COVID-19: Non-binding Guidance: Real-World Evidence in Drug Development and the Impact of the Pandemic

The eleventh installment of Ropes & Gray’s podcast series, Non-binding Guidance, focuses on the current regulatory landscape surrounding the use of real-world evidence in drug development and the impact of the COVID -19 pandemic. Over the course of the COVID-19 pandemic, there has been an increase in reliance on real-world data and real-world evidence by FDA and other regulatory authorities, as well as industry. Innovative approaches and flexibility from the FDA during the pandemic ultimately may serve to accelerate the uptake of real-world evidence approaches post-pandemic. In this episode, FDA regulatory attorneys Kellie Combs and Sarah Blankstein discuss these recent developments and explore remaining impediments facing the use of real-world evidence and real-world data by regulators and industry stakeholders.

Transcript:

Kellie Combs: Hi, I’m Kellie Combs, a partner in the FDA regulatory practice at Ropes & Gray, based in our Washington, D.C. office. 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. Today’s podcast will discuss FDA’s current thinking on the use of real-world evidence in drug development, providing an update on last year's podcast on the same topic. This year, we’ll talk about recent developments, explore remaining impediments, and consider the impact of the pandemic on the use of real-world evidence by regulators and industry stakeholders. I’m joined today by Sarah Blankstein, a colleague of mine based in our Boston office with significant experience advising clients on the use of real-world evidence. 

Before we dive in to our discussion about recent developments and the impact of the COVID-19 pandemic, I’ll start with a brief overview of what we discussed on last year’s podcast just so that everyone is up to speed. As we discussed last year, FDA interprets real-world evidence and real-world data very broadly. Real-world data according to FDA are data relating to patient health care status or the delivery of health care that are routinely collected from a variety of sources, including electronic health records, medical claims and billing data, data from product and disease registries, and so on. Real-world evidence, on the other hand, is the clinical evidence about the usage and potential benefits or risks of a medical product that’s derived from analysis of real-world data. Real-world data and real-world evidence have been steadily gaining visibility and prominence in recent years, but were really given a boost in 2016 with the passage of the 21st Century Cures Act. Cures required FDA to establish a program to evaluate the potential use of real-world evidence to support approval of a new indication for a drug and to help satisfy post-approval study requirements. Cures also required FDA to issue a draft framework for real-world evidence, which the Agency did in 2018, and to issue guidance addressing standards, methodologies, and circumstances under which sponsors can rely on real-world evidence. This guidance has to be released by FDA by the end of next year. 

Real-world evidence approaches, as we discussed last year, are already being used regularly, particularly in the post-approval study requirements context, for example, in the form of registry studies, claims database analyses, and so on. We still have a long way to go before we see routine use of real-world data and real-world evidence in drug development and regulatory decision-making for drug approvals, at least outside the rare disease context, where we have seen companies increasingly use real-world data to generate synthetic control arms in single-arm studies. That said, the COVID-19 pandemic has meaningfully increased the use of real-world data and real-world evidence by regulators and industry alike, and we think this ultimately may serve to accelerate the uptake of real-world evidence approaches post-pandemic. Now with that background out of the way, I’d like to turn it over to Sarah. 

Sarah, looking ahead, what are your thoughts on how the pandemic may ultimately impact real-world evidence?

Sarah Blankstein: Well Kellie, as you noted, there has been an uptick in reliance on real-world data and real-world evidence by FDA and other regulatory authorities, as well as industry, during the COVID-19 pandemic. The COVID-19 pandemic has required flexibility from the FDA in many ways, evidentiary standards and otherwise. And, we’ve seen this, for example, with the rapid issuance of guidance describing areas where the Agency is exercising enforcement discretion as well as the issuance of emergency use authorizations for COVID treatments, PPE, and diagnostics. Looking to real-world data and real-world evidence specifically, we’ve seen utilization of these approaches driven by the desire for innovative and rapid solutions to address COVID-19. And in particular, the lack of approved COVID-19 treatments available to address this new virus has lead to the generation of vast amounts of real-world evidence on off-label treatments as well as unapproved treatments that have been authorized through emergency use authorization or administered through compassionate or expanded access programs. We’ve also seen an increase in real-world data driven by the need to modify and adopt pragmatic approaches in ongoing clinical trials to address hurdles that have been created by the pandemic. 

The importance of real-world evidence in the COVID-19 pandemic response is something FDA Commissioner Stephen Hahn has himself acknowledged and spoken about publicly. In a speech to the Alliance for a Stronger FDA in June 2020, Commissioner Hahn highlighted the important role that real-world data sources have played in the Agency’s response to the pandemic, highlighting in particular the utility of these data for better understanding the disease, addressing potential supply shortages, and evaluating therapies, vaccines, and diagnostics for COVID-19. Importantly, Commissioner Hahn went on to note that innovations and adaptations that have been implemented by FDA in response to the pandemic—such as the use of real-world data and real-world evidence—would be considered by FDA for incorporation in standard Agency procedures moving forward after the pandemic to the extent appropriate. Of course, he emphasized that FDA would not be cutting corners on safety or effectiveness and the Agency’s “commitment to good science and rigorous data is unwavering.” 

Kellie, given Commissioner Hahn’s recognition of the important role real-world evidence is playing during the COVID-19 pandemic, can you speak to some of the ways that FDA has employed real-world evidence? 

Kellie Combs: Sure, Sarah – happy to do that. There’s no question that COVID-19 has brought some urgency to the use of real-world evidence by FDA, and FDA has really been pretty proactive in advancing collaborations with public and private partners to collect and analyze a variety of real-world data sources. There are really too many to name here, but I’ll highlight a few notable examples:

First is the Aetion Collaboration. This May, FDA announced that it would launch a real-world evidence-focused research project to inform its pandemic response. This project was done in collaboration with Aetion, which is a New York-based health care technology company with a powerful evidence platform for conducting real-world analysis. FDA and the company will seek to answer questions about the use of diagnostics and medications during the COVID-19 pandemic as well as to get information about risk factors for COVID-19-related complications in different patient populations.

There’s also what FDA’s doing with its own Sentinel system. They’re using Sentinel to perform real-world evidence analyses related to COVID-19. Sentinel, for those who don’t know, is FDA’s electronic surveillance tool that monitors the safety of FDA-regulated medical products. FDA is using the wealth of real-world data available through Sentinel to assess COVID-19 drug use and shortages and to conduct natural history and treatment impact studies. One project involves, for example, the monitoring of critical drugs and the assessment of natural history for COVID using inpatient electronic health record data from HCA Healthcare. The project aims to describe the natural history of the disease among certain hospitalized COVID-19 patients and also to establish the capacity to monitor critical drugs used in the care of those patients. Another goal is to conduct algorithm validation using diagnosis codes to identify potential hospitalized COVID-19 cases and to validate the algorithms using lab test results.

Finally, there’s the FDA’s Cure ID App. This app was launched in late-2019 by the Agency and at the time had the primary goal of helping health care professionals find treatments for undertreated diseases, with the longer-term goal of informing clinical trial designs and drug development. At a high-level, the app allows health care professionals to rapidly share real-world information about their experiences treating patients – and not surprisingly, the app has been expanded and has really taken on new importance in light of the pandemic. While uptake of the app for COVID-19 was slow to start, as of September 22, the app now includes over 400 case reports, 100 discussion posts and over 1,000 clinical trials related to COVID-19. 

So now that we’ve talked about FDA’s efforts related to real-world evidence in general, let’s talk about how the Agency is reviewing real-world evidence in support of specific product submissions. Sarah, I’ve heard that the Agency is considering real-world evidence as part of its decision-making process on emergency use authorizations for COVID-19 therapies. Can you tell us more about that? 

Sarah Blankstein: Yes, that’s right, Kellie. FDA has considered real-world evidence both in issuing emergency use authorizations and also in withdrawing EUAs for COVID-19 therapies. Of course, this is different from considering real-world evidence in the drug approval context given the lower evidentiary bar needed for EUA authorization as compared to drug approval, but FDA’s consideration of these data in the EUA context provides the Agency with important experience using these data to assess efficacy generally.

Turning to how FDA has used real-world evidence with respect to emergency use authorization, most recently FDA considered real-world evidence in the EUA submission for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients. Specifically, FDA issued that EUA for convalescent plasma largely based on data from an expanded access program conducted at the Mayo Clinic, which had infused approximately 70,000 patients, and they also looked at data from some small and preliminary clinical trials with convalescent plasma. Of note, FDA collaborated with industry, academic and government partners on implementing the Mayo Clinic Expanded Access Program, and that program was developed with funding from the HHS Biomedical Advanced Research and Development Authority (or BARDA). Real-world data has also played an important role in continued assessment of products that have already been authorized under an EUA. For example, FDA considered real-world data showing reports of serious cardiac adverse events and blood disorders when it retracted the EUA for malaria drugs hydroxychloroquine and chloroquine. And, while outside the drug context, real-world data similarly provided the basis for FDA’s revocation of an EUA for an antibody test where the test’s performance did not meet expectations. I expect that FDA’s consideration of real-world data and evidence will continue for treatments currently under emergency use authorization as well as new treatments that emerge. Looking ahead to anticipated authorizations for COVID-19 vaccines, Principal Deputy Commissioner Amy Abernethy has suggested at BIO’s digital convention in June that FDA could use real-world evidence to help evaluate COVID-19 vaccines. And, since FDA is likely to issue an EUA or EUAs for COVID-19 vaccines prior to approval, there would potentially be a vast amount of real-world data for the Agency to consider. 

Now, keep in mind that FDA is not the only regulatory authority considering real-world evidence in the fight against COVID-19. Ex-U.S. regulators are also looking to real-world data sources to inform their understanding of COVID-19 treatments. For example, in anticipation of COVID-19 vaccines being approved in the EU, the EMA has asked the Netherlands-based Utrecht University to identify EU-wide data sources and methods that can be used for monitoring the safety, effectiveness and coverage of COVID-19 vaccines in clinical practice. Additionally, the EMA and Health Canada, as part of the International Coalition of Medicines Regulatory Authorities (or ICMRA) agreed to collaborate in analyzing real-world data to combat COVID-19, such as through research on the impact of the virus and any treatments on pregnant women. 

But, even as FDA and other regulators globally are considering real-world evidence with respect to COVID therapies and gaining more comfort with the data, there are a number of challenges still facing real-world evidence and a long way to go before it has a meaningful place in drug approvals. Kellie, what should we know about the limitations and continued challenges facing the use of real-world evidence in a regulatory context?

Kellie Combs: Well, Sarah, you’re absolutely right – there’s still a long way to go here. Even though FDA has increased its use of real-world evidence in the COVID context and has been giving policy developments related to real-world evidence—so, meaningful attention over the last several years—many, many challenges lay ahead. You mentioned Amy Abernethy earlier – she recently spoke about this in a fireside chat and Q&A session at the Healthcare Analytics Summit at the beginning of September. There she was asked how she would score the value of real-world data to the FDA’s current efforts to deal with COVID, and she was asked to score on a scale of 1-10. While Abernethy would give FDA an 8 or 9 on vision as it relates to real-world data, she gave the Agency only a 2 on execution, noting that there are still a number of hurdles to effectively and reliably gathering and analyzing real-world datasets that the Agency and industry still must tackle. In particular, Abernethy noted that a large amount of effort is needed to understand what datasets are available, how they can be used with confidence, the right methods for using them, the research questions they can address, and so on. In addition, FDA is still trying to figure out how to consider real-world data in conjunction with clinical trial data as part of the totality-of-the-evidence approach to decision-making in the COVID context. 

So still certainly some really important hurdles to address, and there’s really no question that the pandemic has infused a sense of urgency into FDA’s policy developments around real-world evidence, but still quite a bit to do here. One key challenge to address, which has been further highlighted by the use of real-world evidence during the pandemic, is the lack of harmonization across real-world data sources. Sarah, can you speak to some of the recent efforts underway to address this challenge and to move the ball forward on real-world evidence? 

Sarah Blankstein: Sure, Kellie. As you noted, data harmonization challenges are a real issue still facing real-world evidence, and this is something that FDA has been focused on and discussing with stakeholders for several years now, but these efforts have been further fueled by the COVID-19 crisis. For example, FDA, the Reagan-Udall Foundation, and Friends of Cancer Research have worked together to launch the COVID-19 Evidence Accelerator. The Accelerator is a multi-stakeholder forum for major data organizations, government, academic researchers and health systems to explore real-world datasets, as well as develop key research questions about the management of COVID-19 patients. Now one primary goal of the Evidence Accelerator has been to establish a common set of core data elements to embed into existing data collection sources and better allow for rapid aggregation and analysis of real-world data. The common data elements identified through the Evidence Accelerator have been rolled into another real-world data-focused project at FDA called the “COVID-19 Real-World Data Harmonization Project.” An evolving list of the harmonized COVID-19-related data elements is publicly available on FDA’s website. 

Also worth noting is that in July of this year, the Duke-Margolis Center for Health Policy collaborated with the FDA to hold a public meeting to investigate potential approaches to developing a high-quality real-world evidence ecosystem. During this workshop, speakers and panelists included a number of people from FDA, including Jacqueline Corrigan-Curay, the Director of FDA’s Office of Medical Policy, and Amy Abernethy, the Principal Deputy Commissioner of Food and Drugs at FDA, as well as clinical trial experts from both industry and academia. In addition to discussing several examples of real-world evidence studies that have been conducted, data interoperability was a hot topic during this workshop. Many panelists encouraged the use of a standardized set of data elements to facilitate interoperable health information exchange and ultimately move real-world evidence forward. Stakeholders also advocated for the standardization of data collection methods so that data outcomes that guide medical product development are not different from the data routinely collected during health care delivery. Moving forward, I think we can expect continued momentum on data interoperability and real-world data standardization at FDA and in the industry. Kellie, I’d like to turn it back over to you for some closing thoughts. 

Kellie Combs: Great, thanks so much, Sarah. And thank you to our listeners today. That’s unfortunately all the time we have. For more information about our practice or other topics of interest to life sciences companies, please visit our FDA regulatory practice page at www.ropesgray.com. You can also listen to Non-binding Guidance and other RopesTalk podcasts in Ropes & Gray’s podcast newsroom on our website or you can subscribe to this series wherever you listen to podcasts, including on Apple and Spotify. Thanks again for listening.