1. 1 Cross Labeling Combination Products Bradley Merrill Thompson, MBA, JD, RAC Epstein Becker & Green PC

2. 2 One way to make sure crime doesn't pay would be to let the government run it. Ronald Reagan CPC’s Proposed Approach: The cross labeling issue can be addressed under current regulations

3. 3 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 –Not combination products We will show an algorithm for properly classifying products

4. 4 Four Principles 1.FDA should not play matchmaker between companies. 2.The economic incentives that are most likely to lead to important public health breakthroughs are outside of FDA’s control. 3.FDA must approve or disapprove the products as companies propose them, based on the evidence. 4.But FDA, importantly, does have flexibility under the law to weigh the risks.

5. 5 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

6. 6 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

7. 7 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

8. 8 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)

9. 9 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

10. 10 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

11. 11 Look at proposed device labeling: does it, or does it need to in order to be used safely and effectively, individually specify a brand of drug (not just a generic type) expressly or by clear implication? Does the device labeling expressly state that the drug is to be used for a different intended use, dosage form, strength, route of administration or dose than stated in the drug labeling? Does the device IFU imply such a difference? Yes No Yes Flow Chart for Determining Whether Drug and Device Represent Cross Labeled Combination Products Labeled as Such

12. 12 Does the nature of the device, regardless of itsIFU, require such a difference? Are those differences or reasons significant enough, as shown through a risk assessment, that the drug labeling should be changed to assure safe and effective use of the drug? No Cross Labeled Combination Product requiring Cross-Labeling of drug and device Not a Combination Product and No Specific Cross Reference Are there any other reasons why approval/clearance of the device would require a change to the drug labeling No Yes No Yes Not a Combination Product but Includes a Reference to "use only with" a specific brand drug Kit Combination Product with no change to drug labeling Can the safe and effective use of the combination be addressed through the device or kit labeling and co-packaging without requiring a change in the drug labeling? NoYes

13. 13 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

14. 14 Summary Can device B be used safely and effectively with already-approved drug A if the labeling for device B only includes a generic reference to the category of products that contains drug 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 device B may be approved despite any lack of cooperation. –If the answer is no because a specific cross- reference to drug A by brand is necessary to assure safety and effectiveness, we must ask a second question:

15. 15 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 device 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 device B may be approved despite any lack of cooperation.

16. 16 Bottom Line FDA can do the right thing under the existing regulations At it’s heart, much of the problem is with communication between companies Right now FDA has some other important priorities for combination products such as GMPs, post approval modifications, and clinical trial requirements.