Exposure-Response Analysis in Drug Development and Regulatory Decision Making

 

FDA recently announced a public docket entitled “Exposure-Response Analysis in Drug Development and Regulatory Decision Making; Request for Comments” (https://go.usa.gov/xQ4m2) to give interested parties an opportunity to identify areas of scientific policy that may need further clarity or elaboration, as well as any obstacles preventing use of exposure-response analyses in drug development and regulatory review.
The community has been invited to provide detailed information and comments on the use of exposure-response analysis in drug development and regulatory review. Particularly, the following questions have been posed:
  1. In general, are there any aspects of the 2003 guidance for industry titled “Exposure-Response Relationships--Study Design, Data Analysis, and Regulatory Applications” (https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072109.pdf) that merit further elaboration? Additionally, are there any new topic areas that should be addressed?
  2. What are best practices for conducting exposure-response analysis that can be generally applied across development programs and regulatory submissions? Input on best practices can include any of the following topic areas:
    • 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)
    • Communication of results and impact on subsequent drug development or regulatory decisions
  3. What attributes of an exposure-response analysis are critical to effectively inform a drug development or regulatory decision? Additionally, 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 the FDA regarding exposure-response analysis planning? What type of feedback would be useful to inform exposure-response analyses and to reduce uncertainty in regulatory acceptance?
An ISoP working group led by Al Maloney and coordinated by Standards & Best Practices Committee Chair Jonathan French and President-Elect Justin Wilkins prepared a detailed response on behalf of the Society, which was submitted to the U.S. Food and Drug Administration on 5 July 2018. The full contents of the submission are below:
  • Cover letter (PDF)
  • An ISoP Position Statement on the use of Dose-Exposure-Response in Drug Development (PDF)
  • Line-by-line review of the 2003 FDA guidance document “Guidance for Industry: Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications” (PDF)
We thank all those involved in writing and reviewing this submission, particularly Al Maloney and Nick Holford, as well as Mariam Ahmed, Thierry Buclin, Joachim Grevel, David Norris, and Amit Taneja. Others who made contributions include Misba Beerahee, Jason Chittenden, Vincent Duval, Kevin Dykstra, Ruben Faelens, Dave Fairman, Martin Fink, Nathalie Gobeau, Günther Heimann, Charlotte Kloft, Sriram Krishnaswami, Lars Lindbom, Klaas Prins, Jean-Louis Steimer, An Vermeulen, and Stefano Zamuner - many thanks to you all as well.

We hope our contribution will be useful for FDA as it reviews its policy on the role of exposure-response analysis in drug development and regulatory decision-making!