1. 1 Cross Labeling Combination Products and User Fees Bradley Merrill Thompson, MBA, JD, RAC Epstein Becker & Green PC Pharma MedDevice 2007 Conference New York, NY April 25, 2007

2. 1.Combination Products Coalition 2.Background on Cross Labeling Issue 3.An Approach to Address Cross Labeling 4.User Fee Issues Topics

3. Combination Products Coalition 1.History 2.Existing Policy Positions 3.Future Strategies

4. CPC: Purpose  To get promising combinations to market  To clarify and streamline the regulatory paradigm for combination products through enhancements to the existing process  While protecting the public health

5.  Up to 20 drug, device and biologics companies have engaged in CPC activities. Some members include : ►Pfizer ►Baxter ►Roche Diagnostics ►Abbott ►Becton Dickinson  Most active participants are regulatory affairs professionals for member companies.  Diversity of industry representation is encouraged. Membership

6.  Started in 2003 with developing consensus policy positions  Advocating policy positions and working with FDA ►Providing comments to FDA on proposed rules and guidances  Partnered with RAPS to host January, 2005 Summit that drew about 150 people. Topics included-- ►Cross labeling, kit labeling and the labeling of integral products, ►That policy summit resulted in a consensus white paper that was submitted to FDA. Activities

7.  Cross Labeling  Modification of approved combination products  Adverse incident reporting  Quality systems/GMPs  Clarification of OCP role CPC Key Priorities

8.  Companies interested in CPC should visit: www.combinationproducts.comwww.combinationproducts.com ►Membership structure ►Policy Positions

9. Background on Cross-labeling Issues (many slides courtesy of FDA)

10. 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

11.  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 Three Types of Combination Products

12.  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 Examples of Cross-Labeled Combination Products

13.  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 Not Combination Products

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

15. 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?

16. 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? Some of the questions…

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

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

19. A note on terminology  Cross labeling  Mutually conforming labeling Is there any difference?

20. 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

21. 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

22. 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

23. 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

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

25. 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?

26. 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? Points to Consider

27. 27 CPC’s Proposed Approach

28. 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

29. 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.  But FDA, importantly, does have flexibility under the law to weigh the risks.

30. 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

31. 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

32. 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

33. 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)

34. 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

35. 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

38. Not a Combo Product and No Specific Cross Reference Not a Combo Product But Includes Specific Reference Cross Labeled Combo Product Is an agreement between the parties assuring coordination required to approve the device? No Maybe, depending on a risk assessment. This risk assessment would consider: (1)The likelihood that product A will be changed in the future. (2)The consequences of possible changes to product A. (3)The effectiveness of company B’s ability to monitor product A for such changes. (4)The ability of company B to effectively label the combined use without the need to relabel product A. (5)Any other issues that bear on the ability of company B to assure the safety and effectiveness of the combined product without the cooperation of company B. Yes, an agreement between the two companies is required

39. 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:

40. 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.

41. Next Steps  Later this year, FDA plans to publish a straw man proposal  FDA will then hold a public meeting again to get further input  OCP is in transition

42. How are User Fees Applied to Combination Products?

43. User Fee Guidance  Draft User Fee Guidance: ►Single marketing application: fee associated with that type of application ►Multiple marketing applications: fee for each application: Sponsor may choose to submit two marketing applications (limited waivers/reductions possible) FDA may require multiple applications: fees for each application (waivers/reductions possible)

44. User Fee Guidance  Draft User Fee Guidance (cont.) ►Waivers: Innovative combination products (only if FDA requires multiple applications) MDUFMA and PDUFA waivers available

45. CPC Comments  CPC Comments on Draft User Fee Guidance ►FDA needs to address issue of what assignment means ►Specific enhancements recommended: Clarify when multiple filings required Provide automatic waiver of partial fee when FDA requires multiple applications Expand eligibility for Innovative Combination Product waiver to: –Sponsors choosing to file multiple applications –Products approved and labeled for another use –Products that offer significant benefits other than “clinical”

46. 46 Questions?