It’s been over two years since the FDA – in March, 2014 Draft Guidelines and then in its June 2014 “grant” of an industry-submitted citizen’s petition – promised to review its restrictions on so-called “off-label promotion” by regulated drug and medical device manufacturers.  We were skeptical at the time that all we would get is “still more agency bobbing and weaving.”

Then two years with zilch – save more Agency First Amendment losses in off-label promotion cases.  Then industry gets sufficiently frustrated by FDA inaction on off-label communication issues that it starts to take matters into its own hands.

So, a month later, we finally hear from the FDA again.

Finally, some action?

Don’t bet on it.

On August 31, 2016, a notice appeared in the Federal Register entitled “Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products; Public Hearing; Request for Comments.”

Wonderful.  More talk, and the FDA kicks the can further down the road.  Once again the Agency refuses to recognizes the constitutional bind in which it finds itself.  Indeed, the term “First Amendment” doesn’t appear anywhere – not even once – in the notice.  Nor does the FDA so much as utter the phrase “off-label.”  Except for citations, the FDA uniformly uses the more pejorative term “unapproved.”

If not the First Amendment, then, what do we have?

Well, the FDA asks for comments, meaning that regulated manufacturers get to spend more money paying their regulatory lawyers to repeat the same things one more time.  With respect to off-label communication:

FDA is interested in comment on the extent to which additional communications from firms about unapproved uses can provide access to information that is relevant, scientifically sound, responsibly presented, and provides as full an understanding as possible about the limitations of the available evidence, as well as comment on the extent to which health care professionals currently face impediments to accessing such information, whether from firms or from other sources.  FDA is interested in comment and information addressing whether and in what ways firms’ communications of unapproved use information are distinct and perhaps provide unique benefits compared to other sources.

Notice – online version – at “Background.”  OK, while we think this has been done to death, at least the FDA is asking pertinent questions.  To us it has never made any sense that, while any unregulated Tom, Diane or Harry can say whatever s/he wants in about off-label use public on the Internet, the entities with responsibility for researching their products and conducting adverse event reporting are muzzled.

The FDA makes a lot of references to “scientific” or “medical” information that is “relevant,” “truthful,” and “non-misleading.”  We like that kind of information too, but we don’t see how off-label use is so much different.  All information about all drugs and their uses – on- or off-label – should have these characteristics.  The FDA has decades of experience with these considerations already, in the context of indicated uses.  We don’t see what more is necessary.  Granted, “[n]ot all communications of information about unapproved uses help support public health.”  But “communications that emphasize a medical product’s claimed benefits, while minimizing the limitations of the supporting evidence, or minimizing the product’s known or potential adverse effects,” are problematic whether or not the use appears on product labeling.  The FDA already has regulations (and extensive enforcement experience) regarding these concerns in the context of promotional activities generally.  Off-label use isn’t any different in this respect.

The notice contains eight general topics which the Agency seeks comment, most of those broken into multiple subtopics, for a total of about 25.  Here they are in brief:

1. The public health impact of off-label communication by regulated persons:

• Benefits and risks to recipients from increased communication about off-label use, given that the information be “preliminary or inconclusive.”

• Effects on prescribing, development, and research concerning new potential product uses.

• Effects on incentives for patients to enroll in clinical trials, and for manufacturers to conduct them.

• Could the impact be different for drugs, as opposed to biologics, medical devices, and other categories of regulated products?

2. Impact of the changing structure of the health care system, and its need for better data.

• Data needs of payors and formulary committees that influence prescribing decisions.

• Whether changes in the healthcare system preserve, enhance, or reduce incentives for manufacturers to seek FDA review of new uses.

3. The impact of increasing availability of off-label information through various sources on the incentives for manufacturers to engage in such communications, along with other factors (including financial) that affect these incentives.

4. Standards for off-label communication that would minimize the potential for the information to be misleading or otherwise harmful.

• Processes that manufacturers use to determine what evaluate when off-label information is sufficiently reliable to communicate to those in the health care field.

• Criteria that the FDA could use for making the same reliability determinations.

• The extent and variability of health care professionals’ understanding of the reliability of available information about off-label uses, and whether different audiences need different presentations of the same information.

• What off-label information is most important for health care professionals’ ability to evaluate the reliability of off-label information, and whether this varies depending on the audience.

5. Standards for FDA determination whether off-label communications are truthful and not misleading, and what the content of these communications should be (again, we wonder why this is different than for on-label information).

• Appropriate off-label disclaimers and whether these should vary by the means of communication.

• How to determine when communications actually involve off-label uses, and how these determinations are made.

• What kinds of risk, reliability, and regulatory information should accompany off-label communications.

• How to present disclosures in off-label communication so that they are most effective, particularly as to scientific reliability.

• When and under what conditions are off-label communications to the public – patients and other consumers – appropriate.

6. The extent to which non-public data should be disclosed if it forms the basis for an off-label communication.

7. Appropriate types of surveillance and monitoring for the FDA to conduct concerning off-label communications.

8. The FDA has stopped hiding its proposed changes to 21 C.F.R. §§201.128 801.4 that it slipped into a tobacco-related notice (80 Fed. Reg. 57756), and seeks input about:

• Additional regulatory changes concerning communications, including whose concerning “false and misleading,” “adequate directions for use,” and how “labeling” is defined.

• The advantages and disadvantages of alternative regulatory approaches to off-label communications with respect to the FDA’s public health mission.

So here we go again.  A lot of these requests resemble those appearing in prior FDA notices.  For more details, we recommend the FDA Law Blog’s discussion.
Information regarding attendance, registration, commenting, and presenting is also included in the notice.  Comments on the FDA’s proposal will be accepted until January 9, 2017.

  • Cal Adler

    I can’t disagree with the points raised but opening up off-label promotion would be a death knell for large scale trials for “secondary” clinical applications. Though given the ubiquity of generic substitution, extended exclusivity for a new indication isn’t necessarily worth much for the branded manufacturer running those studies. In addition, the industry guidelines would require someone (industry? FDA?) to decide what studies constitute reliable evidence–given the proliferation of for-profit online publications, one can’t just assume that any published study is reliable.