Legacy hERG study data in contemporary integrated risk assessments - mitigating the risk of protocol and positive control article differences.

Testing new molecules against the hERG potassium channel has been a routine component of secondary pharmacology assessments for more than a quarter of a century. In 2005, the ICH S7B guidance required a GLP hERG study prior to first administration of new chemical entities to man. In 2022, the ICH S7B Q&As introduced some 'best practice' recommendations for the hERG assessment. A required component of a QTc integrated risk assessment is an evaluation of how well the hERG assessment met the 'best practice' recommendations. For studies conducted under the 2005 ICH S7B guidance, it is unclear how to assess the differences between study protocols. Many sponsors had been conducting the GLP hERG assay in a manner which was largely compliant with these recommendations but differed subtly in the recording temperature, the voltage-clamp protocol employed and/or in the positive control used in the assay ('Legacy Protocol'). This led many sponsors to consider repeating their earlier hERG assessment using the 'best practice' ('Revised Protocol') recommendations. The current analyses sought to examine whether the differences in practice warranted retesting the compounds or could dispel a concern that prior practice had been less sensitive. The three key positive control articles, dofetilide, moxifloxacin and ondansetron were compared under the 'Legacy Protocol' and best practice 'Revised Protocol'. Furthermore, two prior positive control articles, terfenadine and cisapride, were tested under both protocols. Terfenadine data under the 'Legacy Protocol' were available from separate studies (n = 6) dating from 2003 to 2025. Terfenadine was also tested in four studies using the 'Revised Protocol' in 2023. In addition, the hERG inhibition data for 3627 single concentration positive control article tests with 60 nM terfenadine from studies conducted from 2002 to 2018 were collated. There was no difference for the 3 positive control articles tested under the two different protocols for pooled hERG safety margin. Similarly, the pooled hERG IC values for terfenadine under the two protocols were not different, although the variability in hERG potency was greater under the 'Revised Protocol'. The inhibition of hERG current for 60 nM terfenadine in the 3627 historical examples was also consistent with predictions based on the hERG IC and Hill slope data under the two protocols. Based on the similarity between results collected under 'Legacy' and 'Revised' protocols we conclude that if the 'Legacy Protocol' has been used and the positive control examined was 60 nM terfenadine, there appears to be no need to repeat the hERG assessment.