FDAMA Provision Restricting Dissemination of "Off-Label Information" Held Unconstitutional

In July 1999, the U.S. District Court for the District of Columbia issued the third in a series of decisions in Washington Legal Foundation v. Shalala. The decision further scales back the ability of the Food and Drug Administration (FDA) to regulate the dissemination of information relating to unapproved uses of drugs, biologics and devices that have been approved for other indications (off-label information). Judge Lamberth's initial decisions struck down as unconstitutional FDA policies, embodied in guidance documents, that restricted (1)manufacturer sponsorship of continuing medical education programs and (2)manufacturer distribution of "enduring materials" (reference textbooks and reprints of articles previously published in peer-reviewed medical or scientific journals) to physicians and other medical professionals.¹

In the latest decision, the court held that most of the provisions of section401 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), which authorized manufacturers to disseminate such materials relating to off-label uses subject to compliance with a number of regulatory requirements, are also unconstitutional. Pending appeal, FDA enforcement of the aforementioned activities must be restricted to the terms of the court's final order.

The Final Order--Manufacturer Responsibilities when Sponsoring Continuing Medical Education Programs and Disseminating "Enduring Materials"

Although the Agency is entitled to appeal, the court's final order enjoins the FDA from enforcing the vast majority of requirements created by the guidance documents, section401 of FDAMA and the implementing regulations codified at 21C.F.R. Part99. Some of those requirements, however, survived the court's constitutional analysis and presumably remain in effect. With respect to both continuing medical education programs and the dissemination of enduring materials, a manufacturer continues to be obligated to (1)disclose its interest in the subject drug or device if it "sponsors or provides financial support" for either of the aforementioned activities in which unapproved uses are referenced and (2)disclose the fact that the referenced use has not been approved by the FDA.

In addition, as discussed below, the court's order permits the FDA to impose other regulatory obligations particular to each of these activities.

1. Continuing Medical Education Programs

2. The final order enjoins the FDA from prohibiting manufacturers from suggesting content or speakers in connection with a continuing medical education program, as long as: (1)the manufacturer makes the aforementioned disclosures and (2)the program is administered by an "independent program provider." An "independent program provider" is defined by the order as an entity that (i)has no common ownership or other corporate affiliation with the manufacturer, (ii)engages in the business of creating and producing continuing medical education seminars and (iii)is accredited by a national accrediting organization pertinent to the topic of the seminars, programs or symposia. ²

3. Dissemination of Enduring Materials

The final order also defines the terms under which a manufacturer may disseminate journal articles and excerpts from medical textbooks to physicians or other medical professionals. A journal article may be distributed only if it is published in a "bona fide peer-reviewed journal," defined as a journal that uses experts to objectively review and select, reject or provide comments about proposed articles. Such experts must have demonstrated expertise in the subject of the article under review and be independent from the journal. An excerpt from a reference textbook (including any medical textbook or compendium), or any portion thereof, may be disseminated only if it (1)is published by a "bona fide independent publisher" and (2)is otherwise generally available for sale in bookstores or other distribution channels, where similar books are normally available. A "bona fide independent publisher" is defined as a publisher that has no common ownership or other corporate affiliation with the manufacturer and "whose principal business is the publication and distribution of books through normal distribution channels."³

Other Considerations

1. Dissemination of the Off-Label Information May Not Be False or Misleading
   
   

2. 1. Potential Liability to the Government

Perhaps the most significant factor that manufacturers must continue to consider when deciding whether to disseminate such materials regarding off-label information is whether the material is false or misleading. Paragraph five of the court's order states that the decision does not diminish the Agency's ability to sanction parties for distributing any material that is false or misleading. Hence, even if a manufacturer complies with all of the aforementioned requirements, the FDA may sanction the company with criminal and/or civil penalties if the material is deemed to be false or misleading. Companies should be particularly cautious when the promotional activity includes comparative claims that--when unsubstantiated--are among the most oft-cited types of advertising in FDA warning letters. Moreover, companies should bear in mind that the FDA may be more likely to regard materials as false or misleading if the materials relate to a claim that has previously been considered (and rejected) by the Agency.⁴

The gravity of promoting FDA-regulated products in violation of the FFDCA was illustrated by the recently executed plea agreement between Genentech and the Department of Justice. Pursuant to the agreement, the California biotech company agreed to pay a criminal fine of $30million, as well as restitution in the amount of $20 million, for promoting off-label uses of its approved drug Protropin^. and selling it to patients insured under state Medicaid programs and to patients covered by the CHAMPUS/TRICARE program, which reimbursed those patients.⁵

2. 2. Potential Liability to Competitors

   3. Manufacturers must also be cognizant of the potential for civil liability to competitors under the Lanham Act--especially where the promotional activity makes comparative claims. Recently, the Southern District of New York issued a preliminary injunction against Eli Lilly & Co., pursuant to a complaint filed by Zeneca Inc., for promotional claims that sales representatives were instructed to make relating to the off-label use of Lilly's Evista^. for reducing the risk of breast cancer--a use for which AstraZeneca's Nolvadex^. (tamoxifen) is FDA approved. Lilly was found to be communicating to physicians that (1)Evista^. has been proven to reduce the risk of breast cancer and (2)Evista^. is comparable or superior to tamoxifen in reducing the risk of breast cancer. Interestingly, the court dismissed Lilly's assertion that the claim was based on data that were published in the Journal of the American Medical Association (JAMA), stating, "the mere fact of publication of a peer-reviewed article does not prove that the claim in question is true." ⁶ The injunction requires Lilly to create a new training program for its sales representatives that instructs them not to promote Evista^. for reduction in the risk of breast cancer.

3. Direct-to-Consumer Advertising Rules Not Affected

The constitutionality of FDA regulation of direct-to-consumer advertisements was not before the court and therefore remains unchanged. Indeed, in the July 1998 decision, Judge Lamberth noted that manufacturers may not advertise off-label uses for previously approved drugs directly to the consumer. ⁷

3. Administrative Requirements

4. Because the court did not address whether the activities and materials at issue constituted "advertising" or "labeling," it is difficult to gauge whether certain administrative obligations applicable to advertising and labeling apply. For example, FDA regulations relating to New Drug Applications (NDA) require sponsors of approved drugs to submit to the Agency all advertising at the time of initial publication.⁸ Judge Lamberth struck down the provision in FDAMA that required manufacturers to submit to the FDA a copy of all off-label materials.

Conclusion

The WLF opinion significantly loosened regulatory requirements relating to manufacturer participation in continuing medical education programs and dissemination of "enduring materials." Pending appeal, manufacturers may more freely engage in such promotional activities, subject to the limitations discussed above. As with any advertising, manufacturers must remain mindful of the other potential risks for liability from both the government and competitors.

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