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P109: Impact of the FDA’s Revised Draft Guidance on Renal Impairment PK Studies – Trends, Challenges, and Solutions

Poster Presenter

Sabina Paglialunga

Director, Scientific Affairs
Celerion
United States

Objectives

In 2020, the FDA updated the draft renal impairment (RI) pharmacokinetics (PK) guidance, impacting study design and sample size. An analysis of RI PK studies conducted before and after the guidance release was performed to address how the industry has responded to these recommendations.

Method

Phase I, industry-sponsored, RI study details were obtained from Clinicaltrials.gov for studies starting Pre (01/01/2018 - 12/31/2019) and Post (01/01/2021 – 12/31/2022) the revised guidance was issued. Studies starting in 2020 were omitted from the analysis due to pandemic related cancellations.

Results

During the two years pre-guidance release, 37 studies were completed. Average study sample size was 28 (14-48) participants with approximately 8 (6-14) patients per cohort. Estimated glomerular filtration rate (eGFR) is applied to categorize renal function from normal to kidney failure for RI PK studies. Approximately one-third (27%) of studies enrolled kidney failure patients (eGFR<15 mL/min and/or on dialysis), while patients with severe (eGFR 15-29 mL/min) and moderate (eGFR 30-59 mL/min) disease represented the majority of cohorts evaluated. Nearly half (51%) of the studies were conducted in the US, with 35% run in the EU and 5% in Asia. The remaining studies were in multiple geographies. The overall time to completion was 9 (1-22) months. Of the studies initiated in the two years post-guidance release, 23 were completed and 33 are ongoing. For completed studies, the average number of subjects per study (28, 12-48) and cohort (8, 6-14) were similar to pre-guidance values yet there was a substantial increase (42%) in studies enrolling kidney failure patients. Interestingly, the number of studies conducted in Asia increased to 17% during this period and the time to completion slightly decreased (8, 1-18 months). For ongoing studies, the average sample size jumped to 33 (12-64) subjects, with 9 (6-16) patients enrolled per cohort. A similar number of studies are enrolling kidney failure patients (42%), however, the estimated study duration longer (11, 5-21 months) than completed studies.

Conclusion

The revised guidance recommends to perform sample size justification based on drug PK variability, which can drive number of patient per cohort to 14 or more. While the updated guidance did not seem to have an immediate impact on sample size, ongoing studies are enrolling 5 more participants than previously. This may extend study duration by several months and potentially delay phase 2/3 study initiation. Most drug sponsors are engaging 2 clinical sites for study conduct. Interestingly, fewer studies are being run in the EU, with drug sponsors opting for Asian sites. In addition, more studies are also seeking to enroll kidney failure patients, either as part of a reduced design or because the drug may be intended for this population. Overall, this analysis can assist drug developers plan their future RI studies, as data can be leveraged to set appropriate study timelines and give insight into clinical site geography, to comply with the revised FDA guidance.