The US Food and Drug Administration (FDA) on Thursday announced it is seeking input to better identify areas of scientific policy that may need further clarity or elaboration, as well as any obstacles that prevent the use of exposure-response analyses in drug development and regulatory review.
Almost 15 years ago, FDA published a guidance on the issue of exposure-response relationships
, and given that the latest iteration of the Prescription Drug User Fee Act (PDUFA VI) includes the goal of advancing model-informed drug development
, the agency said it wants to “inform future efforts on providing additional clarity, new insights, and updated recommendations for employing exposure-response analyses in drug development.”
FDA said it is particularly interested in comments on:
1. In general, if there are aspects of the 2003 guidance that merit further elaboration or if there any new topic areas that should be addressed.
2. Best practices for conducting exposure-response analysis that can be generally applied across development programs and regulatory submissions, including “input on planning and design (e.g., data considerations, assumption setting); analytical approaches (e.g., exposure and response metrics, choice and inclusion of predictors, methods for addressing confounding factors); model evaluation and qualification (e.g., goodness-of-fit, assessment of model risk, impact on regulatory decisions); and communication of results and impact on subsequent drug development or regulatory decisions.”
3. What attributes of exposure-response analyses are critical to effectively inform a drug development or regulatory decision? And what are the main obstacles preventing widespread acceptance of exposure-response analyses?
4. During which stages of drug development would it be most productive to interact with FDA on exposure-response analysis planning, and what type of feedback would be useful?
According to the 2003 guidance, exposure-response information is at the heart of any determination of the safety and effectiveness of drugs.
“That is, a drug can be determined to be safe and effective only when the relationship of beneficial and adverse effects to a defined exposure is known,” FDA explains. “There are some situations, generally involving a very well-tolerated drug with little dose-related toxicity, in which the drug can be used effectively and safely at a single dose well onto the plateau part of its exposure-response curve, with little adjustment for pharmacokinetic (PK) or other influences in individuals. In most situations, however, for more toxic drugs, clinical use is based on weighing the favorable and unfavorable effects at a particular dose. Sometimes with such drugs, the doses can be titrated to effect or tolerability. In most cases, however, it is important to develop information on population exposure-response relationships for favorable and unfavorable effects, and information on how, and whether, exposure can be adjusted for various subsets of the population.”
Exposure-Response Analysis in Drug Development and Regulatory Decision Making: Request for Comments