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Targeted randomization dose optimization trials enable fractional dosing of scarce drugs.

ABSTRACT: Administering drug at a dose lower than that used in pivotal clinical trials, known as fractional dosing, can stretch scarce resources. Implementing fractional dosing with confidence requires understanding a drug's dose-response relationship. Clinical trials aimed at describing dose-response in scarce, efficacious drugs risk underdosing, leading dose-finding trials to not be pursued despite their obvious potential benefit. We developed a new set of response-adaptive randomized dose-finding trials and demonstrate, in a series of simulated trials across diverse dose-response curves, these designs' efficiency in identifying the minimum dose that achieves satisfactory efficacy. Compared to conventional designs, these trials have higher probabilities of identifying lower doses while reducing the risks of both population- and subject-level underdosing. We strongly recommend that, upon demonstration of a drug's efficacy, pandemic drug development swiftly proceeds with response-adaptive dose-finding trials. This unified strategy ensures that scarce effective drugs produce maximum social benefits.

SUBMITTER: Boonstra PS

PROVIDER: S-EPMC10615276 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Targeted randomization dose optimization trials enable fractional dosing of scarce drugs.

Boonstra Philip S PS Tabarrok Alex A Strohbehn Garth W GW

PloS one 20231030 10

Administering drug at a dose lower than that used in pivotal clinical trials, known as fractional dosing, can stretch scarce resources. Implementing fractional dosing with confidence requires understanding a drug's dose-response relationship. Clinical trials aimed at describing dose-response in scarce, efficacious drugs risk underdosing, leading dose-finding trials to not be pursued despite their obvious potential benefit. We developed a new set of response-adaptive randomized dose-finding trial ...[more]

PMID: 37903093

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Project description:BackgroundConducting geriatric trials is the most feasible way to address the vast underrepresentation of older adults in clinical trials of cancer therapies. This study is a globally comprehensive examination of geriatric trials for solid tumor worldwide over the last decade.MethodsUp-to-date information on cancer drug trials in older adults aged over 59 years from the beginning of 2012 to the end of 2021 was collected from Trialtrove and Pharmaprojects. The number of identified trials was the dependent variable and corresponding analysis was conducted from the perspective of time trend, status quo and comparisons by region and country, sponsor type and cancer type, study status and phase.ResultsA total of 292 geriatric cancer drug trials were identified, of which 287 were single-region studies, 219 were initiated by academic groups, and 55 (18.8%) were terminated. Decreasing trends in the annual number of all trials (-9.2% per year) and the annual number of trials by academic groups (-9.4%) were observed over time. Of the geriatric trials, 183 were conducted in Asia; this number was significantly higher than that in Europe (74), North America (37), Oceania (4), and South America (1). Similar difference was found in participation rate in trials by academic groups ranging from 71.7% in Asia to 0.5% in South America. Of the trials, 19 and 97 were initiated before drug and indication approval, respectively, and the remaining 176 were initiated after indication approval. Phase II trials accounted for the highest proportion of trials (213, 72.9%), while phase I trials accounted for the lowest proportion (14, 4.8%). Trials by academic groups had a higher termination rate (21.5% vs. 11.0%) and fewer were phase IV trials (8.2% vs. 21.9%). Treatment was explored for 16 different cancers, with lung, colorectal and breast cancers being the most common.ConclusionGeriatric trials of solid tumor drugs are scarce and partially prematurely terminated. Moreover, the number of geriatric trials has decreased and differs according to region. Global guidance and regulatory supervision are needed to facilitate the acquisition of adequate evidence on drug risk-benefit profiles in older adults, and thus to achieve high-quality care and safe medication.

Project description:BackgroundThe dose and dosing time of indocyanine green (ICG) vary among fluorescence cholangiography (FC) studies. The purpose of this prospective, randomized, exploratory clinical trial was to optimize the dose and dosing time of ICG.MethodsPubMed was searched to determine the optimal dose. To optimize the dosing time of ICG, a clinical trial was designed with two parts. The first part included patients with T tubes for more than 1 month. After the patient was injected with ICG, bile was collected at 10 time points to explore the change and trends of bile fluorescence intensity (FI). In addition, the results of the first experiment were used to setup a randomized controlled trial (RCT) that aimed to find the optimal dosing timing for ICG injections for laparoscopic cholecystectomy (LC). During surgery, imaging data were collected for analysis.ResultsAfter performing a systematic review, the ICG injection dose for each patient in the clinical trial was 10 mg. Five patients were included in the first part of the study. Bile collected 8 h after ICG injection had a higher FI than bile collected at other time points (p < 0.05), and the FI of bile collected 20 h after ICG injection was nearly zero. In the second part of the experiment, 4 groups of patients (6 patients per group) were injected with 10 mg ICG at 8, 10, 12 and 14 h prior to surgery. The distribution of bile duct FI (p = 0.001), liver FI (p < 0.001), and common bile duct (CBD)-to-liver contrast (p = 0.001) were not the same in each group. Further analysis with the Bonferroni method revealed the following: (1) the FI of the CBD in the 8 h group was significantly different from that in the 14 h group (adjusted p < 0.001); (2) the liver FI of the 8 h group was higher than that of the 10 h group (adjusted p = 0.042) and the 14 h group (adjusted p < 0.001); and (3) the CBD-to-liver contrast of the 8 h group was lower than that of the 10 h group (adjusted p = 0.013) and the 14 h group (adjusted p = 0.001).ConclusionICG FC enables the real-time identification of extrahepatic bile ducts. The optimal effect of FC can be achieved by performing 10 mg ICG injections 10 to 12 h prior to surgery.

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Targeted randomization dose optimization trials enable fractional dosing of scarce drugs.

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Targeted randomization dose optimization trials enable fractional dosing of scarce drugs.

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