Biology subjects

Norris, D. C.

Publications and source records attributed to Norris, D. C..

3 recordsLinked to original sources

bioRxiv2018

Costing ‘the’ MTD … in 2-D

BackgroundI have previously evaluated the efficiency of one-size-fits-all dosing for single agents in oncology (Norris 2017b). By means of a generic argument based on an Emax-type dose-response model, I showed that one-size-fits-all dosing may roughly halve a drugs value to society. Since much of the past decades innovation in oncology dose-finding methodology has involved the development of special methods for combination therapies, a generalization of my earlier investigations to combination dosing seems called-for.\n\nMethodsFundamental to my earlier work was the premise that optimal dose is a characteristic of each individual patient, distributed across the population like any other physiologic characteristic such as height. I generalize that principle here to the 2-dimensional setting of combination dosing with drugs A and B, using a copula to build a bivariate joint distribution of (MTDi,A, MTDi,B) from single-agent marginal densities of MTDi,A and MTDi,B, and interpolating toxicity isocontours in the (a, b)-plane between the respective monotherapy intercepts. Within this framework, three distinct notional toxicities are elaborated: one specific to drug A, a second specific to drug B, and a third nonspecific toxicity clinically attributable to either drug. The dose-response model of (Norris 2017b) is also generalized to this 2-D scenario, with the addition of an interaction term to provide for a complementary effect from combination dosing. A population of 1,000 patients is simulated, and used as a basis to evaluate population-level efficacy of two pragmatic dose-finding designs: a dose-titration method that maximizes dose-intensity subject to tolerability, and the well-known POCRM method for 1-size-fits-all combination-dose finding. Hypothetical oracular methods are also evaluated, to define theoretical upper limits of performance for individualized and 1-size-fits-all dosing respectively.\n\nResultsIn our simulation, pragmatic titration attains 89% efficiency relative to theoretically optimal individualized dosing, whereas POCRM attains only 55% efficiency. The passage from oracular individualized dosing to oracular 1-size-fits-all dosing incurs an efficiency loss of 33%, while the parallel passage (within the pragmatic realm) from titration to POCRM incurs a loss of 38%.\n\nConclusionsIn light of the 33% figure above, the greater part of POCRMs 38% efficiency loss relative to titration appears attributable to POCRMs 1-size-fits-all nature, rather than to any pragmatic difficulties it confronts. Thus, appeals to pragmatic considerations would seem neither to justify the decision to use 1-size-fits-all dose-finding designs, nor to excuse their inefficiencies

pharmacology and toxicology↗

bioRxiv2017

Precautionary Coherence Unravels Dose Escalation Designs

BackgroundCoherence notions have a long history in statistics, as rhetorical devices that support the critical examination of statistical doctrines and practices. Within the special domain of dose-finding methodology, a widely-discussed coherence criterion has been advanced as a means to guard the conceptual integrity of formal dose-finding designs from ad hoc tinkering. This is not, however, the only possible coherence criterion relevant to dose finding. Indeed, a new coherence criterion emerges naturally when the near-universal practice of cohort-wise dose escalation is examined from a clinical perspective.\n\nMethodsThe practice of enrolling drug-naive patients into an escalation cohort is considered from a realistic perspective that acknowledges patients heterogeneity with respect to pharmacokinetics and pharmacodynamics. A new coherence criterion thereby emerges, requiring that an escalation dose be tried preferentially in participants who have already tolerated a lower dose, rather than in new enrollees who are drug-naive. The logical implications of this precautionary coherence (PC) criterion are worked out in the setting of a 3+3 design. A 3+3/PC design that satisfies this criterion is described and visualized. A simulation study is performed, evaluating the long-run performance of this new design, relative to optimal 1-size-fits-all dosing.\n\nResultsUnder the PC criterion, the 3+3 dose-escalation design necessarily transmutes into a dose titration design. Two simple rules suffice to enable abandonment of low starting doses, and termination of escalation. The process of conducting the 3+3/PC trial itself models the application of a dose titration algorithm (DTA) that carries over readily into clinical care. The 3+3/PC trial also yields an interval-censored dose-survival curve having a semantics that should prove familiar to oncology trialists. Simulated 3+3/PC trials yield DTAs over a median of 6 dose levels, achieving 50% improved population-level efficacy compared to optimal 1-size-fits-all dosing.\n\nConclusionsDose individualization can be accomplished within a trial conducted along algorithmic lines resembling those of the inveterate 3+3 design. The dose-survival curve arising from this 3+3/PC design has semantics that should prove familiar and conceptually accessible to oncology trialists, and also seems capable of supporting more formal statistical treatments of the design. In the presence of sufficient heterogeneity in individualized optimal dosing, a 3+3/PC trial outperforms any conceivable 1-size-fits-all dose-finding design. This fact eliminates the rationale for the latter designs, and should put an end to the further development and promulgation of 1-size-fits-all dose finding.

pharmacology and toxicology↗

bioRxiv2017

Costing ‘the’ MTD

BackgroundAbsent adaptive, individualized dose-finding in early-phase oncology trials, subsequent registration trials risk suboptimal dosing that compromises statistical power and lowers the probability of technical success (PTS) for the investigational drug. While much methodological progress has been made toward adaptive dose-finding, and quantitative modeling of dose-response relationships, most such work continues to be organized around a concept of the maximum tolerated dose (MTD). But a new methodology, Dose Titration Algorithm Tuning (DTAT), now holds forth the promise of individualized MTDi dosing. Relative to such individualized dosing, current one-size-fits-all dosing practices amount to a constraint that imposes costs on society. This paper estimates the magnitude of these costs.\n\nMethodsSimulated dose titration as in (Norris 2017) is extended to 1000 subjects, yielding an empirical MTDi distribution to which a gamma density is fitted. Individual-level efficacy, in terms of the probability of achieving remission, is assumed to be an Emax-type function of dose relative to MTDi, scaled (arbitrarily) to identify MTDi with the LD50 of the individuals tumor. (Thus, a criterion 50% of the population achieve remission under individualized dosing in this analysis.) Current practice is modeled such that all patients receive a first-cycle dose at the MTD, and those for whom MTDi < MTDthe experience a dose-limiting toxicity (DLT) that aborts subsequent cycles. Therapy thus terminated is assumed to confer no benefit. Individuals for whom MTDi[≥] MTDthe tolerate a full treatment course, and achieve remission with probability determined by the Emax curve evaluated at MTDthe/MTDi. A closed-form expression is obtained for the population remission rate, and maximized numerically over MTDthe as a free parameter, thus identifying the best result achievable under one-size-fits-all dosing. A sensitivity analysis is performed, using both a perturbation of the assumed Emax function, and an antipodal alternative specification.\n\nResultsSimulated MTDi follow a gamma distribution with shape parameter {approx} 1.75. The population remission rate under one-size-fits-all dosing at the maximizing value of MTDthe proves to be a function of the shape parameter--and thus the coefficient of variation (CV)--of the gamma distribution of MTDi. Within a plausible range of CV(MTDi), one-size-fits-all dosing wastes approximately half of the drugs population-level efficacy. In the sensitivity analysis, sensitivity to the perturbation proves to be of second order. The alternative exposure-efficacy specification likewise leaves all results intact.\n\nConclusionsThe CV of MTDi determines the efficacy lost under one-size-fits-all dosing at the MTD. Within plausible ranges for this CV, failure to individualize dosing can effectively halve a drugs value to society. In a competitive environment dominated by regulatory hurdles, this may reduce the value of shareholders investment in the drug to zero.\n\nEpilogueThe main result on one-size-fits-all dosing is generalized to regimens with several dose levels. Implications for the ongoing ALTA-1L trial are briefly explored; the 2 dose levels in the brigatinib arm of this trial may lend it a competitive advantage over the single-dose crizotinib arm.

pharmacology and toxicology↗