Purpose: During the development of combination biological products to be administered as subcutaneous (SC) injection, PFS and AI could be introduced at the same time but frequently AI follows the PFS. Demonstrating PK comparability between PFS and AI presentations is critical for the approval of AI presentation because it provides the scientific bridge for the extrapolation from PFS to AI presentation. Our study was designed to assess the current practice in support of regulatory review and approval of AI presentation, to identify potential factors, e.g., the device design parameters and/or clinical study design elements, that may affect the PK results, and to improve clarity on how to support the presentation change between PFS and AI.
Methods: We first identified 17 approved combination biological products from the FDA database which submitted PK comparability studies for PFS and AI presentations. Then we conducted a systematic review of the device designs and the PK comparability studies on these products. As for the device design, we focused on the device parameters that are currently evaluated by FDA, such as syringe category, delivered volume, needle gauge and length, break-loose force, glide force, actuation force, injection depth and injection time. In terms of PK comparability study, we extracted the study specific information, including sample size, study population (healthy subjects vs. patients) and demographics, trial type (crossover vs. parallel), dose regimen (single dose vs. multiple dose), injection sites (abdomen, thigh, or arm), primary endpoint, and statistical analysis methodology (ANOVA vs. ANCOVA). PK comparability results were recorded for each study. The collected data was used to evaluate potential correlations among device parameters, study design parameters, and the PK endpoints. We further explored the effects of injection sites and body-weight or body mass index (BMI) on the PK endpoints.
Results: Among the 17 combination biological products assessed, all needles have the length of 0.5 inch, and needle gauges are either 27 or 29G. However, the documentations for the break-loose force, glide force, actuation force as well as injection time are based on the maximum value (upper limit) for device specification purpose, instead of the measurements from the actual batch tests. The lack of actual measurements on the device parameters makes it impossible to evaluate any potential correlation with the PK results. Meanwhile, more than 2-fold differences on injection depth were observed among the AI devices, with maximum injection depth as 10.5 mm, which poses the risk of intramuscular injection depending on the depth of the subject’s subcutaneous layer. On the other hand, the PK comparability study design also varied. Eight of the 17 studies involve single dose, parallel study design conducted on healthy subjects, and the sample size ranges roughly from 10 to 80 in each stratified treatment group. Abdomen injection was tested in all the PK comparability studies, while seven products were also tested on other alternative injection sites: thigh and /or upper arm. Cmax, AUC0-t, and AUC0-inf have been used as the PK primary endpoints in all the single dose trials, while Css,min was used as the PK primary endpoint for one multiple dose study. The statistical analysis for PK comparability was either ANOVA or ANCOVA with body weight as the covariate. It is worth mentioning that, due to limitation of the database, our study has selection bias because most of these combination products received approval for both PFS and AI presentations. Almost all the PK comparability tests reached the pre-specified bioequivalence criteria, which means the 90% confidence interval (CI) of the geometric mean ratio to be within 80%-125%; only 2 cases had 90% CIs slightly out of the range. In our systematic analyses of study data among different injection sites, and among different body weights/BMIs, we observed inconsistency not only on the effects of injection sites on PK endpoints, but also on the correlations between PK endpoints and body weight/BMI.
Conclusion: Our database revealed variable practices existed on AI device design as well as the clinical study design for evaluating PK comparability between PFS and AI presentations of biological products, which introduced variabilities in the PK endpoints. Among the parameters studied, injection depth of AI and SC injection site may be worth further investigation to clarify the mechanisms of their effects on the PK comparability and to inform how to support the changes between the PFS and AI presentations of biological products.
Jacqueline Gertz– US Food and Drug Administration
Alan Stevens– US Food and Drug Administration
Jie Wang– US Food and Drug Administration
Ping Ji– Pharmacologist, US Food and Drug Administration, Silver Spring, Maryland
Jeffry Florian– US Food and Drug Administration
Yow-Ming Wang– Co-Director of Therapeutics Biologics Program and Master Reviewer, US Food and Drug Administration, Silver Spring, Maryland