On February 28, 2014, the FDA issued its most recent unofficial guidance on distribution by manufacturers of research concerning off-label uses.[1]  With minor textual revisions, this new Guidance essentially restates the safe harbors acknowledged in FDA’s unofficial 2009 “Good Reprint Practices” Guidance[2], and expands them to medical reference texts and clinical practice guidelines.  Under the 2014 Guidance, drug and device manufacturers can engage in some forms of distribution of peer-reviewed research about off-label use of their products without fear this will be used as evidence of misbranding.  In not backtracking from the 2009 reprint reforms, but rather expanding them to embrace other forms of communication, the 2014 Guidance represents continued evolution of FDA’s position on speech concerning off-label use.

This evolution has been tortuous.  FDA’s initial position, in the early 1990s, was that manufacturers were prohibited from providing doctors with any unsolicited information about use of their products for uses not approved (i.e. “indicated”) on product labels.  Originally, FDA attempted to enforce its position, while evading judicial review of its constitutionality, through issuing informal warning letters threatening misbranding actions whenever a manufacturer engaged in communications discussing off-label uses.  After a judicial decision refused to condone FDA engaging in censorship through ad terrorem threats of prosecution[3], in 1996 FDA issued a Guidance which finally made an overt assertion that manufacturers could not distribute reprints or enduring materials like textbooks discussing off-label uses, but were limited to distributing reprints discussing only on-label uses.[4]  Congress itself found FDA’s policy too restrictive, and in 1997 permitted manufacturers to distribute reprints discussing non-approved uses, at least when an application for approval of that use was pending.[5]  The District Court for the District of Columbia found both the 1996 Guidance and the relevant provisions of the Food and Drug Administration Modernization Act (FDAMA) unconstitutional, and put in place an injunction permitting manufacturers to distribute materials frombona fide peer-reviewed journals and textbooks.[6]  On appeal, FDA, which had already abandoned defense of the 1996 Guidance, mooted the case by conceding that neither the FDAMA nor a 1997 Guidance on continuing medical education gave it any enforcement authority, but merely identified safe harbors within which FDA agreed that it would not seek to restrict manufacturer dissemination of information discussing non-approved uses of their products.[7]

In some ways resembling the armistice ending the Korean Conflict, the 2000 Court of Appeals decision in WLF v. Henney left the FDA and manufacturers engaged in an armed truce on opposite sides of the First Amendment.  FDA had tacitly acknowledged the First Amendment protects some forms of distribution of materials discussing off-label uses beyond the conservative minimum safe harbor recognized in the FDAMA, and manufacturers had recognized there is an undefined line – perhaps not quite as liberal as the WLF injunction — which, if crossed would  subject them to the sledgehammer of a misbranding prosecution.  Following the FDAMA expiring by its own terms in 2006, FDA, in an effort at agency-industry détente, sought to define this de facto status quo in its 2009 Good Reprint Practices Guidance.  In the 2009 Guidance, FDA for the first time acknowledged that manufacturers could distribute to doctors, without a prior request from the doctor for information,[8] some unabridged, unedited and un-highlighted reprints of articles primarily written by independent researchers published in bona fide peer-reviewed journals.  This position is carried forward – in many cases in near-identical language – in the new 2014 Guidance.

In the 2014 Guidance, like its 2009 predecessor, FDA seeks to preserve awareness of the distinction between on- and off-label uses by imposing some “time, place and manner” restrictions separating dissemination of off-label materials from distribution of promotional materials concerning approved uses.  The Guidance requires disclaimers that the distributed reprint concerns a use which had not been approved by FDA, discussing all significant risks or safety concerns known to the manufacturer concerning the unapproved use, and enclosing the FDA-approved label.  The Guidance also requires a conflict of interest disclosure of the manufacturer’s interest in the drug and any ties of any author to the manufacturer.  The Guidance also calls for the reprinted article to be distributed with a comprehensive bibliography of adequate and well-controlled studies about the use of the product and, where one exists, a representative publication coming to a different conclusion about the off-label use.

Where the 2014 Guidance goes beyond the 2009 Guidance is in extending the substance of the reprint safe harbors to medical reference texts, which had been covered by the 1996 Guidance but as to which  the 2009 Guidance was silent.  In applying the reprint safe harbors to textbooks, the 2014 Guidance makes some adjustments necessitated by the different context of medical texts.   For example, whereas redistribution of the entire unedited work is required for journal reprints, redistribution of relevant chapters of a medical reference text is permitted.  The 2014 Guidance also applies, with  similar contextual adjustments,  to Clinical Practice Guidelines (CPG) intended to help clinicians make decisions for individual patient care in situations where there are few or no approved products.  Here, the primary restriction relates to a requirement that the CPG be “trustworthy” in that it conform to Institute of Medicine’s standards to ensure that the CPG reflects an adequate systemic review of evidence and assessment of the benefits and harms of alternative care options.

It would be an exaggeration to say the 2014 Guidance reflects a full embrace by FDA of the First Amendment.  It fails to acknowledge the changed landscape resulting from recent pro-speech Supreme Court decisions[9] and in some instances clings to regulatory theories called into question by United States v. Caronia,[10] a decision it studiously ignores.  There has also been long-standing criticism of the First Amendment validity of some of the restrictions in the 2009 Guidance.  In particular, a narrow interpretation of the requirement that reprints discuss only what FDA considers “adequate and well-controlled clinical investigations” – a threshold not always attainable for some off-label uses that may nevertheless represent the standard of care – could become a pretext for censorship and represent a significant government intrusion into clinical research.  The same is true with respect to the requirement that the reprinted article not be “significantly” influenced by anyone having ties to the manufacturer, as it is  common for some of the researchers involved in studies examining cutting edge uses to have ties to the manufacturers who are most interested in exploring these issues. The WLFinjunction had, pointedly, sought to address this issue by requiring disclosure of these interests,  not a bar on circulating publications in which researchers with ties to the manufacturer were involved.  Finally, in practice, the required steps to segregate distribution of reprints from promotional materials at conferences can become an issue of form over substance, while FDA’s efforts to regulate exactly what a manufacturer’s representative can say when handing the reprint to a doctor give rise to obvious substantive and practical problems in reconciling enforcement with the First Amendment, particularly in light of the Second Circuit striking down the enforcement efforts in Caronia.

These details, however, are issues to resolve another day.  Perhaps the most important take-away from the 2014 Guidance is that in it, the Obama Administration did not back away from, but instead essentially embraced and even mildly expanded, an approach outlined in the waning days of the Bush Administration.  The 2009 and 2014 Guidances together thus reflect a bipartisan consensus that manufacturers should be able to distribute some peer-reviewed research about off-label uses:  a striking, and welcome, departure from the Agency’s initial pro-censorship position in the 1990s.