US Drug Approvals Might Skip Second Trial, Rely More On Clinical Pharmacology
This article was originally published in SRA
The US Food and Drug Administration is working to provide more clarity on when clinical pharmacology data can serve as the confirmatory evidence needed to approve a drug on the basis of a single pivotal trial.
FDA is considering revisions to a 1998 guidance document on when a single, adequately controlled trial, coupled with additional data, can support approval, Robert Temple, Deputy Director for Clinical Science at the agency's Center for Drug Evaluation and Research, said at a July 28 meeting sponsored by the Brookings Institution's Center for Health Policy1.
"Whether and how some kinds of pharmacologic evidence or exposure/response information can provide the confirmatory evidence that would support reliance on a single trial [is] something everybody is obviously hysterically interested in," Temple said.
A new guidance that explicitly envisions greater reliance on modern clinical pharmacology methods could make it easier for drugs to reach market with something less than the two randomized, controlled trials that FDA has traditionally required for showing substantial evidence of efficacy.
The Goal: Reducing R&D Failure Rates
The Brookings meeting focused on how better and more systematic application of clinical pharmacology methods and tools, such as modeling and simulation, may help reduce the high failure rate in drug development, particularly in late-stage clinical trials. Topics discussed included optimizing target and compound selection and determining optimal dose before compounds enter Phase III efficacy studies.
The meeting was convened under a cooperative agreement with FDA and in collaboration with the International Consortium for Innovation and Quality in Pharmaceutical Development. The latter, known as the IQ Consortium, is an organization of biopharma companies aimed at advancing science-based and scientifically-driven standards and regulations worldwide.
Comments during the public meeting were intended to inform a July 29 closed-door roundtable discussion among staff from Brookings, FDA and the IQ Consortium.
Gregory Daniel, a fellow in economic studies and managing director for evidence development and innovation at Brookings' Center for Health Policy, said the meeting was also expected to inform potential future guidance documents from FDA and establishment of best practices for the application of emerging clinical pharmacology tools.
CDER is planning to issue several new and revised guidance documents in the clinical pharmacology area in 2015, according to its guidance agenda, including documents on dose selection and exposure-response relationships.
Looking Beyond The Randomized Controlled Trial
In introductory remarks, CDER Director Janet Woodcock noted that drug and disease modeling and clinical trial simulations are increasingly being used by industry in drug development and the agency in its review activities. However, such approaches are not widely accepted and have been carried out largely on an ad hoc basis, she said.
"We have to think about how do we move this to a more routine part of drug development," Woodcock said, suggesting there may be a need to formalize early interactions with FDA around clinical pharmacology programs.
The CDER director nevertheless highlighted a key barrier to greater reliance on clinical pharmacology data in regulatory decision-making and clinical practice.
"The triumph of clinical medicine has been the randomized clinical trial and evidence-based medicine," she said. "That is the gold standard and that's what the clinical world relies upon. That's not modeling, that's not mechanistic data."
However, because randomized clinical trials can only test a single hypothesis at a time, "you lose a vast amount of information about the patients in that trial," Woodcock said.
"I think the greatest barrier is going to be the tension between how much can we inform drug development with all these models and mechanistic data and how can we make that reliable enough that it feeds logically into that confirmatory Phase III trial that is done, or trials that are done, and that we honor that information equally to the randomized controlled trial information," she said.
This tension between the empirical evidence-based tradition and an approach that relies heavily on mechanistic understanding and modeling needs to be acknowledged and discussed, Woodcock said.
"This underlies a lot of the failure to progress. I think that this dichotomy is seen in companies, I think it will be seen in FDA, and I think you will see it in the clinical community as well. And to some extent we're seeing that with the biosimilars programs that we're now trying to implement."
Temple: Working On Giving More Examples
Temple said the agency is open to use of clinical pharmacology data to support a demonstration of efficacy but acknowledged that the situations in which such an approach is acceptable might not be clear to sponsors.
He pointed to a 1998 guidance2: "Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products." The document was written in response to an FDA Modernization Act provision that gave the agency permission to rely on data from one adequate and well-controlled trial, plus confirmatory evidence, as the basis for drug approval.
The guidance identified a number of situations in which a single controlled trial could provide substantial evidence of effectiveness, such as cases where there was a trial in another population or a closely related disease or with a different dose.
References
- Brookings Institution, Improving productivity in pharmaceutical research and development, The role of clinical pharmacology and experimental medicine, July 28, 2015, www.brookings.edu/events/2015/07/28-clinical-pharmacology-and-experimental-medicine
- FDA Guidance for Industry, Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, May 1998, www.fda.gov/downloads/Drugs/.../Guidances/ucm078749.pdf
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