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. 2023 Oct 30;18(10):e0287511.
doi: 10.1371/journal.pone.0287511. eCollection 2023.

Targeted randomization dose optimization trials enable fractional dosing of scarce drugs

Philip S Boonstra  1   2 , Alex Tabarrok  3 , Garth W Strohbehn  2   4   5   6   7
Affiliations

Targeted randomization dose optimization trials enable fractional dosing of scarce drugs

Philip S Boonstra et al. PLoS One. .

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.

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Conflict of interest statement

PSB has received research funding from Bristol Myers Squibb and Janssen outside of the submitted work. AT has no conflicts to disclose. GWS serves as an uncompensated Director of the Optimal Cancer Care Alliance. GWS is a co-inventor of a patent held by the University of Chicago covering the use of low-dose tocilizumab in the treatment of viral infections. GWS reports no material conflicts of interest with regards to contract research organizations, biostatistical firms, or vaccines. GWS is employed by the United States Department of Veterans Affairs; this work does not represent the official position of the United States Department of Veterans Affairs. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. True dose-response distribution (conditional on dose level) used in simulated clinical trials.
Curves were selected to capture a range of MDSEs and rates at which efficacy declines in response to dose de-escalation. Hill equation parameters of true dose-response curves are summarized in S1 Table in S1 Appendix.
Fig 2
Fig 2. Heat map of true MDSE identification probability.
Cells contain the percentage of simulated trials that identified the true MDSE for a given combination of dose allocation strategy and dose-response curve across N = 500 simulated trials, using HS prior distribution, sample size n = 102, and Hill equation parameters corresponding to those in S1 Table in S1 Appendix. Darker green color represents a higher probability of this ‘good’ event; darker red represents a lower probability of this ‘good’ event. Abbreviations: EA, equal allocation; Naïve, naïve allocation; Gr, Greedy allocation; TRInd, targeted randomization (individual); TRCoh, targeted randomization (cohort, comprising 1/3 of study population).
Fig 3
Fig 3. Heat map of probability of estimating MDSE less than true MDSE.
Cells contain the contain the percentage of simulated trials that estimated an MDSE that is lower than the true MDSE for a given combination of dose allocation strategy and dose-response curve across N = 500 simulated trials, using HS prior distribution, sample size n = 102, and Hill equation parameters corresponding to those in S1 Table in S1 Appendix. Darker green color represents a lower probability of this ‘bad’ event; darker red represents a higher probability of this ‘bad’ event. Abbreviations: EA, equal allocation; Naïve, naïve allocation; Gr, Greedy allocation; TRInd, targeted randomization (individual); TRCoh, targeted randomization (cohort, comprising 1/3 of study population).
Fig 4
Fig 4. Heat map of probability of administering to an individual subject in the trial a dose less than the true MDSE (underdosing).
Cells contain the average percentage of subjects that were assigned to a dose lower than true MDSE for a given combination of dose allocation strategy and dose-response curve across N = 500 simulated trials, using HS prior distribution, sample size n = 102, and Hill equation parameters corresponding to those in S1 Table in S1 Appendix. Darker green color represents a lower probability of this ‘bad’ event; darker red represents a higher probability of this ‘bad’ event. Abbreviations: EA, equal allocation; Naïve, naïve allocation; Gr, Greedy allocation; TRInd, targeted randomization (individual); TRCoh, targeted randomization (cohort, comprising 1/3 of study population).
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