Clinical dose–response for a broad set of biological products: A model-based meta-analysis

Characterizing clinical dose–response is a critical step in drug development. Uncertainty in the dose–response model when planning a dose-ranging study can often undermine efficiency in both the design and analysis of the trial. Results of a previous meta-analysis on a portfolio of small molecule co...

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Bibliographic Details
Published in:Statistical methods in medical research 2018-09, Vol.27 (9), p.2694-2721
Main Authors: Wu, Joseph, Banerjee, Anindita, Jin, Bo, Menon, Sandeep M, Martin, Steven W, Heatherington, Anne C
Format: Article
Language:English
Subjects:
Analysis
Bayesian analysis
Biological effects
Biological products
Dosage
Drug development
Efficacy
Mathematical models
Meta-analysis
Occupancy
Parameters
Uncertainty
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Summary:Characterizing clinical dose–response is a critical step in drug development. Uncertainty in the dose–response model when planning a dose-ranging study can often undermine efficiency in both the design and analysis of the trial. Results of a previous meta-analysis on a portfolio of small molecule compounds from a large pharmaceutical company demonstrated a consistent dose–response relationship that was well described by the maximal effect model. Biologics are different from small molecules due to their large molecular sizes and their potential to induce immunogenicity. A model-based meta-analysis was conducted on the clinical efficacy of 71 distinct biologics evaluated in 91 placebo-controlled dose–response studies published between 1995 and 2014. The maximal effect model, arising from receptor occupancy theory, described the clinical dose–response data for the majority of the biologics (81.7%, n = 58). Five biologics (7%) with data showing non-monotonic trend assuming the maximal effect model were identified and discussed. A Bayesian model-based hierarchical approach using different joint specifications of prior densities for the maximal effect model parameters was used to meta-analyze the whole set of biologics excluding these five biologics (n = 66). Posterior predictive distributions of the maximal effect model parameters were reported and they could be used to aid the design of future dose-ranging studies. Compared to the meta-analysis of small molecules, the combination of fewer doses, narrower dosing ranges, and small sample sizes further limited the information available to estimate clinical dose–response among biologics.
ISSN:0962-2802
1477-0334
DOI:10.1177/0962280216684528