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

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?

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.

Diversity of regulated products requires risk based approach:

Test Strips

Infu

sion

pu

mp

Patient Examination Table

Heart Valve

Contact Lens

Hip Implant

Pacemaker

Biopsy Device

Blood Pressure Cuff

Stethoscope

From Design to Obsolescence: Medical Devices and Center for Devices and

Radiological Health, FDA{Total Product Life Cycle}

Design, Lab/Bench Clinical FDA PostmarketModification Testing Testing Review Evaluation

MDR ProgramPostmarket SurvEpidemiologyField InspectionPostapproval (PMA)

‘Design’ Device evolution ‘Obsolescence’

{Industry/Customers}

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)]

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

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

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

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

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

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

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.

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?

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

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.

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)

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