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The Use of Total Versus Unbound Exposures for Reporting Safety Margins During Drug Development: An IQ Consortium Analysis of Pharmaceutical Industry Practice
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DOI：10.1016/j.yrtph.2026.106123.png)
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Abstract
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• Most companies follow a standard approach within their organization for safety margin reporting, which is often shaped by perceived regulatory expectations and prevailing industry practices. • Regulatory guidance remains inconsistent—while ICH S7B and M12 support the use of unbound exposure in specific contexts, other guidances like ICH S3A and S5(R3) provide only limited direction, resulting in diverse industry practices. • Companies predominantly report safety margins using total exposure for in vivo studies and unbound exposure for in vitro assays, reflecting distinct methodological and translational considerations. • There is inconsistency across industry regarding the impact of species differences in unbound fraction on safety margin reporting. • Selection of total versus unbound exposure for safety margin calculation should be guided by scientific rationale, translational relevance, regulatory expectations, and the potential impact on patient safety, rather than a fixed threshold or single methodological preference. • Pharma-Health Authority interactions would be welcome to ensure future consistency in reporting safety margins across the pharmaceutical industry.
Keywords:
Total exposure
Unbound exposure
Safety margins
Drug development
Regulatory guidance
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