Combination Products: Cross Labeling and Single Entity Labeling

2. Combination Products: Cross Labeling and Single Entity Labeling Bradley Merrill Thompson, MBA, JD, RAC Epstein Becker & Green PC RAPS 2008 Annual Meeting Boston September 15, 2008

3. Agenda • Cross labeling • Background • CPC’s proposed approach • Labeling for single entity combination products • FDA reviews of labeling changes I feel like Zsa Zsa Gabor’s fifth husband. I know what I'm supposed to do but I don't know if I can make it interesting. Al Gore

4. Background on Cross-labeling Issues (many slides courtesy of FDA) Politics gives guys so much power that they tend to behave badly around women. And I hope I never get into that. Bill Clinton

5. What is a Combination Product? • Statute -- 503(g)(1) • Products that constitute a combination of a drug, device, or biologic • Combination products are diverse: • Drug-device • Device-biologic • Drug-biologic • Drug-device-biologic

6. Three Types of Combination Products • 21 CFR 3.2(e) • Single-entity: a product comprised of two or more regulated components that are physically, chemically or otherwise combined or mixed as a single entity • Kits: two or more separate products packaged together (e.g., drug and device products) • Cross-labeled: provided separately but intended for use together where both are required to achieve the intended use and where cross labeling is needed

7. Examples of Cross-Labeled Combination Products • Drug requiring specific device for administration • Diagnostic device required for use with a specific drug or biological product • Photodynamic therapy drug and laser/light source

8. Not Combination Products • Most concomitant use of drugs, devices and biologics • Drug-drug, device-device, or biologic-biologic combinations; e.g., • Products with two biologics, even if shared CDER and CBER role • General devices intended for use with a class or otherwise unspecified drug/biologic products • Unfilled syringe or diagnostic test without specifying a particular drug

9. What is Cross Labeling? • 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…. 21 CFR 3.2(e)(3)

10. What’s so hard about that? Hypothetical Company A is the sponsor of approved drug product A. Company B wants to obtain premarket approval for device B which will administer product A in a new dosage form, strength, route of administration, or intended use. Company A does not want to cooperate with Company B in this venture. Can FDA approve device B?

11. Some of the questions… What does individually specified mean? What if product B has other approved intended uses? When does label of Product A “need to be changed?” If labeling of Product A does need to be changed, but Company A does not want to submit a supplement to its marketing application, does that mean that Product B cannot be approved?

12. Public Workshop • May 10, 2005 • Transcript and presentations accessible on OCP website: http://www.fda.gov/oc/combination/ • Comments available on docket

13. Why is a cross labeling policy important? • Confusion about whether Company A must participate may deter product development • Greater clarity may be more efficient

14. Situations where cross labeling issues arise • Product B enhances safety or effectiveness of Product A • Product B uses Product A in a new route of administration

15. More cross labeling situations…. • Product B uses Product A for new indication, new patient population • Product B is a new component of an already approved combination product • originally approved under two applications • originally approved under one application

16. And still more… • Labeling of Product B and Product A will be inconsistent in some way • Labeling of Product B and Product A will be contradictory

17. Categories of Issues • Labeling issues – possible end user confusion • No ongoing relationship between manufacturers issues – what if product A is reformulated or redesigned • Will reviewing application covering Product B necessarily rely on proprietary information in application covering Product A? • Pathway issues

18. Why is this so challenging? • Company A’s proprietary interests • FDA’s core beliefs about labeling • Company B’s commitment to Product B

19. Protect and Promote the Public Health • FDA prefers cooperation • In the absence of cooperation, FDA’s goal is to identify a regulatory pathway for Product B while ensuring adequate regulatory oversight. • What should be FDA’s default position?

20. Points to Consider Consider whether labeling of Product A “needs to be changed” • Is Product A intended to be used for a new intended use, dosage form, strength, or route of administration, • Is end user confusion likely? • What would happen if Product A is reformulated or redesigned without notice to Company B? • Would Company B rely on proprietary information in application covering Product A?

21. CPC’s Proposed Approach One way to make sure crime doesn't pay would be to let the government run it. Ronald Reagan

22. The Answer Requires Greater Precision in the Definition of a Combo Product • Most of the questions disappear when products are properly categorized into: • Combination Products • Nearly combination products, but not • Clearly not combination products • We will show an algorithm for properly classifying products

23. Four Principles • FDA should not play matchmaker between companies. • The economic incentives that are most likely to lead to important public health breakthroughs are outside of FDA’s control. • FDA must approve or disapprove the products as companies propose them, based on the evidence. • ButFDA, importantly, does have flexibility under the law to weigh the risks.

24. Why Companies Don’t Always Want to Collaborate • Potential impact on their product’s safety-effectiveness profile • Intellectual property and confidentiality concerns • Conflicting business strategies • Resource priorities • Costs • Product liability issues • Interest in competing products (drugs or delivery systems, for example) • Existing partnerships

25. Why Companies Don’t Want to Collaborate • Control • Risk of having someone else’s “issues” control your resources • Potential limits on flexibility • Changes have greater impact • Manufacturing and quality concerns • Desire to develop and retain internal expertise • Familiarity or lack of familiarity with a potential “partner” or product • Differing perceptions on market size and what constitutes “success” • Ex: A sizeable market to a small device company may not appear as large to a major pharmaceutical company • Additional regulatory exposure

26. FDA’s Authority • FDA derives its authority from the Food, Drug and Cosmetic Act (“Act”). • The Act gives FDA broad authority. For example, FDA can: • Promulgate regulations for enforcement of the Act • Some limitations • Approve drugs and devices, license biological products • Regulate use of drugs, biologics and devices, including those used for investigational purposes • Require manufacturers to include “adequate directions for use” in labeling

27. FDA’s Authority Limits • FDA’s authority is not all-encompassing. For instance, FDA does not have the authority to: • Require that companies work together • Mandate that a manufacturer seek approval for new uses of its product • Association of American Physicians and Surgeons, Inc. v. FDA • Force manufacturers to “mutually conform” their labeling to include new uses • Open or reference proprietary information in a drug sponsor’s file for another sponsor seeking approval of a combination product • Except: 505(b)(2)

28. Tools for Encouraging Collaboration • FDA cannot require companies to work together, but FDA can encourage companies to collaborate in a way that leads to innovation. • Existing tools include: • User fee waivers • Expedited review and approval times • Power of persuasion – “just ask”—but don’t lean

29. Return to the Categorization Question • A proper determination of whether a product is truly a combination product answers many of FDA’s questions • A risk assessment is a key determinant of whether the product must be treated as a combination product • FDA has more flexibility when a product is not a combination product

31. No Are those differences or reasons significant enough, as shown through a risk Yes Does the nature of the device, assessment, that the drug labeling should be regardless of its IFU , require changed to assure safe and effective use of such a difference? the drug? No Yes Yes Are there any other reasons why Can the safe and effective approval/clearance of the device use of the combination be No would require addressed through the a change to the drug labeling device or kit labeling and co-packaging without requiring a change in the drug labeling? No No Yes Not a Combination Product Cross Labeled Not a Combination Product Kit Combination but Includes a Reference to Combination Product and No Specific Cross Product with no change "use only with" a specific requiring Cross-Labeling Reference to drug labeling brand drug of drug and device

33. Summary • Can product B be used safely and effectively with already-approved product A if the labeling for product B only includes a generic reference to the category of products that contains product A? • If the answer is yes, the two products together are not combination products, there does not need to be any cooperation between the two manufacturers, and product B may be approved despite any lack of cooperation. • If the answer is no because a specific cross-reference to product A by brand is necessary to assure safety and effectiveness, we must ask a second question:

34. Summary • Do the two companies need to cooperate to ensure that the products can be used together safely and effectively? For example, does company A need to agree to change its labeling to permit the combined use of the products? • If the answer is yes, the product is a combination product, and by definition cooperation between the two companies is required for the agency to approve product B. • If the answer is no, the two products are not combination products, and there does not need to be cooperation between the two manufacturers, and product B may be approved despite any lack of cooperation.

35. CPC’s assessment of the importance Case where no cooperation Public Health Benefit Risk assessment for proceeding independently

36. Next Steps • FDA is working on a contrast agent guidance mandated under the user fee agreement, and will publish a draft soon • FDA plans to publish a straw man proposal on the larger cross labeling issues • Sometime this fall?

37. Single Entity Labeling I've often wondered how some people in positions of this kind . . . manage without having had any acting experience. Ronald Reagan

38. Single Entity Labeling Issues • Current drug, device and biologic labeling regulations are not integrated • Melding the labeling can lead to duplicative, and lengthy labeling • This is particularly problematic when the packaging for the combination product is small • It is also difficult to give the two components appropriate focus • International harmonization is usually helpful

39. CPC Proposed Single Entity Labeling Template is available on our website at www.combinationproducts.com

40. Labeling Review What orators lack in depth, they make up for in length. Charles-Louis De Secondat Montesquieu

41. Labeling Review Issues • Hypothetical • Novel drug approved through NDA with existing inhaler • Later the manufacturer needs to revise the device labeling to clarify an ambiguity • NDA supplement? • User fee and time frame issue • Solutions: • FDA self impose a shorter time frame • FDA accept imbedded submissions (e.g., a 510(k) within an NDA)

42. Questions? Arguing with a lawyer is like mud wrestling with a pig: after a while you realize that the pig actually enjoys it.

45. Combination Products: Cross Labeling and Single Entity Labeling Bradley Merrill Thompson, MBA, JD, RAC Epstein Becker & Green PC

46. Combination Products: Cross Labeling and Single Entity Labeling Bradley Merrill Thompson, MBA, JD, RAC Epstein Becker & Green PC RAPS 2008 Annual Meeting Boston September 15, 2008

47. Agenda • Cross labeling • Background • CPC’s proposed approach • Labeling for single entity combination products • FDA reviews of labeling changes I feel like Zsa Zsa Gabor’s fifth husband. I know what I'm supposed to do but I don't know if I can make it interesting. Al Gore

48. Background on Cross-labeling Issues (many slides courtesy of FDA) Politics gives guys so much power that they tend to behave badly around women. And I hope I never get into that. Bill Clinton

49. What is a Combination Product? • Statute -- 503(g)(1) • Products that constitute a combination of a drug, device, or biologic • Combination products are diverse: • Drug-device • Device-biologic • Drug-biologic • Drug-device-biologic

50. Three Types of Combination Products • 21 CFR 3.2(e) • Single-entity: a product comprised of two or more regulated components that are physically, chemically or otherwise combined or mixed as a single entity • Kits: two or more separate products packaged together (e.g., drug and device products) • Cross-labeled: provided separately but intended for use together where both are required to achieve the intended use and where cross labeling is needed