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FDA officials see ‘missed opportunity’ with patient outcomes in clinical trials

SAN DIEGO — Drug regulators are beginning to look at more than primary endpoints when evaluating new products.

Particularly in the last few years, the Food and Drug Administration has shown an interest in patient-reported outcomes, meaning the information patients can provide about their disease burden, the drugs they take, and associated feelings and experiences.

The information is seen as a valuable tool for improving clinical trial designs, guiding drug approvals and supporting label decisions. A six-minute walk test, after all, doesn’t necessarily indicate whether a patient could make it down the hall to the bathroom in his own home.

Yet the reach of patient-reported outcomes, or PROs for short, has been limited, in good part because of the varied ways clinical trial investigators collect and assess them.

Two studies of chronic migraine medications, for example, may ask participants to answer differently-worded questionnaires about their pain level. The studies might also use different tools — a wearable versus neural imaging — to measure and validate the responses.

The disparities have troubled regulators, who are tasked with evaluating the merit of clinical data. And they’ve presented obstacles for trial sponsors and operators. Michelle Hoiseth, chief data officer at Parexel, noted researchers aren’t generally going to gamble on a multi-million-dollar clinical trial with data collection methods they don’t think will be accepted.

As a result, PROs rarely get top-billing in the hierarchy of study endpoints.

“That’s often a missed opportunity: when a well-developed endpoint, a patient-centric endpoint isn’t given the proper attention that it deserves,” said Elektra Papadopoulos, associate director of clinical outcome assessments staff in the FDA’s Center for Drug Evaluation and Research.

Papadopoulos, along with other FDA leaders, went over the agency’s most recent efforts to guide and understand PRO use during a panel discussion at the Drug Information Association’s annual meeting.

From 2013 to 2017, CDER staff met two dozen times with patients who had certain chronic illnesses to discuss treatment burden and unmet needs. Input from those meetings helped streamline disease-specific guidances, according to Papadopoulos.

From left: Bray Patrick-Lake, Duke Clinical Research Institute; Robyn Carson, Allergan; Telba Irony, CBER; Michelle Tarver, CDRH; Elektra Papadopoulos, CDER.
 Credit: Jacob Bell

CDER and its equivalent biologics division, CBER, rolled out last June the first in a four-part series of guidances about collecting and submitting patient experience data. The first in the series, while still a draft guidance, focused on from whom and why researchers or sponsors should gather data.

It recommends tapping statisticians and other subject matter experts when deciding what sampling method to use for PROs. The FDA also nudged trial organizers to meet early and often with the agency to iron out whether the intended data collection methods and strategies align with their studies’ objectives. 

Broadly, regulators are trying to make the PRO process consistent. The FDA recently launched a pilot program aimed at creating publicly available, standard sets of Clinical Outcome Assessments (COAs) measures for distinct indications. The program already has buy-in from the National Institutes of Health, which is offering grants for qualified participants.

The agency’s argument was that there were so many independently developed PRO protocols and tools, it created a “continued learning curve” as well as higher costs and less long-term sustainability. The variability also threatened the quality of COAs, which “both limits their value to decision makers and can potentially undercut confidence in these data,” the FDA said.

Not everyone is sold on this push.

One audience member noted the problem of buy-in during a Q&A with the panel. He said a potential corporate partner of his doesn’t feel the need to submit PROs for a drug it’s working on because the drug has breakthrough status and only needs to show biomarker data to gain approval.

During a separate DIA panel, an audience member who identified herself as a licensing specialist from Merck explained how, at times, the level of competition in the pharma industry can be counterproductive. She voiced concerns about whether standardization would exacerbate the issue, especially if the FDA chooses a go-to COA that uses expensive data collection and measurement tools.

“I might pay $400,000 for a measure that’s the gold standard. And that’s where companies start using those measures less and less,” she said.

There were also concerns about the public nature of the standardized COAs.

“When you have something in the public domain, it is one of the hardest measures to license and to translate because it’s not regulated,” the Merck licensing specialist said. “People don’t have that incentive to actually structure it, so it’s a lot harder to access and to make sure that the validity over time is consistent.”

Panelists in both sessions acknowledged there will be problems left to solve even with the implementations of PRO programs. Still, they maintained that doing something is better than leaving the system as is.

“If every company develops their own outcome set, it will just not fly,” said Anton Hoos of Patient Focused Medicine Development.