FDA-Cangene Meeting Minutes
FDA Teleconference - VariZIG
A teleconference between FDA and Cangene took place on December 3, 2012. The following discussion took place between FDA and Cangene.
FDA: Basil Golding, Iftekhar Mahmood, Carl-Michael Staschen.
Cangene: Christine Hall, Chris Sinclair, Yi Hua, Bojan Drobic, Laura Saward, Steve McGregor, Terry Kraynyk, Reem Rahil Khazen.
FDA requested a teleconference with Cangene to discuss the potency and baseline adjusted PK parameters regarding bioequivalence (study VZ-008 Comparative Bioavailability of VariZIG™ and VZIG™ in Normal Healthy Volunteers). This study was submitted as part of the BLA submission June 29, 2012.
FDA requested clarification and rationale on the different corrections used in study VZ008 (Tables 11-2, 11-3 and 11-4 in the BLA submission). Cangene had the following clarification:
Subject screening tests for the anti-VZV were performed by a local laboratory and the results were confirmed by a central lab. Due to time constraints and near expiry of the comparator product VZIG, subjects had both screening anti-VZV and the confirmatory tests done simultaneously.
The confirmatory test performed by the central laboratory used ----b(4)---------------------------------------------------------- assay while the local lab used the –b(4)---------------------------. As a result, discrepant results were observed between the two laboratory tests. Where discrepant test results were obtained, subject eligibility for enrollment was based on the central lab results.
Prior to dosing, the potency of VariZIG and VZIG was tested by qualified –b(4)------- method, the measured potency for VariZIG was ---b(4)----potent than the VZIG product (-----b(4)-----------------------------. To ensure no un-blinding occurred, subjects were dosed by label claim. To minimize variability between subjects due to weight differences, the study utilized a weight based dosing regimen (12.5 IU/kg). Potency correction was implemented during PK statistical analysis as pre-defined in the statistical analysis plan for study VZ-008.
Pharmacokinetic Study: The study aimed at recruiting anti-VZV negative subjects to observe the pharmacokinetic profile of VariZIG and VZIG in the absence of background anti-VZV levels. A validated ---b(4)------ assay was used for the pharmacokinetic assay which did not correlate to the screening anti-VZV testing. This resulted in numerous enrolled subjects having higher than expected baseline anti-VZV levels. To account for the unexpectedly high baseline anti-VZV concentrations, a baseline correction was implemented for a post-hoc analysis. This post-hoc analysis was performed excluding subjects with extremely high baseline anti-VZV levels > 200 mIU/mL.
• FDA requested the data with post-hoc baseline correction but without the potency correction.
The requested PK data was submitted in BLA 125430- sequence 0013 (response to labeling information request of November 29, 2012).
Additional Discussion points:
Cangene required clarification on some points in the PK section of the Prescribing Information:
• Reporting of clearance as CL/F
• Elimination of half-life: FDA agreed that it can be reported for some subjects
• AUC 0-∞ : Cannot be reported for all subjects, depending if elimination half-life can be calculated
• Cangene proposed one table for PK data excluding the subjects with anti-VZV levels > 200 mIU/mL FDA proposed to add a footnote in the table giving the range of the baseline. Also an explanation of the potency and baseline correction in the text may be added.
Iftekhar Mahmood, Ph. D.
Clinical Pharmacology Reviewer
Division of Hematology
Office of Blood Review & Research