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 evidence that 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 evidence that 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: Test Strips Infusion pump Patient Examination Table Heart Valve Contact Lens Hip Implant Pacemaker Biopsy Device Blood Pressure Cuff Stethoscope

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

6. Isnt 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