Brave New Real World: FDA Draft Guidance Takes First Steps to Move RWE from Dystopia

May 14, 2019By Larry J. Bauer, Senior Regulatory Drug Expert & James E. Valentine

On May 8, 2019, the FDA published a new draft guidance for industry titled “Submitting Documents Using Real-World Data and Real-World Evidence to FDA for Drugs and Biologics.”

This draft guidance was produced as a joint effort from CDER and CBER and is intended to provide guidance about how to use Real World Data (RWD) and Real World Evidence (RWE) in regulatory submissions to the agency.

The use of RWD and RWE is an area of great interest yet has little regulatory precedent. The Agency was mandated by section 3022 of the 21st Century Cures Act to, among other things, provide guidance to industry on how RWE might be used to support drug development and new drug and biologic approvals (see previous coverage of the 21st Century Cures Act and this provision here). Section 3022 required the Agency to track submissions to INDs, NDAs, and BLAs that use RWE to support regulatory decisions related to safety and efficacy.

The draft guidance clearly defines the terms RWD and RWE which is helpful. One of the most significant parts of the draft guidance is that it clearly states that RWE may be used in single arm studies that use RWE as an external control. This is a paradigm shift for the Agency and opens doors to many potential, as of yet unexplored and untested, approaches to drug development.  On the topic of external controls, FDA similarly discussed the use of natural history data as historical controls in a recent draft guidance, which the Agency does not view as RWE (see coverage here).  Beyond use as an external control, the draft guidance also notes that RWE may be captured through (1) conduct of randomized clinical trials, (2) observational studies to support an efficacy supplement, and (3) studies to fulfill postmarketing requirements to further evaluate safety and effectiveness.

The draft guidance does not provide much detail on how RWE might be used and barely mentions any caveats.  Therefore, this draft guidance should be viewed in combination with FDA’s December 2018 “Framework for FDA’s Real-World Evidence Program” (available here), where the Agency began to articulate how it will assess fitness of RWD for use in regulatory decisions.  Existing precedent has been limited to using data on historical response rates drawn from chart reviews and expanded access, primarily in cancer and rare diseases; however, FDA seems to instead be promoting the generation of RWE through randomized trial designs that take place in “pragmatic clinical trial” settings that more resemble real-world care and use. This seems to be the most promising “type” of RWE to support evidence of safety or effectiveness for a new product approval, which the draft guidance notes is a potential use for this evidence.

It is well known that there is an enormous amount of RWD in existence but there are also many challenges to figuring out how to use that data. There are issues related to getting informed consent from the people who are the source of the data, issues of statistical analysis and the introduction of bias, issues of data quality, lack of comparability between the RWE control arm and the study population, and generally the potential for making flawed conclusions.  In the words of FDA’s past Principal Deputy Commissioner:

Thus, although we are optimistic about long-term prospects for the evolution of mature, robust methodologic approaches to the incorporation of real-world evidence into therapeutic development and evaluation given the intensive efforts now under way, caution is still needed, and expectations of “quick wins” resulting from the use of such evidence should be tempered accordingly.

Sherman, et al. Real-World Evidence – What Is It and What Can It Tell Us? 375 NEJM 23, at 2295 (December 8, 2016)

Much of this will have to be figured out by trial and error and lots of conversation. This area of development holds a lot of promise but will require a lot of scientific thought and evaluation to find a path forward.