Kellie Combs: Welcome to Non-binding Guidance, a podcast series from Ropes & Gray focused on current trends in FDA regulatory law, as well as other important developments affecting the life sciences industry. My name is Kellie Combs, and I am a partner in Ropes & Gray’s life sciences regulatory and compliance practice, based in Washington, D.C. I am here today with two other Washington, D.C.-based colleagues: Doug Hallward-Driemeier, a partner in Ropes & Gray’s litigation & enforcement practice and head of the firm’s appellate & Supreme Court practice, and Josh Oyster, a senior associate in our life sciences regulatory and compliance practice group. Doug, Josh, and I have worked together extensively over the years advising our life sciences clients on product communication issues and how FDA’s promotional framework intersects with the First Amendment. In particular, we worked together to represent Pacira in its litigation against FDA, and also worked together on amicus briefs in the Caronia, Amarin, and Facteau and Fabian cases.
Today, we are discussing one of the most fundamental concepts in FDA law: intended use. On August 2, FDA issued a final rule amending its drug and medical device regulations describing the types of evidence the Agency considers relevant to determining a product’s “intended use.” The new regulations took effect just on September 1. As we’ll discuss in more detail today, the final rule represents the culmination of a nearly six-years-long rulemaking process that generated extensive comments from industry, raises complex statutory and constitutional issues, and impacts how manufacturers market, sell, and communicate about their products.
In the preamble to the final rule, the Agency stated that the amended regulations were intended to “better reflect the Agency’s current practices” and explained that “one of the purposes of this rulemaking is to put to rest any dispute about FDA’s interpretation of its statute and regulations, and its policy… regarding evidence that may be relevant to establishing intended use.” Nonetheless, despite FDA’s goal of providing more clarity to industry, significant questions remain regarding how the Agency will apply the amended intended use regulations in practice going forward and what other regulatory changes related to manufacturer communications may be forthcoming.
Josh, let’s start with you—before we get into the specifics of the new final rule, could you explain the history of the rulemaking and how we got there?
Josh Oyster: Yes, of course, Kellie—happy to do so. FDA’s intended use regulations for drugs and medical devices were first issued by FDA nearly seven decades ago (back in 1952) and they’ve long been controversial, particularly because of the inclusion of language suggesting that a firm’s knowledge of an off-label use might be sufficient to establish a new intended use of a product.
That controversy is compounded by the fact that FDA has historically taken a broad view of intended use and has long looked to a wide range of sources, such as promotional claims, internal documents, and how the products are distributed as evidence of intended use. Industry has long argued that this broad view of intended use raises constitutional issues and exceeds the Agency’s statutory authority. Causing some further confusion for manufacturers, FDA and the Department of Justice have at times made conflicting statements regarding the evidence that may be relied upon by the government in determining intended use, including the relevance of a manufacturer’s knowledge (e.g., that its product will be used off-label).
This most recent rulemaking—this six-year-long process—FDA first published a proposed rule in 2015 to amend the regulatory definitions of intended use. Those proposed amendments were very targeted, focused only on a manufacturer’s knowledge of how its product would be used. Then in January 2017, FDA issued a final rule that was a bit of a switcheroo because the Agency adopted a new “totality of the evidence” standard for determining intended use; and pursuant to that final rule, the government could have considered any form of evidence—including a manufacturer’s knowledge—when determining intended use. In response, the Medical Information Working Group, a consortium of pharmaceutical and medical device companies (to which Ropes & Gray serves as co-counsel), and the trade associations PhRMA and BIO, raised concerns with this final rule and petitioned FDA to reconsider the amendments. FDA, in turn, delayed the effective date of the final rule until March 2018, and then in March 2018, they delayed the effective date of the rule indefinitely. For two-and-a-half years, there was basically silence on this issue.
FDA came back in September 2020 and published a new proposed rule that withdrew the portions of the 2017 rule that never became effective. Then, they put forth this new proposed rule that purported to provide more clarity about the types of evidence relevant when FDA determines the intended use of a product—this proposal is what FDA recently finalized.
Kellie Combs: Josh, that sounds like quite the saga. Tell us where we actually ended up—can you walk through the key changes in the regulations as a result of the final rule?
Josh Oyster: Yes. The new final rule amended the existing regulations in two key respects.
First, FDA has added language clarifying that a firm will not be regarded as intending an unapproved new use for an approved drug or a legally marketed medical device based “solely” on the firm’s knowledge that the product is being prescribed or used by health care providers for the off-label use. Because off-label use of medical products is generally legal and in some cases may represent the standard of care, manufacturers have long argued that knowledge of off-label use should not trigger potential criminal liability, so this was a welcome change. FDA and DOJ had previously stated from time-to-time that a firm’s “mere knowledge” of an off-label use would not establish a new intended use, but prior to this final rule, this policy had never been codified in the regulatory text.
The other thing that the new final rule does is FDA added language stating that a firm’s intent may be shown by the “design or composition” of an article. This new language is in addition to pre-existing text that permitted FDA to consider a “firm’s expressions” as well as the “circumstances surrounding the distribution of an article.”
More generally in the final rule, FDA has made clear that it will continue to take a broad view of what evidence, including manufacturer communications and other information about the product, may be considered when determining intended use.
Kellie, I’ve talked about what the actual changes were to the regulatory text. I know FDA’s preamble touched on some important topics like manufacturer communication safe harbors—can you tell us what we learned from the preamble on those issues?
Kellie Combs: Sure, Josh. I think this is certainly a case where the preamble is more interesting than the regulatory text itself. Industry had requested that FDA make clear in the regulations that safe-harbored speech about off-label uses like scientific exchange, responses to unsolicited requests, and reprint dissemination—that would all be excluded from the intended use inquiry. Unfortunately, the Agency declined to do that. In the preamble, all they say is that the “final rule does not disturb any of FDA’s acknowledged ‘safe harbors,’ including those that encompass various types of scientific exchange,” and that knowledge in combination with “safe-harbored” speech would not be “determinative” of intended use, whatever that means.
Although FDA appears to have acknowledged that some, but not all, scientific exchange would be excluded from the determination of intended use, it didn’t really provide any clarity as to when safe-harbored speech, including but not limited to scientific exchange, would be regarded by FDA as relevant to the intended use determination—in other words, what is in and what is out? We don’t really know. The Agency rejected requests to codify the various safe harbors that appear only in non-binding guidance, like the reprints guidance or the guidance on unsolicited requests. FDA said that those sorts of requests from industry were really outside the scope of the rulemaking.
The Agency did acknowledge, though, that it’s been continually engaged in a “comprehensive review” of regulations and policies regarding manufacturer communications to evaluate consistency with constitutional and statutory requirements. Now, that comprehensive review is something that the Agency committed to all the way back in 2014, and we unfortunately don’t have an update from FDA about when that review might be complete or what other actions might be a part of it.
In addition to the interesting language in the preamble about the safe harbors, I thought the preamble was also noteworthy for how the Agency responded to comments from industry on constitutional issues. Doug, can you explain FDA’s position in the preamble?
Doug Hallward-Driemeier: Thanks, Kellie. The preamble to the final rule addressed comments from a number of industry stakeholders that had questioned FDA’s interpretation of intended use on a number of grounds. On essentially every issue, FDA doubled-down on the positions it had taken in the past.
Taking first the constitutional considerations that you had mentioned—several industry stakeholders argued that the proposed rule, and the intended use regulations more broadly, raised important First Amendment concerns and threatened to chill truthful, non-misleading manufacturer communications about, for example, unapproved uses. As you mentioned, many times those unapproved uses may be standard of care. In response, FDA argued that the final rule did not implicate the First Amendment because in their view, the particular changes that were being made to the codified language did not directly involve speech. FDA added that a “categorical exclusion of all truthful speech from regulatory review,” they thought, “would undermine FDA’s ability to promote and protect the public health through premarket review of medical products, including review of proposed labeling, and postmarket regulatory surveillance and actions.” Now, this was the first time that FDA had codified any change to its manufacturer communication regulations since several really key developments in First Amendment law in this area, including the Supreme Court’s decision in 2011 in Sorrell v. IMS Health, the Second Circuit’s decision the year after in United States v. Caronia, and then the district court decision in the Southern District in New York that applied Sorrell and Caronia in 2015 in Amarin v. FDA. Many industry participants and observers had expected that the Agency might at least make some nod to the limits of the First Amendment and how it operates as some constraint on the regulatory regime, but in the preamble, FDA really was unwilling to concede that these cases provide any meaningful limits on the Agency’s authority.
FDA also reaffirmed the arguments from its 2017 memo addressing First Amendment issues, called the “Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products.” FDA emphasized the public health interests that are served by the Agency’s current regulatory approach and it asserted that the various proposed alternative approaches would be inadequate. That’s noteworthy for several reasons. One, FDA had not relied on that memo in over four years, and also, the Agency obviously continues to take what many regard as an overbroad, all-or-nothing approach when it comes to regulating speech. They tout the communications safe harbors when they need to, but as you mentioned a moment ago, those safe harbors have not been codified nor has the Agency made efforts to more carefully tailor the restrictive framework.
Those are, I think, very serious First Amendment issues that were presented, and FDA kind of gave them the back of the hand. The industry commentators had also argued that the rulemaking raised concerns under the Due Process Clause of the Fifth Amendment because the intended use regulations fail to provide sufficient clarity regarding the boundaries of permitted or prohibited communications. The industry had argued, for example, that regulating the dissemination of truthful, non-misleading scientific and medical information through only non-binding, often draft guidance documents, fails to provide that precision or clarity that is required by the Due Process Clause, especially in the First Amendment context. FDA disagreed with this argument, asserting that it is not required to regulate with “meticulous specificity.” FDA noted that in its view, “courts have repeatedly rejected due process challenges to the [FDCA] as unconstitutionally vague or ambiguous.” But, all the cases cited by FDA notably predate the most relevant Supreme Court precedent on that subject, which is the FCC v. Fox Television Stations, Inc. case from 2012, which held that the government must provide regulated parties with “fair notice of conduct that is forbidden or required,” particularly when it comes to speech. It’s also notable that FDA asserted that—in the almost 70 years since the intended use regulations were first issued—in its view, manufacturers have had “little difficulty” understanding how FDA applies the regulation. But that assertion was in the face of extensive industry comments pointing to the lack of clarity in the regulatory regime and the confusion that they found were caused by the intended use regulations.
Kellie Combs: Thanks, Doug. I’ve heard you say that in addition to constitutional concerns, that industry and others have raised statutory and other concerns as well. So, how does FDA address those in the preamble?
Doug Hallward-Driemeier: It’s interesting because in a way, the statutory arguments might provide FDA a basis for narrowing, clarifying, focusing the scope of what would be regarded as evidence of intended use in order to address these constitutional issues. It’s very common—a doctrine called constitutional avoidance states in order to avoid constitutional issues, you’ll construe a statute in a certain way. These statutory arguments that commentators have made with respect to evidence of intended use suggested that the Agency should take a narrower view. FDA explained its view that, for the intended use of a product that FDA could look to “any relevant evidence,” including promotional claims as well as other evidence—circumstances surrounding the distribution of a product, for example. Comments on the proposed rule had argued that considering evidence other than promotional claims—that type of thing that would be most analogous to the intended use in the label (the indicated use in the label)—would exceed the Agency’s statutory and regulatory authority. Again, that might have avoided some of the constitutional concerns, but FDA disagreed with those comments in the preamble—argued that nothing in the statute, the legislative history, or the existing regulations supported, in FDA’s view, an approach that intended use is exclusively based on promotional claims.
Kellie Combs: It certainly seems that between the new regulations themselves and the preamble, there’s a lot to digest here, Doug.
Doug Hallward-Driemeier: I would agree with that, Kellie, and it falls to you because you advise many participants in the industry on a day in, day out basis. What do you think this is going to mean for the drug and medical device industry? Do you think these amended regulations will provide the industry any clarity?
Kellie Combs: I wish that I could say more, Doug, but unfortunately, I don’t think we’re really getting the clarity that we need here. FDA has said many times that the new regulations really just reflect longstanding interpretations of the Agency, but industry has been confused by that interpretation for a long time now, so unfortunately, I don’t think FDA has accomplished its goal here. The Agency claims that the amendments to the regulation regarding knowledge should reduce manufacturer uncertainty, and I do agree that that’s a helpful clarification. It’s something that the Medical Information Working Group and other industry commentators have been asking for quite some time, really due to some of the confusion that was caused by conflicting statements from DOJ and FDA over the years. Even though we have that clarification, I think it remains to be seen what the practical impacts will be.
What the amended regulations really do is say that a new intended use will not be based “solely” on knowledge of an off-label use, but that the Agency would still be free to consider a manufacturer’s knowledge of an off-label use in conjunction with other evidence, including labeling, advertising, statements of company representatives, and other “circumstances surrounding distribution” of a product—and FDA has broadly interpreted that authority in the past. As a practical matter, when thinking about whether a new, off-label intended use exists for a medical product, FDA would almost certainly assert that other evidence besides knowledge of the off-label use helps to establish that intended use such that the Agency is not going to be relying “solely” on a firm’s knowledge. To put it another way, a manufacturer is almost always going to know, in some cases, whether a product will be put to an off-label use, and because knowledge will so frequently exist and because FDA has said that it can look to “any relevant source” of other evidence, it’s not certain whether we have much of a practical change here.
Additionally, the Agency stated that it “welcomes and will continue to consider comments” related to the safe harbors and to scientific exchange, but the Agency’s refusal to address the safe harbors at the same time as the intended use rulemaking really does leave a ton of open questions for industry regarding the scope and contours of those safe harbors. We have a regulatory safe harbor (scientific exchange), and even that is not fully protected according to FDA because only some scientific exchange would be excluded from the intended use determination. They also have many non-binding guidance documents, many of which say that if you follow the recommendations in the guidance documents, that the communication will not be considered as evidence of intended use. That’s memorialized in those non-binding draft guidance documents, but is not actually codified in the regulatory text, and that’s frustrating because industry is left in a position where they could follow all of the guidance and still potentially be nailed for off-label promotion.
FDA also refers to its “continuing review” of manufacturer communications that I mentioned earlier, but again, provides no details regarding what changes manufacturers might expect in the future or whether it will be finished.
Finally, FDA’s statements in the preamble regarding the breadth of the intended use inquiry and the Agency’s recommitment to that 2017 First Amendment memo I think could really set the stage for a more aggressive approach to promotional enforcement. It’s really, in my perspective, FDA laying a marker down—and as a result, I think manufacturers should continue to evaluate on a case-by-case their promotional materials as well as other non-promotional initiatives, including those that sit within safe harbors. To the extent that initiatives are on the margin or present risk, I think it’s important to evaluate those very carefully in the context of the risk tolerance of the company and to monitor very carefully FDA enforcement activity going forward.
Josh, you do a lot of advising in this space as well, and while the regulations are certainly important, we know here that FDA’s not the only actor, and sometimes DOJ and the courts get involved as well. What other developments related to intended use may be coming in the near future?
Josh Oyster: That’s absolutely right, Kellie—it’s a great question. Although the final rule reflects a lot of careful consideration by FDA on the critical issue of intended use, FDA’s not the only stakeholder involved here—sometimes the situation presents itself where the courts get involved. That’s why the timing of the intended use final rule from FDA is really interesting because it came only days after various industry groups submitted amicus briefs in an appeal currently before the First Circuit regarding the misdemeanor FDCA convictions of two former medical device executives, William Facteau and Patrick Fabian.
Facteau and Fabian had been charged with various criminal offenses related to off-label promotion of a medical device called the Stratus Microflow Spacer. The Stratus device had been FDA-cleared many years ago for use as a perforated sinus spacer device able to release saline to moisten the sinuses. However, the company’s internal design documents show that the Stratus was actually specifically designed to deliver steroids—and not saline—into the sinuses, and had a larger pore size that made the device incapable of retaining saline for more than a few minutes. Evidence introduced at the trial of Facteau and Fabian also established that the company seemed to market the Stratus really only for use with a steroid, specifically a substance known as Kenalog-40 that was more viscous than saline and other liquid drugs.
Following the convictions of Facteau and Fabian, they appealed to the First Circuit. In briefing before the First Circuit that was recently filed, the defendants and the various industry groups have argued that the government’s interpretation of intended use in this case raised serious constitutional concerns. These arguments are very similar to those that industry raised to FDA as part of the intended use rulemaking. Briefing in the Facteau and Fabian appeals is still ongoing, but it will be interesting to see how the court ultimately rules in this case and whether it will have an impact on FDA’s interpretation of intended use going forward.
Kellie Combs: Thanks, Josh. And Doug and Josh, thanks both of you so much for joining me today. Thanks as well to our listeners. For more information on intended use or other topics affecting the life sciences industry, please visit our website at ropesgray.com or contact us directly. You can also subscribe to this podcast series wherever you regularly listen to podcasts, including on Apple, Google and Spotify. Thanks again.