title: Improper selection of a pre-specified primary dose-response analysis delays regulatory drug approval.
abstract: Dose-response analysis is one of the accepted efficacy endpoints to establish effectiveness. The purpose of this research was to inform selection of an appropriate pre-specified primary dose-response analysis to demonstrate drug efficacy in a registration trial. The power and the type I error rate of the placebo-corrected (i.e., simply adjusting the observed treatment value by subtracting the placebo mean) and the placebo-anchored (i.e., including the placebo data as dose 0 in the regression) slope analyses were assessed based on regulatory submission data for two antihypertensive drugs and simulated data from hypothetical clinical trials. In the simulated hypothetical trials, the impact of different dosing strategies (i.e., the fixed dose versus the weight-based per kilogram dose), sample size, and scenarios governing the drug exposure-response relationship (e.g., E(max), ED(50), and SD) was also evaluated. For each scenario, a total 300 replications were simulated. The placebo-anchored slope analysis is always more powerful to demonstrate effectiveness in all plausible scenarios. The difference between the placebo-anchored and the placebo-corrected analyses was maximum when the studied doses were too high. However, the dose-response analysis is not sensitive to the dosing strategies. Furthermore, the type I error rate of these two methods was also found to be comparable. The design of dose-response studies should carefully consider these results to justify the inclusion of placebo and the analysis method. The pharmaceutical industry and the regulatory agencies are equally responsible for using the appropriate methods of primary analysis and providing justification in the protocol.
authors: Division of Pharmacometrics, Office of Clinical Pharmacology, CDER, FDA, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA. jiang.liu@fda.hhs.gov
authors: Jiang
authors: J
authors: Liu
authors: Pravin
authors: P
authors: Jadhav
authors: Yaning
authors: Y
authors: Wang
authors: Jogarao
authors: J
authors: Gobburu
mesh_terms: D000293:Adolescent; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects*; D002648:Child; D002985:Clinical Protocols; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D054796:Drug Dosage Calculations; D023381:Endpoint Determination; D006801:Humans; D016014:Linear Models; D008790:Metoprolol / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016032:Randomized Controlled Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D015203:Reproducibility of Results; D012107:Research Design / Q000706:statistics & numerical data; D018401:Sample Size; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D008790:Metoprolol; C081643:candesartan