TBD: Oncology Drugs in Clinical Trials with Healthy Populations: Old Challenges or New Opportunities
Weidong (David) Yu
Senior PK Scientist
Biopharma Services Canada
Using healthy volunteers(HV) in clinical trials on oncology drugs commonly raised concerns about the subject's safety which were addressed in this review by pooling and analyzing the safety and PK results from trials on oncology drugs conducted at Biopharma Services Inc. (BPSI) in the past 15 years.
All clinical studies in HV conducted at BPSI over the last 15 years (including at least one oncology drug as IP) were selected as pooling data. All studies are summarized per drug classification, pooled safety results were analyzed, and PK data from a recent study was presented as an example.
Each regulator can have different opinions and practices on the identical IPs for the study population. The decision-making process is based on an assessment of the non-clinical, clinical, and quality data submitted by the applicators, e.g., FDA has PSG on which groups should participate in clinical trials for all the drugs we studied, while EMA only has PSG for some IPs. For some IPs, FDA recommends using patients for BE clinical trials, whereas the EMA recommends using HV. The agency's requirement was compared to the studies done in-house and summarized in a table.
A total of 176 clinical trials on 36 oncology drugs in HV were reviewed including 03 cytotoxic chemotherapy drugs, 10 hormonal therapy drugs, 4 immunotherapy drugs, and 19 targeted therapy drugs per British Columbia Cancer classification. A total of 129 BPSI studies had available safety data that was carried further analysis.
The safety results indicate there is no critical concern about drug safety to HV and the PK assessment was feasible for all studies as planned. Among 3300 observed AEs, all were either mild or moderate except 3 resolved severe AEs (one AE was unrelated to the IP). Approximately 18% of reported AEs were unrelated to IPs. The dropout rate due to AEs was low (<2%). Overall, all listed oncology drugs were tolerated in HVs and deemed safe. The adverse events (AEs) were summarized as per severity and relationship to the investigational product by drug class and the most common AEs were reviewed.
In the case of pazopanib, for example, FDA recommends patients undergo BE clinical trials, whereas EMA recommends HV. From the past 08 BE studies in HV, approximately 370 subjects were dosed with 200 mg or 400 mg of pazopanib, all AEs were mild or moderate, and the most common AEs (=10%) were somnolence, headache, and nausea. Among all dosed subjects, 4 subjects (1.08%) did not complete their studies due to safety reasons. The PK profiles of pazopanib were all well characterized.
Among all the clinical trials on oncology drugs conducted by BPSI, only one drug (methotrexate) belongs to cytotoxic chemotherapy based on drug classification, other drugs falling into the category of hormonal therapy, immunotherapy, and targeted therapy, the largest percentage was targeted therapy drugs acting on different kinases.
Enrolled HV in clinical trials can be beneficial to both manufacturers and patients when adapted to specific study objectives and can be applied to both non-oncology and oncology drug development. The enrollment of the HV population can not only reduce the recruitment obstacles but also mitigate the medical ethics of recruiting patients with disease at subtherapeutic doses for short-term studies.
The use of HV in the early phase clinical development of oncology drugs is more limited compared to non-oncology drugs but is still useful for assessing PK, drug metabolism, food effects, potential drug interactions, effects of hepatic and renal impairment, and other pharmacological parameters critical to clinical decision-making. However, assessment of pre-known toxicity and pharmacology before planning the clinical trials in HV and/or patients is critical to ensure the safety of all participants.
BPSI’s experience showed that many oncology drugs were well tolerated in HV. Despite the lack of a standardized guide for the study population for oncology IPs, clinical trials in HV with PK endpoints are feasible for many oncology IPs with the support of adequate medical, scientific rationale, and appropriate risk mitigation plan.