*6.2. Discrepancies*

The discrepancies observed during our evaluation can be categorized into two groups: discrepancies between the information provided by EMA and FDA, and discrepancies between di fferent published articles. Table 1 summarizes the cases where data provided by FDA and EMA data were not congruen<sup>t</sup> in terms of reported OATP-inhibitory properties of TKIs. Specific discrepancies of interest are highlighted below. Authors do acknowledge that reporting an IC50, even when it is relatively low, does not guarantee a significant clinical impact, unless special formulas are implemented, therefore the inconsistencies reported here, address instances where the guidance is not followed and the reported IC50 is not further explored:


However, the FDA guidance on DDI potential states that a drug has the potential to inhibit OATP1B1 or OATP1B3 in vivo if the R-value is >1.1


Some of the potential explanations for these discrepancies are similar to those responsible for the apparent discrepant data between di fferent published articles and are discussed in more detail below. However, some interesting points might explain the inconsistencies in regulatory data, such as the equations used to establish whether a clinical evaluation is indeed necessary for the drug or not. While EMA suggests calculating (R = 1 + Iu,in,max/Ki or IC50) ≥ 1.04, FDA uses a di fferent equation and di fferent cuto ff criteria (R = 1 + Iu,in,max/Ki or IC50) ≥ 1.1). This latter equation has been suggested in the latest FDA draft guidance, although prior versions of this document have proposed alternative criteria for consideration. It has also been suggested recently that, while most of the proposed equations and criteria hold merit, they are di fferent in terms of their potential to ultimately arrive at false positive and false negative predictions. In particular, it has been suggested that the equation applied in the EMA guidance has a lower positive predictive value than the one proposed in the current FDA guidance, which o ffers arguably more dependable predictions [65]. When comparing data from these two regulatory agencies, this aspect should be taken into consideration, along with di fferent manners of data reporting (either with or without calculation of the R-value), and variation in reported IC50 values that could be due to di fferences in the applied methods.

The results of our comparative literature survey also show that there are instances of substantial inconsistency between reports in the published literature as well as between published studies and publicly-available data reported by manufacturers. Since all this collective work is ultimately aimed at improving clinical decision making, it is pertinent to establish an unequivocal, dependable approach to data interpretation. The following are some of the elements that can potentially contribute to the reported inconsistencies:



predominantly through an indirect, kinase-mediated mechanism involving post-translational events that a ffect tyrosine phosphorylation. This suggests that a comprehensive evaluation of TKI-transporter inhibition studies require careful consideration and optimization of preincubation times in order to derive translationally useful DDI predictions.





**Table 2.** *Cont.*


#### **Table 2.** *Cont.*




**Table 2.** *Cont.*

UNK indicates not mentioned in the study/Unknown. NI is not indicated
