(T0930-11-64) Cost-Effective Strategy - An Innovative Approach Assessing the Drifting Bioavailability of Fixed-Dose Combination Formulations

Purpose: The development of generic fixed-dose combination (FDC) has seized increasing industry interest due to its advantages in disease management, patient compliance, and market benefits. In general, for a generic FDC submission, the innovator has established the first bridge between FDC and co-administration of mono-components (mono-components), and the generic sponsor only demonstrates the second bioequivalence (BE) bridge between generic and innovator FDCs. However, these two BE bridges increase the risk of bioavailability drifting from original mono-components to generic FDC and regulatory agencies can require evidence to prove the absence of “drifting” bioavailability. Determining this phenomenon by a direct BE study between a generic FDC with the combination of medicinal products poses complicated issues in practice due to multiple comparison bridges, large numbers of FDC strengths, difficulty in securing the right reference listed drug (RLD) for each regulatory agency, discontinued RLDs, and ethical issues of exposing more healthy subjects to unnecessary medication. To substitute direct comparison studies, adjusted indirect comparison (AIC) is the most appropriate and feasible approach which utilizes BE data from published articles to assess their equivalence.¹ This abstract used published data to validate the AIC method and its role in assessing drifting bioavailability, cutting development costs, and shortening the time for generic FDC to market.

Methods: The AIC uses aggregated data (i.e., T/R ratios and CIs) from BE studies to compare the interventions of interest by adjusting the results with a common treatment group, enabling a direct assessment of bioavailability drift between generic FDC and mono-components.^2–4

An AIC analysis was performed with two BE studies: the 1^st BE bridge (the original BE study of innovator FDC vs. co-administration of mono-components, i.e., AB vs. A+B) and the 2^nd bridge (the inherent BE study of generic FDC vs. the innovator FDCs, i.e., A’B’ vs AB).

1^st BE bridge: AB = A+B ⇔ A+B = AB

2^nd BE bridge: A’B’ = AB

AIC result: A’B’ = A+B

To demonstrate the validity of AIC in assessing BE drift, the results of the AIC analysis were subsequently validated with the published direct comparison study, which assessed generic FDC and mono-components.⁵

An example of FDC, Dutasteride/Tamsulosin 0.5/0.4 mg capsule was selected based on published data availability for the first two BE bridges and a direct BE study on the same FDC.⁶ Using the AIC approach, the pairwise, indirect comparisons among 1) AB: Jalyn®/ Duodart®, as the reference FDC, 2) A + B: Avodart® + Flomax®/Omnic® coadministration as the mono-component RLDs and 3) A’B’: Dutasteride/Tamsulosin manufactured by Teva, as the test FDC, were evaluated.

The data used for AIC analysis were obtained from the public assessment reports of the innovator Jalyn® and the generic FDC by TEVA, including the Test/Reference GMRs, 90% confidence intervals (CI), and study design details (e.g., sample size, study condition). AIC results were then compared to the direct BE study between generic FDC by TEVA and mono-components. The tamsulosin RLD used in the AIC and the direct BE study were Omnic® in Europe and Flomax® in the U.S., which have different excipients.⁶

Results: Data used for AIC analysis are summarized in Table 1.

To evaluate the soundness of the AIC approach, the results of AIC and direct BE comparison⁵ between generic Dutasteride/Tamsulosin 0.5/0.4 mg capsules by TEVA and co-administration of Avodart® and Omnic® are compared in Table 2.

Both methods showed that the T/R ratios and CIs of C_max and AUC_t were contained within the acceptance range 80.00% - 125.00%, indicating BE between the generic FDC by TEVA and co-administration of the RLD (Avodart® and Flomax®), eliminating the possibility of bioavailability drift. The consistency between the two results supported the validity of AIC in evaluating BE drift between generic FDC and mono-components.

Figure 2 is a forest plot that compares the results obtained from AIC and a direct BE study, demonstrating the bioavailability of dutasteride and tamsulosin in generic FDC as compared to mono-components. The significant overlapping CIs indicated similarities between the direct BE study and AIC. The non-overlapping CIs, for C_max under fed conditions, raised the possible limitation of the current data manipulation from different studies. Despite having direct BE comparison results to validate the AIC results, study differences such as excipients in the mono RLD for tamsulosin, inter-subject variability, and study conduct could deviate results from the two approaches. Nonetheless, the higher C_max variability of both compounds observed in the fed conditions could increase the variability of the outcome.⁷ Thus, more data pooling of different generics should be conducted to uphold the validity of this useful tool in the future.

Conclusion: Not only is AIC known as an appropriate methodological approach that utilizes available data from the literature to accelerate generic FDC development and support interchangeability between generics effectively, but in this study, it also reinforces the safety and efficacy of generic FDCs by assessing the potential bioavailability drift without additional development cost.

References: 1. Gwaza L. Adjusted Indirect Treatment Comparisons of Bioequivalence Studies.; 2016. https://dspace.library.uu.nl/handle/1874/337474
2. Herranz M, Morales-Alcelay S, Corredera-Hernández MT, et al. Bioequivalence between generic tacrolimus products marketed in Spain by adjusted indirect comparison. Eur J Clin Pharmacol. 2013;69(5):1157-1162. doi:10.1007/s00228-012-1456-6
3. Pejčić Z, Vučićević K, García-Arieta A, Miljković B. Adjusted indirect comparisons to assess bioequivalence between generic clopidogrel products in Serbia. Br J Clin Pharmacol. 2019;85(9):2059-2065. doi:10.1111/bcp.13997
4. Gwaza L, Gordon J, Welink J, et al. Statistical approaches to indirectly compare bioequivalence between generics: A comparison of methodologies employing artemether/lumefantrine 20/120 mg tablets as prequalified by WHO. Eur J Clin Pharmacol. 2012;68(12):1611-1618. doi:10.1007/s00228-012-1396-1
5. S.A. LL. Public Assessment Report Scientific discussion Dutasteride/ Tamsulosin Hard Capsules. Published online 2018:1-12.
6. GSK. Clinical Pharmacology and Biopharmaceutics Review - Dutasteride and Tamsulosin hydrochloride. Published online 2010:1-78.
7. Teva. Public Assessment Report Scientific discussion - Dutasteride/ Tamsulosin hydrochloride Teva. Published online 2019:1-15.


Table 1: Data used for the adjusted indirect comparison.


Table 2: Bioequivalence results of Dutasteride/Tamsulosin 0.5/0.4 mg capsules by TEVA versus co-administration of Avodart® 0.5 mg and Flomax® 0.4 mg capsules using adjusted indirect comparison.


Figure 1: The Test/ Reference ratio and its corresponding 90% confidence interval of Cmax and AUCt for Dutasteride and Tamsulosin using AIC and direct comparison.