BioSeek: Explaining a Clinical Adverse Event - Bridging the Gap from In Vitro to In Vivo

BioSeek: Explaining a Clinical Adverse Event - Bridging the Gap from In Vitro to In Vivo


Our client, a global integrated pharmaceutical company, had completed Phase I studies with an investigative therapeutic, Drug A, for a cancer indication. In the Phase I study, a small number of patients experienced a specific serious adverse event (AE). This AE was correlated with the patients’ recent use of a second and unrelated therapeutic, Drug B. While Drug B was known to be associated with this type of AE, the affected patients had discontinued Drug B for some time prior to initiating Drug A. The client faced the possibility that initiation of Phase II trials could be delayed by regulatory authorities if the AE was not explained and steps were not taken to mitigate it. The client needed to test among three hypotheses: (1) the AE was caused by the client’s investigative drug, Drug A; (2) the AE was caused by prior courses of Drug B; or (3) low residual levels of Drug B in patients could synergize with Drug A to induce the AE.

Due to the small number of affected patients, there was limited clinical data on which to base a hypothesis, without which a risk evaluation and mitigation plan was not possible. Laboratory studies in animal models were not appropriate because both Drugs A and B were specific to humans. Studies in cell lines might not yield physiologically relevant results because of the clinical complexity of the AE. Human primary cells were a more physiologically relevant experimental system to test hypotheses that might then inform clinically relevant explanations of the AE. The client wanted to gain as much information as possible to bridge the gap from in vitro to clinical insights about possible drug interactions.