Defining Therapeutic Window for Viral Vectors: A Statistical Framework to Improve Consistency in Assigning Product Dose Values

by Nancy Sajjadi and Janice D. Callahan
Volume 19, Open Access (Revised Aug 2023)

NOTE: Page 7 of this article has been revised to correct an error in the original article which stated that "..the probability of failing a lot when it actually is not equivalent, becomes 1-2*α." The correct equation, 1-α, has replaced the errant one and a single sentence following it was added to further clarify this concept.

ABSTRACT: Pre-clinical and clinical trials conducted to establish the minimum effective dose and the maximum tolerated dose of a viral vector assume that the assigned dose values are comparable across studies. Toxicity has been associated with high dose administration of both adenovirus and adeno-associated virus-based vectors, and increased attention must be paid to assays used to measure dose. High assay variability can be mitigated by replication and the reporting of a mean value for product lot release. The establishment of a dose specification and a testing strategy must take into account the risk of errant quality control decisions. This can be accomplished by linking assay qualification information to measurement uncertainty through a statistical framework. By adopting an equivalence approach, the risk of releasing lots with unacceptably high or low dose values is minimized by reducing measurement uncertainty. This article provides a worked-through example to introduce applicable statistical concepts and the equations necessary to facilitate their implementation in the field.

Sajjadi N, Callahan J. Defining therapeutic window for viral vectors: A statistical framework to improve consistency in assigning product dose values. BioProcess J, 2020; 19.

Originally posted online October 25, 2020. Revised article posted online August 23, 2023.