Several easy-to-use Phoenix templates, that require minimum user input, have been developed to address a series of BE regulatory guidances. In this article, we discuss the purpose of each Phoenix workflow template, show you how to download templates, and teach you and how to use them.
Template Downloads
Disclaimer: These Phoenix templates are provided resources to support your workflow; however, they have not undergone formal software validation or comprehensive quality review. Users are responsible for verifying the appropriateness of the template for their specific use case and for validating all results generated. Use of this template is at your own risk.
Assessing Reference Scaled Average Bioequivalence (RSABE) for Highly Variable Drugs (HVD) - FDA + EMA
RSABE Introduction
Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater (σWR > 0.294 )
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.
To avoid unnecessary human testing, the US Food and Drug Administration's Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. 1
1 Reference: Bioequivalence Recommendations for Specific Products, Progesterone, revised 2/2011
How to use the FDA RSABE project template with a Full Replicate Design
How to use the FDA RSABE project template with a Partial Replicate Design
Assessing Reference Scaled Average Bioequivalence (RSABE) for Narrow Therapeutic Index Drugs (NTID) - FDA
Please ensure you replace any earlier versions you may have saved with the updated file (provided August 2025). Two versions are provided: Phoenix 8.3.5 and Phoenix 8.6 (utilizing the FINV function).
Disclaimer: These Phoenix templates are provided resources to support your workflow; however, they have not undergone formal software validation or comprehensive quality review. Users are responsible for verifying the appropriateness of the template for their specific use case and for validating all results generated. Use of this template is at your own risk.
Drugs with a narrow therapeutic index (NTIDs) have a narrow range between therapeutic and toxic dose levels. Traditional average bioequivalence (ABE) methodology may be unacceptable for NTIDs, because small differences (e.g., 20%) in drug exposure may lead to serious therapeutic failures and/or adverse drug reactions. The usual average ABE limits of 80.00 to 125.00% are not considered sufficient for NTIDs, and several regulatory agencies have narrowed the limits for bioequivalence, typically to 90.00 to 111.11%.
A Phoenix template is provided to do RSABE for NTIDs using Phoenix WinNonlin, per the FDA guidance for Warfarin Sodium:
Instructions to use the template project are embedded in a pdf document inside the template project.
The following poster shows how to do RSABE for NTIDs in Phoenix WinNonlin, and was presented at the AAPS 2017 conference in San Diego.
Assessing Bioequivalence to Methylphenidate Hydrochloride (Concerta) - FDA
BE Analysis to Methylphenidate Hydrochloride (Concerta)
Download the Phoenix Template (Version 8.3.3)
Disclaimer: These Phoenix templates are provided resources to support your workflow; however, they have not undergone formal software validation or comprehensive quality review. Users are responsible for verifying the appropriateness of the template for their specific use case and for validating all results generated. Use of this template is at your own risk.
Methylphenidate Hydrochloride (Concerta®) is approved as a multiphasic modified-release formulation, designed to achieve both rapid onset of activity and sustained activity with a duration of 12 hours. Concerta is prescribed to school children for attention deficit hyperactivity disorder (ADHD). The FDA guidance for Methylphenidate Hydrochloride recommends that partial area under the curve (pAUC) metrics are calculated in addition to the traditional metrics (Cmax and AUC0-∞) to ensure that a generic formulation (test) is therapeutically equivalent to Concerta® (reference). These additional pAUC metrics are intended to better characterize systemic exposure responsible for the early onset of response, for sustaining the response in the middle of the once-daily dosing interval, and for maintenance of the response in late stage of the once-daily dosing interval. The guidance requires establishing average bioequivalence by calculating 90% confidence intervals of the geometric mean test/reference (T/R) ratios for the pAUCs, Cmax and AUC0-∞, and showing that they fall within the limits of 80-125%. In addition, to ensure the switchability between Concerta® and generic products, a subject-by-formulation test for each PK metric based on individual bioequivalence methods is recommended. Phoenix® WinNonlin® templates can be used to guarantee standardization and accuracy of the calculations and statistical analysis needed to show bioequivalence for generic products and Concerta®.
Certara has developed a template project to do BE Analysis using Phoenix WinNonlin, per the FDA guidance for Methyphenidate Hydrochloride:
Instructions to use the template project are embedded in a pdf document inside the template project.
Assessing ABE and PBE for In Vitro Data of Inhaled Products (Guidance on Budesonide) - FDA
Certara has developed a Phoenix Template Project project to do InVitro PBE Analysis using Phoenix WinNonlin, per the FDA guidance for Budesonide and Cyclosporine
Templates for Phoenix Version 8.4 or Above.
Download Template for In Vitro PBE - This Phoenix Template is associated with AAPS Poster 2023
Download Template for In Vitro PBE for only 1 stage. Please note this template has not been validated.
Disclaimer: These Phoenix templates are provided resources to support your workflow; however, they have not undergone formal software validation or comprehensive quality review. Users are responsible for verifying the appropriateness of the template for their specific use case and for validating all results generated. Use of this template is at your own risk.
Previous Templates for Phoenix Version 8.3.3 - Associated with Nov2021 Webinar below
Recording of Webinar on ABE and PBE for InVitro Data of Inhaled Products (by Dr. Cardot and Dr. Radhakrishnan):
What can you achieve with this Phoenix templates?
In Vitro PBE developed based on US FDA Guidelines and nasal and inhaled products
What is not available?
Conventional PBE – using D10, D50, D90 &Span
Earth mover’s distance (EMD)
Instructions to use the template project are embedded in a pdf document inside the template project.
Disclaimer: These templates has been tested by the authors but it has not followed Certara Software Development validation process.