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1.  Improper Selection of a Pre-specified Primary Dose–Response Analysis Delays Regulatory Drug Approval 
The AAPS Journal  2013;15(2):407-414.
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., Emax, ED50, 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.
PMCID: PMC3675735  PMID: 23307587
dose–response; power; type I error
2.  Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate Multiphasic Modified Release Formulations 
The AAPS Journal  2012;14(4):925-926.
PMCID: PMC3475859  PMID: 22976173
attention deficit hyperactivity disorder; bioequivalence; generic drugs; methylphenidate; pAUC
3.  Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report 
The AAPS Journal  2010;12(3):371-377.
Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.
PMCID: PMC2895434  PMID: 20440588
bioequivalence; interchangeability; modified release; pharmaceutical equivalence; therapeutic equivalence
4.  Impact of pharmacometrics on drug approval and labeling decisions: A survey of 42 new drug applications 
The AAPS Journal  2005;7(3):E503-E512.
The value of quantitative thinking in drug development and regulatory review is increasingly being appreciated. Modeling and simulation of data pertaining to pharmacokinetic, pharmacodynamic, and disease progression is often referred to as the pharmacometrics analyses. The objective of the current report is to assess the role of pharmacometrics at the US Food and Drug Administration (FDA) in making drug approval and labeling decisions. The New Drug Applications (NDAs) submitted between 2000 and 2004 to the Cardio-renal, Oncology, and Neuropharmacology drug products divisions were surveyed. For those NDA reviews that included a pharmacometrics consultation, the clinical pharmacology scientists ranked the impact on the regulatory decision(s). Of about a total of 244 NDAs, 42 included a pharmacometrics component. Review of NDAs involved independent, quantitative evaluation by FDA pharmacometricians, even when such analysis was not conducted by the sponsor. Pharmacometric analyses were pivotal in regulatory decision making in more than half of the 42 NDAs. Of the 14 reviews that were pivotal to approval related decisions, 5 identified the need for additional trials, whereas 6 reduced the burden of conducting additional trials. Collaboration among the FDA clinical pharmacology, medical, and statistical reviewers and effective communication with the sponsors was critical for the impact to occur. The survey and the case studies emphasize the need for early interaction between the FDA and sponsors to plan the development more efficiently by appreciating the regulatory expectations better.
PMCID: PMC2751253  PMID: 16353928
regulatory decisions; modeling; simulation; FDA; dose-response

Results 1-4 (4)