PI-108 - BALANCING BROADENED ELIGIBILITY CRITERIA AND NECESSARY RESTRICTIONS IN ONCOLOGY CLINICAL STUDIES FOR ORGAN IMPAIRMENT

S. Drescher¹, K. Collins², R. Mittapalli³; ¹Pfizer, Inc., La Jolla, CA, USA, ²Pfizer, La Jolla, CA, USA, ³Pfizer, San Diego, CA, USA.

Background: While eligibility criteria must be restrictive during early clinical drug development due to limited clinical information, overly restrictive criteria carried through development can limit patient access and slow recruitment. The aim of this study was to evaluate the current inclusion/exclusion criteria (I/EC) of renal impairment (RI) or hepatic impairment (HI) related to clinical oncology (oncol.) studies, assess the impact of RI/HI on dose modification for FDA label, and identify potential areas for improvement in harmonizing I/E criteria for oncol. protocols

Methods: We summarized the regulatory guidance on I/EC for RI/HI related to clinical pharmacology and reviewed relevant literature. Additionally, we collected FDA feedback on I/EC during IND submission for Pfizer FIP oncol. programs. Lastly to understand the impact on the label language, we conducted a meta-analysis to understand the impact of RI/HI on dose adjustment. FDA oncol. approvals between March 2017 and March 2022 were reviewed, focusing on the primary excretion pathway, dose-proportionality, plasma protein binding, reported exposure of normal and RI/HI, and exposure-response (ER) relationship for safety and efficacy.

Results: IND submissions for 21 Pfizer compounds were reviewed for renal and hepatic I/EC. For RI, all but 2 IND submissions proposed or were requested by FDA for CrCl inclusion of ≥50 or 60 mL/min. FDA requested reduction in CrCl inclusion from ≥60 to 30 mL/min for only 1 biologic during IND. For HI, AST/ALT and total bilirubin inclusion were standard at ≥2.5x and ≥1.5x ULN, respectively.
The literature reported no differences in response rates and safety between non-restrictive and restrictive protocol for RI, but the median accrual time was significantly shorter for non-restrictive protocols.
Out of the 68 FDA oncol. approvals an organ impairment study was conducted for 35% for RI and 71% for HI. 15% of the compounds had dose adjustments for RI, 28% compounds had dose adjustments for HI.

Conclusion: I/E at the time of IND are often poorly justified and remain unchanged during development. With evolving data and experience and if key considerations are met regarding the modality, route of excretion, and preclinical safety of a compound, loosening of RI/HI eligibility criteria may be supported from early- to late-phase development.