non-Significant Risk Devices require only IRB approval prior to clinical study initiation IDE presumed, unless FDA notified Sponsor that application is required

IDE Application Contents Administrative Details Sponsor responsibility 3 copies of submission required All correspondence related to IDE sent by registered mail or by hand IDE approval required prior to study initiation

IDE Application Contents An Overview Sponsor name & address Report of prior investigations & investigational plan Description of methods, facilities, controls used for device manufacture, processing, packaging, storage & use Names of proposed investigators & example of proposed investigator agreements Certification that all investigators will sign agreement prior to study participation

IDE Application Contents An Overview List of name, address & chairperson of each IRB reviewing study If device will be “sold”, amount to be charged and rationale for why sale does not constitute commercialization Environmental exemption/assessment Proposed device labeling “Caution – Investigational Device Limited by Federal (or US) Law to Investigational Use” Copies of all informed consent documents

IDE Contents Report of Prior Investigations Reports of all prior clinical, animal & lab testing of device – should be adequate to justify proposed study Bibliography of related publications Summary of unpublished info Non-clinical lab studies (in compliance with GLP)

IDE Contents Investigational Plan Study purpose Proposed protocol Risk analysis Device description Monitoring procedures Labeling Consent materials

IDE Contents Investigational Plan IRB info Info on core labs, reading centers, etc. Add’l records & reports

IDE Review/Approval FDA’s Considerations Approval/disapproval decision Rendered in writing Rendered  30 days of FDA receipt Approval may be denied/rescinded if: Sponsor fails to comply with applicable regulations Sponsor is non-responsive to requests for add’l info Subject risks outweigh benefits Unreasonable to proceed due to inadequacy of investigational plan, manufacturing or monitoring

Prohibited Practices Under IDE Sponsors & Investigators Promotion of investigational product Representing device as safe or effective for use in the study Commercializing device by charging more than cost-recovery Unduly prolonging study Enrolling more subjects than necessary

IDE Supplements Necessary When: Changes made to investigational plan that may affect: Scientific soundness of study Rights, safety or welfare of study subjects Changes in device design Changes in device manufacturing Addition of study investigators

“Treatment” IDE Appropriate When: Device intended to treat or diagnose serious or life-threatening condition No satisfactory alternative available Controlled clinical trials in progress under IDE Or when trials completed & FDA review of request to market is pending Sponsor actively pursuing device marketing approval with FDA

Sponsor Responsibilities Subpart C Selection of qualified investigators & maintenance of ongoing communications Appropriate monitoring of study Special emphasis on device-related adverse events Confirmation of IRB review/approval Submission of IDE application to FDA Prompt notification of significant new information to FDA, IRB

Sponsor Responsibilities Subpart G – Records Maintenance of records: Study-related correspondence Device shipment/disposition Signed investigator agreements & financial disclosure info Non-significant risk justification (if applicable) Adverse device effects & complaints Record retention ≥ 2 yr after study completion or date no longer required for PMA application Record custody transferable with notice to FDA

Sponsor Responsibilities Subpart G – Inspections Must permit access by FDA employees to inspect facility where devices are held Must permit access by FDA employees to inspect & copy study-related records

Sponsor Responsibilities Subpart G – Reports Unanticipated adverse device effects – 10 working days Withdrawal of IRB approval – 5 working days Withdrawal of FDA approval – 5 working days Current investigator list – every 6 months Progress reports – at least yearly Device recalls & disposition – 30 working days

Sponsor Responsibilities Subpart G – Reports Study completion (significant risk) - 30 working days Final report - 6 months Use of device without written consent – 5 working days Significant risk determination – 5 working days

IRB Responsibilities Subpart D Membership, duties & functions in accordance with 21 CFR 56 Review of research Initial review prior to study initiation Significant risk determination, if necessary Continuing review throughout study

IRB Responsibilities Subpart G – Records & Reports Records maintained in accordance with 21 CFR 56

IRB Responsibilities Subpart G – Inspections Must permit access by FDA employees to inspect & copy study-related records

Investigator Responsibilities Subpart E Compliance with: Investigational plan Investigator agreement(s) Applicable FDA regulations Protection of subject rights & welfare Control of investigational devices Obtaining consent in accordance with 21 CFR part 50 Repeated noncompliance with assigned responsibilities may result in investigator disqualification by FDA

Investigator Responsibilities Subpart G – Records Maintenance of records: Study-related correspondence Product receipt, use, or disposition Subject case records Protocol & amendments Record retention ≥ 2 yr after study completion or date no longer required for PMA application Record custody transferable with notice to Sponsor, FDA

Investigator Responsibilities Subpart G – Inspections Must permit access by FDA employees to inspect facility where devices are held Must permit access by FDA employees to inspect & copy study-related records Must permit access by FDA employees to inspect & copy records identifying subjects, if: Suspicion that adequate consent was not obtained Required investigator reports incomplete, inadequate, false

Investigator Responsibilities Subpart G - Reports Unanticipated adverse device effects – 10 working days Withdrawal of IRB approval – 5 working days Progress reports – at least yearly Deviations from investigational plan – 5 working days Device use without documentation of consent – 5 working days Final report - 3 months

IDE Regulation Reference Documents & Links (www.fda.gov/cdrh) Guidance on IDE Policies & Procedures (1/1998) Early Collaboration Meetings Under FDA Modernization Act (FDAMA), Final Guidance for Industry & CDRH Staff (2/2001) Guidance on Significant & Non-Significant Risk Device Studies 7/25/86 (D86-1) The Least Burdensome Provisions of FDA Modernization Act of 1997: Concept & Principles; Draft Guidance for FDA & Industry (5/3/2001)

IDE Regulation Reference Documents & Links (www.fda.gov/cdrh) FDA Guidance for Financial Disclosure by Clinical Investigators FDA Guidance for IRBs & Clinical Investigators FDA Guidance for Monitoring Clinical Investigations FDA/ORA Compliance Program Guidance for Bioresearch Monitoring of Clinical Investigations FDA CDRH Device Advice