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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: Hi. I’m Kellie Combs, a partner in the life sciences regulatory and compliance practice at Ropes & Gray. 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 here today with two of my colleagues, Josh Oyster, a partner in the life sciences regulatory and compliance practice, based in D.C., and Sarah Blankstein, a counsel in our practice based in Boston. We’ve 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.
Today, we’re discussing a new draft guidance document that FDA issued on October 23, entitled, “Communications From Firms to Health Care Providers Regarding Scientific Information on Unapproved Uses of Approved/Cleared Medical Products – Questions and Answers.” The draft guidance is a revision to FDA’s 2014 draft guidance on “Distributing Scientific and Medical Publications on Unapproved New Uses,” which was itself a revision to a 2009 final guidance on “Good Reprint Practices.” We’ll refer to the new draft guidance as the “SIUU Draft Guidance” and the communications described in the guidance as “SIUU communications.” We previously published a client alert titled, “Try, Try Again: FDA Issues Draft Guidance on Communication of Scientific Information on Unapproved Uses of Medical Products,” which walks through a lot of the detail in the draft guidance. We’ll not repeat all of that detail here, but the alert is available in the Insights section of our website, for those who are interested.
Josh, let’s start with you. Would you mind giving us a brief overview of the new draft guidance, and some of the key changes from 2014?
Josh Oyster: Sure—thanks, Kellie. The SIUU Draft Guidance describes FDA’s enforcement policy for firms’ communication of scientific information on unapproved uses of approved or cleared medical products to health care providers. As in the 2014 draft guidance, FDA recognizes that firms can disseminate certain limited types of truthful, non-misleading, factual, and unbiased scientific information related to these unapproved uses, subject to the expectation that the communication include extensive disclosures and describe a study or analysis meeting a particularly rigorous and restrictive substantiation standard that we’ll talk about more today. Beyond that, though, it really is a substantial rewrite of the 2014 draft guidance, and includes significant changes, some of which are helpful, and some that are more problematic. Of particular note, the new draft guidance goes beyond the 2014 draft guidance to include not just reprints, clinical practice guidelines, and reference texts, but also firm-generated presentations derived from accompanying reprints, and materials from what FDA calls “independent clinical practice resources.” FDA also recognizes, at least implicitly in the guidance, that social media and other outlets, like dedicated websites, can be an appropriate medium for SIUU communications. Those are really the most helpful changes in the new draft guidance.
Sarah, can you talk about some of the less helpful changes in the draft guidance, that may be more problematic for industry?
Sarah Blankstein: One big change that on the whole I would say is problematic is FDA’s articulation of a new substantiation standard for the types of studies and analyses that can support an SIUU communication. Under the new draft guidance, studies should be scientifically sound and clinically relevant. This is really an ambiguous standard that would be hard to apply, it leaves FDA a lot of discretion, and from the discussion in the draft guidance, has the potential to be interpreted by FDA in a restrictive fashion. We’ll dig into the problems with the standard in more depth during this discussion, but it characterizes some of the problems with the draft guidance as a whole. The draft guidance is really full of ambiguous standards and recommendations—and as a result, it raises significant constitutional concerns and operational challenges. Overall, while there are some helpful changes, as you noted, Josh, this new draft guidance carries forward FDA’s piecemeal and restrictive approach to off-label communications. It also carries forward FDA’s expansive approach to intended use. Kellie, is that something that you can speak to?
Kellie Combs: Sure thing, Sarah. And if you’re having déjà vu, it’s because this is a continuation of a discussion from one of our podcasts back in 2021, when FDA had issued its final rule revising the definition of intended use. Now, not surprisingly for those of us who have been following this topic closely, in the new draft guidance, FDA continues to advance a very broad view of the evidence it can consider in establishing that a product has a new intended use, or an off-label use, for purposes of enforcement. Echoing language in the Federal Register preamble to the 2021 intended use rule, FDA says in the draft guidance that a product’s intended use may be established by, among other things, promotional claims, advertising, and “any other relevant source” of evidence. Industry has long taken the position that FDA’s broad view exceeds its statutory authority and presents pretty significant constitutional issues. The Agency obviously disagrees. I won’t rehash those arguments here, but you can revisit our podcast on the topic from 2021.
I think for purposes of this new draft guidance, though, it’s important to keep this broad articulation of intended use in mind for another reason, and that’s because the version FDA issued in 2014 of the guidance is significantly different from the new version, in terms of how intended use is described for purposes of the enforcement policy. FDA says in the new draft guidance that it does not intend to use communications consistent with the guidance “standing alone” as evidence of a new intended use. The addition of the phrase “standing alone” is a significant caveat that did not appear in the 2014 version. It seems to be an effort by the Agency to preserve its ability to consider communications in line with the guidance as evidence of off-label intended use in an enforcement action, so long as there is any other evidence of off-label intended use—and given FDA’s broad conception of intended use, this is a very low bar. Practically speaking, this may make companies more nervous about engaging in some of the new types of communication that are described in the draft guidance, and in particular firm-generated presentations. This reluctance is really exacerbated by the fact that many of FDA’s safe harbors for off-label communications—like scientific exchange, just as one example—have been poorly defined by the Agency and may themselves be considered evidence of new intended use, at least in some circumstances.
Josh, let’s come back to you. How should companies be thinking about one of the new categories of communications acknowledged in the guidance, these firm-generated presentations?
Josh Oyster: Thanks, Kellie. Firm-generated presentations weren’t contemplated in previous iterations of the guidance—so, this is new, and it is, in some respects, helpful to have FDA explicitly recognize that company-generated SIUU communications can be appropriate, including through channels like social media, dedicated web pages, and booths at commercial exhibit halls at scientific conferences. And there are undoubtedly some companies that may have stayed away from these types of proactive communications about unapproved uses of their products in the past. They may not have been comfortable doing this under the more general framework of scientific exchange, which we can talk about more in a minute, without specific FDA guidance affirming their ability to do so. In that sense, this change in the new draft guidance might make companies more comfortable engaging in these types of communications as a general matter.
On the other hand, practically speaking, it’s not clear that this is going to trigger a major shift for industry. There’s a lot of other content in the draft guidance, including the new framing of the enforcement policy we discussed, as well as the restrictive and ambiguous standard for what’s appropriate, and the onerous disclosure requirements. All of those things may make some companies hesitate a moment before moving forward with firm-generated presentations.
One last point on firm-generated presentations is that it’s not clear from the draft guidance how FDA is really thinking about this type of communication on the spectrum of scientific exchange to promotion, and who should be engaging in this type of communication. Can sales reps do it? Should this type of communication be just limited to medical personnel? What’s your take on these issues, Sarah?
Sarah Blankstein: Those are really good questions, Josh, and the draft guidance unfortunately isn’t at all clear about this. To your question about who can actually do this: sales reps and marketing, or only medical personnel? In this update, FDA actually removed language that was in the 2014 draft guidance that had said that sales reps could deliver reprints to health care providers, but should refer any questions about those communications, or about off-label uses, to medical personnel. FDA also adds language in this draft guidance, saying that firms should avoid persuasive marketing techniques, like celebrity endorsers and premium offers, when communicating SIUU information. So, this suggests perhaps that SIUU communications can appropriately come from either sales or medical. On the other hand, FDA says in the draft guidance that SIUU communications should be separate and distinct from promotional communications about approved uses of the product, and FDA recommends that firms use dedicated vehicles, channels, and venues for sharing SIUU communications that are separate from those used for their promotional communications about approved uses of their product. On some level at least, sales reps could be viewed as a vehicle for promotional communications about a product, so it may be that FDA is of the view that SIUU communications should come from somewhere else, like medical. I think in any case, practically, there will be more execution risk if these communications are coming from sales reps or marketers, as opposed to medical—and it’s going to raise some complex compliance issues, for example, related to incentive compensation arrangements. Some companies may be more comfortable limiting this to medical anyway.
As for the question of whether we’re talking about something that’s promotional or scientific exchange with this guidance, I think we’re actually talking about something else entirely, and I’ve heard a lot of different perspectives on this. It doesn’t really seem like FDA is treating the communications it describes in this guidance as a form of scientific exchange outside of its regulatory purview. The draft guidance never once mentions scientific exchange, or FDA’s regulation on scientific exchange at 21 CFR 312.7. Given the lack of mention of scientific exchange, as well as the limited scope of the draft guidance focused only on approved products, and FDA’s caveats that it doesn’t intend to convey any views on communications outside the scope of the guidance, I think that means that scientific exchange remains a separate, albeit poorly defined, category of non-promotional communication. And, I’d be remiss if I didn’t mention that “scientific exchange” remains poorly defined despite industry’s repeated requests for FDA to clarify the concept, and the fact that FDA itself sought comments from industry on this over a decade ago and subsequently committed to providing guidance.
At the same time, I don’t think that FDA is thinking of these firm-generated presentations as promotional communications—certainly they’re not expecting that they be submitted to FDA on Form 2253, for example. They’re referring to them as “scientific information” and underscoring that they should be factual and unbiased, and distributed separately from what the Agency calls “promotional communications” about the product. I’d say that we’re not talking about promotional communications here either. But, “promotional” is another term that’s not defined in this draft guidance or elsewhere by FDA, and it’s hard to know exactly what FDA is thinking.
Speaking of trying to discern what FDA might be thinking, what are your thoughts, Josh, on the new substantiation standard FDA articulates in the draft guidance?
Josh Oyster: Thanks, Sarah. And before we actually get there, I just want to follow back up on scientific exchange, because I think that’s a scenario where it really is unclear how to discern what FDA is thinking, especially when you have a scenario where a decade ago FDA solicited comments from industry, later committed to issuing guidance, and didn’t do so. Then just a couple of years ago, when FDA issued the intended use final rule, whenever FDA talked about scientific exchange, it always did so in quotes, and kind of dismissed the concept in some respects. Now, in this new guidance, FDA never once utters the phrase “scientific exchange”—never once references the actual regulation on scientific exchange. It really is an open question as to what FDA thinks scientific exchange is in 2023.
In the interest of circling back to your question on substantiation, as we talked about earlier, one of the key changes from the 2014 draft guidance is this new scientifically sound and clinically relevant standard for studies and analyses that are appropriate for a communication consistent with the guidance. The earlier versions of the guidance applied a restrictive, but at least well-known and understood standard of “adequate and well-controlled studies” for communications about drugs, and had a more permissive standard for devices. Theoretically at least, the new scientifically sound and clinically relevant standard may offer some more flexibility, and arguably, FDA seems to be paying some lip service to that in the draft guidance, saying that different types of well-designed and well-conducted studies and analyses could be scientifically sound and clinically relevant. And they provide various examples that could potentially satisfy the standard, like real-world evidence and meta-analyses. But the devil’s in the details, and there’s a lot in the draft guidance to suggest FDA’s likely to take a pretty restrictive view here of what is scientifically sound and clinically relevant. More to the point, even though conceptually having information be scientifically sound and clinically relevant sounds reasonable—and this is something companies would probably say they ensure as a matter of course anyway—where the issue comes in is what a company could reasonably consider to fall under this category versus what FDA considers to fall in the category. The new standard described in the draft guidance is ambiguous, it’s harder to interpret and apply, and leaves FDA with a lot of discretion.
Kellie, we haven’t covered it yet, and I want to make sure we leave time for it: What are the constitutional issues raised by the new draft guidance?
Kellie Combs: There are lots of constitutional issues raised by the new guidance. The substantiation standard, at least from my perspective, is one of the most significant. But let’s take a step back and look at the draft guidance as a whole. The First Amendment issues that we’re seeing here are certainly not new. As we mentioned, the Agency is once again putting forward a pretty restrictive policy that excludes valuable, truthful, non-misleading speech that would be subject to First Amendment protection. And aside from some references to the 2017 First Amendment Memo and FDA’s careful balance of health care professionals’ interests in these sorts of communications against the interest in preserving FDA’s pre-market review, there’s no specific discussion of why FDA has drawn the lines that it did in the draft guidance.
Going back to the substantiation standard that Josh was discussing earlier, just as one example, FDA says it generally does not consider preliminary scientific data to be clinically relevant, and that early-stage data are unlikely to be clinically relevant, but doesn’t provide a detailed justification. While FDA may be trying to avoid a First Amendment problem by saying “generally” and “unlikely” rather than taking a hard “no” position, that’s generally insufficient from a First Amendment perspective. And FDA’s policy here is still likely to chill companies from sharing truthful and non-misleading early-stage data, including in fields where that type of data may be heavily relied on, and may in fact be clinically relevant to the prescriber or to the patient—so, think about areas like pediatric medicine, rare disease, and oncology, where off-label use is certainly more prevalent.
Additionally, it’s a fundamental principle of First Amendment law that more speech is better than less speech, and that, where possible, disclaimers and disclosures should be used rather than policies that would restrict certain forms of speech altogether. This is something that industry has long pointed to when discussing FDA’s approach to off-label communications, and it’s an issue with the new draft guidance as well. If we’re thinking again about early-phase data, couldn’t that be made truthful and non-misleading if the appropriate context and disclosures were provided? Similarly, for significant non-clinical investigations, in this version of the guidance, FDA says that non-clinical investigations would generally not fall within the enforcement policy because they are unlikely to be clinically relevant. This actually seems like a step backwards from the 2014 draft, where FDA contemplated that reprints on significant non-clinical investigations could actually be appropriate for medical devices.
Apart from the First Amendment issues, the draft guidance also raises really significant issues under the Fifth Amendment. Again, the types of issues that we see from a Fifth Amendment perspective are similar to those that we saw in prior versions of the guidance and with FDA’s regulation of manufacture communications on the whole. In particular, the Fifth Amendment requires precise boundaries for the regulation of speech. The substantiation standard that FDA introduces in the draft guidance, that communications describe scientifically sound and clinically relevant analyses, is ambiguous, as Josh pointed out, and gives FDA significant leeway to make post hoc determinations of whether clinical relevance has been met in FDA’s opinion. This is just one example, I think, of many cases where the draft guidance isn’t clear, including on issues like the distinction between promotional and non-promotional speech, and other sorts of content.
I want to turn now to Josh and Sarah to talk about some practical concerns. You both work all the time with companies in the life sciences industry on advertising and promotion and non-promotional communications. What are the big takeaways from the new draft guidance from your perspective? Let’s start with you, Josh.
Josh Oyster: Thanks, Kellie. At the end of the day, this new draft guidance is another example of FDA’s piecemeal and restrictive approach to regulating off-label speech. When we saw that FDA had submitted their draft guidance on communicating scientific information to the White House Office of Management and Budget—a draft guidance that wasn’t even on CDER’s guidance agenda and that no one outside of FDA seemed to know was in the works—I wasn’t sure what to expect. It seemed like maybe FDA was finally, after years of requests from industry, going to clarify scientific exchange, but that’s really not what we have here. It’s also not even 100% clear how FDA views this new draft guidance relative to earlier versions of the guidance. The 2009 guidance on “Good Reprint Practices” that we mentioned earlier says on its face that it represents the “current thinking” of the FDA. The 2014 and 2023 draft guidances, because they’re drafts, say that they “will represent” the FDA’s current thinking “when finalized”—but neither of them has been finalized. The 2009 version of the guidance has technically never been withdrawn—yet the 2009 version isn’t even posted on FDA’s website any longer. So what’s the controlling policy here? That’s just yet another issue with the new draft guidance. Sarah, what big takeaways do you see on your end?
Sarah Blankstein: It’s a very interesting draft because there are certain elements—like the recognition that firm-generated communications can be appropriate, and that many different channels, including social media, can be used—that seem like an effort by FDA to acknowledge and accommodate some of the constitutional and practical realities, and to move the ball forward somewhat. But at the same time, there are certain elements that almost make it seem like FDA is giving with one hand and taking with the other. For example, the draft guidance illustrates an ongoing effort by FDA to seemingly distance itself from language that was in earlier drafts of this guidance, acknowledging that unapproved uses can sometimes constitute the standard of care, or at the very least that there’s a public health value for sharing information about unapproved uses. Instead, in this guidance, FDA interestingly says only that health care providers have an interest in scientific information on unapproved uses of approved products, so really no mention of the value of this information or its importance.
Josh Oyster: Thanks, Sarah. Beyond that, there’s also a topic that’s totally out of scope from the new draft guidance that we haven’t talked much about—that’s communications about wholly unapproved products. If we’re to take the draft guidance at face value, those types of communications are out of scope, and FDA explicitly says it does not intend to convey any views on those communications. And the question is: In practice, is FDA going to apply the principles from the new draft guidance to these pre-approval communications about unapproved products, even if the draft guidance says otherwise or says that the draft guidance isn’t addressing this topic? It’s an interesting question that development-stage companies will have to ponder going forward, in terms of: Do you take the principles that FDA puts in this new draft guidance for truthful, non-misleading communications—communications that provide sufficient context for HCPs to determine the strengths, weaknesses, validity, and utility of information? Do you take those principles and apply them to your pre-approval communications? We’ll see how FDA’s approach plays out in the coming months and years, in terms of what types of enforcement it pursues for pre-approval promotion activities and pre-approval communications more generally.
Kellie Combs: Thanks so much, Josh and Sarah. You’ve certainly raised a lot of interesting issues for our consideration, and I have no doubt that we’ll continue to talk about this with clients and we’ll hear a lot more perspectives as time goes on. We here at Ropes & Gray will of course continue to monitor these developments. Unfortunately, though, I think we’re out of time for today. Thanks very much to everybody for tuning in to our podcast, Non-binding Guidance, which is brought to you by our attorneys in the life sciences regulatory and compliance practice at Ropes & Gray. For more information about our practice or 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 subscribe to Non-binding Guidance and other RopesTalk podcasts at Ropes & Gray’s podcast newsroom on our website, or by searching for Ropes & Gray podcasts in iTunes, Google or Spotify. Thanks again for listening.