FDA Finalizes Off-Label Dissemination Rule

James G. Dickinson

February 1, 1999

11 Min Read
FDA Finalizes Off-Label Dissemination Rule

Medical Device & Diagnostic Industry Magazine
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An MD&DI February 1999 Column



The agency's codification of requirements for companies communicating unapproved-use information reflects stringent interpretation of FDAMA.

James G. Dickinson

When device manufacturers want to disseminate independent reviews of their technology or product performance to anyone—including practitioners, procurement agencies, or even end-users—they must operate according to a new FDA rule. Enforceable as of November 20, 1998, the final rule, titled Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices, provides scant comfort to those drug and device marketers who had been hoping that today's kinder, gentler FDA might adopt lenient interpretations to ameliorate less-than-friendly provisions of the FDA Modernization Act (FDAMA).

The 34-page, 36,000-word opus declines all such industry requests presented in the proposal stage, opting almost uniformly for stringent interpretations of the act. In the final rule, marketers lost out in the following ways:

  • Only those publications listed in the Index Medicus will be allowed to be used in disseminating new-use information.

  • Verbal communication of unapproved uses is outlawed.

  • Final manuscripts that have been accepted for publication in qualifying journals must not be disseminated until actual publication has occurred.

  • Admitting that peer-reviewed reference books will be disseminated less often now than before as a direct result of its final rule, FDA stipulated that only whole books—not just selected chapters—containing new-use information may be disseminated. Pending a final court decision in the Washington Legal Foundation case, however, FDA said such books may be disseminated without meeting all of the final rule's other requirements if the company does not focus on or point to a specific unapproved use and it includes a disclaimer that the publication includes information about unapproved uses.

  • The Internet was rejected as a source of balancing information (warnings, contraindications, etc.) for new uses described in disseminated articles.

  • The phrase "to the best of my knowledge" was rejected as a qualifier for corporate executives who might otherwise use it to certify the completeness of their documentation regarding existing negative information about a new use.

In all, FDA estimates that the annual industrywide cost for companies seeking permission to disseminate unapproved-use information will be approximately $1.8 million.

Against these restrictive losses, there were some modest gains for device manufacturers reflected in the final rule. For instance, FDA yielded to objections to its proposal to include comparative claims involving approved products among "new uses" that must be the subject of clinical study. The agency also toned down a related definition that would have put all subgroup analyses (e.g., the product's use in children, the elderly, different genders, etc.) into the new-use category.


In addition, FDA actually turned down an opportunity to interpret FDAMA as requiring additional paperwork from industry. Section 533(b) gave FDA free rein to require companies to keep records of the names of all persons receiving unapproved-use information, but the agency opted to do so only when public health was at risk.

FDA also heeded industry comments in abandoning complex criteria it had proposed for requests for exemption from FDAMA's requirement that clinical studies be conducted under an FDA-issued supplement for any new uses being disseminated. Those exemption requests, citing "economically prohibitive" grounds, will now be available to more companies and be a lot simpler than FDA had initially proposed.

However, the agency rejected a commenter's suggestion that it exempt a manufacturer from the new rule if the unapproved use of its product has been accepted as standard medical practice in such authoritative compendia as USP-DI or the American Hospital Formulary Service. FDA held that such citations may be used to apply for an exemption in specific cases.


Regarding Internet dissemination of unapproved-use information, FDA said in the preamble to the final rule that the practice could be permissible if manufacturers met all of the rule's requirements. For example, the manufacturer "would have to ensure that the recipients of the information are appropriately limited and that all of the required information and disclosures can be attached. . . . FDA may, in the future, issue guidance on this subject."

Responding to objections about FDAMA's quixotic provision that manufacturers should not use each other's published studies without prior permission when disseminating new-use information, FDA clung tight to the letter of the act. Even though a publication may have entered the public domain, said FDA, "the fact that an article has been published does not eliminate the need to get permission from the researching company. If it did, this requirement in the statute would be meaningless, because all information disseminated under this part must be published."

In a major concession, FDA abandoned its proposed eight-element definition of what constitutes "scientifically sound" clinical information that may be disseminated. The agency's new approach considers all qualifying journal articles and reference publications to be scientifically sound except "letters to the editor; abstracts of a publication; those regarding Phase 1 trials in healthy people; flagged reference publications that contain little or no substantive discussion of the relevant clinical investigation; and those regarding observations in four or fewer people that do not reflect any systematic attempt to collect data, unless the manufacturer demonstrates to FDA that such reports could help guide a physician in his/her medical practice."


One comment on the proposed rule asked what FDA would do if an article discussed multiple unapproved uses but the manufacturer wanted to focus on just one unapproved use. In its preamble, FDA said it expected requirements to be met for all such uses, but that it may consider exceptions—on a case-by-case basis—when the use of interest is the predominant one discussed in the article.

To a comment asking about separation of unapproved from approved uses during detail visits to a Web site, FDA said it did not intend to prohibit mixing the two kinds of visits, but that "any unapproved-use information . . . must be kept physically distinct from the promotional materials, and the sponsor may not verbally promote the unapproved use or include materials about the unapproved use, beyond those permitted or required. . . ."

As mentioned previously, not all of FDA's interpretations of FDAMA followed a stringent line. One comment urged the agency to require that disseminators of new uses list by name all the drugs approved for that use, rather than just say that other therapies have been approved. FDA responded, in the preamble to the final rule, that the statute doesn't require this, and that although such a stipulation would be useful, "it would be difficult to develop a complete and accurate list. Moreover, the information could be misleading if the manufacturer merely provided a list of names."


As authorized by FDAMA, FDA also volunteered to meet with any manufacturer that it decides must include additional material with its disseminated information. And FDA agreed to tighten wording that critics feared would allow it to extend the 60-day deadline FDAMA gives the agency to review materials before they can be disseminated. The concern, FDA acknowledged, was that it would, for example, advise a manufacturer on day 59 that the company's submission was not complete and that therefore the 60-day time period had not yet begun. "FDA is committing to give manufacturers a final decision within 60 days," the agency said in revising the appropriate section. The final rule also abandons the proposal's attempt to require disseminated new-use information to bear the phrase "and is being disseminated under section 551 of the Federal Food, Drug, and Cosmetic Act."

How much of the information that companies submit in seeking FDA permission to disseminate unapproved-use information should be open to the public? In its final-rule preamble, FDA said it received comments ranging from support for full release of all information to total confidentiality. Some even urged FDA to publish, in the Federal Register, the fact that a submission seeking dissemination had been received; to include the citation for the article and the bibliography; and to solicit additional published information that might be appropriate for dissemination.

FDA has decided not to require a notice-and-comment process before permitting dissemination to proceed or before granting an exemption. However, the agency said that "the Freedom of Information Act and FDA's regulations will dictate what information submitted under this provision can be disclosed." FDA will "continue to examine these issues separately."

What if the additional studies needed to justify dissemination of information about a new use would be unethical to conduct in human subjects? Both the proposal and the final rule include provisions for exemptions to be sought on this particular ground.


Extensions of the 36-month deadline set by FDAMA for conducting the studies required for new uses under the dissemination rule will be granted in two situations. For studies already under way at the time permission to disseminate is sought, the deadline may be extended one time, by 24 months. For studies not yet begun, FDA can grant unlimited extensions of the 36-month deadline.

If, after the dissemination begins, data come into FDA showing that the new use is either not effective or poses a public health risk, or if a company fails to comply with the rule's requirements, FDA may order corrective action. This generally will take the form of required "Dear Doctor" letters or corrective advertisements, although the rule gives FDA considerable flexibility to fashion the corrective action so as to remedy the underlying problem or deficiency. The agency may mandate that warning labels be placed on the affected products or require revised labeling that includes warnings. However, although commenters asked FDA to explicitly spell out its options with respect to possible corrective actions, this is not done in the final rule.

Further information about the new rule can be obtained from Byron L. Tart, FDA, Center for Devices and Radiological Health (HFZ-302), 2098 Gaither Rd., Rockville, MD 20850; 301/594-4639.

FDA's final regulation on the dissemination of unapproved-use information requires the following disclosures:

Copyright ©1999 Medical Device & Diagnostic Industry

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