1. 1 Food and Drug Administration and Drug Information Association Cross-Labeling Workshop Kathryn L. Gleason On behalf of AdvaMed Bethesda, MD May 10, 2005 Combination Products and Mutually Conforming Labeling: LEGAL ISSUES

2. 2 OVERARCHING PRINCIPLES FOR PROPOSING SOLUTIONS TO CROSS-LABELING ISSUES Optimal flexibility needed to encourage innovation and advancement of public health Combination law includes framework for analyzing when cross-labeling is needed (21 C.F.R. § 3.2(e)(3)) Combination law provides separate and distinct authority from drug and device laws, and permits flexibility -- “any agency resources … necessary” to accomplish combination law objectives (Section 503(g)(2) of the Act) Flexibility is seen in Intercenter Agreement principles and precedents; this flexibility should be preserved and expanded

3. 3 OVERARCHING PRINCIPLES FOR PROPOSING SOLUTIONS TO CROSS-LABELING ISSUES Fairness: Non-cooperating entity (Co. A) must be protected against undue responsibility/liability Co. A proprietary information must be preserved consistent with rights offered by existing law New regulatory paradigm not needed: Existing statutory authority provides sufficient fundamental legal structure Clarifications may be made within this framework All issues of safety and efficacy must be addressed (risk-based principles to be applied)

4. 4 QUESTION 1: REASONS MANUFACTURERS DO NOT COOPERATE: EXAMPLES Legal/Regulatory ConcernsCommercial Concerns Product liabilityProtecting intellectual property/assets FDA exposure (QSR, postmarket compliance, etc.) Protecting/directing business strategies Fraud and abuseCompeting R&D and/or partnership interests with respect to drug delivery system Intellectual propertyCompeting R&D and/or partnership interests with respect to drug New safety/use concerns that could adversely affect drug franchise Cost/resources/expertise in dealing with new regulatory and science issues Non-related commercial disputes (e.g., between Co. A and Co. B) Customer relations concerns

5. 5 QUESTION 1: REASONS MANUFACTURERS DO NOT COOPERATE (cont’d) Involvement of FDA at premarket stage No statutory authority for FDA to require cooperation, and new statutory/regulatory authority not desired FDA intervention (even to request cooperation) not desirable, absent Co. B concurrence. If Co. B concurrence, should not be barrier to FDA intervention. Incentives (e.g., user fee waivers/reductions) could be considered, but should not require legislative fixes Note: Reasons for non-cooperation often cannot be fixed by regulatory solutions FDA INVOLVEMENT IN ENCOURAGING COOPERATION

6. 6 QUESTION 1: REASONS MANUFACTURERS DO NOT COOPERATE (cont’d) Postmarket involvement by FDA: Greater authority to require more active involvement by Co. A Supplemental requirements (21 C.F.R. § 314.70(b)) GMP requirements Postmarket vigilance (notification to FDA of safety problems) (21 C.F.R. §§ 310.305, 314.80) Postmarket labeling changes (Section 201(n) of the Act; 21 C.F.R. § 201.128) FDA INVOLVEMENT IN ENCOURAGING COOPERATION

7. 7 QUESTION 2: INFORMATION THAT MAY AND MAY NOT BE USED IN SUPPORT OF COMPANY B’s PREMARKET REVIEW Information that may not be used: Any solution must protect data to which Co. B does not have a right to reference Section 505(l) of the Act provides protection of Company A’s safety and effectiveness data through date of approval of first ANDA Any 505(b)(2) debates (e.g., including questions about “inherent” reliance) should be resolved under drug law -- not a combination law issue

8. 8 QUESTION 2: INFORMATION THAT MAY AND MAY NOT BE USED IN SUPPORT OF COMPANY B’s PREMARKET REVIEW (cont’d) Information that may be relied on: Both drug and device laws permit use of information in public domain to support approvals (e.g., 505(b)(2) process; 21 C.F.R. §§ 814.9(f)- (h), 814.20(b)(8), 20.81)) Drug laws recognize that changes in dosage, route of administration, and indication could be supported by public domain information (FDA, Applications Covered by Section 505(b)(2) (Draft, Oct. 1999)) Combination policies historically have acknowledged that prior approvals may reduce efficacy data demands for combined drug/device products CDER/CDRH ICA: “an additional showing of clinical effectiveness of the drug when delivered by the specific device will generally not be required”

9. 9 QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING Adequacy of Labeling from Regulatory Perspective Law allows for differentiating adequacy of drug label from labels of those products subject to combination law Section 503(g)(2): “[n]othing shall prevent us[e] [of] any agency resources … necessary to ensure adequate review of the safety, effectiveness, or substantial equivalence of an article” Questions Co. A will ask with respect to the regulatory adequacy of its labeling: Sections 201(n), 502 of the Act; 21 C.F.R. § 201.128 -- Does awareness of new use impute obligation to revise labeling? Supplemental laws (Section 505 of the Act, 21 C.F.R. § 314.70) -- Does awareness of new use trigger notification requirements under NDA/BLA laws?

10. 10 QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING Adequacy of Labeling from Regulatory Perspective (cont’d) FDA clarifications will be required to protect Co. A from needless regulatory exposure FDA should more expressly acknowledge that combination law represents a unique regulatory category, and that combination law can be defined separately from drug and device laws (Sections 503(g), 563 of the Act) FDA could stipulate that Company B will be solely responsible for premarket review of labeling adequacy (including adequate directions for use) FDA could stipulate that approval/clearance of Co. B’s labeling would not itself cause misbranding of Co. A’s product FDA may wish to retain some postmarket misbranding authority, if, for example, Co. A begins to promote the combined use of its drug with Co. B’s devices

11. 11 QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING (cont’d) Adequacy of Labeling From a Commercial (e.g., Product Liability) Perspective Where product is “individually specified” (branded, proprietary) in labeling Concerns with adequacy of warnings and related theories, since Co. A will be aware of new uses Co. A concerns with confusion/conflicts created by Co. B labeling Protections that FDA offers to mitigate these concerns Possible preemption if reviewed under device law; theories untested Ordinary course of business: contractual agreements need to define roles/responsibilities of parties to address these liability concerns

12. 12 Where product is not “individually specified” (i.e., not branded, proprietary) in labeling: Co. A product will not be cited specifically in Co. B labeling Thus, Co. A liability should not be a significant concern All clinically relevant information on use of device with drug will be included in device labeling QUESTION 3: ENSURING ADEQUACY OF COMPANY LABELING (cont’d) Adequacy of Labeling From a Commercial (e.g., Product Liability) Perspective

13. 13 QUESTION 4: EXCLUSIVITY IMPLICATIONS Principal purposes of FDA exclusivity laws: protection against inappropriate generic drug competition and inappropriate use of proprietary data Assuming no reliance on proprietary drug data and no generic drug competition, drug marketing exclusivity should not impede device (PMA/510(k)) review of Co. B product If patent issues, Co. A and Co. B would address those issues through appropriate (non-FDA) legal recourse Even with these safeguards, AdvaMed nonetheless believes that contractual agreements between Co. A and Co. B will be required in this context

14. 14 QUESTION 4: USE OF GENERICS OR OTHER “PUBLIC DOMAIN” DRUGS (e.g., USP) (cont’d) Drugs for which non-proprietary information may be available: ANDA drugs; drugs otherwise off-patent and without market exclusivity; USP, grandfathered, DESI, and OTC drugs Existing law recognizes that these drugs should not require mutual conformance in Co. A labeling These drugs would not be “individually specified” (i.e., by brand) in Co. B labeling 21 C.F.R. § 3.2(e)(3) affords optimal flexibility where drugs are not individually specified; cross-labeling not required Change management less of an issue; existing laws for these drug categories do not allow for significant changes

15. 15 QUESTION 5: REGULATORY TOOLS TO ENSURE APPROPRIATE ONGOING FDA OVERSIGHT Co. B conditions of approval; special controls for 510(k) devices 21 C.F.R. §§ 814.44(e), 814.82 Section 513(a)(1)(B) of the Act Co. A and Co. B notification to FDA of drug specifications/manufacture changes, as required Sections 505, 506A of the Act; 21 C.F.R. §§ 314.70(b), 807.81(a)(3), 814.39 Co. A and Co. B GMPs/QSRs Sections 501(a),(h), 520(f) of the Act; 21 C.F.R. Parts 211 and 820

16. 16 QUESTION 5: REGULATORY TOOLS TO ENSURE APPROPRIATE ONGOING FDA OVERSIGHT (cont’d) Co. A and Co. B postmarket reporting mechanisms E.g., Section 519 of the Act; 21 C.F.R. §§ 310.305, 314.80, Part 803 Authority of FDA to require changes to Co. A and Co. B labeling as needed Section 201(n) of the Act; 21 C.F.R. §§ 201.128, 801.4 Conclusion: FDA has ample oversight authority over Co. A and Co. B products used together

17. 17 QUESTION 6: OPTIMAL APPROACH FOR CLARIFYING RELEVANT LAW Clarifications needed; ideally accomplished through guidance Examples of clarifications needed to encourage innovation and allow Co. B to proceed Cross-labeling standards should be applied with optimal flexibility to allow efficient, cost-effective development of innovative products Terms of “cross-labeling,” “mutual conformance,” and “individually specified” should be defined Device labeling alone may address drug used with device, where the drug is not “individually specified” (i.e., branded, proprietary)

18. 18 QUESTION 6: OPTIMAL APPROACH FOR CLARIFYING RELEVANT LAW (cont’d) Examples of clarifications needed to encourage innovation and allow Co. B to proceed (cont’d) Combination law is distinct from device and drug law and permits flexible solution: “any agency resources … necessary” to accomplish regulatory objectives (Section 503(g)(2) of the Act) Drugs for which historical safety and effectiveness information is available in the public domain, should not be considered “individually specified” Further clarification of information that may be relied on in the public domain, to support reviews (see slide 8) Clarification that ICA principles of flexibility will be sustained and expanded

19. 19 QUESTION 6: OPTIMAL APPROACH FOR CLARIFYING RELEVANT LAW (cont’d) Examples of clarifications needed to protect Co. A Affirmation that Co. A’s proprietary information is to be protected consistent with current law Clarifications needed to protect Co. A from undue responsibility/liability E.g., clarification that Co. B alone is responsible for premarket review concerning adequacy of labeling, testing, and design of delivery system/drug Enumeration/affirmation of postmarket regulatory oversight tools

20. 20 QUESTION 7: OTHER LEGAL CONSIDERATIONS Roles of/relationship between Co. A and Co. B on such issues as: respective responsibilities with regard to inspections; promotion; recalls; and other compliance activities relating to labeling Scenario 1 (branded, proprietary drug) -- Roles/responsibilities to be determined by contractual agreement Scenario 2 (drug is not “individually specified”) -- Co. B would be principal point of contact with FDA Other legal issues addressed during public health discussion (e.g., degree of labeling conformance required)

21. 21 Food and Drug Administration and Drug Information Association Cross-Labeling Workshop Kathryn L. Gleason On behalf of AdvaMed Bethesda, MD May 10, 2005 Combination Products and Mutually Conforming Labeling: LEGAL ISSUES