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