Objectives:
The response of patients to drugs can be affected by intrinsic/extrinsic factors. Genetic diversity is such factor that can lead to a different response. For example, genetic differences in CYP450 may result in different genotypes leading to a range of phenotypes. The frequency distribution of genetic polymorphs may differ between populations, which however, is identified only after a large number of patients have been treated, and may be mitigated with pharmacogenetic (PG) assessment. Nevertheless some Asian regulators require Phase 1 (Ph1) data in Asians before joining global Ph2/3 trials. Here, we discuss inherent limitations of Ph1 ethnic sensitivity studies (ESS) to identify potential interethnic differences.
Methods:
Internal data was collected from NDAs submitted/approved in Japan and China between 2010 and 2018.
Results and discussions:
There were nearly 25 NDAs submitted in Japan and China. No interethnic differences in safety or PK profiles were found in any of the Ph1 studies conducted in Japanese and/or Chinese subjects for these submissions, apart from eltrombopag. This suggests that the Ph1 ESS data were not of marked value in identifying the need for dose adjustment for NDAs submitted in both Japan and China. Therefore, we propose a new drug development paradigm: if relevant safety, PK, and PG data are available from the original Ph1 study population, it might be possible to extrapolate those data to Asian for their inclusion in Ph2/3 trials without a separate ESS, especially for the following drugs: (1) therapeutic biologics; (2) drugs with no systemic activity; (3) drugs predominantly metabolized by CYP enzymes with known polymorphisms of no functional relevance; (4) drugs predominantly metabolized by functionally polymorphic CYP enzymes with PG collected in Ph2/3 studies; and (5) drugs for an orphan indication.
Conclusions:
This proposed approach could help to expedite drug development in Asia while still addressing regulatory requirements.