1. The Regulatory Authority for Off-Label Promotion
The Medical Device Regulatory, Reimbursement and Compliance Congress
Harvard University
March 29, 2007
Pamela Furman, Esq., Partner, King & Spalding, LLP
Scott Willoughby, Managing Director, Huron Consulting Group
Marc Farley, Executive Director of Compliance, Cordis Corporation

2. Objectives Today Review of regulatory authority
Interactive case study: Risk Management of Off-Label Sales

3. FDA Legal and Regulatory Framework

4. General Principles
FDA views “off-label” promotion as evidence that a device is intended for an unapproved/ “uncleared” use.
Introduction into interstate commerce of a device for an unapproved/ “uncleared” use is prohibited.

5. Rationale for Prohibition Against Off-Label Promotion
“If a manufacturer of a drug [or device] legally marketed for one use were free to market the drug for additional, unapproved uses, that would effectively quash the incentive for the manufacturer to expend the substantial resources necessary to demonstrate safety and effectiveness for the additional uses.” See Letter from Margaret M. Dotzal, Associate Commissioner for Policy, to Daniel J. Popeo and Richard A. Samp, Counsel to the Washington Legal Foundation (Jan. 28, 2002).

6. Legal Authority
A device without the required premarket approval (PMA) or 510(k) clearance is “adulterated” or “misbranded.” 21 U.S.C. §§ 351(f) & 352(o).
Introducing an adulterated or misbranded device into interstate commerce is a “prohibited act.” 21 U.S.C. § 331(a).
Introducing a device into interstate commerce that is subject to the 510(k) requirement, but does not have 510(k) clearance, is a “prohibited act.” 21 U.S.C. § 331(p).

7. Legal Authority Devices subject to the 510(k) requirement:
A new 510(k) clearance is required where “[t]he device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be significantly modified in intended use.” 21 C.F.R. § (a).

8. Legal Authority 510(k)-exempt devices:
“[M]anufacturers of any commercially distributed class I or II device for which FDA has granted an exemption from the requirement of premarket notification must still submit a premarket notification to FDA before introducing or delivering for introduction into interstate commerce the device when the device is intended for a use different from the intended use of a legally marketed device in that generic type of device.” See e.g., 21 C.F.R. §

9. Legal Authority Definition of “intended use”:
“The words intended uses refer to the objective intent of the persons legally responsible for the labeling of devices. The intent is determined by such persons’ expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements made by such persons or their representatives ” 21 C.F.R. §

10. Legal Authority Definition of “labeling”:
“The term ‘labeling’ means all labels and other written, printed, or other graphic matter (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.” 21 U.S.C. § 321(m).
FDA broadly interprets “labeling” to include traditional box labels; package inserts and operator manuals; print ads; journal, magazine, and newspaper articles; website materials; press releases; videos; speeches; etc.

11. Practice of Medicine
Device manufacturers may only market devices for their cleared/approved uses.
However, under the FDC Act’s “practice of medicine” provision, physicians may use approved devices for unapproved uses. See U.S.C. § 396.

12. Interactive Case Study

13. Hypothetical Case – Assumptions
Company X makes and sells biliary stents -- flexible tubular devices cleared to drain the biliary tract and to keep the bile duct open.
Biliary stents are frequently available in larger sizes than approved vascular stents, and doctors commonly use them to prop open large arteries (e.g., leading to legs and kidneys).
80% of biliary stents are sold to catheterization laboratories and used off-label in such arteries.
Sales representatives are present in catheterization labs during all procedures using stents.

14. Hypothetical Case – Assumptions (cont’d)
We are all part of Company X’s review team (legal, regulatory, marketing, compliance).
We have read numerous articles about increased scrutiny of improper off-label activity in our market.
We are tasked with setting guidelines for our firm’s statements and activities related to biliary stents.

15. Hypothetical Case – Your Task
Balance business objectives, market competition, and regulatory requirements by setting guidelines for Company X’s activities
Discuss appropriate guidelines re:
Advertising and promotional materials
Sales projections
Sales rep presence and activities in cath lab
Sales rep compensation
Responses to questions on off-label uses and clinical studies
Medical education activities and company infrastructure
Other key issues / guidelines we need to consider

16. Hypothetical Case
Advertising and promotional materials

17. Hypothetical Case
Sales projections

18. Hypothetical Case
Sales rep presence and activities in cath lab

19. Hypothetical Case
Sales rep compensation

20. Hypothetical Case
Responses to questions on off-label uses and clinical studies

21. Hypothetical Case
Medical education activities and company infrastructure