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Sarah Blankstein: Hi, I’m Sarah Blankstein, counsel in the life sciences regulatory and compliance practice group 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 my colleague David Peloquin, a partner in our health care practice whom I have had the pleasure of collaborating with frequently on clinical trials issues. David and I are both based in Ropes & Gray’s Boston office. On today’s podcast, we’ll discuss developments in the area of clinical trial diversity, and, in particular, FDA’s new draft guidance on diversity action plans to improve enrollment of underrepresented populations in clinical studies, which it published in June.
We put out an alert on the draft guidance when it was released, which includes a detailed description of what was in the guidance for those who are interested, and we won’t rehash that all here. Briefly, though, the draft guidance fulfills a mandate under the 2022 Food and Drug Omnibus Reform Act (“FDORA”), which granted FDA new authority to require diversity action plans and directed the FDA to issue new or revised draft guidance on diversity action plans by the end of 2023. The statute further requires that FDA finalize the guidance within nine months of comments closing, which—if FDA abides by that timeline—would put us in June 2025. By statute, sponsors will then need to comply with diversity action plan—which we will refer to as “DAP”—requirements for clinical studies for which enrollment begins 180 days after publication of the final guidance. Now, what the DAP draft guidance aims to do at a high level is to increase clinical trial enrollment for populations that have been historically underrepresented in clinical trials. The focus is on four aspects of diversity defined in the statute—age, sex, race, and ethnicity—though the draft guidance does also encourage consideration of other facets of diversity as well, like geographic location, socioeconomic status, sexual orientation, and pregnancy and lactation status. The DAP guidance would accomplish this by requiring that sponsors develop and submit a diversity action plan for certain drug and device clinical trials—specifically, phase 3 or other pivotal trials of a new drug or clinical studies of an investigational device, other than those that are exempt from investigational device exemption (“IDE”) requirements, designed to collect definitive evidence of safety and effectiveness. The DAP would need to describe the sponsor’s enrollment goals along the four aspects of diversity, the rationale for those enrollment goals, and the sponsor’s plan to meet those goals.
Now, David, I’d like to turn it to you to provide a little more color on what some of the key aspects of the draft guidance are that sponsors should be prepared for.
David Peloquin: Thank you, Sarah. There’s indeed a lot to unpack in the draft guidance, and sponsors will want to be prepared to develop and submit diversity action plans once the requirements apply. Today, I’d like to talk about a couple of specific points:
The first is establishing enrollment goals. This is one of the more controversial aspects of the draft guidance. As Sarah mentioned, the DAP would have to present enrollment goals for a clinical study, disaggregated by race, ethnicity, sex, and age group. The draft guidance specifies that those goals should be based on the estimated prevalence of the relevant disease in the U.S. intended use population. While that sounds straightforward, it presents a number of significant challenges. First, in many cases, it will be difficult to arrive at a prevalence estimate for a condition in the U.S. The draft guidance identifies a number of publicly available and non-publicly available sources that may be useful, like registries, literature, and electronic health records. However, as FDA has addressed at length in the guidance documents it has put out on real-world data sources, there’s not a perfect source of information—and sponsors will need to consider the limitations and potential biases of each data source, and potentially rely on multiple data sources to come up with a prevalence estimate for their DAP. Failing the ability to determine prevalence through health-related sources, the DAP draft guidance states it may be acceptable to set enrollment goals based on, for example, general U.S. population demographics or a broader disease category for which demographic information is available. But that is going to provide a pretty crude estimate that may not well reflect the actual prevalence of the disease being studied, leading to significant enrollment challenges down the line. Another challenge with setting enrollment goals relates to studies conducted in multiple countries, which many phase 3 and other pivotal clinical trials are. The draft guidance actually does address multiregional clinical trials, but it states that sponsors should set enrollment goals for the entire study—including ex-U.S. sites—with the goal of enrolling a population that is representative of the U.S. intended use population. Certainly, this could present a dilemma for companies that run large, multi-regional clinical trials with the intent of using them to support approval in multiple countries. But beyond that, there will be a number of logistical issues trying to set enrollment goals for the entire study worldwide to align with U.S. prevalence estimates. FDA says as much in the draft guidance, acknowledging that “the lack of uniformity across the globe in the use of population descriptors such as race and ethnicity may pose challenges when setting enrollment goals for international sites.”
The other aspect of the draft guidance I want to touch on is the description of measures to meet enrollment goals that would need to be included in the DAP. FDA’s draft guidance provides a
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number of examples of different measures that sponsors should consider implementing to meet diversity enrollment goals in their clinical trials. I won’t discuss all of them, but one that I want to call out is the use of a decentralized study design in appropriate circumstances. Now, this is not the first time FDA has said decentralization has the potential to assist in reaching underrepresented groups in clinical trials, and, at least theoretically, that’s the case not just along the four aspects of diversity required for DAPs, but also for geographic and socioeconomic diversity, such as enrolling rural populations that live a great distance from the academic medical centers at which most clinical trials have historically been conducted. So, the recommendation isn’t earth shattering, but I do think it adds to the momentum we’ve seen among industry and other stakeholders as well as at FDA itself to foster the use of decentralized trials in cases where a decentralized design may make sense. For any of our listeners interested in learning more about decentralized trials, I’ll note that FDA put out two new guidance documents in September—one, a final guidance on conducting clinical trials with decentralized elements, and the other, a draft guidance on integrating randomized clinical trials into routine clinical practice. I, along with some of my Ropes & Gray colleagues, published an alert describing those two guidances.
There’s a lot more to say on the DAP draft guidance, but, Sarah, let me turn to you with a question I’ve heard come up a lot: What happens if a sponsor sets their goals, submits the DAP, but at the end of the day, they miss their enrollment goals?
Sarah Blankstein: Thanks, David. That’s definitely a question that’s been on everyone’s mind since the draft guidance came out, and it came up in the comments submitted on the draft guidance as well. The draft guidance doesn’t answer the question of what happens when enrollment goals are missed. And, as a statutory matter, the requirement is to submit the DAP, but there’s not an enforcement mechanism for failure to meet the goals spelled out in the DAP. But FDA has tools it can use here, and it remains to be seen how, in practice, failure to meet enrollment goals may, for example, impact FDA advice during development, submission timelines, or FDA’s action on marketing applications. Realistically, I’d expect it to depend on a variety of factors like how far off the sponsor was, the impact of the missed goal on the sufficiency of the data in a given subgroup, the reasons the sponsor missed their goal, as well as the interactions that they’ve had with FDA along the way.
One possibility is that FDA uses post-marketing requirements (“PMRs”) and post-marketing commitments (“PMCs”) to have sponsors collect additional data on underrepresented subgroups post-approval. And there’s precedent for this: A recent AgencyIQ analysis of PMRs and PMCs identified 55 recent examples—primarily in the oncology
space—of FDA requiring post-marketing studies to obtain additional data in diverse populations that weren’t sufficiently represented in studies prior to approval. The PMRs and PMCs ranged from requiring entirely new clinical trials, to conducting a prospectively designed observational study, or performing additional data analyses and assessments. The idea of post-marketing studies to achieve diversity goals was also something expressly contemplated by a 2022 draft guidance on voluntary diversity plans. However, that draft guidance was replaced by the new DAP draft guidance, which no longer mentions post-marketing studies. Another possibility for studies that don’t meet enrollment goals is that it could go to an advisory committee. Another is that it’s really left to the court of public opinion. The DAP draft guidance strongly encourages sponsors to publicly post information about their DAPs, so that is a possibility. And another possibility is that FDA provides some public information about DAPs and failure to meet DAP enrollment goals, though that’s not something that’s currently contemplated in the draft guidance, and it would be an added burden that FDA may or may not be interested in taking on.
Now, David, let’s turn it back to you. I’d like to talk about some of the other big open questions from the DAP draft guidance. But first, I’m hoping that you can share some thoughts on probably the most open question of all: What is the impact here of the presidential election and what might we see from a Trump administration?
David Peloquin: That is the question of the hour, Sarah—and not surprisingly, it’s hard to predict. The DAP draft guidance was issued to fulfill a statutory mandate from Congress to issue the guidance, and the requirement for sponsors to submit DAPs is in the statute. We’ve certainly seen FDA miss statutory deadlines—in fact, they missed the deadline to issue the DAP draft guidance by six months or so. But, at the end of the day, there is a statutory requirement for FDA to finalize a guidance on DAPs with a deadline in June. So, assuming there’s no legislative change, we’ll presumably see a final guidance out of FDA at some point. But then the question becomes: What does that look like? The answer is that it could potentially look quite different from the draft guidance. There were a lot of comments on the guidance and, perhaps more importantly, President-elect Trump has made a variety of statements critical of certain diversity, equity, and inclusion (“DEI”) efforts. Maybe DAPs don’t get wrapped up in any efforts to minimize focus on DEI generally, but it’s certainly possible, and in that case, maybe we see a much less rigorous version of the DAP guidance when it’s finalized.
Sarah Blankstein: Thanks, David. That’s interesting, and it’s something we’ll have to see play out. But rather than let it stop us from delving into some of the key issues and open questions with the draft guidance, I think it’s worth talking about them—because these are areas where there were a lot of comments and, if we’re going to see changes in the final guidance under a new administration, this might be where they are. One I want to mention that we haven’t talked about yet is waivers. The statute permits FDA to issue a waiver from DAP requirements if it determines that a waiver is necessary based on what is known about the prevalence of the disease in terms of the patient population that may use the new drug. Now, when I read this, I thought this was potentially going to be an important point for sponsors developing drugs to treat rare diseases, particularly where there may be a real unmet need. But FDA took the position in the draft guidance that waivers would be infrequent. And, on the topic of rare diseases specifically, the draft guidance notes that even if a rare disease study is too small to draw meaningful comparisons among subpopulations, representative enrollment is still necessary and important because it may, over time, inform hypothesis generation and future studies. Not surprisingly, industry groups have pushed back on the FDA’s approach to waivers, and the prejudgment that they’ll be unusual, in a lot of the comments—so, we will see what happens. I’ll also point out that there’s a lot the draft guidance didn’t answer about waivers at all, like when—even if unusual—might a waiver be appropriate? When might a full vs. a partial waiver be appropriate? And for that matter, what might be waived in the case of a partial waiver of DAP requirements?
David, let me turn it back to you for some final thoughts on any open questions or challenges that are on your mind.
David Peloquin: Sure, Sarah. We’ve covered a lot of the challenges and open questions with the guidance already. The one that I want to flag is the issue of data privacy. As sponsors collect information to satisfy DAP requirements, they should be mindful of compliance with U.S. state and ex-U.S. privacy laws, like the GDPR in the EU, for example. These privacy laws often treat categories of information pertinent to the DAP process—for example, race and ethnicity information—as sensitive or special categories of information that are deserving of heightened protection. Additional notices, consents, and opt-out requirements related to the collection of sensitive information may be required to satisfy state and ex-U.S. privacy laws in the jurisdictions in which clinical trials are conducted.
Sarah Blankstein: This is certainly an area to watch, and we, here at Ropes & Gray, will continue to monitor these developments. Thanks very much everyone 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 or Spotify. Thanks again for listening.