Combination Products and Mutually Conforming Labeling

1. Combination Products and Mutually Conforming Labeling David Eveleth Pfizer Inc.

2. Our view on combos without cooperation • There are issues that do not lend themselves to a regulatory solution • Safety • CMC • Legal • If the companies are not cooperating, ask why • In the long term, if the companies are not cooperating this usually means that approval is impractical • FDA’s role is NOT to broker business deals • FDA should be very cautious about this situation

3. Risk Assessment • Factors impacting the degree of risk • Severity of impact of failure of efficacy • Degree to which the device/drug combo is linked to the therapeutic effect in the patient or physicians mind • Copackaging and the opportunity to use both the device and the drug for multiple applications other than the one under consideration • Potential for variation within specifications to influence efficacy and safety for indication B differentially from indication A • Impact of mutually conforming or nonconforming labeling on risks

4. Clinical Safety issues independent of labeling • What will the mechanism of safety reporting and data sharing between two companies be? • How will attribution of adverse events be determined……was it the device or drug? • Will FDA mandate this or will the FDA take responsibility for attribution and ensure the correct events are reported to the appropriate label? • Should the agency establish and maintain a single safety database? Would both sponsors have any access to this? • How to deal with different underreporting and bias in the different populations • Risk management plans • How would FDA deal with two RMPs?

5. Safety Issues related to CMC • Specifications of each component are not transparent to the other manufacturer • Changes to specifications by either A or B will not be transparent to the other • Safety, Efficacy, Performance may be impacted • No practical way to determine that variance within the specification (in the absence of data) does not pose a safety risk for usage with the device or in the indication B • What if company A wants to change the specification and has adequate evidence that this is safe in indication A – does FDA take responsibility for risk assessment for indication B? • What happens when FDA concludes there is a risk

6. Efficacy • What if company submits a sNDA for new indication, is it necessary to conduct clinical studies to ensure the drug/device combination is safe and effective? • If that indication is similar to the drug/device combination indication? • If the combination studies are required but not conducted in the new population whose label is out of compliance? • If studies are required, FDA is defacto mandating that throughout the products life, both drug and device manufacturer must collaborate on all clinical development activities

7. Summary • Significant safety issues arise in the absence of cooperation • Conforming labeling has limited impact • There are issues that do not lend themselves to a regulatory solution • If the companies are not cooperating, ask why • In the long term, if the companies are not cooperating this usually means that approval is impractical • FDA’s role is NOT to broker business deals