We first presented these results as a poster at the 2013 AAPS annual meeting. I developed these templates with my Certara colleague, Linda Hughes, and Helmut Schütz from BEBAC. However, RSABE can be performed in Phoenix WinNonlin using reusable template projects and workflows for both EMEA and FDA approaches.
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The Phoenix WinNonlin software provides a BE module to perform average bioequivalence, but this module is not currently designed for a complete RSABE analysis. What tools are available to help you perform RSABE analysis? The specifics of RSABE methodology vary between regulatory agencies, but both the European Medicines Agency (EMEA) and the FDA require that subjects receive the reference drug more than once, eg, replicated 3-period (RRT/RTR/TRR) or 4-period (RTRT/TRTR) crossover designs, so that the BE analysis accounts for within-subject variability. The extent to which the acceptance limits can be widened depends on the intra-subject variability for the reference formulation. This method allows for wider BE acceptance limits.
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Indeed, a 2012 AAPS Journal article states that the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products. Reference-scaled average bioequivalence (RSABE) methodology is increasingly used to demonstrate bioequivalence for HV drugs. Demonstrating BE turns out to be more complex than you might think due to the prevalence of HV drugs-those for which the within-subject variability (%CV) in BE measures is 30% or greater. In traditional BE, the 90% confidence interval for the geometric least squares mean ratio of the test formulation over the reference formulation for C max and AUC must fall between the BE limits, set from 80% to 125%. The rate and extent of drug absorption are determined from the following pharmacokinetic parameters: peak concentration (C max) and the area under the concentration-time curve (AUC), respectively. The generic drug is considered bioequivalent to the reference drug if they do not differ significantly in their rates and extents of absorption. The FDA requires that drug manufacturers demonstrate BE between the generic product and the corresponding reference product. In this post, I’ll discuss an approach that addresses this problem as well as a tool that can help you streamline this type of analysis. This increases the expense of BE studies, places more subjects at risk, and ultimately, limits the availability of generics. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects, even when the formulations themselves have no significant mean differences. A study by the FDA Office of Generic Drugs (OGD) reviewed over 1000 bioequivalence (BE) studies of 180 drugs, of which over 30% were highly variable (HV).
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