Customer Requirement
A pharmaceutical company specializing in generic drug development was in the process of seeking market approval for a generic product. During the regulatory review process, the benefit-risk department of the regulatory authority raised a query related to the statistical analysis of the submitted bioequivalence (BE) study data. The company required a comprehensive and scientifically sound justification to resolve the regulatory query and avoid a potential rejection of the application.
Problem Statement
The regulatory authority reanalyzed the pharmacokinetic (PK) data submitted in the BE study and found that the ratio of AUC (0-t) / AUC (0-∞) was less than 80% in the majority of the study volunteers. A detailed justification was requested to address this concern.
The Clinical Research Organization (CRO) attempted to address the issue using the reference SmPC, which indicated that fasted administration of the drug resulted in approximately 60% exposure (AUClast) compared to administration in a fed state. However, this justification, based solely on the reference product information, was not accepted by the authority. A more robust and statistically grounded explanation was demanded.
Key Objective
To develop a comprehensive, evidence-based justification for the AUC (0-t) / AUC (0-∞) ratio findings that satisfied the regulatory authority’s requirements and ensured the continued progress of the market approval process.
DDReg Solutions & Processes Adopted
DDReg’s dedicated medical writing team thoroughly reviewed the pharmacokinetic data provided in Module 5 of the submission. The team identified that the explanation offered by the CRO lacked clarity and depth.
Upon deeper analysis, DDReg discovered that the drug in question is known to exhibit high variability in the terminal elimination phase—an attribute also observed in the innovator’s bioavailability studies. According to the study protocol, T1/2 and AUCinf values were not estimated for subjects whose plasma concentration-time profiles did not define a terminal linear phase. This resulted in missing PK parameters, which skewed the AUC (0-t) / AUC (0-∞) ratio calculation.
DDReg’s team recalculated the ratios after excluding subjects with missing AUCinf values. It was found that only 6 subjects in each of the test and reference groups had AUC0-t/AUC0-inf values below 80%, accounting for fewer than 20% of the total observations. This statistical insight and the inherent high variability of the molecule formed the basis of the robust justification submitted to the authority.
Business Impact
The justification developed and submitted by DDReg led to the successful resolution of the regulatory query. Addressing this unresolved query was critical, as it could have led to the rejection of the product’s market authorization application. The intervention ensured the product remained on track for approval and highlighted DDReg’s capability in resolving complex regulatory challenges with data-driven insights.
Key Learning
To enhance the statistical defensibility of regulatory submissions, it is crucial to verify not only the availability of pharmacokinetic data but also the completeness of required calculations. Early identification of data gaps and their implications on statistical outcomes is essential in minimizing regulatory setbacks.
Read more case studies from DDReg experts here: Project Management to Overcome Leadership & Timeline Delays