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W 33: A Comparison of Single-Dose Pharmacokinetics Studies in Subjects with Various Degrees of Renal Impairment
Director, Clinical Pharmacology and Regulatory Affairs
Algorithme Pharma Canada
To evaluate and compare the impact of different types of designs on study start-up and reporting activities in renal impairment trials.
Compare conduct and analysis from protocol to results of 2 renal impairment trials. Study F5 was designed as a full renal impairment study while trial M9 was a reduced PK study. Moderate and severe impaired patients were enrolled at a hospital site;mild impaired and normal subjects at the CRO site.
Study F5 was a full PK study in patients with mild, moderate, and severe renal impairment compared to normal subjects. Study M9 was an adaptive trial conducted first in patients with severe renal impairment and subjects with normal renal function using a reduced PK study design. Moderate renal impaired patients were enrolled subsequently based on safety data and substantial changes in drug exposure. Protocols were reviewed by the hospital and CRO investigators and finalized within 13 days for F5 and within 15 days for M9. The average timeline of the studies from submission to approval was 30 days for the hospital IRB, and 10 days for the central IRB. The NOL from Health Canada was issued < 30 days after submission of the CTA for both trials. The First Patient In (FPI) was within 3 weeks of regulatory approvals for study F5, and within 2 weeks for trial M9. The duration of the trial in study F5 was 6 months, while it was 4 months in the reduced design trial M9 (FPI to Last Patient Out (LPO)). Noncompartmental PK analysis was performed and a regression analysis was used to evaluate the relationship between renal function and the PK parameters. If the correlation was significant, an ANOVA was performed. The PK and statistical results were completed 15 days after reception of concentrations values for study F5. In study M9, results were provided faster after the first two groups in order to assess promptly the need for the moderate group. Final analyses were available 20 days after reception of concentrations values.
The 2010 FDA guidance on renal impairment provides recommendations on the design and conduct of pharmacokinetics studies in patients with impaired renal function. The impact of renal impairment on the pharmacokinetics of a drug can be determined with a reduced PK study design, comparing subjects with normal renal function and patients with severe renal impairment. A full renal impairment study in patients with intermediate levels of renal impairment is then conducted if differences in the pharmacokinetic profiles are observed. Some companies also decide to develop projects as a full study from the beginning.
Multiple factors can influence the study start-up period of a clinical trial, and also availability of the final report at the end of a study. However, the approach to describe the impact of renal impairment did not seem to influence these activities. Current enrolment data were compared to selected studies on ClinTrial.gov, which were completed and included matching healthy subjects to evaluate the impact of renal impairment on a pharmacokinetic profile of a drug. The analysis included a total of 71 studies performed between 2012 to 2015. The FPI to LPO timeframe lasted on average for 213 calendar days. Our multi-center approach permitted to lessen this timeframe to 181 days for F5 and 122 days for M9.