Challenges in Using a Formal Decision Analysis Approach to Medical Device Approval

1. Challenges in Using a Formal Decision Analysis Approach to Medical Device Approval Larry Kessler, Sc.D. Director, Office of Science and Engineering Laboratories CDRH, FDA

2. Our Legal Mission • Evidence for Safety • Are there reasonable assurances, based on valid scientific evidencethat the probable benefits to health from use of the device outweigh any probable risks? • Evidence for Effectiveness or Clinical Utility • Is there reasonable assurance based on valid scientific evidencethat the use of the device in the target population will provide clinically significant results?

3. RANGE OF REGULATED PRODUCTS CDRH regulates a diverse group of medical devices, from contact lenses to condoms, and from pregnancy test kits to MRI machines, and a wide assortment of radiological devices.

4. Diversity of regulated products requires risk based approach: Heart Valve Patient Examination Table Blood Pressure Cuff Contact Lens Stethoscope Infusion pump Pacemaker Hip Implant Biopsy Device Test Strips

5. From Design to Obsolescence: Medical Devices and Center for Devices and Radiological Health, FDA{Total Product Life Cycle} {Industry/Customers} Clinical Community Design, Lab/Bench Clinical FDA Postmarket Modification Testing Testing Review Evaluation MDR Program Postmarket Surv Epidemiology Field Inspection Postapproval (PMA) ‘Design’ Device evolution ‘Obsolescence’ Clinical Community

6. Isn’t this simple? • Why not just enumerate risks and benefits, put on some common scale (e.g., QALYs) and approve or clear if net is positive? • Can be done with “high risk” products! • Legal and regulatory challenge with “me too” products [510(k)]

7. The 510(k) Pathway • By statute, requires only substantial equivalence to products marketed in 1976 • Submissions generally contain inadequate information for developing a thorough risk-benefit profile • N.B. The vast majority of products, even many innovative ones, come to the market with this approach

8. However… • “High risk” 510(k) products have been identified • The data requirements for these do include clinical study (not always RCTs) • With guidance, FDA should be able to ask for a rough risk assessment

9. PreMarket Approval (PMA) • Although only a few products, 40-60 original PMAs per year, these represent cutting edge technology • FDA asks for information that would allow a risk-benefit analysis • The legal requirement of “reasonable assurance of safe and effective” close to but not exactly = risks>benefits

10. Another however… • Practical considerations in conducting formal decision-analysis for devices: • Clinical studies usually small or not available • Many device risks are unanticipated, many involve use error – how to count? • As usual, risks and benefits not on the same scale and difficult to quantify • Device use denominators rarely available • Off label use common – less known

11. A Hypothetical Example • MANUFACTURER: KESSLER MANUFACTURING • PRODUCT: BIOPSY FORCEPS - REUSABLE • PROCODE/GMDN CODE: FLN/48321 • MARKET PATHWAY: 510(k) • INDICATION FOR USE: Polyp removal for precancerous or cancerous lesions in the proximal and distal colon. • PROJECTED POPULATION EXPOSURE/USE • 1 millions uses/year

12. Benefits • ENUMERATE BENEFITS: • Resection of colorectal polyps – reduction in morbidity from cancer: Minimally invasive procedure compared to colon surgery • Resection of colorectal polyps – reduction in mortality from cancer

13. Risks • ENUMERATE KNOWN RISKS: • Perforation from endoscope used to gain access for forceps (does this belong to this device or the procedure? Do we count this here to be “comprehensive”?) • Infection from incompletely sterilized forceps • ANY UNKNOWN OR SUSPECTED RISKS: • Forceps break during procedure requiring surgical resection to retrieve forceps ends and to complete the polypectomy.

14. Quantification Challenges • NUMBER OF PEOPLE, SIZE OF RISK OR BENEFIT (IN QALYs), PROBABILITY OF EFFECT OR OCCURRENCE: are data available? • Biopsy forceps with an endoscopic procedure • Less invasive than colon surgery • Reduction in morbidity with respect to the treatment of colon cancer. • Compare “new” device to no treatment, placebo, or current therapy?

15. Off Label Use • FDA has limited legal authority with off label use • If off label use causes adverse events, then this new paradigm will be able to incorporate such information into the analysis • If risks are significant • Dialogue with professional societies • Work with company • Labeling • Recalls in severe cases

16. Incorporating Postmarket Data • KNOWN RISKS • Infection reports due to poor cleaning: first year after marketing, 42 MDR reports sent to FDA claiming infection resulted from poor cleaning of device. • UNKNOWN/UNSUSPECTED RISKS • Forceps tear tissue causing bleeding and surgical repair. Data from a study of colon cancer treatment by NCI relating to patterns of care. In 4,000 cases, 8 bleeds and subsequent surgery occurred causing 2 extra days in hospital at a cost of $33,000 per case.

17. Regulatory Challenges • Risk acceptability is the province of the manufacturer! • 510(k) statutory language limits FDA • Who values each risk and benefit? Is FDA in a position to “judge” such estimation which will often be subjective? • A very large number of products require NO submissions to FDA (class I)

18. A Pilot Project? • Designing a pilot project • Formal decision analysis • Will work with a class of products (e.g., catheters, infusion pumps) • First, retrospective (we know the answers) • Evaluate and improve