Category: Clinical Pharmacology
Purpose: A pharmacokinetic (PK) study in patients with impaired hepatic function should be conducted in the following situations: 1) If hepatic metabolism and/or excretion accounts for a substantial portion ( >20 percent of the absorbed drug) of the elimination of a parent drug or active metabolite; 2) in the case of a narrow therapeutic range drug, and; 3) if metabolism of the drug is unknown. The design and conduct of these trials may have evolved since the latest versions of the relevant guidance documents from the FDA (2003) and EMA (2005). The objective of this retrospective analysis is to uncover recent trends in the design and conduct of hepatic PK studies, based on a review of FDA novel drug approvals and ClinicalTrials.gov.
Methods: All NDA review documents for small molecules approved in 2017 and 2018 were searched to gather information on the hepatic impairment studies that were conducted. Only drugs with systemic absorption were retained. In addition, ClinicalTrials.gov was surveyed using “hepatic impairment”, “healthy”, and “Phase I” as search terms, for studies first registered between 01-JAN-2016 and 31-DEC-2018. Elements reviewed included the following: stages of hepatic impairment being evaluated (mild, moderate, severe), use of reduced or adaptive designs, and use of Population PK approach as an alternative to a dedicated hepatic impairment PK study.
Results: ClinicalTrials.gov review: A total of 46 studies were retained – one was removed due to lack of information on the stage of impairment being evaluated. Of those, 41% included mild, moderate, and severe impairment cohorts, 30% included only mild and moderate, and 11% included only moderate and severe, in addition to healthy controls. A reduced study design involving only patients with moderate hepatic impairment was used in 7% of the cases, while studies limited to severe hepatic impairment were also observed in 7% of the cases. An adaptive approach or two-stage design was adopted in 4% of studies. For the 21 studies where criteria to categorize the degree of hepatic impairment was mentioned, Child-Pugh Classification was used.
NDA review: From the total of 61 NDAs that were retained, a dedicated hepatic study was conducted in 37 cases (61%). When considering the 34 studies for which the drug administration details were available, 30 studies were conducted under single-dose administration, while only 4 were conducted under multiple-dose conditions. Average number of subjects per cohort was 8.3. Moreover, 43% of these hepatic studies included mild, moderate, and severe impairment cohorts, 22% included only mild and moderate, and 5% included only moderate and severe, in addition to healthy controls. A reduced study design involving only patients with moderate hepatic impairment was used in 19% of the cases, while only one study (2.7%) was limited to only patients with mild hepatic impairment. An adaptive approach or two-stage design was adopted in 8% of studies. A Population PK approach was used as an alternative to a dedicated hepatic study in 11 NDAs; however, for 6 of those, a hepatic study was required by the FDA as a post-marketing commitment.
Conclusion: The stages of hepatic impairment that were frequently evaluated may differ from the full or reduced study design recommendations included in the FDA Guidance on hepatic impairment studies. In fact, even though the FDA guidance suggests the option of a reduced study design involving control subjects and patients with moderate hepatic impairment cohort, this approach does not appear to be widely used in the industry based on our results. In addition, a considerable amount of studies involved only mild and moderate hepatic patients, which may be due to specific PK characteristics of the study drug, its contraindications or intended labeling considerations. The relatively high proportion of NDAs that did not include a dedicated hepatic study may be explained by the elevated number of priority and orphan reviews, the high prevalence of oncology products, in addition to the use of Population PK approach. Absence of a dedicated study has also been justified for drugs intended for single-dose administration, or drugs with minimal hepatic metabolism and/or excretion. The trends that were identified in this retrospective analysis may help guide sponsors on current approaches that are used in the conduct of PK studies in patients with impaired hepatic function.