Clinical Pharmacology Corner: Exposure Response Analysis

FDA Announces Availability of a Public Docket, “Exposure-Response Analysis in Drug Development and Regulatory Decision Making; Request for Comments”

On April 6, 2018, the U.S. Food and Drug Administration (FDA) announced the availability of a public docket entitled “Exposure-Response Analysis in Drug Development and Regulatory Decision Making; Request for Comments” 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 Prescription Drug User Fee Act of 2017 (PDUFA VI), part of the FDA Reauthorization Act of 2017 (FDARA), highlights the goal of advancing model-informed drug development (MIDD). Exposure-response analysis is a MIDD strategy that has been used in drug development and regulatory decision making. On May 6, 2003, FDA issued a guidance for industry titled “Exposure-Response Relationships – Study Design, Data Analysis, and Regulatory Applications” (available athttps://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072109.pdf). This guidance provides recommendations for the use of exposure-response analyses in the development of drugs, including therapeutic biologics. Since then, FDA and drug developers have gained a wealth of experience performing exposure-response analyses and leveraging the results to influence drug development and inform regulatory review, and have identified obstacles limiting its routine application. FDA wants to capture the public’s experience to inform future efforts on providing additional clarity, new insights, and updated recommendations for employing exposure-response analyses in drug development.

Interested persons are invited to provide detailed information and comments on the use of exposure-response analysis in drug development and regulatory review. FDA is particularly interested in responses to the following questions and will consider all information and comments submitted:

1. In general, are there any aspects of the 2003 guidance for industry titled “Exposure-Response Relationships--Study Design, Data Analysis, and Regulatory Applications” 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?

The “Exposure-Response Analysis in Drug Development and Regulatory Decision Making; Request for Comments” public docket is available at https://go.usa.gov/xQ4m2. Please refer to the public docket for more details.

FDA established this public docket to collect public comments. You may submit your comments to this public docket by July 5, 2018 to the Docket No. FDA-2018-N-0791 available athttps://www.regulations.gov. Your comments do make a difference and can impact the outcomes of FDA regulatory policy. Share your knowledge and experience, and make your voice count.