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). 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. This increases the expense of BE studies, places more subjects at risk, and ultimately, limits the availability of generics. 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.
How is BE determined?
The FDA requires that drug manufacturers demonstrate BE between the generic product and the corresponding reference product. The generic drug is considered bioequivalent to the reference drug if they do not differ significantly in their rates and extents of absorption. The rate and extent of drug absorption are determined from the following pharmacokinetic parameters: peak concentration (Cmax) and the area under the concentration-time curve (AUC), respectively. In traditional BE, the 90% confidence interval for the geometric least squares mean ratio of the test formulation over the reference formulation for Cmax and AUC must fall between the BE limits, set from 80% to 125%. 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.
What is RSABE, and why should you care?
Reference-scaled average bioequivalence (RSABE) methodology is increasingly used to demonstrate bioequivalence for HV drugs. 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. This method allows for wider BE acceptance limits. The extent to which the acceptance limits can be widened depends on the intra-subject variability for the reference formulation. 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.
What tools are available to help you perform RSABE analysis?
The Phoenix WinNonlin software provides a BE module to perform average bioequivalence, but this module is not currently designed for a complete RSABE analysis. However, RSABE can be performed in Phoenix WinNonlin using reusable template projects and workflows for both EMEA and FDA approaches. I developed these templates with my Certara colleague, Linda Hughes, and Helmut Schütz from BEBAC. We first presented these results as a poster at the 2013 AAPS annual meeting. These templates were developed in accordance to the RSABE methodology suggested in the FDA “Draft Guidance on Progesterone (Apr 2010; Revised Feb 2011)” and the widening BE limits methodology for highly variable drugs outlined in the EMEA “Guideline on the Investigation of Bioequivalence (2010)”.
These Phoenix template projects require minimal user input to be used with any data set from a replicated 3-period or 4-period crossover design. For the FDA workflow template, we’ve shown that the Phoenix results match SAS® results obtained by using the SAS code supplied by the FDA for progesterone. For more information, you can read the full FDA draft guidance.
The Phoenix RSABE templates can be downloaded for free when you contact us. Disclaimer: these templates have been tested by the authors but did not follow the formal testing and validation procedures for Phoenix software development.
The FDA invites Certara to teach the use of Phoenix RSABE templates
Determining bioequivalence for HV drugs is a hot topic these days. In fact, last month, the FDA invited my colleague, Chris Mehl, to come and teach them how to use Phoenix templates to perform RSABE. I’ve included Chris’s slides to give you a deeper dive into this topic.
Leverage Phoenix RSABE templates to support approvals of HV drugs
While many drugs are highly variable, RSABE is a method for demonstrating BE for regulatory agencies without spending excessive time and money on large sample sizes. Phoenix templates make performing RSABE in WinNonlin much easier and faster than performing manual coding. If you’d like to see me demonstrate using Phoenix WinNonlin 6.3 RSABE templates, please watch my webinar. Note that executing workflows in Phoenix WinNonlin 6.4 is even simpler and quicker!
Are you working with HV drugs? What approaches are you using to show BE? Let me know in the comments section!
Learn more about model-based drug development for generic products
Demonstrating bioequivalence of generic products to the branded product is often a straight-forward process based on the experience of the formulation team. As innovators plan ahead to protect their product lines, however, they have made this task more difficult. Whether by utilizing unique and patented delivery technology, or by modifying the dissolution and absorption characteristics of the active ingredient through novel formulation, the innovator may confound the efforts of generic formulators.
Read our white paper to learn how these challenges may be overcome by using a model-based drug development approach.