1 3.051J/20.340J Lecture 24 FDA Approval Process for Medical Devices The Medical Device Business - $77B U.S. Market (2002) - 13,000 Registered U.S. Manufacturers (2003) many with no commercial products! - 300,000 U.S. Workers (2003) Top 20 devices by revenue (1999): 1) Incontinence supplies 11) Prosthetic knee implants 2) Blood glucose monitoring 12) Lens care products 3) Wound closure products 13) Prosthetic hip implants 4) Implantable defibrillators 14) Patient-montioring equipment 5) Soft contact lenses 15) Mechanical wound closure 6) Orthopedic fixation devices 16) Wound suture products 7) Pacemakers 17) Absorbable polymers 8) Examination gloves 18) Hearing Aids 9) Coronary stents 19) Wheelchairs and scooters 10) Arthroscopic accessories 20) Peritoneal dialysis sets Biomaterials are not regulated—medical devices are Biomaterials are approved for use as part of a specific medical device2 3.051J/2O.340J Regulation History 1906 Food and Drug Act - established the FDA - no provisions on medical devices (regulated by the U.S. Postal Service under postal fraud statutes) 1938 Food, Drug and Cosmetic Act - FDA regulation of device misbranding/adulteration (inadequate authority/resources for wide scale regulation) 1976 Medical Device Amendment Classified Devices & Regulatory Standards for Safety & Efficacy Class I: low risk, general controls sufficient over the counter products-e.g., adhesive bandages, hospital beds Class II: performance standards & general control physician controlled distribution-e.g., oxygen masks, blood-pressure cuffs, powered wheelchairs Class III: require pre-market approval devices that: “support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential unreasonable risk of illness or injury” Further regulation by the FDA under: 1990 Safe Medical Devices Act 1992 Medical Device Amendments 1997 FDA Modernization Act (Section 204)3 3.051J/20.340J FDA Regulatory Branches Center for Device and Radiological Health (CDRH): medical devices Center for Drug Evaluation and Research (CDER): drugs Center for Biologic Evaluation and Research (CBER): biological therapeutics combination products (therapeutic + device) may fall under any of above Premarket Approval Process for Class III Devices Established in: Title 21 Code of Federal Regulations (CFR) Part 814 1. Administrative and limited scientific review - conducted by FDA personnel within 45 days of receipt - determines if application is of sufficient quality for filing - “filing” initiates 180-day review clock 2. In-depth scientific, regulatory and Quality System review - conducted by FDA personnel - includes inspection of manufacturing facility - usually results in a “deficiency letter” voices FDA concerns with an application Major deficiency letter – stops the 180-day clock Minor deficiency letter – 180-day clock continues - applicant has 30 days to respond 3. Advisory panel review43.051J/20.340J - first-of-a-kind devices - 5 outside experts in field of device, + industry & consumer reps. - public hearing on safety & efficacy of device including applicant - Panel makes recommendation to FDA 4. FDA notification - generally concurs with panel - usually 6-18 months after panel decision - outcomes: Approval order – private license granting applicant permission to market device - A PMA may be sold to another company - licensees must submit a PMA application showing substantial equivalence Approvable letter – device substantially meets FD&C Act; specific info. required or conditions for approval e.g., labeling requirements, sale restrictions, post-approval study Not approvable letter – device fails to meet safety and efficacy std. - applicant may amend PMA - file petition for reconsideration - withdraw the PMA (default) PMA Review Fees Established by: Medical Device User Fee and Modernization Act 2002 Standard fee (2006): $259,600. Small Businesses (gross sales < $100M): $98,648. Fees waived for 1st time applicants with sales < $30M5 3.051J/20.340J What Goes into the PMA Application? 1. Applicant name & address 2. Table of Contents 3. Summary 4. Device Description including components, composition, principles of operation, methods of manufacture, packaging, storage, and use 5. Reference to performance or voluntary standards American Society for Testing and Materials (ASTM) standards compositions, mechanical testing, corrosion testing, device standards Association for the Advancement of Medical Instrumentation device standards, procedure standards (e.g., sterilization processes) International Standards Organization (ISO) 10993 guidelines biocompatibility tests Applicant demonstration of how device meets standards 6. Technical data on safety and efficacy - Non-clinical laboratory studies: biocompatibility, stress, wear, shelf-life - Clinical studies 7. Justification if single-investigator study 8. Bibliography of all related published reports with synopsis 9. Samples of the device 10. Proposed labeling of the device 11. Environmental assessment of device 12. Financial certification and disclosure statement 13. Other information requested by the FDA6 3.051J/20.340J What Biocompatibility Testing is Required? Recommended tests depend on the category of device I. Non-contact devices II. External contact devices A. Intact surfaces: contact with external body surfaces only e.g., electrodes, external prostheses, monitors B. Breached or compromised surfaces e.g., burn dressings, wound-healing devices, occlusive patches III. Externally communicating devices A. Intact natural channels e.g., contact lenses, urinary catheters, colonoscopes B. Blood path, indirect: conduit for fluid entry to vasculature e.g., solution and blood administration sets C. Blood path, direct: contact circulating blood e.g., IV catheters, dialyzers and tubing, oxygenators and tubing IV. Internal devices A. Bone e.g., orthopedic plates & pins, bone prostheses, cements B. Tissue and tissue fluid (incl. prolonged mucous membrane) e.g., pacemakers, drug delivery devices, breast implants, IUDs C. Blood e.g., pacemaker electrodes, vascular grafts, heart valves7 3.051J/20.340J FDA Biocompatibility Test Matrix FDA Recommended Testing (1995) II III IV A B A B C A B C Irritation tests X X X X X X X X Sensitization assay X X X X X X X X Cytotoxicity X X X X X X