US FDA Officials Provide Primer On 'Real-World' Data
Executive Summary
In a journal article, Center for Drug Evaluation and Research Director Janet Woodcock and colleagues describe the sources of real-word evidence and study designs that can be used to generate such evidence.
FDA made a commitment to explore the use of real-world evidence in evaluating the safety and effectiveness of medicines in its negotiations with the biopharmaceutical industry over the reauthorization of the Prescription Drug User Fee Act (PDUFA VI). With the enactment of legislation reauthorizing the user fee program, the agency is highlighting its focus on this issue.
In a viewpoint article in the Aug. 22/29 issue of the Journal of the American Medical Association, FDA's Jonathan Jarow, senior medical advisor to the director of the Center for Drug Evaluation and Research, Lisa LaVange, director of CDER's Office of Biostatistics, and CDER Director Janet Woodcock define "real-world" evidence and describe how it is being used.
"Real-world evidence can be generated from any study design as long as the data source is from routine care and … the trial design and conduct closely approximate the eventual use of the product in clinical practice." – CDER officials
"There is substantial enthusiasm for the use of real-world data sources to generate so-called real-world evidence (RWE), but confusion remains about what RWE means," the CDER officials said. "Real-world evidence is defined by the data source and degree of pragmatism independent of study design. Generation of RWE therefore is not limited to observational studies but also includes randomized trials conducted in clinical settings."
The JAMA article is another step in agency officials' efforts to describe how they view the nature and role of real-world evidence to support regulatory decision-making.
Lead author Jarow described what would be "nirvana" for use of real-world evidence in a panel discussion at the Drug Information Association's (DIA) annual meeting in Chicago in June. He cited standardized data structure; complete linkage of data between hospitals, pharmacies, outpatient clinics, social media and death registries; and open access with consent for full use of de-identified data. (Also see "Real World Evidence: Between 'Nirvana' And Electronic Roadblocks" - Pink Sheet, 21 Jun, 2017.)
In another session at the DIA meeting, FDA's Robert Temple, CDER deputy director for clinical science, discussed when real-world evidence can be used in lieu of a randomized controlled trial (RCT) to support regulatory decisions about drugs. (Also see "When Will Real World Evidence Be Persuasive? FDA's Temple Offers Perspective" - Pink Sheet, 29 Jun, 2017.)
Numerous FDA officials penned an article in the New England Journal of Medicine in December describing how real-world evidence can be used in the research setting. In addition to lead author Rachel Sherman, who was named principal deputy commissioner on Aug. 17, the authors included Temple, Woodcock and then-Commissioner Robert Califf.
Designing Clinical Trials With Real-World Data
The JAMA piece, "Multidimensional Evidence Generation and FDA Regulatory Decision Making," further expounds on the topic. Jarow and his colleagues say "real-world evidence can be generated from any study design as long as the data source is from routine care and the design is highly pragmatic, meaning the trial design and conduct closely approximate the eventual use of the product in clinical practice."
They note that there are advantages and disadvantages to the use of real-world data for evidence generation. "Real-world data are more proximate to the patient and often include primary source data; however, there is greater potential for data elements to be missing or collected in an unstructured fashion because the data are collected for patient care rather than research," they write.
They point out that real-world data may also be combined with traditional clinical trials to increase their efficiency and reduce costs. Such data may be used to help design a clinical trial by assisting in the selection of study sites that are more likely to enroll study participants and providing an external control group, to reduce duplication of data input, and to ascertain endpoints by gathering deaths from the National Death Index or tumors from a tumor registry.
Real-World Evidence May Support Orphan Drug Efficacy
FDA uses real-world evidence for regulatory decisions, primarily for those related to safety, the authors noted. However, for some drugs the demonstration of efficacy has been based on real-world evidence from case series or registries. In these applications, the drug treated a rare disease for which a randomized study may not have been feasible, and both the pathophysiology and natural history of the disease were understood well enough to provide confidence in establishing causality, the CDER officials said.
"Many questions about a drug remain unanswered at the time of approval; some of them involve optimal dosing regimen, longer-term outcomes, and outcomes in various subpopulations," the authors concluded. "It is not feasible to answer all of these questions with traditional RCTs. Using RWE to begin to address these questions is preferable to having no evidence whatsoever."
FDA will further explore the potential use of real world data through public workshops and other projects. The agency's PDUFA reauthorization goals for fiscal years 2018-2022 negotiated with industry include a commitment to hold one or more public workshops with key stakeholders by the end of FY 2018 to gather input on issues related to real-world evidence to use in regulatory decision-making. (Also see "FDA To Join The 'Real World' Under PDUFA VI" - Pink Sheet, 15 Jul, 2016.)
On Sept. 13, the Duke-Margolis Center for Health Policy, in conjunction with FDA, will hold a workshop to discuss various topics related to the use of real-world data and real-world evidence in drug development and regulatory decision-making. Topics will include an update on FDA’s implementation of the 21st Century Cures Act’s provisions related to real-world evidence, development of a framework for tackling challenges related to regulatory acceptability, and opportunities to improve the data development activities, study designs and analytical methods.
The agency also agreed under PDUVA VI to initiate activities, such as pilot studies or methodology development projects, to address key outstanding concerns and considerations in the use of real-world evidence for regulatory decision-making. By the end of FY 2021, FDA will publish draft guidance on how such evidence can contribute to the assessment of safety and effectiveness in regulatory submissions, such as the approval of new supplemental indications and the fulfillment of postmarketing commitments and requirements.
On Aug. 18, President Trump signed into law the FDA Reauthorization Act, which renews the agency's prescription drug, medical device, generic drug and biosimilar user fee programs for another five years, beginning Oct. 1. (Also see "FDARA Takes Effect With Under-The-Radar Presidential Signature" - Pink Sheet, 19 Aug, 2017.)