Regulatory Focus™ > News Articles > New Report Calls on FDA to Clarify Use of Real-World Evidence

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Posted 23 June 2016 | By Zachary Brennan 

New Report Calls on FDA to Clarify Use of Real-World Evidence


As legislation to speed the process by which the US Food and Drug Administration (FDA) approves new drugs and devices continues to stall in Congress, mostly because of disagreement over funding for the National Institutes of Health (NIH) and patient safety concerns, a nonprofit on Thursday released a new report calling for FDA to clarify ways real-world evidence can be used to support clinical trials and postmarket commitments.

The Bipartisan Policy Center’s 32-page report, released alongside a forum for Sen. Lamar Alexander (R-TN) to continue to push for passage of his Senate version (19 separate bills) of the House-passed 21st Century Cures bill, offers a number of rehashed arguments that try to place at least part of the blame for the slow drug and device development process on FDA and the regulatory pathways by which drugs and devices are approved.

As the report notes, the evidence requirements for the approval of drugs date back to 1962, when the Kefauver-Harris Amendments to the Federal Food, Drug and Cosmetic Act included provisions requiring manufacturers of drug products to establish a drug’s effectiveness by substantial evidence and adequate, well-controlled investigations.

“Neither definitions for ‘adequate and well-controlled’ investigations included in the law nor in the FDA’s recent guidance preclude the use of real-world evidence for regulatory decision-making,” the report says, though it also notes that real-world evidence, which some EU professors recently called “a euphemism for observational evidence,” has rarely been used beyond post-market surveillance.

“The broader use of real-world evidence in regulatory decision-making, for example, for label expansions, new indications, or to support new drug approvals, is not yet routinely considered by the FDA,” authors of the report, including former congressmen, Andrew von Eschenbach, MD, president, Samaritan Health Initiatives and former FDA commissioner, Mark McClellan, MD, PhD, director of the Margolis Center for Health Policy at Duke University and former FDA commissioner, and billionaire Patrick Soon-Shiong, MD, chairman and CEO, Institute for Advanced Health and CEO of the immunotherapy company NantKwest, write.


sors and investigators would pursue the use of real-world evidence to augment and support clinical trials and post-marketing commitments if there were more clarity from the FDA regarding the types of real-world evidence that would be accepted for various decisions, and the methods required to establish confidence in analyses using real-world data,” they claim.

FDA Support and Progress

The report comes as current FDA Commissioner Robert Califf said last month that leveraging real world evidence to inform FDA decision making is the top programmatic priority for his tenure.

Similarly, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, told a public workshop on real-world evidence in March that the question on everyone's mind is "can we randomize people within the healthcare system to do a trial inside the healthcare system utilizing the data collection methods of the healthcare system?"

She also noted that it's easy to find "really terrible side effects because they're very dramatic." But in terms of "huge treatment effects," she added, "that really isn't the problem with most drugs…most of them only have an incremental effect…That's where we need randomization, because you don't just have something that hits you in the face."

Robert Temple, deputy director for clinical science at CDER, also has said he sees promise for trials conducted using real world evidence to answer questions like how long patients should take a drug.

"I think you could conceivably do such a study in a randomized environment," he said.

Thursday’s report also calls on FDA to develop formal guidance regarding the use of real-world evidence to inform regulatory decision-making, including the circumstances under which real-world data could be used as well as the types of real-world data, methods and the levels of evidence that would be acceptable. FDA and industry groups are hammering out those details in the latest iteration of the Prescription Drug User Fee Act (PDUFA).

FDA is also, as the report asks the agency to, engaging with representatives of regulated industry, patient and disease research organizations, academia, experts in the use of electronic data, experts in statistical methods, and experts in privacy policy in the development of the guidance as part of the PDUFA talks.

And on the device side, FDA has outlined plans to create a new user fee proposal under the Medical Device User Fee Act (MDUFA) that would be related to real-world evidence. Under that plan, FDA would add 15 full-time employees to develop and implement a framework for using real-world evidence for premarket decision-making as part of work at a new medical device coordinating center.


Among aspects of the report that FDA has not offered any position on recently is a call for “full transparency on how FDA reaches its conclusions. Transparency in the FDA’s methods will provide invaluable insight into how regulators deal with problems like missing information, lack of outcomes data, and disparities in sample populations compared with the real world.”

And as technology outpaces the agency’s developments in some areas, the report notes that the systems that capture data for clinical research are currently “very different from the systems that capture data for clinical care. Often the data required for clinical research does not exist in the EHR [electronic health record] or other clinical systems. Poor interoperability among systems, the lack of adoption of common data standards, and the need for more effective methods for matching patient data across disparate systems, also serve as barriers to the effective aggregation and use of real-world data for clinical studies.”

But areas where the report may raise some eyebrows with respect to patient safety include the authors' call on FDA to create a new pilot program to develop and test “a new adaptive pathway approach,” apparently in addition to the accelerated approval pathways the agency already offers, and to allow for “iterative phases of development, beginning with initial marketing authorization to a restricted patient population, then expanding to wider populations based on risk-benefit ratios…[and] Gathering evidence through close-monitoring and other real-world evidence, to supplement RCTs [randomized controlled trials].”

This idea of speeding up the approval process even further is drawing its fair share of critics, as many note that the agency is already approving drug applications at the fastest pace in its history.

But an area where there seems to be lots of agreement from FDA and industry is that real-world data can continue to have a positive impact on postmarket surveillance efforts, which as the report notes, FDA is working on.

Part of that work is in response to the FDA Amendments Act of 2007, which required FDA to develop a system for post-market risk identification and analysis of drugs and FDA implemented its Sentinel Initiative.

“Traditional adverse event reporting from clinicians, patients, and manufacturers remains the primary source of safety information at the FDA. There is considerable opportunity to further leverage real-world evidence to support post-market surveillance efforts,” the report says. “Circumstances under which real-world evidence can make an immediate impact include supporting regulatory decision-making associated with a label extension or a new indication for an approved drug, supporting confirmatory studies for drugs approved under the FDA’s existing expedited programs, and improving the efficiency of Phase IV post-market monitoring and ongoing post-market surveillance.”

Report on Using Real-World Evidence to Accelerate Safe and Effective Cures


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