Power calculations for cluster randomized trials (CRTs) with right-truncated Poisson-distributed outcomes: a motivating example from a malaria vector control trial

Abstract Background Cluster randomized trials (CRTs) are increasingly used to study the efficacy of interventions targeted at the population level. Formulae exist to calculate sample sizes for CRTs, but they assume that the domain of the outcomes being considered covers the full range of values of the considered distribution. This assumption is frequently incorrect in epidemiological trials in which counts of infection episodes are right-truncated due to practical constraints on the number of times a person can be tested. Methods Motivated by a malaria vector control trial with right-truncated Poisson-distributed outcomes, we investigated the effect of right-truncation on power using Monte Carlo simulations. Results The results demonstrate that the adverse impact of right-truncation is directly proportional to the magnitude of the event rate, λ, with calculations of power being overestimated in instances where right-truncation was not accounted for. The severity of the adverse impact of right-truncation on power was more pronounced when the number of clusters was ≤30 but decreased the further the right-truncation point was from zero. Conclusions Potential right-truncation should always be accounted for in the calculation of sample size requirements at the study design stage. </jats:sec

Postmarketing Assessment of Antibody-Drug Conjugates: Proof-of-Concept Using Model-Based Meta-Analysis and a Clinical Utility Index Approach.

Antibody-drug conjugates (ADCs) are a promising class of targeted cancer therapies. However, they need careful dose optimization to maximize effectiveness and minimize side effects. Sometimes, safety issues may only become apparent after approval, so ongoing evaluation is important. This study aimed to assess the benefit-risk profiles of two approved trastuzumab-drug conjugates: trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). A systematic search of MEDLINE on May 1, 2024, identified clinical trials reporting the pharmacokinetics, pharmacodynamics, safety, and efficacy of T-DM1 and T-DXd. Summary-level data from 103 trials was used along with model-based meta-analysis to develop population pharmacokinetic and exposure-response models for both ADCs. The study combined the objective response rate (ORR) and dose-limiting toxicity (DLT) into a composite score called the clinical utility index (CUI) to determine optimal drug exposures and doses that maximize the benefit-risk balance. Different ORR/DLT weights and CUI thresholds representing desired minimum effect size were tested in three scenarios ("only phase I trials," "phase I/II trials," and "all phases"). Using a CUI threshold of 10%, the approved T-DM1 dose of 3.6 mg/kg for breast cancer was found to align with an efficacy-safety (ORR-DLT) ratio of 81:19 with all phases. Applying these weights to the T-DXd analyses successfully predicted the approved T-DXd dose (5.4 mg/kg, breast cancer), showing a CUI improvement compared to the 3.2 mg/kg dose of 8.3%, 8.2%, and 2.4% in the three respective scenarios. Overall, this proof-of-concept assessment of ADCs can save time and costs for pharmaceutical companies and optimize dosing to maximize patient benefit

Pharmacokinetic and Pharmacodynamic Modeling To Determine the Dose of ST-246 To Protect against Smallpox in Humans

ABSTRACT Although smallpox has been eradicated, the United States government considers it a “material threat” and has funded the discovery and development of potential therapeutic compounds. As reported here, the human efficacious dose for one of these compounds, ST-246, was determined using efficacy studies in nonhuman primates (NHPs), together with pharmacokinetic and pharmacodynamic analysis that predicted the appropriate dose and exposure levels to provide therapeutic benefit in humans. The efficacy analysis combined the data from studies conducted at three separate facilities that evaluated treatment following infection with a closely related virus, monkeypox virus (MPXV), in a total of 96 NHPs. The effect of infection on ST-246 pharmacokinetics in NHPs was applied to humans using population pharmacokinetic models. Exposure at the selected human dose of 600 mg is more than 4-fold higher than the lowest efficacious dose in NHPs and is predicted to provide protection to more than 95% of the population.</jats:p