title: In vitro versus in vivo concordance: a case study of the replacement of an animal potency test with an immunochemical assay.
abstract: Early in its development, the potency of Merck's recombinant hepatitis B vaccine, RECOMBIVAX HB, was monitored using an assay performed in mice. A specification was determined to be the lowest potency which induced acceptable response in clinical trials. As a post-licensing commitment, Merck was asked to replace its mouse potency assay with an in vitro procedure for product release in the US market. Early studies with a commercial enzyme immunoassay (EIA) yielded highly variable results. That assay, combined with a sample pretreatment step, proved more dependable and predictive of potency in the mouse assay. Based on measurements made on manufactured materials, combined with experiments contrived to yield a wide range of reactivity in the two assays, concordance was established between the EIA and the mouse potency assay. This concordance was used to calibrate a specification for the in vitro assay that is predictive of a satisfactory response in vivo. Data from clinical trials established a correspondence between human immunogenicity and these potency markers.
authors.affiliation: Merck Research Laboratories, West Point, PA 19486, USA. tim_schofield@merck.com
authors.forename: T
authors.initials: T
authors.lastname: Schofield
mesh_terms: D000826:Animal Testing Alternatives; D000818:Animals; D002986:Clinical Trials as Topic; D017325:Hepatitis B Vaccines / Q000276:immunology / Q000378:metabolism / Q000592:standards*; D006801:Humans; D007120:Immunochemistry; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D011786:Quality Control; D015203:Reproducibility of Results; D013223:Statistics as Topic; D014614:Vaccines, Synthetic / Q000276:immunology / Q000378:metabolism / Q000592:standards*
chemical_list: D017325:Hepatitis B Vaccines; C075655:Recombivax HB; D014614:Vaccines, Synthetic