Rep. Henry Waxman, D-Calif., is pushing FDA to require companies to submit reprints of journal articles on off-label use before providing them to practitioners, should the agency go forward with guidance permitting off-label promotion.

That was one priority highlighted by Ann Witt, health counsel for Waxman's House Government Reform and Oversight Committee, in a Sept. 8 appearance at the Food & Drug Law Institute's conference on advertising and promotion, in Washington, D.C.

Waxman has closely monitored and strongly criticized any efforts to provide more latitude for off-label promotions. Witt's presentation at FDLI suggested there will be no letup in Waxman's efforts.

Commenting on FDA's February ¹ draft guidance on good reprint practices, Witt advocated modeling any final guidance on language in an 1998 rule, which drew upon authorities in a since-expired provision of the FDA Modernization Act. Provisions of that rule included pre-submission of reprints.

FDA "Cherry Picked" From FDAMA

"The guidance that FDA put out last February includes none of those protections [that were in FDAMA]," Witt said. "The guidance cherry-picked some of the conditions from the FDAMA regime - but not many of them and not the key ones."

The draft "doesn't require companies to ever seek approval for the use, it doesn't provide any mechanism for FDA review of the reprints before they're out there. While it has some provisions about not disseminating false or misleading reprints, it does not require companies to also disseminate contrary articles if they are out there."

In a later interview, Witt said that Waxman's priorities for any reprint policy are that it require pre-submissions of journal articles to FDA and require sponsors to intend to file for a supplemental indication for off-label use described in reprints.

While the previous policy would have required intent to file, the draft guidance says that studies described in a journal reprint should be "adequate and well-controlled investigations."

At the FDLI session, Witt and FDA Principal Deputy Chief Counsel Jeffrey Senger engaged in a back-and-forth discussion of FDA's authorities in this area, including the impact of a court injunction against FDA's earlier regulatory effort.

Senger said "this guidance represents the agency's judgment on the appropriate balancing of the First Amendment and all of the other considerations ... in light of all the issues that happened between FDAMA's onset and sunset."

A series of district court rulings in the late 1990s found that the earlier rule violated companies' First Amendment free speech rights in restricting off-label promotion. However, a later appellate court ruling said much of the case was moot, based on FDA's assurances that the rule was aimed to define a "safe harbor" for permissible promotion activity. (² Also see "FDA Off-Label Notice Stands, But Enforcement Still Vulnerable - Judge" - Pink Sheet, 11 December, 2000. p. 16). The challenges were brought by the Washington Legal Foundation, which may consider challenging the draft policy if made final without substantial changes (³ Also see "FDA’s Off-Label Reprint Guidance Is Unlikely To Clarify Anything Very Soon" - Pink Sheet, 28 April, 2008., p. 14).

Citing the appellate ruling, Witt remarked: "I'd be interested in how the First Amendment might prevent you from requiring FDA review or a promise to seek approval [of an indication]."

The Waxman aide also said that the draft raises questions about both how FDA can enforce its policy and how the policy might limit the tools prosecutors have for cases involving off-label promotion.

"Muddying" The Enforcement Waters

One "troubling aspect" of the guidance is "what it means for FDA's enforcement activity in the future," she said. Case law history in this area "made it clear FDA retains the authority to use reprint dissemination as evidence of intended use in enforcement actions, as evidence of illegal marketing." But the guidance says "here's your safe harbor ... and nowhere suggests that if you go outside the limits of the guidance that FDA can do anything about it."

The "idea that FDA is going to be out there somehow figuring out what reprints are being disseminated ... and whether they meet the terms of the guidance is laughable," Witt asserted.

Witt expressed concern that the draft could "cause problems for attorneys general who would like to cite rules for acceptable promotion or not."

Asked during the session's question-and-answer period to elaborate on that issue, Witt explained: "Our concern is that this [guidance] will diminish current activity that state attorneys general and the DoJ are engaging in by muddying the water about what kind of reprint dissemination they can use as evidence in illegal promotion," said Witt. "Many of those cases included, as evidence of off-label promotion, misuse of reprints in a misleading way."

In a separate session at FDLI, FDA Division of Drug Marketing, Advertising & Communications Director Tom Abrams said Department of Justice interest in various industry promotional practices appears to be on the upswing (see ⁴ Also see "DoJ, Congress Want Ad Oversight: FDA Sounds Ready To Respond" - Pink Sheet, 15 September, 2008.).

A July 28 report on off-label use from the Government Accountability Office cites 11 lawsuits referencing disseminated materials. Reflecting the challenge of proving improper promotion, the GAO notes, "These settlements often involved promotional practices that are more difficult for FDA to detect, such as violative discussions between physicians and drug company sales representatives" (⁵ Also see "Academic Detailing Bill Could Be Interim Step To Comparative Effectiveness" - Pink Sheet, 4 August, 2008. p. 21).

Late last year, Waxman sought agency documents related to development of the draft policy. One document reported that, in a meeting with FDA's former chief counsel Dan Troy, members of the Sidley Austin law firm "spoke about their perceptions as well as the effect and consequences of the sunset [FDAMA] provision." They provided an overview of the problems companies face with reprint dissemination, and "expressed concerns about federal prosecutors pursuing distributors of this information for criminal misconduct," according to the document.

Witt interpreted the meeting as an intent to urge FDA to issue a guidance, much like the one put forth in February.

"Among the documents received are [those] reflecting a meeting with FDA's chief counsel held with lawyers representing a number of companies with the subjects of these enforcement actions by the Department of Justice and state attorneys general," Witt said. Documents suggest the attorneys "were urging FDA to issue a guidance that looked like this one in order to protect them or to shield them from these actions."

Witt also suggested that any final guidance should ensure that physicians receive thorough information, such as highlighting which other studies are inconsistent with the reprint. "To imagine that the doctor is going to go off and try to dig up those studies and read them all - it's just completely unrealistic."

According to the draft guidance, scientific or medical information that is distributued should:

be in the form of an unabridged reprint, copy of an article, or reference publication;

not be marked, highlighted, summarized, or characterized by the manufacturer in any way;

be accompanied by the approved labeling for the drug or medical device;

be accompanied by a comprehensive bibliography of publications discussing adequate and well-controlled clinical studies published in a medical journal or medical or scientific text that have been previously published about the use of the drug or medical device covered by the information disseminated (unless the information already includes such a bibliography);

in cases where the conclusions of the article or text to be disseminated have been specifically called into question by another article(s) or text(s), be disseminated with a representative publication that reaches contrary or different conclusions regarding the unapproved use;

be distributed separately from information that is promotional in nature.

But the issues related to this policy seem unlikely to be resolved anytime soon. FDA's Senger declined to estimate when FDA will issue a final good reprints policy or whether companies should consider the draft guidance provisions reliable enough to take into account when shaping their upcoming marketing efforts.

- Carlene Olsen (c.olsen@elsevier.com)

Reprinting FDAMA Approach: Waxman Urges FDA Review Of Off-Label Articles

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