Take it away Lindsey:
Last week, the FDA released new draft guidelines that represent its latest recommendations for what drug and device manufacturers should do when they wish to distribute information on unapproved or “off-label” (this FDA prefers the more pejorative term “unapproved”) uses of their drugs and devices via scientific articles, scientific or medical reference texts and clinical practice guidelines (CPGs) to any health care entity. See Guidance for Industry Distributing Scientific and Medical Publications on Unapproved New Uses – Recommended Practices, 79 Fed. Reg. 11793-796 (FDA March 3, 2014) (“Draft Guidance”). The draft guidance itself is availableonline here:
We’re most concerned with the guidance as it applies to clinical and scientific articles and reprints. For more comprehensive coverage of the guidance as it applies to medical reference texts and clinical practice guidelines CPGs, check out what the FDA law blog has to say.
While members of Congress still are mum on the issue of yet another case of the FDA testing ("breaching") the bounds of the First Amendment, it doesn’t sit well with us. We at DDLaw have a storied romance with off-label use itself. Notwithstanding the risks of using medical drugs and devices that have not cleared the hurdles of the FDA’s approval process, off-label uses offer substantial benefits to many patients, which is why the practice is so common. In still others, such uses can offer acute conveniences that might not justify additional testing, but sure as heck improve a patient’s quality of life and care. For example, this guest author routinely uses a continuous blood glucose monitor in areas of the body where the FDA has yet to OK marketing for use in adults. Why? Because doctors know the device was extensively studied (and is approved) for use in locations other than the abdomen for children, but has not yet undergone the expense of the required separate testing before approving alternate sites in adults. Rather than accumulate scar tissue by using the device in a very small area, engaging in off-label use allows me to preserve and maintain healthy tissue and use the device in a way that’s significantly more comfortable, day in and day out, without compromising the accuracy of the blood glucose readings themselves.
As we’ve discussed before, drug and device manufacturers can’t always justify the expenses associated with having a product FDA- approved for additional uses. To obtain FDA approval for a new use, manufacturers are required to demonstrate, through clinical trials, the safety and efficacy of a new drug for each intended use or indication. 21 U.S.C. §355(d). Manufacturers have reduced incentive to pursue having additional uses printed on their labels where drugs are soon to be off-patent and where the population who could benefit from the now off-label use is not large enough to justify the expense of studies, to name a few examples.
Let’s be clear: if you engage in off-label promotion, the government (or some plaintiff) may bring an action against you. But there is a fine line between off-label promotion of a drug and allowing manufacturers to communicate dosing or other important information on off-label uses to practitioners in cases where they already plan (as is their right) to invoke off-label use in a treatment plan. Just see Wells v. Allergan, 2013 WL 389147 (W.D. Okla. 2013), where the trial court denied summary judgment on a failure to warn claim where the FDA had rejected proposed warning language speaking to dosage for off-label use of Botox in pediatric patients with cerebral palsy. Id. at *1. There, although the FDA prohibited the manufacturer from warning about dosage limitations and lack of studies of Botox in pediatric patients, the court was not willing to grant the defense summary judgment on the failure to warn claim. Id. at *7. In fact, the court seemed appalled that when the plaintiff’s physician specifically asked the manufacturer for dosing information for the off-label use, the manufacturer did not produce all of the relevant studies in its possession (presumably for fear of an FDA action based on off-label promotion). In that case, the plaintiff’s injuries may have been avoided altogether if the manufacturer had felt comfortable sharing all of its known dosing information for the off-label use. Wells demonstrates that physicians often decide to pursue off-label use with or without the benefit of the most up to-date dosing information - because the FDA actively inhibits such dissemination. It certainly would have been better for that plaintiff’s physician to have as much information about dosing as possible, as the manufacturer had dosing information that likely could have prevented his injuries. Instead, Wells makes manufacturers feel as though they are damned if they do issue warnings on off-label uses (when it’s misconstrued as off-label promotion) and damned if they don’t (by a viable failure to warn claim).
[Editor's Note: Bexis would argue that after Bartlett the claim in Wells is preempted because the FDA requires by regulation (and here rejected) all warnings about the risks of off-label use have prior agency approval before they may be included in the labeling. That's impossible to square with a tort duty to do so immediately.]
Even the FDA recognizes the longstanding right of physicians to prescribe drugs beyond the uses and populations included in their label. The agency says so in its 2009 Guidance on this subject:
Once a drug or medical device has been approved or cleared by FDA, generally, healthcare professionals may lawfully use or prescribe that product for uses or treatment regimens that are not included in the product's approved labeling (or, in the case of a medical device cleared under the 510(k) process, in the product's statement of intended uses). These off-label uses or treatment regimens may be important and may even constitute a medically recognized standard of care. Accordingly, the public health may be advanced by healthcare professionals' receipt of medical journal articles and medical or scientific reference publications on unapproved new uses of approved or cleared medical products that are truthful and not misleading.
Doctors engage in these uses where they find the benefits of the particular use outweigh the risk for the individual patient. And the most valuable tools for helping a physician make this risk-benefit analysis are often the very clinical studies the new Guidance seeks to make more cumbersome for physicians to obtain from the most likely source – whoever is the manufacturer of that particular drug or device.
So long as we are talking about truthful (and not misleading) information on off-label uses, it’s hard to see how limiting the informational environment on off-label use helps anyone – it certainly doesn’t help physicians trying to determine dosing for an off-label use and least of all the patient for whom an off-label use represents a last resort. Manufacturers are the logical source (and sometimes the only source) for the most robust and up-to-date compliment of information outside of a drug’s label itself. They are, after all, chiefly responsible for monitoring post-market results of their own products.
The authors of the FDA Guidance certainly are aiming to make it less likely that physicians can get information on off-label use from the hand of a manufacturer, even where that manufacturer had nothing to do with the act of publishing itself. But before we get into the Draft Guidance itself, it’s worth emphasizing – it is just that,(1) a draft subject to a notice and comment period that ends May 2, 2014 and (2) guidance: it doesn’t have the effect of binding anyone:
“If a manufacturer who chooses to distribute scientific of medical journal articles that include information on unapproved or uncleared uses of its product(s) does so in accordance with the recommendations of this guidance, the FDA does not intend to use that distribution as evidence of the manufacturer’s intent that the product(s) be used for an unapproved new use.” (Draft Guidance).
The agency itself characterizes the Draft Guidance as recommendations, and states the word “should” as used in the document means that something is suggested or recommended, but not required. (Draft Guidance).
Now that we’ve clarified these housekeeping issues, this is how the Draft Guidance applies to scientific or medical journal articles that a manufacturer wishes to distribute and which contain information on off-label use.
The organization that publishes the articles:
· Should have an editorial board that uses experts who have demonstrated expertise in the article’s subject matter.
· Should review and objectively select, reject or provide comments on articles considered for publication.
· Should follow a publicly stated disclosure policy including any conflict of interests or biases of the article's authors, contributors, or editors.
· Be peer reviewed
· Be an unabridged reprint or copy (no excerpts)
· Contain information addressing “well-controlled” clinical studies that are considered scientifically sound . There’s a an exception for devices allowing for “significant investigations” that aren’t other “well-controlled,” including proof-of-hypothesis, animal and bench testing.
· Be accompanied by the FDA-approved labeling for the product it pertains to.
· Also be accompanied by a comprehensive bibliography, when such a thing exists, of all other published “well-controlled” studies that concern this particular off-label use.
· Also be accompanied by “representative” publications reaching contrary or different conclusions about the particular off-label use (again, if they exist).
· Not be accompanied by promotional materials. Indeed, the FDA doesn't even want the same sales reps distributing the material. Talk about throwing up roadblocks.
The article must not:
· Be false or misleading (however the FDA chooses to define that term).
· Recommend any use of the product that would be dangerous.
The article should not:
· Be in a special supplement or some other one-shot publication funded by the product's manufacturer.
· Have any markings, highlighting, summary or other description added by the manufacturer that emphasizesthe off-label use.
· Only be available through the product's manufacturer. It should be available through other, independent distribution channels.
· “Be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer.”
· Be attached to information specifically about the product (except for FDA-approved labeling).
· “[A] prominently displayed and permanently affixed statement disclosing” that the information discusses an off-label use.
· The financial interest of the authors, including compensation amount received by the author from the manufacturer.
· Anybody that has provided funding for the study discussed in the article.
· Any significant risks or safety concerns associated with the off-label use, both those discussed in the article and not.
Our reaction to the Draft Guidance is simply, “the more things change, the more they stay the same.” The FDA is still trying to test the bounds of the First Amendment, but its Draft Guidance isn’t imposing any new source of liability. And even if it were, it’s been this blog’s longstanding position that off-label promotion is constitutionally protected speech, where it is (1) truthful and (2) involves scientific information about off-label use.
For just a few of our favorite First Amendent decisions that you won't find cited in the FDA's latest draft, see Thompson v. Western States Medical Center, 535 U.S. 357 (2002) (holding a FDA provision that a compound drug prescription must be unsolicited and that pharmacists cannot advertise or promote compounding any drug is unconstitutional restriction of commercial speech under the Central Hudson test); United States v. Caronia, 703 F.3d 149, 169 (2d Cir. 2012) (holding that the government cannot prosecute pharmaceutical manufacturers under the FDCA for speech promoting the lawful, off-label use of an FDA-approved drug); Sorrell v. IMS Health Inc., 131 S.Ct. 2653, 2659 (2011) (“Speech in aid of pharmaceutical marketing…is a form of expression protected by the Free Speech Clause of the First Amendment.”).
All of these cases are more recent (and thus supersede) all of the cases that the FDA decides to cite in the Draft Guidance. Rather than confront its more recent losses, the FDA has chosen to stick its head in the sand. Because the FDA appears to have no answer, we still think the First Amendment has enough mojo to defeat any FDA legal challenge that might invoke the Draft Guidance.
If you haven’t yet seen the finale episode of True Detective, this is where this blog post should end for you. Throughout the episode, we could see that the more things changed, the more they stayed the same --- Rust and Marty’s relationship, the shots of the bayou, and the winding roads we saw in previous episodes. At the end, Rust and Marty gaze up at the stars, and Rust says “Once there was only dark, if you ask me the light is winning.” And so it is here at the Drug and Device Law Blog. Once there were only a few cases giving our clients the right to communicate about off-label uses with physicians per the First Amendment. With time, and possibly additional legal challenges to whatever final form the Draft Guidance takes, maybe we can have a few more stars to cite in briefs, and maybe enough light will be shed on off-label uses for the people who need it most, the patients.