title: Development of the ICH guidelines for immunotoxicology evaluation of pharmaceuticals using a survey of industry practices.
abstract: An anonymous survey of pharmaceutical industry practices for immunotoxicology evaluation was conducted. This was in support of the development of the guideline on the preclinical evaluation of unintended modulation of the immune system for the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. The survey was conducted in two phases in 2003 and 2004. A total of 64 responses were received of which 45 were included in the formal evaluation. The remaining compounds were excluded because they were cytotoxic anti-neoplastic drugs (N = 7), or due to insufficient information (N = 12). The purpose of the survey was to gather data on the correlation between routine toxicology studies (RTS) and additional immunotoxicological studies (AIS). The results of the survey were evaluated by the Expert Working Group (EWG) and classified as to positive or negative findings in RTS and AIS. The results of the survey showed that for 27 of 45 compounds (60%), the RTS and AIS endpoints were in agreement. In 12 of 45 cases (27%), the RTS endpoints showed immune modulation not observed in the AIS assays. Finally for 6 of 45 drugs (13%) a response was seen with the AIS methods where no significant effect was observed in the RTS endpoints. Length of dosing and the number of tests evaluated were similar in all groups. The groups where RTS detected signs of immunosuppression were more likely to have been dosed at or above MTD. This data contributed to the consensus in the EWG that routine immune function testing as an initial screen for all new drugs is not required. Instead, a weight-of-evidence approach including RTS and other causes for concern is recommended to identify the need for additional immunotoxicity studies.
authors.affiliation: Division of Applied Pharmacology Research, CDER, U.S. FDA, Silver Spring, Maryland 20993-0002, USA. James.Weaver@fda.hhs.gov
authors.forename: James L
authors.initials: JL
authors.lastname: Weaver
authors.forename: Naohisa
authors.initials: N
authors.lastname: Tsutsui
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hisada
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Vidal
authors.forename: Steven
authors.initials: S
authors.lastname: Spanhaak
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Sawada
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Hastings
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: van der Laan
authors.forename: Henk
authors.initials: H
authors.lastname: van Loveren
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Kawabata
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sims
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Durham
authors.forename: Osamu
authors.initials: O
authors.lastname: Fueki
authors.forename: Tibor I
authors.initials: TI
authors.lastname: Matula
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kusunoki
authors.forename: Peter
authors.initials: P
authors.lastname: Ulrich
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Nakamura