The FDA recently opened a promising path to capture real-world data and evidence to complement traditional clinical trials and open new avenues of research.

“Framework for FDA’s Real-World Evidence Program” fulfills a 2016 requirement in the 21st Century Cures Act that the FDA use real-world data (RWD) and evidence to improve interventions and treatments. According to the FDA report, RWD may “include data derived from electronic health records; medical claims and billing data; data from product and disease registries; patient-generated data, including from in-home-use settings; and data gathered from other sources that can inform on health status, such as mobile devices.”1

The idea is to use such data to “develop information and real-world evidence (RWE) that can better inform regulatory decisions,” FDA Commissioner Scott Gottlieb, MD, said in a statement. “Because they include data covering the experience of physicians and patients with the actual use of new treatments in practice — and not just in research studies — the collective evaluation of these data sources has the potential to inform clinical decision-making by patients and providers.”

The FDA action was hailed by a medical ethicist in the Working Group on Compassionate Use and Pre-Approval Access (CUPA) at New York University School of Medicine. CUPA has been pursuing a similar idea in a new project called Ethics and Real-World Evidence (ERWE), says Alison Bateman-House, PhD, MPH, MA, assistant professor in the division of medical ethics at NYU Langone Medical Center.

This “clinical trial light” approach for real-world evidence may ultimately provide greater patient access to needed effective drugs and treatments, she says.

“We have been sort of this crazy voice in the wilderness talking about it,” Bateman-House says. “The FDA is now saying it looks like it would be useful data. It looks like it is actually happening. I’m sure we will run into some unintended consequences along the way, but I’m personally really excited about it.”

It removes an initial hurdle, which is that physicians are much more familiar with clinical trials than with nontrial investigational drug pathways like expanded access and right to try, she explains.

“Clinical trials typically involve payment to the doctors, which expanded access doesn’t,” Bateman-House says. “So that will knock down another disincentive.”

For example, many physicians in the neurological disease community do not seek FDA expanded access “because they don’t get reimbursed for their time, and that makes their hospitals unhappy,” she says.

The RWD movement has the potential to tap into resources that bring in people typically excluded from clinical trials for various reasons, she adds.

“Sometimes, people are too sick to be in trials — they have comorbidities that keep them from meeting the [inclusion] criteria,” she says. Sometimes, they live too far away or face other barriers and obstacles to get into clinical trials.

“We can’t fix all of this with this particular policy push, but the idea behind this is what if you set up a clinical trial of the people who did not meet the clinical trial criteria?” Bateman-House says. “A less intense clinical trial, where maybe you don’t have to go in for as many clinical scans or have as much bloodwork but investigators still track you and get information.”

There appear to be incentives for research companies to support RWE programs, which could bring in research subjects that reflect a broader range of people and may show better product efficacy in the general population after market, she notes.

“One of the huge problems with clinical trials is that with the people who get into clinical trials, you come out with data on blood pressure, for example, and [the product] is approved by the FDA, goes on the market, and doesn’t work,” she says. “Unfortunately, we see this all too frequently with approved drugs.”

IRBs would still have an oversight role, although the FDA is preparing to use more electronic verification measures as demanded by the various data sources.

“It’s set up like a clinical trial, so IRBs would have the exact same role, though the data measures may be less frequent and/or less intensive,” Bateman-House says. “For example, instead of going in every two weeks for a blood draw and a scan, maybe these patients would have one at intake and then another at four weeks in.”

The use of electronic health records (EHRs) and other “data-capture technology, together with new trial and study designs using RWD, has the potential to streamline and improve the efficiency of clinical studies,” the FDA report states. “Nevertheless, these advances may also raise new questions about the applicability of certain regulatory requirements, including requirements for informed consent and appropriate oversight and monitoring.”

The FDA has previously issued guidance documents to capture electronic data while “maintaining adequate documentation for FDA to validate the source and reliability of the data,” according to the report. “…Additional guidance may be needed to address different study designs using RWD to generate RWE for effectiveness determinations.”

Hybrid Design

As described in the framework document, clinical trials may use a hybrid design that could include “collection and analysis of RWD extracted from medical claims, EHRs, or laboratory and pharmacy databases.”

The FDA notes that researchers could collect other data using methods typical of a traditional clinical trial. A hybrid trial could use RWD for one clinical outcome, while incorporating more conventional criteria and other endpoints for the more traditional arm of the study.

“Clinical trial designs can also include some elements that more closely resemble routine clinical practice, which are sometimes described as ‘pragmatic’ elements,” the report states. “These pragmatic clinical trials often rely on RWD and have the potential to generate RWE.”

In any case, real-world data could be used to “improve the efficiency of clinical trials” even if it does not reach the threshold of real-world evidence on a given product’s effectiveness. FDA examples of this kind of RWD use include:

• “generating hypotheses for testing in randomized controlled trials;

• identifying drug development tools (including biomarker identification);

• assessing trial feasibility by examining the impact of planned inclusion/exclusion criteria in the relevant population, both within a geographical area or at a particular trial;

• identifying prognostic indicators or patient baseline characteristics for enrichment or stratification.”


1. FDA. Framework for FDA’s Real-World Evidence Program. December 2018. Available at: