Pharmaceutical Industry Perspectives on Exposure-Response Confounding in Large Molecule Therapeutics: Results From an...

Exposure-response (ER) analyses assessing the efficacy of large molecule therapeutics are often susceptible to confounding, where associations between drug exposure and patient disease severity can obscure true ER signals and complicate dose selection. To better understand the pharmaceutical industry perspectives on this challenge, the IQ consortium conducted a comprehensive survey targeting clinical pharmacologists, pharmacometricians, and statisticians. The survey, completed by 125 individuals from 23 pharmaceutical companies, aimed to assess awareness, perceived prevalence, mitigation strategies, and the overall role of ER analyses in the context of confounding. Results revealed strong industry awareness, with 88.0% of respondents acknowledging the relevance of ER confounding. However, uncertainty regarding its pervasiveness persists, particularly in non-oncology settings (31.2% unsure). A consensus emerged on the value of dose-ranging study designs as an effective mitigation strategy (81.6% agreement). In contrast, the use of advanced statistical methods for causal inference is inconsistent (45.6% usage), and confidence in their reliability is mixed, with 32.8% of respondents expressing uncertainty and most others rating them only moderate or somewhat reliable. While the majority agreed that confounded ER analyses should be interpreted with caution (79.2%), opinions diverged regarding their value in decision-making when dose-ranging data is insufficient. This uncertainty, coupled with a recognized need for additional alignment with health authorities, led to a call for best-practice guidance (92.8% view as valuable). Overall, the survey findings highlight a need for an industry-wide common approach and the development of clear frameworks to manage and interpret ER confounding for large molecule therapeutics.