1. Cross-Labeling: Legal and Regulatory Issues David M. Fox Hogan & Hartson LLP 555 13 th Street, NW Washington, DC 20004 202-637-5678 dmfox@hhlaw.com

2. FDA/DIA May 20052 Issues Does the Food, Drug, and Cosmetic Act (FDCA) require mutually conforming or cross-labeling of combination products? Is there room under the FDCA to create a cross- labeling policy that allows, e.g., medical devices to be approved for uses that essentially create new conditions of use for approved drug products? Why do we have a “cross-labeling issue” and is it solvable?

3. FDA/DIA May 20053 Statutory Origins of the Cross-Labeling Issue Section 301, The following acts and the causing thereof are hereby prohibited: Introducing a misbranded drug or device into commerce, misbranding a drug or device while it is in commerce, or receiving a drug or device in commerce that is misbranded Doing “any other act” while an article is held for sale that results in the article being misbranded Introducing an article into commerce in violation of the new drug approval requirements of the FDCA

4. FDA/DIA May 20054 Misbranding Section 502, A drug or device shall be deemed misbranded if  its labeling is false or misleading in any particular, or  its labeling fails to bear adequate directions for use [for each intended use]. 21 CFR 201.128, “intended use” includes uses to which the manufacturer knows the product will be put; the manufacturer is “required to provide adequate labeling... which accords with such other uses to which the article is to be put.”

5. FDA/DIA May 20055 New Drug Approval Section 505(a), No person shall introduce a new drug into commerce unless an approved application is effective with respect to such drug Section 505(d), A new drug must be shown to be safe and effective for use under the conditions prescribed, recommended or suggested in the labeling thereof

6. FDA/DIA May 20056 Labeling Section 201(m), “Labeling” means “all labels and other written, printed, or graphic matter...  upon any article or any of its containers or wrappers, or  accompanying such article Kordel v. United States, 335 U.S. 345 (1948)  the materials need not travel with the product to be “labeling”  “textual relationship” between the written material and the product  the presence of an “integrated distribution program” may also be a factor What is the status of third-party written materials? Can one person’s labeling create intended uses for another person’s product?

7. FDA/DIA May 20057 Questions Can a person misbrand or cause the misbranding of another person’s marketed drug product? Can a person suggest uses of another person’s drug that, in turn, trigger the labeling and drug approval requirements of the FDCA? Is FDA required by law not to authorize the marketing of a product that would render another person’s product misbranded or unapproved?

8. FDA/DIA May 20058 Examples Requiring Cross-Labeling and Reciprocal Approvals FDA Regulatory Letter on marketing a device for use with terbutaline and other drugs: You have “established a commercial market and intended use for these drugs for currently unapproved therapeutic uses” (1989). Letters (1994) to device manufacturers rescinding or suspending 510(k) clearances:  You may neither label nor promote your device for use with specific drugs, nor may you package drugs with your device prior to FDA having approved the drugs for device administration.  Your 510(k) includes “inappropriate labeling” for use with an approved new drug for an unapproved use.

9. FDA/DIA May 20059 Examples Requiring Cross-Labeling and Reciprocal Approvals RFD decisions (circa 1993-98) to device sponsors requiring drug approval for “novel, unapproved drug uses” proposed by the device Aerosolized talc (1994-96); Insulin pumps for IV administration (1998) FDA Warning Letter (1999): “[Y]ou cannot make any claims related to... any... specific drug or class of drugs for use in the [iontophoresis device] unless the drug has been cleared for use in your device by the FDA.”

10. FDA/DIA May 200510 Untying the Knot What statutory provisions might allow FDA to authorize the marketing of Product A for use with Product B without requiring conforming labeling for Product B? What are the key points of statutory interpretation?

11. FDA/DIA May 200511 Combination Product Statutes Section 503(g)  Authorizes FDA to assign jurisdiction for combination products based on the product’s primary mode of action (PMOA)  Nothing in this subsection shall prevent FDA from using any agency resources to ensure adequate review of the safety, effectiveness or substantial equivalence of an article Is section 503(g) more than jurisdictional?  Is it substantive?  Does it put combination products in a special or separate class?  See section 563, recognizing stand-alone category of “combination products”

12. FDA/DIA May 200512 Section 503(g) Interpreted to allow a single marketing application for both the drug and device articles in a combination product, based on PMOA. See 21 CFR 3.1, 3.4(b). Implemented with a delegation to CDER, CDRH, and CBER senior management of all authority “necessary for premarket approval of any product that is a biologic, a device, or a drug, or any combination of two or more of these products.” 21 CFR 5.701. I.e., “Umbrella NDAs” and “Umbrella PMAs”

13. FDA/DIA May 200513 Examples Albuterol MDIs, NDA-only Transdermal Patches, NDA-only Drug-eluting stents, PMA-only INFUSE® Bone Graft, PMA-only

14. FDA/DIA May 200514 Statutory Basis for Umbrella Approvals NDA-only  Section 201(g)(1), “drug” definition, amended in 1990 to eliminate “device” exclusion  Permits device articles in combinations to be regulated as drugs  Permits NDA sponsors to use single application to incorporate a novel use of a cleared device PMA-only  Section 201(h), “device” definition, includes a component provision, but likely not enough to regulate a “drug” as a “device”  However, FDA has effectively allowed drugs and biologics to be approved for new uses without an NDA or a BLA. See, e.g., drug- eluting stents.

15. FDA/DIA May 200515 Non-combination, Device-only Approach For devices that do not require an “individually specified” drug product. See 21 CFR 3.2(e) Device approval that includes a novel drug use but is not so “product specific” that it triggers the statutory requirements of drug product approval and labeling. Policy issue: interpreting whether and when device labeling that describes the use of a class of drugs or a specific drug (but not a specific drug product) creates a new intended use for the drug

16. FDA/DIA May 200516 Third Party Labeling Example IntronA®PegIntron® Rebetol® (ribavirin) Cross-labeled* Generic ribavirin Cross-labeled*No cross- label *Includes cross-labeled MedGuides

17. FDA/DIA May 200517 Four Easy Questions Points of statutory interpretation that bear on future cross-labeling policies  When does third party labeling create a new intended use for a drug?  Can a drug be approved under a PMA?  Is 503(g) essential? Does the drug have to be part of a combination for FDA to have the authority to approve a new use of the drug under a PMA?  Can drug labeling -- and only the labeling -- be approved as part of a PMA?