This episode of Ropes & Gray’s podcast series Non-binding Guidance continues our exploration of recent trends and updates on the use of real-world evidence in drug development. Join Ropes & Gray FDA regulatory attorneys, Kellie Combs and Sarah Blankstein, as they discuss four new draft guidance documents released by FDA in 2021 addressing the use of real-world evidence to support FDA decision-making on safety and effectiveness. Tune in to this episode to learn more about FDA’s current approach to real-world evidence, these recent draft guidances, and what we can expect from FDA looking ahead in 2022 and beyond.
This is the third episode in Ropes & Gray’s Non-binding Guidance series focused on real-world evidence. Part one discusses FDA’s framework for real-world evidence, and provides highlights from a 2019 public workshop on real-world evidence. Part two explores the regulatory landscape surrounding the use of real-world evidence in drug development and, in particular, the impact of the COVID-19 pandemic.
Kellie Combs: Hi, everyone—I’m Kellie Combs, a partner in the FDA regulatory practice at Ropes & Gray, and based in Washington, D.C. I’m joined today by Sarah Blankstein, a colleague of mine, based in Boston. 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. On today’s podcast, we’ll discuss recent FDA guidance and developments on the use of real-world evidence in drug development, providing an update on our previous podcasts on the same topic.
As we’ve previously discussed, FDA’s been working to foster the use of real-world evidence in drug development for several years now. The 21st Century Cures Act, enacted in December 2016, mandated that the Agency publish a framework—which it did in 2018—for evaluating the potential use of RWE to support the approval of a new indication for a drug and to help satisfy post-approval study requirements. It further required that FDA issue draft guidance within five years addressing the circumstances under which sponsors could rely on RWE and the standards and methodologies for collection and analysis for such purposes.
To fulfill its obligation under 21st Century Cures and to further clarify its approach, the Agency published four new draft guidance documents on real-world evidence at the end of 2021. Sarah, can you tell us a little bit about the new draft guidance that we’ve seen from FDA?
Sarah Blankstein: Sure—thanks, Kellie. Well, as you mentioned, FDA published those four new draft guidance documents:
- The first of the four guidance documents, which was published in September, addresses considerations related to the use of electronic health records (or EHR) and medical claims data.
- The second one, which was published in October, deals with a more technical topic of application of FDA’s data standards to electronic submission of real-world evidence.
- The third, published in November, addresses registry data.
- And, finally, the fourth new draft guidance, which was published in December of last year, addresses some practical considerations with the use of real-world evidence to support regulatory decision-making for drugs and biologics, and particularly in the context of non-interventional (or observational) studies.
These draft guidances reflect the principles that FDA had previously outlined in its Real-World Evidence Framework, such as the importance that real-world data be relevant and reliable, and the guidances also build on FDA’s experience evaluating real-world evidence and information that the Agency has gathered from stakeholder meetings over the past several years on this topic.
Across the new draft guidance documents, we see that FDA continues to encourage early engagement with the Agency on plans to incorporate real-world evidence in drug development. FDA also continues to emphasize that sponsors should thoroughly document and justify data source selection, and finalize the protocol and statistical analysis plans prior to reviewing any outcome data or, particularly, performing any analyses, in order to prevent the potential for bias. And more generally, FDA makes very clear that the use of real-world evidence is not intended to be a shortcut as compared to randomized clinical trials, and the approval standards have not changed simply by incorporating real-world evidence.
Kellie Combs: Thanks, Sarah. So, obviously, we have a lot of ground to cover in today’s podcast, but can you start by giving us the highlights from the two guidance documents that deal with specific data sources?
Sarah Blankstein: Happy to do that, Kellie. The first of those two guidances is the one dealing with electronic health records and medical claims data. And that guidance outlines considerations when proposing to use those data sources in clinical studies to support a regulatory decision on effectiveness or safety. The guidance provides recommendations on things like selection of relevant data sources, and defining and validating study variables, such as eligibility criteria, treatments, and outcomes. The guidance also provides recommendations on ways to maintain the provenance (or intactness) and the reliability (or quality) of the data.
The second guidance—the registry studies guidance—provides considerations for sponsors that are either seeking to design a registry or use existing registry data to support a regulatory decision about effectiveness or safety. And that can be done, for example, by providing data for an external control arm in a single-arm trial or using registry data to form the basis of an observational study assessing drug safety or efficacy—that’s all covered in this guidance. And the guidance addresses a number of topics, such as factors impacting the registry’s fitness for use in regulatory decision-making, as well as including some of the recommendations that I mentioned earlier in order to support FDA’s review of submissions, like engaging early with the Agency, prespecifying data sources and analyses, and ensuring patient-level data are available for FDA review.
Kellie Combs: Thanks, Sarah. That’s helpful, and it’s clear there’s a lot of information that companies will need to digest in the new draft guidance when planning studies that include registry, EHR, or claims data. What about the other new draft guidances?
Sarah Blankstein: Sure. The other two draft guidances that FDA put out don’t deal with specific data sources, but rather, they deal with more general considerations applicable to the use of real-world evidence in drug development programs.
The new data standards guidance is a technical guidance, and it includes considerations for the use of FDA-supported data standards in applicable drug submissions containing real-world data. FDA, for background, can support only certain data standards, and data submitted in NDAs, ANDAs, BLAs, and certain INDs have to be in one of those electronic formats that FDA can process, review, and archive. And in the draft guidance, while FDA recognizes that there are definitely challenges with conforming real-world data to the existing data standards, and the Agency notes that it plans further guidance on this and potentially updates to the Data Standards Catalog, for now companies submitting real-world data must adhere to the current data standards or obtain a waiver.
The second new guidance that I wanted to talk about is the guidance on Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making. And, this draft guidance addresses additional considerations with the use of RWE in drug development, particularly in the context of non-interventional studies. One thing of note is that FDA clarifies that the IND requirements in Part 312 generally would not be triggered by non-interventional studies, and that’s the case even if they include ancillary protocol-specified activities or procedures to collect additional data. However, sponsors still must adhere, of course, to any applicable IRB and informed consent requirements in Parts 50 and 56 of FDA’s regulations. The draft guidance goes on to describe FDA’s expectations for those non-interventional studies which, while not subject to IND requirements, are nevertheless intended to support FDA decision-making. And those expectations include, as I teed-up with some of the other guidances, early engagement with FDA, transparency regarding data collection and analysis, access to patient-level data, but also, fulfillment of various typical sponsor responsibilities, like compliance with 21 CFR Part 11, selection of qualified researchers, adherence to the protocol, and maintenance of study records.
Now that I’ve given a brief overview of what’s covered in the new FDA draft guidance, Kellie, what would you say are some of the key takeaways that stakeholders should be thinking about?
Kellie Combs: Sarah, we’ve certainly seen some important new detail on how FDA’s thinking about real-world evidence, and while this new information is a welcome step toward advancing the use of real-world evidence and may—to some extent—foster greater adoption of real-world evidence in the future, a number of questions or roadblocks to greater adoption of real-world evidence remain.
In particular, none of the new draft guidance documents provide insight into scenarios when FDA would actually rely on real-world evidence in regulatory decision-making, for example, to support a new indication. The Agency states only that “the evidence submitted by the sponsor to support safety or effectiveness has to satisfy the applicable legal standards.” We still don’t know when and under what circumstances the Agency would actually consider an observational study to adequately meet this standard.
Additionally, the draft guidance documents present a variety of non-binding “considerations” related to the use of real-world data, but the Agency routinely emphasizes the importance of case-by-case consultation. Ultimately, the study designs, the analytical methods, and data sources that will be acceptable to the Agency in regulatory submissions remain largely an open question. FDA has repeatedly emphasized that sponsors interested in using real-world evidence for regulatory purposes should consult with FDA early and often to align on expectations. Just as a practical matter, I’ve personally seen cases where failure to engage with FDA early on in the process has led to some pretty significant delays once the data or application are submitted to the Agency.
Additionally, while FDA has provided some specific recommendations in the new draft guidance documents, there are some controversial provisions. For example, many stakeholders have objected to the Agency’s decision to provide the same recommendations for EHR and medical claims data, despite some pretty important differences in those data sources.
Likewise, the Agency’s expectations regarding justification and documentation supporting data source selection and analysis across each of the new draft guidance documents are pretty substantial and—even if sponsors were realistically able to meet FDA’s standards—there’s a burden there, and that burden combined with the uncertainty in FDA’s response to the data may ultimately discourage widespread adoption. Even though the Agency is open to, and has encouraged, discussions with sponsors prior to use of real-world evidence and submission, the lack of clear guidance and uniform standards for RWE is certainly likely to take a toll.
Given the continued need for case-by-case consideration, Sarah, have you seen any notable new approvals relying on real-world evidence that might be instructive for companies that are considering a drug development strategy incorporating real-world data?
Sarah Blankstein: Happy to discuss that, Kellie. So, to start with, I’d say that one area where RWE has really taken off has been in oncology approvals. FDA’s Oncology Center of Excellence actually presented an analysis of this at ASCO in 2021, looking at oncology applications containing real-world data and real-world evidence. That analysis looked at 94 applications that were submitted from 2011-2020, and showed that inclusion of real-world data to support regulatory decision-making has increased dramatically over that period. In 2020 alone, there were 28 submissions for oncology products that contained real-world data. And just to break that down a little, 62% of the real-world data studies had an effectiveness objective (as opposed to safety), and the most commonly referenced real-world data sources in those applications were EHR and clinical data, representing 54% of the real-world data studies. And the most frequently used real-world data endpoints were overall survival and response rate outcomes.
Outside of the oncology context, probably the most notable recent example of an approval relying on RWE is the July 2021 approval of a new indication for Astellas’ drug Prograf (or tacrolimus) for the prevention of organ rejection in lung transplant patients. The approval there was based on a non-interventional study providing real-world evidence of effectiveness. And FDA’s press release when they announced the approval noted that the approval was “significant because it reflects how a well-designed, non-interventional study relying on fit-for-purpose real-world data, when compared to a suitable control, can be considered adequate and well-controlled under FDA regulations.”
A second interesting recent approval is the December 2021 approval of the supplemental BLA for Orencia to prevent graft versus host disease. The application there included data from a randomized clinical trial, with additional evidence of effectiveness provided by a registry-based clinical study that was conducted using real-world data from the Center for International Blood and Marrow Transplant Research. And that registry study analyzed outcomes of 54 patients treated with Orencia for the prevention of graft versus host disease, in combination with standard immunosuppressive drugs, versus 162 patients treated with the standard immunosuppressive drugs alone, and showed efficacy in that indication.
So, that’s a brief rundown of some of FDA’s recent activity with real-world evidence. Kellie, what should we expect next from FDA in this area?
Kellie Combs: Well, Sarah, as we’ve discussed, there’s definitely room for FDA to provide some more clarity, but that said, the new guidance is certainly a step in the right direction, and we expect the Agency to continue to advance policy developments in the future. So, in terms of immediate next steps, on CDER’s 2022 Guidance Agenda, there are two new draft guidances listed. The first relates to considerations for design and conduct of externally-controlled trials for drug and biological products. And the second involves using clinical practice data in randomized controlled clinical trials for regulatory decision-making for drugs and Biologics.
Also, in the Agency’s September 2021 PDUFA Commitment Letter, FDA said that it intends to focus on advancing the use of real-world evidence in regulatory decision-making, including by taking a number of steps. For example, the Agency will establish a pilot Advancing Real-World Evidence Program to identify approaches for generating real-world evidence that meets regulatory requirements and also to develop Agency processes that promote consistent decision-making and shared learning. The Agency also plans to report aggregate and anonymized information at least annually that would describe real-world evidence submissions to CDER and CBER, including information about the type of application, data sources used, study design employed, and the type of regulatory request. This, in particular, I think could be really helpful to those of us in industry advising clients on the use of real-world evidence. The Agency also plans to convene another public workshop—this one would be focused on discussion of real-world evidence case studies, and approaches for generating real-world evidence that can potentially meet regulatory requirements in support of labeling for effectiveness or for meeting post-approval study requirements. And then, the Agency also plans to update existing real-world evidence-related guidance documents or to publish new ones.
We’re also continuing to follow the Cures 2.0 legislation, which was introduced in the House last November, and contains some additional provisions to increase use of real-world evidence for FDA-regulated products, including a requirement that the Agency publish guidance addressing the use of real-world evidence to satisfy post-approval study requirements for accelerated approval, breakthrough, and fast track products. The accelerated approval product category has gotten a lot of attention of late, and Commissioner Califf mentioned this in his confirmation hearings at the end of last year, so we’ll be paying close attention to that one. Overall, I’m encouraged by the Agency’s very clear signaling that it’s prepared to continue working to clarify its approach and to promote the use of real-world evidence in drug development, and I think we can expect these efforts to drive utilization of real-world evidence and innovation in this field for the months and years to come.
That’s unfortunately all the time we have for today’s episode. We want to thank all of our listeners for tuning in. For more information about our practice or other topics of interest, 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 our website, or you can subscribe to this series wherever you listen to podcasts, including on Apple, Google and Spotify. Thanks again for listening.
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