1. Legal Considerations in Cross Labeling Policy Nancy Stade Assoc. Chief Counsel, Devices FDA/DIA Combination Products and Mutually Conforming Labeling Workshop May 10, 2005 Nancy Stade Assoc. Chief Counsel, Devices FDA/DIA Combination Products and Mutually Conforming Labeling Workshop May 10, 2005

2. Legal Considerations in Cross Labeling Policy 20 Questions with subparts 20 Questions with subparts

3. Legal Considerations in Cross Labeling Policy Can FDA legally approve Product B without the cooperation of Company A and without conforming labeling on Product A?

4. Legal Considerations in Cross Labeling Policy What is the simple, elegant answer that avoids thorny legal questions, complicated analysis, and potentially controversial applications of authority?

5. Legal Considerations in Cross Labeling Policy That would be: NO NO

6. Legal Considerations in Cross Labeling Policy The simple, elegant interpretation of FDA’s authorities may not be the interpretation that yields the best public health results, so…

7. Legal Considerations in Cross Labeling Policy Let’s embrace the complication.

8. Legal Considerations in Cross Labeling Policy Can FDA Make Cooperation More Attractive?Can FDA Make Cooperation More Attractive? What Legal Issues Arise When Labeling Does Not Conform?What Legal Issues Arise When Labeling Does Not Conform? Would Changes to the Regulation Help?Would Changes to the Regulation Help? Can FDA Make Cooperation More Attractive?Can FDA Make Cooperation More Attractive? What Legal Issues Arise When Labeling Does Not Conform?What Legal Issues Arise When Labeling Does Not Conform? Would Changes to the Regulation Help?Would Changes to the Regulation Help?

9. Can FDA Make Cooperation More Attractive? Cooperation is always preferred: Relieves concerns about interfering with Company A’s proprietary interests;Relieves concerns about interfering with Company A’s proprietary interests; Allows continued control over the two products as a combination.Allows continued control over the two products as a combination. Cooperation is always preferred: Relieves concerns about interfering with Company A’s proprietary interests;Relieves concerns about interfering with Company A’s proprietary interests; Allows continued control over the two products as a combination.Allows continued control over the two products as a combination.

10. Can FDA Make Cooperation More Attractive? What incentives might make the drug companies willing to play?

11. Can FDA Make Cooperation More Attractive? User fee waivers and reductions Are waivers/reductions available in the cross labeling context?Are waivers/reductions available in the cross labeling context? PDUFA: “significant barrier to innovation”.PDUFA: “significant barrier to innovation”. Some Product As subject to NDA or BLA likely to qualify for waiver/reduction (see guidance).Some Product As subject to NDA or BLA likely to qualify for waiver/reduction (see guidance). User fee waivers and reductions Are waivers/reductions available in the cross labeling context?Are waivers/reductions available in the cross labeling context? PDUFA: “significant barrier to innovation”.PDUFA: “significant barrier to innovation”. Some Product As subject to NDA or BLA likely to qualify for waiver/reduction (see guidance).Some Product As subject to NDA or BLA likely to qualify for waiver/reduction (see guidance).

12. Can FDA Make Cooperation More Attractive? User fee waivers and reductions Would user fee waivers or reductions suffice to overcome the reservations of drug & biological product makers that have refused to cooperate? User fee waivers and reductions Would user fee waivers or reductions suffice to overcome the reservations of drug & biological product makers that have refused to cooperate?

13. Can FDA Make Cooperation More Attractive? User fee waivers and reductions Note MDUFMA is more restrictive than PDUFA so waivers may be available when Product A is a drug or biological product, but not when it is a device. User fee waivers and reductions Note MDUFMA is more restrictive than PDUFA so waivers may be available when Product A is a drug or biological product, but not when it is a device.

14. Can FDA Make Cooperation More Attractive? Exclusivity Would an exclusivity term make cooperation more attractive for Company A?Would an exclusivity term make cooperation more attractive for Company A? Does Company B’s labeling affect the availability of exclusivity?Does Company B’s labeling affect the availability of exclusivity?Exclusivity Would an exclusivity term make cooperation more attractive for Company A?Would an exclusivity term make cooperation more attractive for Company A? Does Company B’s labeling affect the availability of exclusivity?Does Company B’s labeling affect the availability of exclusivity?

15. What Legal Issues Arise When Labeling Does Not Conform? Would the approval affect the adequacy of Company A’s labeling?Would the approval affect the adequacy of Company A’s labeling? What are the exclusivity considerations?What are the exclusivity considerations? Does the availability of generics matter?Does the availability of generics matter? Can FDA ensure s & e post-market?Can FDA ensure s & e post-market? Would the approval affect the adequacy of Company A’s labeling?Would the approval affect the adequacy of Company A’s labeling? What are the exclusivity considerations?What are the exclusivity considerations? Does the availability of generics matter?Does the availability of generics matter? Can FDA ensure s & e post-market?Can FDA ensure s & e post-market?

16. What Legal Issues Arise When Labeling Does Not Conform? Would the approval infringe Company A’s protected interests? For 505(b)(2)s, concern about inherent reliance upon data submitted by pioneers.For 505(b)(2)s, concern about inherent reliance upon data submitted by pioneers. What data must Company B include about Product A to overcome this concern in the cross labeling context?What data must Company B include about Product A to overcome this concern in the cross labeling context? Would the approval infringe Company A’s protected interests? For 505(b)(2)s, concern about inherent reliance upon data submitted by pioneers.For 505(b)(2)s, concern about inherent reliance upon data submitted by pioneers. What data must Company B include about Product A to overcome this concern in the cross labeling context?What data must Company B include about Product A to overcome this concern in the cross labeling context?

17. What Legal Issues Arise When Labeling Does Not Conform? Adequate Directions for Use A drug/device is misbranded unless its labeling bears adequate directions for each intended use;A drug/device is misbranded unless its labeling bears adequate directions for each intended use; Could approval of product B create a new intended use for product A?Could approval of product B create a new intended use for product A? Adequate Directions for Use A drug/device is misbranded unless its labeling bears adequate directions for each intended use;A drug/device is misbranded unless its labeling bears adequate directions for each intended use; Could approval of product B create a new intended use for product A?Could approval of product B create a new intended use for product A?

18. What Legal Issues Arise When Labeling Does Not Conform? Exclusivity Would approval of Product B infringe Company A’s existing exclusivity term?Would approval of Product B infringe Company A’s existing exclusivity term? Would approval of Product B affect the availability of exclusivity?Would approval of Product B affect the availability of exclusivity? Even though Product B is a device or biological product?Even though Product B is a device or biological product?Exclusivity Would approval of Product B infringe Company A’s existing exclusivity term?Would approval of Product B infringe Company A’s existing exclusivity term? Would approval of Product B affect the availability of exclusivity?Would approval of Product B affect the availability of exclusivity? Even though Product B is a device or biological product?Even though Product B is a device or biological product?

19. What Legal Issues Arise When Labeling Does Not Conform? Exclusivity If Product A acquires exclusivity after approval of Product B, should Product B’s labeling be changed to specify Product A by brand? Exclusivity

20. What Legal Issues Arise When Labeling Does Not Conform? Can FDA assure safety & effectiveness of the two products used together post- market? When Product B is approved by PMA, conditions of approval can require monitoring of Product A;When Product B is approved by PMA, conditions of approval can require monitoring of Product A; When Product B is cleared by 510(k), special controls might be available.When Product B is cleared by 510(k), special controls might be available. Can FDA assure safety & effectiveness of the two products used together post- market? When Product B is approved by PMA, conditions of approval can require monitoring of Product A;When Product B is approved by PMA, conditions of approval can require monitoring of Product A; When Product B is cleared by 510(k), special controls might be available.When Product B is cleared by 510(k), special controls might be available.

21. 21 CFR 3.2(e)(3) “A drug device or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved, individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose.”

22. 21 CFR 3.2(e)(3) Could changes to the regulation (or to how the regulation is interpreted) remove legal obstacles to approval of Product B?

23. 21 CFR 3.2(e)(3) What is the effect of the language “individually specified”? Does this mean Product B’s labeling refers to brand name? Form? Strength?Does this mean Product B’s labeling refers to brand name? Form? Strength? Or can this mean Product B’s labeling refers to a particular chemical entity, regardless of maker, strength, or route of administration?Or can this mean Product B’s labeling refers to a particular chemical entity, regardless of maker, strength, or route of administration? What is the effect of the language “individually specified”? Does this mean Product B’s labeling refers to brand name? Form? Strength?Does this mean Product B’s labeling refers to brand name? Form? Strength? Or can this mean Product B’s labeling refers to a particular chemical entity, regardless of maker, strength, or route of administration?Or can this mean Product B’s labeling refers to a particular chemical entity, regardless of maker, strength, or route of administration?

24. 21 CFR 3.2(e)(3) What is the effect of the language “individually specified”? Read narrowly, the regulation allows more flexibility to review products as single entity products. What is the effect of the language “individually specified”? Read narrowly, the regulation allows more flexibility to review products as single entity products.

25. 21 CFR 3.2(e)(3) What does it mean that “labeling of the approved product would need to be changed”? This is the critical question because this language determines whether Product B can be approved without the cooperation of Company A.This is the critical question because this language determines whether Product B can be approved without the cooperation of Company A. Can we develop criteria that will allow the agency to find that in some cases, the labeling will not need to be changed?Can we develop criteria that will allow the agency to find that in some cases, the labeling will not need to be changed? What does it mean that “labeling of the approved product would need to be changed”? This is the critical question because this language determines whether Product B can be approved without the cooperation of Company A.This is the critical question because this language determines whether Product B can be approved without the cooperation of Company A. Can we develop criteria that will allow the agency to find that in some cases, the labeling will not need to be changed?Can we develop criteria that will allow the agency to find that in some cases, the labeling will not need to be changed?

26. 21 CFR 3.2(e)(3) Interpretations of the regulatory language affect whether a particular combined use will be considered a combination product.Interpretations of the regulatory language affect whether a particular combined use will be considered a combination product. It is unlikely that any interpretation will remove all of the difficulties that come into play when Company A refuses to cooperate.It is unlikely that any interpretation will remove all of the difficulties that come into play when Company A refuses to cooperate. Interpretations of the regulatory language affect whether a particular combined use will be considered a combination product.Interpretations of the regulatory language affect whether a particular combined use will be considered a combination product. It is unlikely that any interpretation will remove all of the difficulties that come into play when Company A refuses to cooperate.It is unlikely that any interpretation will remove all of the difficulties that come into play when Company A refuses to cooperate.

27. ConclusionConclusion The position that the agency can never approve Product B without conforming labeling on Product A is simple and may be legally defensible in many cases.

28. ConclusionConclusion We are eager to hear legally supportable alternatives to this position so we can arrive at the best public health outcome.