Information Request Letter, June 21, 2013- Eloctate

DEPARTMENT OF HEALTH & HUMAN SERVICES  

Public Health Service

Food and Drug Administration
 1401 Rockville Pike
 Rockville, MD 20852-1448


Our Reference: BL 125487/0

Biogen Idec Inc.
 Attention: Ms. Debra Segal
 June 21, 2013
 Sent by email

Dear Ms. Segal:

We are reviewing your March 7, 2013 biologics license application (BLA) for Antihemophilic Factor (Recombinant), Fc Fusion protein. We are providing the following comments:

1. We recognize that the submitted population PK (PopPK) analyses and subsequent stochastic simulations for your recombinant coagulation factor product rFVIIIFc can be supportive for recommending dosing regimens for the patient populations under consideration. However, as noted below, we have found deficiencies in your PopPK analysis that need to be taken into consideration for future analyses, but not for the current submission. Specifically:

Pharmacometric Study Report “Population PK analysis of rFVIIIFc data”. Report Number: CPP-12-026-BIIB031

In Section 4.3.3: Population Analysis Methodology (p.20) it is stated: “Weight (WT) and Study (STUD), although technically assumed covariates, are considered by some modelers as intrinsic to the basic model as their inclusion can be postulated a priori.”

Please note that in a population PK (PopPK) analysis a base model should be defined as a PK model without any covariate. The resulting report of the base model analysis should include the structural parameter estimates (and precision) as well as the estimated between-subject variability (BSV) (and precision). Identifying covariates is important in explaining BSV and thus increasing the predictive value of the underlying model. However, it is essential to contrast the BSVs of the structural parameters estimated in the final PopPK model (including covariates) with the BSVs estimated in the base model (without covariates).

In Section 5.2 Base Model Development (p.24) it is stated: “Adding IIV terms on Q (model F82fin01) or V2 (model F82fin02) was rejected.”

Please note that all structural parameters in the PopPK model should be estimated together with all their respective BSVs. It is not acceptable to subjectively exclude a BSV estimate because it is considered “too large”. Omitting random variability of the population parameter estimate would lead in subsequent stochastic simulations to be biased and optimistic statistical confidence intervals, rendering the predictions less informative.
 Note that depending on study design and data sampling schedule, it is not uncommon for a 2-compartment model that the estimated BSV for the intercompartmental clearance (Q) is 80% or higher.

If you have any questions, please contact me at (301) 827-6116.

Sincerely,



Leigh Pracht
 Regulatory Project Manager
 FDA/CBER/OBRR/DBA/RPMB
