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A Ropes & Gray (RopesTalk) podcast series, focused on current trends in FDA regulatory law, as well as other important developments affecting the life sciences industry.
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. I’m Kellie Combs, a partner in the life sciences regulatory and compliance practice in Ropes & Gray’s Washington, D.C. office. I’m joined today by my partner, Josh Oyster, also from the life sciences regulatory and compliance group.
Today’s episode continues our 2024 U.S. life sciences regulatory outlook podcast series. We will be discussing key developments and trends related to medical product advertising and promotion today. We’re going to cover the latest enforcement trends, revisit FDA’s most recent guidance on the communication of off-label scientific information, and also discuss the implications of a long-awaited First Circuit decision that was announced in December. Let’s jump in. Josh, what ad/promo enforcement did we see in 2023? Were there any big surprises from the Agency?
Enforcement Trends
Josh Oyster: Yes, Kellie—happy to take that one. Enforcement remains relatively “light,” as compared to where it was 10 years ago from an ad/promo standpoint. In 2023, we were in a world where there were just four untitled letters and one warning letter, but that wasn’t a big surprise, because it has been the trend in recent years from the Office of Prescription Drug Promotion (“OPDP”). Where there has been a bit of a shift is, there’s a trend recently toward more “CFL-focused” enforcement—and what I mean by that is, letters that are taking issue with claims that are misleading because they aren’t necessarily complying with some of the recommendations set forth in the CFL guidance (the “Consistent with FDA-required Labeling” guidance).
Just to cover a few of the examples from 2023, there was that one warning letter I mentioned—it was issued in August 2023 to a large pharma company related to promotion of a drug for the treatment of chronic obstructive pulmonary disease (“COPD”). FDA took issue with what they considered to be false or misleading efficacy claims, including one statement about a study where there had been “an observed difference” in time to all-cause mortality. FDA faulted that claim because it wasn’t statistically significant, because there had been a statistical testing failure with an endpoint earlier in the sequence of the statistical analysis plan. Therefore, FDA didn’t like a claim based on an endpoint lower in the hierarchy. However, the statement in this case was just “observed difference,” not “significant difference”—and there was a statement below the claim, below a graph, that said, “These results are observational in nature, and any comparisons between treatment arms should be interpreted with caution.” FDA said that disclaimer didn’t mitigate the misleading impression. Part of the reason, I think, FDA said this is that no COPD product has been shown to improve all-cause mortality to date—in other words, no product has been approved with reduction in all-cause mortality in the product label. FDA pointed this out in the warning letter, so it probably contributed to why FDA was so concerned here (FDA thinking about this particular claim, which on its face just said, “observed difference,” in the context of the overall product profile and the competitive landscape of COPD products).
Jumping from that warning letter to some of the untitled letters, in June 2023, there was an untitled letter to a pharma company related to a drug for a rare metabolic condition. In that letter, FDA cited false or misleading efficacy claims, as well as the minimization of risk information. One of the claims at issue involved a material that said, “67% of patients who moved on to the second part of the study had normal cortisol levels by the end of the study.” FDA then disputed that claim by citing information directly from the package insert that contradicted what the claim said.
Then, in August 2023, FDA sent an untitled letter to a pharma company related to a social media-sponsored post for a birth control drug. One of the issues in that letter was the complete omission of risk information from the social media post, which is something that FDA will commonly cite if there’s just no risk information at all in a promotional piece.
Jumping ahead, in October, FDA issued another untitled letter to a company related to a direct-to-consumer brochure for a contraceptive drug. FDA faulted the company for presenting the benefit information in a false or misleading way, by saying, among other things, that “99% of pregnancies were prevented per act of sex,” and continuing to say, that means the drug prevented pregnancy 99% of the time. FDA criticized the way those numbers were presented, because in FDA’s view, “per act of sex,” is not a validated measure to demonstrate the efficacy of contraceptive products. Essentially, that 99% number and the way the company was calculating it was overstating the efficacy of the product.
Then, also in October, FDA sent an untitled letter to a company related to a TV advertisement for a depression drug. In that instance, one of the claims FDA was concerned about said, “when added to an antidepressant, this drug was proven to reduce depression symptoms 62% more than the antidepressant alone.” FDA thought this claim was misleading, essentially based on the way that the company was treating the denominator. FDA thought the comparison should be made against the baseline score in the study, as opposed to the score of the other arm, the antidepressant arm.
The important thing perhaps to think about for all these untitled letters, notwithstanding that they’re all public, FDA issued close-out letters in each case within a couple of months—meaning that FDA had gotten a response from the company, and FDA issued a letter back to the company, saying, “We’ve gotten your response, and we think it adequately addresses the concerns that we had raised.” It’s interesting that in all these cases, despite FDA’s original concerns, FDA was comfortable closing all of them out in relatively short order.
Kellie, in light of all that I just covered, what lessons can we glean from FDA’s more recent letters, and what big takeaways are you providing to clients?
Kellie Combs: Thanks, Josh, for that helpful overview. I think in 2023 and then even going back for the last few years, we’ve seen more of a focus, as you said, on CFL-type claims—and there are, I think, some lessons we can glean from those letters if we read them all together.
Number one, I think that companies should be avoiding bold claims and characterizations regarding CFL data, especially where there are study design or statistical limitations—for example, post-hoc analyses, failed endpoints in the hierarchy, situations where analyses are not controlled for multiplicity. These are just a few examples, and the idea here is that it’s important to carefully consider use of that data and how any sort of claim or presentation will be handled in the piece. So, it will be lower risk, for example, to present data in a neutral way without significant characterization by the company—in other words, let the data speak for itself.
Additionally, it’s going to be important to use robust disclaimers. Those should be prominent, they should be complete in disclosing the limitations, and they should also be clear about the value of the data and whether clinical conclusions can be drawn from it.
We saw in the AstraZeneca letter, and we’ve seen in other letters, that FDA expresses concern when a disclaimer just said something like “interpret the data with caution.” From FDA’s perspective, this might not be enough—you need to present the data with more detailed disclaimers. That’s also going to be important from a First Amendment perspective when you’re evaluating whether the content is truthful and not misleading.
It’s also going to be important to present CFL data in context—in other words, as supportive of other existing data such as data from your label, and not as a central focus of the piece or creating a brand-new piece simply focused on CFL data. FDA says in the CFL guidance that data should generally be presented in the context of information from product labeling, rather than as stand-alone data or claims. We see some of these concepts really coming through in many of the letters that we’ve seen over the last few years.
It’s also, of course, fundamental that your underlying study or analysis is, in fact, scientifically sound. FDA makes clear in the CFL guidance that in some cases, your study or analysis just may lack the scientific rigor that’s needed to support presentation of the data—in other words, there may be cases where the study, the analysis, the data, simply is not adequate regardless of any disclaimers or disclosures that are presented to support that promotional claim.
It’s also important to consider the regulatory history surrounding the data as well as the product profile and the competitive landscape of the product. So, what do we mean when we’re talking about the regulatory history? There may well be prior correspondence with FDA that’s relevant and can be very helpful in evaluating how FDA would evaluate the claim and what sort of risk it will pose. For example, did the issue, did the data, did the claim come up in the context of labeling negotiations with the Agency? And what was the FDA’s view there? To the extent that FDA struck data or struck certain language from the labeling that you now want to use in your promotional material, what was FDA’s rationale for doing that? There is a different standard, of course, for including information and labeling than for promotional material, so I’m certainly not saying that you can never use data or claims in promotion that FDA didn’t permit in the labeling, but it will give you a view into whether FDA considers the data, or would consider the claim, to be false or misleading. It may also be informative in terms of what sort of context is necessary, or what sort of disclaimer should be provided. There might also be information that was shared by FDA during the clinical development process, concerns that FDA may have with a particular endpoint or something along those lines. Also, be thinking about the product profile and the competitive landscape. For example, the all-cause mortality endpoint that was at issue in the AstraZeneca warning letter, the fact that it was that endpoint was apparently important to FDA, important enough to call out in the warning letter and to note that no other product had this claim in their labeling.
So, you need to be thinking about all of these things when determining whether to move forward with CFL data and to make sure you’re doing it in a thoughtful way.
Josh, I want to turn it back to you. What should we be making of the fact that FDA recently seems to be more aggressive in terms of the types of claims that it’s citing in warning and untitled letters, but the number of letters still remains pretty low? As you suggested, FDA’s closing out those untitled letters pretty quickly. What does it all mean?
Josh Oyster: At bottom, I’d say that the low number of letters is still likely driven by just the limited resources that FDA and, in particular, OPDP has. OPDP has a number of responsibilities, including the enforcement aspects that it handles through untitled letters and warning letters, but also a robust research agenda. They provide advisory comments. They provide comments on launch materials. So, there’s a lot of work that OPDP is involved in, and likely they’re focusing their enforcement efforts on areas of significance to them and that they see as very important. Whether we start to see a shift there in the coming years, either because the number of letters goes up or perhaps because there are heightened expectations on companies that are receiving letters in terms of corrective actions or preventive actions, I think we’ll just have to see.
Scientific Information on Unapproved Uses
Kellie Combs: Thanks, Josh. Let’s move on now to our next topic and talk about FDA’s recent revised draft guidance on communication of scientific information on unapproved uses. This guidance document was issued in October and certainly was one of the most significant policy developments related to off-label communications in a very long time. This was a revised draft of a prior draft that had been on the books since 2014, so certainly a long time coming. We had covered this draft guidance in some detail in a prior client alert and also in a podcast that we released in November, so we don’t need to repeat all of that discussion here.
Josh Oyster: Comments to the draft guidance were due to FDA in early January after we did our podcast and our client alert. Kellie, now that you’ve had a chance to take a look at the comments that industry had, what was the reaction to the new guidance?
Kellie Combs: Let’s talk about some of the core themes that are coming out of the comments submitted by industry groups and life sciences companies. I’ll just give a few examples and won’t talk about these in detail. There was, I think, a general sense of appreciation from industry that FDA was moving forward in providing more guidance in this area. As we mentioned, it had been a decade since FDA had released any guidance on this topic, and many in industry did point out a few very welcome developments and changes in the guidance. For example, I think folks were generally appreciative that FDA has acknowledged that companies can have off-label discussions based on an accompanying reprint and can generate presentations based on reprints—that’s not an activity that FDA had explicitly sanctioned in the past. Also, acknowledgments by industry groups and companies that FDA had specifically acknowledged social media as an appropriate form of communication, at least in certain cases as it related to scientific communications, as well as scientific communications that occur in commercial exhibit halls.
Also, there were many concerns expressed with the way that the guidance refers to intended use. As we know, FDA finalized a new intended use rule a couple of years ago and continues to assert very broad authority to consider not just advertising and labeling, but also, all sorts of evidence with respect to the determination of when a company is promoting its product for a new intended, or off-label, use.
One of the important changes that we saw from the draft guidance that existed in 2014 and this new revised draft is, FDA essentially says in this revised draft that if a company complies with the recommendations in the guidance, that it will not use dissemination of scientific information under the guidance “standing alone” as evidence of a new intended use. That “standing alone” language is an important caveat and certainly has significant implications, because it suggests that a company can follow the guidance to a T, and if there’s anything else that FDA can point to with respect to the off-label use, the guidance can still be considered as one of perhaps many sources of evidence that FDA would look to as part of an intended use inquiry. That is significant because FDA does assert such sweeping authority to consider all sorts of evidence when it comes to intended use. So as a practical matter, the concern is, there’s almost always going to be something else that the government can point to in the intended use determination.
Many commenters also took issue with the way that the guidance is framed, and, in particular, with statements in the guidance about how scientific communications provided under the guidance should be provided to HCPs that are engaged in clinical practice decisions for the care of an individual patient. This is language that did not occur in prior iterations of the guidance, and many commenters expressed concern that this was too narrow of a formulation, this individual patient formulation. For example, folks expressed concern that this wouldn’t necessarily cover HCPs who are engaged in broader care decisions, for example, for a group of patients, for a population of patients and so on. It also doesn’t expressly cover other very legitimate purposes for HCPs to receive information about unapproved uses of approved products, for example, for research purposes or for the purpose of other scientific discussion.
Then, finally, I think that the most robust discussion coming out of comments from the industry groups and the companies related to various concerns associated with a clinically relevant and scientifically sound standard—that’s the new substantiation standard that FDA introduced in the guidance. As a general matter, commenters expressed concern that the substantiation standard was poorly defined and overly restrictive and burdensome. Some made the point that the substantiation standard, in many ways—especially if you look at the examples that FDA cites about what meets and what doesn’t meet the standard—really feels more like a drug approval standard or, in some cases, even higher than the device approval or clearance standard, as opposed to a truthful and non-misleading standard that would be more appropriate for non-promotional scientific communications. A number of commenters honed in on the statement in the guidance where FDA says that early stage data are unlikely to be clinically relevant as an example that is particularly overly restrictive. And many concerns expressed that clinical relevance is really something that is in the eye of the beholder—meaning the health care professional that is evaluating the information. Certainly, the industry groups, the life sciences companies have no interest in disseminating junk science, no concern with the concept of clinical relevance, no concern with the concept of scientifically sound, but a lot of concerns expressed with the way that FDA is articulating and defining those concepts in a way that might be burdensome to the companies.
Josh, let me turn it back to you now. Putting aside the substance of the guidance for a moment, commenters had asked FDA for an extension of the comment period, but as it turned out, FDA granted only a very short extension. It appears that FDA is motivated to finalize the guidance, and in light of the comments that FDA has received, do we really expect that to happen this year?
Josh Oyster: Great question, Kellie. I think there’s a decent chance that FDA does actually finalize the guidance in 2024. One, some FDA officials have indicated at conferences and in other public venues that the Agency does intend to finalize the guidance. Second, and more generally—this isn’t specific to the SIUU draft guidance—we see FDA at the beginning of 2024 gearing up to try and get a lot done early in the year before the upcoming presidential election. Whether FDA is successful on all fronts in doing everything it wants to accomplish remains to be seen, but certainly, that’s the intent. I’ll caution that we don’t know exactly what’s on the CDER guidance agenda for 2024 because it hasn’t been released yet. Last year, in the 2023 CDER guidance agenda, the SIUU guidance wasn’t even on it, but FDA released the draft anyway. It was a guidance that no one knew to expect but it came anyway. So, here, it is possible that we could get the final guidance in 2024, and I think industry should be on the lookout for that one.
Facteau/Fabian Decision and Its Implications
Kellie Combs: As our last topic, let’s turn to the decision in the Facteau/Fabian case from the First Circuit. We talked about the decision in a recent client alert on our website, but, Josh, can you set the stage and remind us why we were waiting intently for that decision for so long?
Josh Oyster: Sure, happy to. On December 14, the U.S. Court of Appeals for the First Circuit issued a long-awaited opinion affirming the convictions of two former executives of Acclarent, on misdemeanor adulteration and misbranding charges under the Federal Food, Drug, and Cosmetic Act (“FDCA”) related to their involvement in the off-label promotion of a medical device. This was a long time coming, because the defendants, Facteau and Fabian, were initially convicted of misdemeanor charges and acquitted on felony charges in a jury trial that happened in 2016. Then, four years later in 2020, the district court upheld their convictions when it ruled on some post-trial motions. The defendants appealed after that to the First Circuit, but the case had been lingering there for the past couple of years.
The district court had struggled with a lot of the complicated charging theories under the Food, Drug, and Cosmetic Act and had even called into question whether the conduct at issue in this case was really what Congress had intended to criminalize under the Food, Drug, and Cosmetic Act. The First Circuit didn’t seem to have the same existential concerns with what it was doing. The First Circuit rejected essentially all of the defendant’s arguments and backed the government’s positions, many of which we’ve seen FDA express in other contexts over the years, such as in the preamble to FDA’s intended use final rule from a couple years ago that you were talking about earlier, Kellie.
As an example, the First Circuit rejected a challenge to the jury instructions on First Amendment grounds. The First Circuit found no issue under the First Amendment with using speech—even truthful, non-misleading speech—as evidence of an unapproved, uncleared intended use for a medical device. And the basis for this is a longstanding Supreme Court decision called Wisconsin v. Mitchell that has nothing to do with medical products or FDA but had established the principle that using speech as evidence of intent did not run afoul of the First Amendment.
The First Circuit distinguished the case of United States v. Caronia, that seminal case from the Second Circuit a decade ago. The First Circuit viewed Caronia as being about a different misbranding theory for a different type of defendant (in that case, a sales rep) and—perhaps most importantly—as a case where the government did not actually limit its use of speech solely to evidence of intended use.
The First Circuit also found that FDA’s safe harbor policies embodied in guidance documents (such as FDA’s reprints guidance or its guidance on responding to unsolicited requests) do not burden protected speech within the meaning of the First Amendment, because they “expand” rather than contract the amount of speech that the government shields from consideration as evidence of intended use.
Furthermore, the First Circuit rejected the defendant’s argument that only external promotional claims can qualify as evidence of intended use. And the First Circuit backed the FDA’s position on what can qualify as evidence of intended use, the one that Kellie was just talking about a moment ago.
The First Circuit also rejected the argument that FDA’s intended use regime was unconstitutionally vague. The Court acknowledged that the intended use regulation will “cast a wide net” and conceded that there could be some uncertainty when “in a close case” there will be sufficient evidence to prove that a manufacturer marketed a device for an off-label intended use.” But the First Circuit emphasized that “this was not a close case” in terms of the evidence that had been offered to establish the objective intent of the defendants, Facteau and Fabian. It’s worth noting that despite the apparent decisiveness in the First Circuit’s rejection of the defendant’s arguments, there still remains a lot of disagreement among industry stakeholders about this opinion.
Kellie Combs: Thanks, Josh. What do you think the key takeaways are for the medical product industry going forward? The First Circuit decision is technically just relevant in one circuit, but because it backs up a lot of FDA’s prior positions, what do we think the Agency or the government more generally does with this decision?
Josh Oyster: That’s a great question, and it’s going to be interesting to see a bit, because post-Caronia, FDA downplayed that decision for many years, went to great lengths to try and confine that holding to its facts and to say Caronia was really about just the particular jury instruction at that case and the way that it had been handled. It will be interesting if, in contrast, FDA tries to position Facteau/Fabian in the First Circuit as having broader, more universal implications, but there are important things to keep in mind about the First Circuit opinion that suggests it may in some respects be limited to its facts. For one, the court emphasized repeatedly that the scope of the evidence that supported the defendant’s convictions—and, as I just mentioned a moment ago, this wasn’t a close case. I think we’ll just have to see in the coming years how, if at all, it plays into FDA’s enforcement going forward.
One thing along those lines, a question I have is: Do we expect to see more FDA enforcement in 2024, or at least more enforcement outside of traditional areas? For example, might we see more enforcement based on evidence of intended use other than promotional claims? What do you think, Kellie?
Kellie Combs: Yes, Josh, I think it’s certainly possible. If you look at the arc of Agency activity in the ad/promo space dating back for a few years, it feels like FDA’s laying the groundwork for more aggressive promotional enforcement. Certainly, with the finalized intended use rule a couple of years ago and in the Federal Register preamble, FDA made some very sweeping statements about its authority related to intended use, not just with respect to promotional claims but with respect to all sorts of evidence, including certain types of scientific exchange. We also had renewed attention as evidenced through the SIUU guidance we were talking about. And, of course, all of those letters based on CFL data and presentations where FDA is taking issue not only with bold promotional claims and presentations of data, but in some cases, really calling into question the underlying data set itself. Josh, what do you think?
Josh Oyster: The conditions suggest that FDA might look to pursue more enforcement in 2024 and subsequent years, and I say that with some hesitation. Especially after the intended use final rule, that in FDA’s mind clarified a lot of its authority. FDA put forth in writing its position that was supposed to articulate once and for all its stance on evidence of intended use. But in the couple of years since that rule, we haven’t seen FDA exercising more aggressive enforcement in that regard. Now, in light of other developments, like the First Circuit opinion in Facteau/Fabian, might we see more—that’s the big thing that I’ll be watching in 2024.
Kellie Combs: Thanks, Josh. Unfortunately, that’s all the time we have for today’s episode in our Outlook 2024 series. We hope that you stay tuned for the fourth and final episode in our series in the coming days. For more information about our practice and other topics of interest to life sciences companies, please visit our FDA Regulatory and Life Sciences Practice pages at www.ropesgray.com. You can also listen to Non-binding Guidance and other RopesTalk podcasts in our podcast newsroom on the Ropes & Gray website, or you can subscribe to this series wherever you listen to podcasts, including on Apple and Spotify. Thank you again for listening.