Animal extrapolation in preclinical studies: An analysis of the tragic case of TGN1412. (February 2017)

• Record Type: Journal Article
• Authors: Lemoine, Maël
• Is Part Of: Studies in history and philosophy of science. Volume 61(2017)
• Page Start: 35
• Page End: 45
• Publication Date: 2017-02
• Subjects: Animal extrapolation -- Preclinical studies -- Experimental organism -- Prediction -- Mechanistic thinking; Ab Antibody -- ADCC Antibody-Dependent Cell-Mediated Cytotoxicity -- ADME Absorption, Distribution, Metabolism, Excretion -- CDC Complement-Dependent Cytotoxicity -- CT Clinical Trial -- CT1 Phase I clinical trial -- CRS Cytokine Release Syndrome -- Fc Fragment Crystallizable region -- FIM First-in-man -- LOAEL Low Observable Adverse Effect Level -- LOEL Low Observable Effect Level -- MAb Monoclonal Antibody -- MABEL Minimal Anticipated Biological Effect Level -- NOAEL No Observable Adverse Effect Level -- NOEL No Observable Effect Level -- PCS Preclinical Studies -- Treg Cells regulatory T Cells -- TCR T Cell Receptor; Biology -- Periodicals; Natural history -- Periodicals; Biology -- Philosophy -- Periodicals; Medicine -- History -- Periodicals; Medicine -- Philosophy -- Periodicals; Bioethics -- Periodicals; Biologie -- Histoire -- Périodiques; Biologie -- Philosophie -- Périodiques; Sciences de la santé -- Histoire -- Périodiques; Sciences de la santé -- Philosophie -- Périodiques; Médecine -- Histoire -- Périodiques; Médecine -- Philosophie -- Périodiques; 570.1
• DOI: 10.1016/j.shpsc.2016.12.004
• Languages: English
• ISSNs: 1369-8486

Abstract

Abstract: According to the received view, the transportation view, animal extrapolation consists in inductive prediction of the outcome of a mechanism in a target, based on an analogical mechanism in a model. Through an analysis of the failure of preclinical studies of TGN1412, an innovative drug, to predict the tragic consequences of its first-in-man trial in 2006, the received view is challenged by a proposed view of animal extrapolation, the chimera view . According to this view, animal extrapolation is based on a hypothesis about how human organisms work, supported by the amalgamation of results drawn from various experimental organisms, and only predicting the 'predictive grid', that is, a global framework of the effects to be expected. Highlights: Animal extrapolation does not always consist in an inductive, analogical argument based on the observation of mechanisms. It often relies on the hypothesis of a mechanism with piecemeal support of various animal models, i.e., an amalgamation of evidence. It is reliable at predicting kinds of effects to be expected, but not at predicting their magnitude.