Executive Summary

Officials are enthusiastic about the possibility of ‘real world evidence’ supporting the regulatory process – but are also eager to tamp down expectations (or fears) that it will make a big difference any time soon.

Real world evidence is definitely a “hot topic” at FDA.

That phrase was used twice in one week by two different drug review officials from two different divisions in two very different contexts to describe the concept of applying evidence derived from actual use of medicines to enhance regulatory decisions:

• The first was Division of Bone, Reproductive and Urologic Products Director Hylton Joffee during a Dec. 6 advisory committee discussion of clinical trial endpoints for non-testosterone therapies for hypogonadism.
• The second was from Office of Hematology & Oncology Products Lead Medical Officer Gideon Blumenthal during a Dec. 13 National Academies of Medicine workshop on the drug development paradigm in oncology.

The shared use of the phrase “hot topic” also reflected a broader shared message from the agency in the context of those two events: as eager as many inside and outside of FDA are to expand the boundaries for evidence collection to support regulatory decisions, there is still a ways to go before that will happen. Real world evidence, in other words, isn’t a regulatory reality just yet.

During the advisory committee meeting, the role of “real world evidence” was not central to the discussion by FDA or the committee. Fundamentally, the panel provided support for FDA’s view that non-testosterone therapies should be held to same (relatively new) standard applied for testosterone agents: any indications for use in the “Low T” population should be supported be evidence of clinical benefit – not just elevated testosterone levels. (Also see “Hypogonadism Trial Designs: FDA Panel Favors Symptom Assessments, Fertility Measures” – Pink Sheet, 6 Dec, 2016.)

That means, most likely, a multi-year process to develop appropriate endpoints – including patient reported outcomes – and then confirm benefit in pivotal studies. (Also see “FDA’s Tough Stance On Patient-Reported Outcomes Underscored At Repros Meeting” – Pink Sheet, 7 Dec, 2016.)

Real world evidence is “a real opportunity,” but it has a “longer horizon for its greatest payoff than its proponents think.” – CDER Director Janet Woodcock

But an exchange on the potential role of real world evidence may point to a very different approach to developing evidence in cases of broad off-label use in the future – and to different levels of enthusiasm for doing so in industry and within FDA.

The subject was raised by the industry representative on the committee, Bayer VP Gerard Nahum. In the context of proposed trial designs, he asked Joffe, what role might “real world evidence” have to “supplement the label and augment the indications?”

Joffe responded by acknowledging that “real world evidence is a hot topic these days,” and stressing that the agency is “always open to hearing proposals if companies have ideas on how to leverage data.”

However, he added, “the devils are in the detail. How good is the evidence? What exactly is it showing?” He noted the prior discussion of published studies using unvalidated PROs as an example of what might look like strong “real world evidence” that may not be interpretable in practice. So discussing the role of real world evidence in this context, Joffe said, “is hard in the abstract.”

‘Stop Talking About It And Start Doing It’

The discussion of real world evidence (RWE) in the role of oncology development was more literally part of the agenda at the National Academies of Medicine (NAM) event, but FDA’s message was essentially the same.

In his presentation on FDA’s willingness to accept non-randomized trials in the context of extremely large effect sizes for oncology drugs, Blumenthal listed a number of considerations, including “Can RWE play a role for post-marketing studies?” That issue, Blumenthal added, is a “very hot topic” at FDA.

However, as Center for Drug Evaluation & Research Director Janet Woodcock made clear during introductory remarks at the NAM conference Dec. 12, while RWE is “a real opportunity,” it has a “longer horizon for its greatest payoff than its proponents think.” And there is never “going to be a button we can push and get answers.”

Woodcock has been playing the role of curbing enthusiasm for RWE in a number of different settings. During a November Prevision Policy/Friends of Cancer Research conference, she pointedly noted that, for all the projects fleshing out RWE under way inside FDA and outside, the exact state of the effort “is still a bit of a mystery to me.” (Also see “FDA/CMS Collaboration: “Sleeper Group” Goes Public With Call For Real-World Evidence” – Pink Sheet, 9 Nov, 2016.)

That message has apparently been delivered directly to some of the leading advocates for the approach in academia. During the NAM meeting, Harvard Pilgrim’s Jeffrey Brown – who has worked with Richard Platt on the FDA Sentinel Initiative – began his by citing recent meeting he had with FDA Commissioner Robert Califf. According to Brown, the commissioner told him, bluntly, “Stop talking about it and start doing it.”

Woodcock’s more pointed comments Dec. 12 also reflected a sensitivity to critics of the just-signed 21st Century Cures Act, who point to relatively open-ended provision on RWE as evidence that the law will undermine patient safety. FOCR Founder Ellen Sigal followed Woodcock’s opening remarks by more directly noting that fear: “So I shouldn’t believe everything I read in the press about Real World Evidence?” she joked.

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