Officials from the US Food and Drug Administration (FDA) discussed the agency’s new authorities to accept real-world evidence (RWE) to support new drug and device authorizations and discussed their views on how industry can advance these applications at the Food and Drug Law Institute’s (FDLI) annual meeting in Washington, DC on 18 May.
During the meeting, the officials explored the current state of FDA’s RWE efforts, discussed the number of RWE approvals and offered insights on the agency’s 2021 draft guidance that provides regulatory considerations for using non-interventional or observational studies for RWE.
New milestones specified in legislation
John Concato, associate director for real-world evidence analytics in the Office of Medical Policy at the FDA’s Center for Drug Evaluation and Research (CDER), said that efforts to boost use of RWE in the US were bolstered in the latest Prescription Drug User Fee Act (PDUFA VII) agreement and the Food and Drug Omnibus Reform Act.
The agency published its goals under the PDUFA VII for RWE in a notice published last year. (RELATED: FDA starts PDUFA VII programs for real-world-evidence in innovative trial for-real-world-designs, Regulatory Focus 19 October 2022)
The first goal, which must be met by 31 December 2022, is for FDA to establish a program for advancing RWE and to identify approaches for RWE that meet regulatory requirements.
The second goal, which must be met by 30 June 2024, requires the agency to report annually on the number of RWE submissions and the types of regulatory requests for these submissions. FDA is also tasked with convening a public workshop to discuss RWE case studies by 31 December 2025 and to apply lessons learned to update existing RWE guidance by 31 December 2026.
FDORA also gave the agency new tools to for RWE; Section 3629 of the law requires FDA to issue or revise existing guidance one year after the date of enactment on using RWE to support new drugs for emergency use. It also requires FDA to submit a report to Congress within two years after enactment on the number of applications to which RWE was used to support a regulatory decision.
Industry uncertainty
Nicole Mahoney, executive director of US regulatory policy and intelligence at Novartis, offered an industry perspective on their adoption of RWE.
“We use real-world data to drive a number of internal decisions but also external decisions,” she said, noting that her company uses the 2021 guidance to address questions on how to address an unmet medical need or to incorporate such data in a regulatory submission.
Yet she admitted there is uncertainty among the industry about the appropriate data to use for submissions. “Industry is working to understand how and when real-world evidence can be suitable in a submissions package … we are working to make sure that we are generating real-world evidence that meets regulatory requirements.”
While the December 2021 guidance is “very useful,” Mahoney said it “does not provide a step-by-step way or step-by-step manual on how to actually conduct real world studies or to think about every particular situation.” She added that “this is okay because it’s up to us to synthesize the wealth of guidance that we have.”
RWE examples
FDA officials were asked to discuss the number of applications they approved using real-world data. They also addressed the purpose of the 2021 RWE guidance and its limitations.
In terms of product approvals, Concato said that in 2021 FDA approved a new indication for Prograf (tacrolimus) based on a non-interventional RWE study. The drug was originally approved to prevent organ rejection in patients receiving liver transplants, and the company subsequently sought a new indication related to its use in lung transplants.
Felipe Aguel, deputy director of the Office of Clinical Evidence and Analysis in the FDA’s Center for Device and Radiological Health (CDRH) said that over the past decade the center has authorized 90 devices using real-world evidence, asserting that “there is a long history at the center of its use.”
Concato also addressed the top reasons why applications involving RWE are rejected. Either the data “is not reliable or relevant,” the study design and analysis is inadequate, or the data is not there to support approvals. He said that “most of the time, the data is not there.”
Aguel further noted that the 2021 guidance on RWE is not meant to serve as a checklist for industry or for industry to “cut and paste” the document for their own uses.
“We have something that is vague and high level.” He said that “at the same time we recognize that there are many ways to do this, there is no one right approach, and we don’t want to put out there something that makes it seem like there is a checklist, that you must do all of these things” before FDA approves it.
Concato concurred, saying that “FDA is unlikely to generate a checklist.” He added that FDA’s guidance on external controls and other guidance documents “are not meant as a ‘how to’ but is honestly [are] all about the fundamentals. These studies are not new, observational studies have been done in academia for decades, so it is not as if we’re poking around in the dark trying to find out what is right or wrong.”
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