In March, we covered FDA’s revised guidance for manufacturers seeking to distribute scientific journal articles that cover unapproved new uses of its products. The new guidelines update the 2009 guidance by including two additional categories of materials in addition to journals: medical reference texts and clinical practice guidelines (CPGs). It also provides long checklists of what manufacturers distributing texts should and should not do. Notably, while FDA’s guidance is just that—guidance—the Agency is clear that manufacturers who distribute materials with off-label information “in accordance with the recommendations,” will not have those materials used against it as evidence of off-label promotion.
What about manufacturers who disregard the “guidance”? Good luck. One respondent, Millennium Medical Education Resources, noted that they have experienced the cancellation of a number of contracts, and several projects in review have been put on hold by companies that thought they were in compliance with the 2009 Guidance, but were not sure they could comply with this version.
Stakeholders had the opportunity to comment on FDA’s recommendations for journal articles and CPGs through early May. We tracked the responses and noticed a number of similarities. Most argued that the guidance is overly restrictive and could chill the flow of important off-label information to healthcare professionals. Furthermore, respondents noted that FDA’s authority to limit scientific exchange is limited by the First Amendment.
Free Speech and First Amendment Issues
The Washington Legal Foundation (WLF) argued that FDA is subject to a permanent injunction from 1999 which limits FDA’s authority to suppress manufacturer’s dissemination of certain journal articles and medical texts discussing off-label uses. Moreover, WLF lawyers recently played a key role in overturning on First Amendment grounds the criminal conviction of a Division of Dockets Management pharmaceutical representative whose “crime” consisted of speaking truthfully about off-label uses of a drug manufactured by his company. We recently covered the year anniversary of this Caronia decision. Despite the injunction and First Amendment issues, however, the revised guidance makes no mention to the limits on FDA’s power.
WLF notes that, “indeed, the Draft Guidance omits any reference to the First Amendment. That omission is particularly glaring when one considers that, in the five years since release of the 2009 Guidance, both the U.S. Supreme Court and the U.S. Court of Appeals for the Second Circuit have issued important decisions that strengthened the First Amendment rights of drug and device manufacturers to speak truthfully about off-label uses of their products. As numerous court decisions make clear, FDA can no longer get by with its “the First Amendment does not apply to us” approach.”
WLF believes the Draft Guidance is “constitutionally acceptable to the extent that it imposes reasonable disclaimer requirements on manufacturers seeking to disseminate enduring materials that discuss off-label uses of their products. But the First Amendment does not tolerate the Draft Guidance’s efforts to prevent such dissemination altogether, except when the materials are so deficient that they could not possibly meet minimal scientific standards-in which event they would not be appearing in a medical textbook or peer-reviewed journal in the first place.”
“Adequate and Well-Controlled Studies”
In WLF’s response, they argue that FDA should eliminate any reference to “adequate and well-controlled clinical investigation,” a reference that likely will be interpreted as imposing severe limitations on the types of journal articles that may be disseminated. The term “adequate and well-controlled study” is often used by FDA as a term of art, WLF notes, to refer to “double-blind placebo studies, i.e. studies that are sufficient to support a new drug application to FDA.”
WLF states that “many valuable studies have passed through the peer-review process and been accepted for publication by reputable journals without meeting FDA’s usual definition of an ‘adequate and well-controlled study.'” An “open study,” for example, can impart valuable information about a drug, but is generally not deemed as authoritative as a double-blind study.
Navidea Biopharmaceuticals notes that the 2009 guidance “appropriately permitted both pharmaceutical and device manufacturers to disseminate reprints regarding certain well-designed trials not fitting the four corners of the regulatory definition of ‘adequate and well-controlled studies.'” These include historically controlled studies, pharmacokinetic and pharmacodynamic studies, and meta-analyses. The draft “would appear to have the practical effect of limiting the types of reprints that can be disseminated by drug manufacturers.” The reality is that the study methodologies of clinical trials involving radiopharmaceuticals, specifically, “do not always fit neatly into the four corners of FDA’s definition of “‘adequate and well-controlled studies.'”
Bibliography
LifeCell Corporation argues that the guidance’s limitations are “burdensome and unpredictable.” For example, FDA recommends that every medical journal be disseminated with a “comprehensive bibliography…of publications discussing adequate and well-controlled clinical studies published” about the use of the drug or device. But LifeCell notes that manufacturers may “inadvertently omit a study that in FDA’s opinion is relevant.” Would FDA consider this off-label promotion? LifeCell also notes the additional cost and resources required to distribute such articles with accompanying bibliographies and studies. WLF also believes that the bibliography aspect of the guidance should be dropped.
Financial Disclosures and Potential Conflicts of Interest
Both the 2009 and 2014 reprint guidance have required companies to disclose in a cover note to reprints the: (1) identity of authors known to the manufacturer as having a financial interest in the product or manufacturer, (2) affiliation of the author, (3) nature and amount of such financial interest, and (4) identity of any person known to the manufacturer who has provided funding for the study. The 2014 guidance includes this requirement for medical reference texts as well as for CPGs.
Navidea Biopharmaceuticals notes that perhaps this requirement should be changed in light of the Physician Payments Sunshine Act. In 2009, only a handful of states required pharmaceutical manufacturers to report payments made to physicians. Now, in 2014, the Sunshine Act requires this from all companies.
The Guidance also states: “To be consistent with the recommended practices described in this guidance, a scientific or medical journal article regarding an unapproved use that is distributed by a manufacturer should not…be edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.”
However, this is nearly impossible, as most medical journal editors and authors are doctors whom have extensive use of medical devices from multiple manufacturers.
The clinical research consultant Greenlight Groups, generally supportive of FDA’s guidance took issue with this point. “If someone is going to comment on their individual experience using a device or drug off-label,” they argue, “it only makes sense to include those whom actually have significant experience in the field, which will certainly include financial ties to manufacturers, whether via clinical study research agreements, medical devices or drugs being provided at no cost as part of a research grant from a manufacturer, and certainly those would be included as a financial interest.” Greenlight argues—conversely to other respondents—that this should be offset by “rigorous potential financial conflict disclosure.”
Other issues with the Guidance
LifeCell also takes issue with vagueness surrounding many important provisions of the guidance. In terms of the Clinical Practice Guidelines (CPGs), FDA recommends manufacturers should only distribute CPGs that are considered “trustworthy.” FDA relies “heavily on the Institute of Medicine (IOM) standard for CPG ‘trustworthiness.'” LifeCell notes that this is a vague standard and that FDA should provide an example of an appropriate CPG within the guidance. The FDA also states: “a CPG that discusses unapproved new uses of a manufacturer’s product should not be primarily distributed by a drug or device manufacturer…” Primarily, however is not properly defined and is subjective in nature. Moreover, since CPGs are generally accessible online, LifeCell argues that FDA should not dictate the mode they are disseminated.
Other aspects of the Guidance embrace antiquated methods for distributing medical texts. For example, FDA states that to be consistent with the recommended practices a medical reference text, or an individual chapter, that is distributed should not: (1) “Be primarily distributed by a drug or device manufacturer; rather, it should be generally available in bookstores or other independent distribution channels (e.g., subscription, Internet) where textbooks are sold.” Commenters noted that this is extremely rare practice.
Also, FDA makes strange, seemingly arbitrary lines in the sand about distributing off-label material. While they allow scientific or medical reference texts to be distributed at medical or scientific conferences in settings appropriate for scientific exchange, they disallow it in promotional exhibit halls or during promotional speakers’ programs. However, Millennium notes that the guidance explicitly contemplates the delivery of both reprints and books to a health care provider’s office by the sales rep. If that is allowed, “having shrink-wrapped books on a table at the commercial booth does not create any additional risk, and the prohibition of that activity seems quite arbitrary.”
We will follow FDA’s response to the reprint guidance. This is an important issue. WLF notes that in some fields, such as oncology, the great majority of medically-accepted treatments involve off-label uses of FDA-approved drug and medical devices. If doctors were limited to using therapeutic products only as labeled, doctors would be providing sub-optimal care to their patients.
Full Comments from Stakeholders
Council of Medical Specialty Societies