Comment from Certara Inc.
AnonymousSupportIndividual
Summary: The commenter supports the draft guidance but argues that it is disproportionately weighted toward in vitro systems. They request that the document be balanced to include more specific mentions and technical details regarding in silico approaches and secondary pharmacology profiling.
We welcome this draft guidance document, which helps steer the pharmaceutical industry into an exciting new era. However, the guidance document is very heavily weighted towards advanced in vitro systems with little mention of in silico approaches (bioinformatics;QSAR; QSTR; molecular docking; biological systems modeling; qAOPs; off-target PKPD; PBPK; etc.). There are only 3 mentions of ‘in silico’, with the last being on line 122 of a 288-line document. Examples with technical details are provided of advanced in vitro test systems from lines 113 to 249, with no equivalent mention of in silico modeling. In the excellent and informative review of NAMs in regulatory submissions to CDER over the past 15 years (Dao & Sadrieh, 2026; PMID: 41360337), the two main categories (in silico and in vitro), were roughly equally represented (in silico 49%; in vitro 44%). Therefore, could the guidance document be balanced-up to reflect this? There is also no mention of secondary pharmacology as a NAM. Secondary pharmacology profiling, and its interpretation in terms of off-target safety assessment, represents a significant NAM activity during preclinical safety assessment. The last 15 years has seen a significant increase in the number of published articles focusing on the value of secondary pharmacology in predicting off-target safety, including 5 publications by FDA authors. Analysis of the relationship between off-target Ki and unbound plasma concentration is predictive of off-target pharmacodynamics (Redfern et al., 2025; PMID: 39577752). Secondary pharmacology should therefore at least be mentioned/listed.