Navigating Innovation and Ethics in Early Phase Oncology Clinical Trials

Abstract

Early phase clinical trials are pivotal to advance development of new anticancer drugs. During this phase, the toxicity profile of the new drug and the optimal dose and dosing scheme for further clinical development are assessed. Innovation carries ethical implications, as patients included in these early phase trials are subjected to potential risks. This thesis aimed to evaluate the ethical considerations for patients that enter early phase trials from a pharmacological perspective, as well as from a clinical perspective. Early phase clinical trials includes a pharmacological evaluation of the new drug, which involves collecting biological samples (e.g tissue, blood) to characterize the pharmacokinetic and pharmacodynamic profiles. The risks and burden for obtaining patient material for these assessments must be appropriately balanced in relation to the anticipated benefit and scientific value. The risks associated with collecting patient material for these pharmacological analyses potentially include complications such as bleeding, infection, or injury to other structures. This thesis showed that invasive procedures were often performed without a clear description of how the pharmacodynamic data would be used. These practices raise ethical concerns and show the need for appropriate sample-size planning, and suitable methods to ensure meaningful contribution of the pharmacological assessments to the dose selection. The collection of biomaterials may be justified as it helps to understand drug response, the proposed mechanism of action and resistance mechanisms. The data obtained from these procedures should be publicly available to facilitate transparency and reproducibility. Even though ethical and regulatory frameworks exist, biomaterials for pharmacological evaluation are sometimes collected and analyzed, but their results remain unpublished. This is not an isolated issue as, in a broader context, the underreporting of clinical trial results in general is a well-documented problem. However, early phase clinical trials are frequently underrepresented in such analyses, which often focus on pivotal late stage clinical trials. Underreporting of early trials raises particular ethical concerns because these studies involve higher risks for the patient due to the limited experience with the new compound and the incomplete understanding of its side-effects. This thesis found that discontinued compounds were especially prone to delayed or absent dissemination. Key barriers for publishing early phase trials were; practical barriers, insufficient resources, limited motivation, and inadequate collaboration. Recognizing and acknowledging these barriers is crucial to develop effective strategies to improve the publishing and public sharing of results.