title: Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations.
abstract: An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. jvahle@lilly.com
authors.forename: John L
authors.initials: JL
authors.lastname: Vahle
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Finch
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Heidel
authors.forename: David N
authors.initials: DN
authors.lastname: Hovland
authors.forename: Inge
authors.initials: I
authors.lastname: Ivens
authors.forename: Suezanne
authors.initials: S
authors.lastname: Parker
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Ponce
authors.forename: Clifford
authors.initials: C
authors.lastname: Sachs
authors.forename: Ronald
authors.initials: R
authors.lastname: Steigerwalt
authors.forename: Brian
authors.initials: B
authors.lastname: Short
authors.forename: Marque D
authors.initials: MD
authors.lastname: Todd
mesh_terms: D000818:Animals; D001702:Biopharmaceutics / Q000379:methods*; D001709:Biotechnology / Q000379:methods*; D015197:Carcinogenicity Tests / Q000379:methods*; D017277:Drug Approval / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans