The decision of the U.S. District Court for the District of Columbia in Washington Legal Foundation v. Shalada (WLF) may severely restrain the Food and Drug Administration's (DFS or Agency) ability to control what companies may say regarding unapproved uses of approved pharmaceuticals and medical devices (i.e, off-label uses.) Washington Legal Foundation v. Shalala, 13 F. Supp 2d 51 (D.D.C. 1998). Members of the pharmaceutical and medical device industries have been battling against the FDA for decades over the right to disseminate a truthful and non-misleading information pertaining to off-label uses. The agency fears that permitting manufacturers to disseminate such information would lead doctors to prescribe a treatment based on incomplete information, and would discourage manufacturers from seeking FDA approval of new uses. In contrast, industry believes that doctors are sophisticated enough to make their own conclusions as to whether information pertaining to a particular use is enough to warrant prescribing the product for the off-label use, and that government attempts to prohibit dissemination of any information that is truthful and not misleading is a violation of the First Amendment. In WLF, Judge Lamberth ruled in the industry's favor, finding that two FDA guidance documents which placed severe restrictions on the dissemination of such information were unconstitutional.
FDA Guidances on Continuing Medical Education and Enduring Scientific Materials Held Unconstitutional
The plaintiff in WLF ( a nonprofit public interest law and policy center) sought to enjoin the FDA from enforcing policies expressed in two guidance documents that restricted certain activities relating to the dissemination of off-label information. The activities included:
- pharmaceutical manufacturers' sponsorship of continuing medical education (CME) seminars (the "CME Guidance"); and
- the free distribution of journal articles or textbook excerpts describing off-label uses (the Enduring "Materials Guidances").
The CME Guidance was designed to distinguish between continuing medical education programs that are not vulnerable to the substantive influence of the supporting company from programs in which the manufacturer is in a position to influence the presentation of information. The Enduring Materials Guidances sought to strike a balance between the need for the free exchange of scientific information and the prohibition on promoting products for unapproved uses. Specifically, they restricted manufacturer distribution of textbook excerpts and article reprints from medical and scientific journals when the publications, describing the pivotal registration trails, addressed incidental off-label uses for the company's approved products.
In a July 1998 decision, the court held that the guidances violated the industry's First Amendment right to disseminate truthful and non-misleading information. Finding that the activities regulated by the guidances constituted "commercial" speech, the court reviewed the constitutionality of the Agency's restrictions on speech under the following four point analysis delineated in Central Hudson Gas & Electric v. Public Service Commission of NY. 447 U.S. 557 (1980).
- Is the speech inherently unlawful or misleading?
- Does the government have a substantial interest in regulating the speech?
- Does the regulation directly advance the asserted interest?
- Is the regulation more extensive than necessary to advance the government's asserted interest?
First, the court held that information regarding off-label uses is not "inherently" misleading. While acknowledging that such information has the potential to be misleading, the court based its holding upon a finding that the speech is not "more likely to deceive the public than inform it." Moreover, the court noted that prescribing an approved product for an unapproved use is not an unlawful activity; therefore, speech that promoted such activity was not inherently unlawful. Second, the court acknowledge that the FDA has a substantial interest in protecting the health and safety of the public, and in providing manufacturers with ample incentive to get previously unapproved uses on the label. However, the court rejected as overly paternalistic the Agency's asserted interest in ensuring that physicians are not misled. In addressing the final two points the court held that, although the guidance documents advance "in a direct and material way" the government's substantial interest in providing manufacturers with an incentive to get off-label information on the label, the restrictions were unconstitutional because they were "considerably more extensive than necessary." Significantly, the court stated that the agency could achieve its objectives through "full, complete and unambiguous disclosure by the manufacturer," suggesting that a rule limited to this restriction would be in accordance with the First Amendment.
Impact on the new FDAMA Rule
In November 1998, the FDA issued a final rule pursuant to Section 401 of the Food and Drug Administration Modernization Act of 1997 (FDAMA) that delineates the circumstances under which certain printed information regarding unapproved uses may be disseminated to various segments of the health care industry. In a supplemental ruling to the original WLF decision, Judge Lamberth held that the court's original decision was not limited to the specific guidance documents at issue in this case, but rather extended to the policies underlying those guidances. The holding therefore casts serious doubt upon the constitutionality of section 401 of the FDAMA and its implementing regulations. This could represent a major setback for the Agency and may enable industry to engage more freely in the dissemination of information pertaining to off-label uses. The parties are currently briefing the issue of whether the FDAMA rule is constitutional. Once Judge Lamberth decides this issue, the case will likely be appealed to the U.S. Court of Appeals for the D.C. Circuit.
Subject to judicial scrutiny, the final rule permits drug, biologic and device manufacturers to disseminate to health care practitioners, pharmacy benefit managers, health insurance issuers, group health plans and government agencies certain written information regarding the safety, efficacy, or benefits of an off-label use of an approved product. However, the dissemination of such information under the rule would be subject to a comprehensive set of rules that:
- limit the type of information that may be disseminated;
- require certain disclosures to be made; and
- require specified information to be submitted to the agency, including a certification that the manufacturer will submit a supplemental application for the new use within 36 months.
To comply with the rule, the information must pertain to an approved drug or device (or a cleared device) and come in one of two forms:
- an unabridged reprint of a peer-reviewed article that is about a scientifically sound clinical investigation4 or
- an unabridged reference publication.
In addition, the dissemination of the information must not pose a significant risk to public health or be false or misleading. This requires, for example, that it also include information from unfavorable publications and that the conclusions be reasonably supported by the study results. Letters to the editor, abstracts, information on Phase I trials are all specifically prohibited.
Importantly, the provider of any off-label drug information must make the following disclosure:
This information concerns a use that has not been approved by the Food and Drug Administration.
If the information relates to both the approved and unapproved uses, the disclaimer has to be modified to identify the unapproved or uncleared new use. If applicable, the manufacturer also is required to state that the manufacturer is funding the dissemination of the information and reveal the names of any authors who were employees of, consultants to, or received compensation from the manufacturer. In addition, the manufacturer is required to disclose that other approved products are available and identify any person that has provided funding for the conduct of a study relating to the new use.
Sixty days before disseminating information relating to the off-label use, the rule also requires the manufacturer to submit to the Agency an identical copy of all information to be disseminated; any other clinical trial information that the manufacturer has relating to the effectiveness or safety; an explanation of the method for selecting the bibliography; and other information, depending on whether or not the manufacturer has submitted a supplemental application for the new use, including a certification that a supplemental application will be submitted within a period of time specified by the regulation.
Conclusion
Pharmaceutical and medical device manufacturers have good reason to be encouraged by the WLF decision, but the court's ruling should not be interpreted as a license to freely disseminate any information pertaining to off-label uses. Judge Lambert has not yet decided the fate of the FDAMA rule. Although the court has enjoined the FDA from enforcing the guidance documents, and questioned the legality of the FDAMA rule, the rule technically remains in effect. Moreover, the Agency may still take enforcement action against claims it deems to be false and misleading under its traditional statutory authority. A warning letter sent to Ell Lilly for claims regarding unapproved uses of Evista. made in a couple of direct to consumer advertisements remind of the continued availability of the "false and misleading" standard as an enforcement tool. Rather than state that the ads constituted promotion of an "off-label" use, the FDA characterized the advertisement as "misleading because it overstates Evista's benefits." In addition to Agency action, companies also must be cognizant of the implications dissemination of off-label information could have in the context of patient safety, product liability, and potential competitor claims under the Lanham Act.
Most importantly, the WLF decision acknowledges that there are certain instances where it is better to let the recipients of the information make the decision on its worth, rather than subject its dissemination to strict parental controls. A similar rationale to the one applied in WLF was used to strike down an FDA role that required dietary supplement manufacturers to establish that there was significant scientific agreement to support any claims that characterized the relationship of a dietary ingredient to a disease or health-related condition. In Pearson v. Shalala the court held that the FDA's failure to permit the use of proper disclaimers for claims whose support did not rise to the level of "significant scientific agreement" rendered the regulation unconstitutional. 52 F.3d 1072 (11th Cir. 1999). While these decisions seem to indicate a trend towards loosening government restrictions, it is unclear how far they will be extended. For example, although the WLF decision appears to suggest that the Agency cannot prohibit the distribution of reprints of articles from scientific journals (as long as adequate disclosures are made), it does not address whether the FDA could restrict other materials pertaining to off-label uses. Moreover, it is unclear whether the court would invalidate a rule restricting off-label promotion in direct-to-consumer advertisements. In light of all of the questions that remain, the parameters under which information regarding off-label uses may be disseminated are far from established.
*article courtesy of Buchanan, Ingersoll, & Rooney, PC.