
@article{simon_accelerated_1997,
	title = {Accelerated titration designs for phase {I} clinical trials in oncology},
	volume = {89},
	issn = {0027-8874},
	abstract = {BACKGROUND: Many cancer patients in phase I clinical trials are treated at doses of chemotherapeutic agents that are below the biologically active level, thus reducing their chances for therapeutic benefit. Current phase I trials often take a long time to complete and provide little information about interpatient variability or cumulative toxicity.
PURPOSE: Our objective was to develop alternative designs for phase I trials so that fewer patients are treated at subtherapeutic dose levels, trials are of reduced duration, and important information (i.e., cumulative toxicity and maximum tolerated dose) needed to plan phase II trials is obtained.
METHODS: We fit a stochastic model to data from 20 phase I trials involving the study of nine different drugs. We then simulated new data from the model with the parameters estimated from the actual trials and evaluated the performance of alternative phase I designs on this simulated data. Four designs were evaluated. Design 1 was a conventional design (similar to the commonly used modified Fibonacci method) using cohorts of three to six patients, with 40\% dose-step increments and no intrapatient dose escalation. Designs 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxic effects or two patients experienced grade 2 toxic effects (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Designs 3 and 4 used 100\% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resorted to standard cohorts of three to six patients, with 40\% dose-step increments. Designs 2 through 4 used intrapatient dose escalation if the worst toxicity is grade 0-1 in the previous course for that patient.
RESULTS: Only three of the actual trials demonstrated cumulative toxic effects of the chemotherapeutic agents in patients. The average number of patients required for a phase I trial was reduced from 39.9 for design 1 to 24.4, 20.7, and 21.2 for designs 2, 3, and 4, respectively. The average number of patients who would be expected to have grade 0-1 toxicity as their worst toxicity over three cycles of treatment is 23.3 for design 1, but only 7.9, 3.9, and 4.8 for designs 2, 3, and 4, respectively. The average number of patients with grade 3 toxicity as their worst toxicity increases from 5.5 for design 1 to 6.2, 6.8, and 6.2 for designs 2, 3, and 4, respectively. The average number of patients with grade 4 toxicity as their worst toxicity increases from 1.9 for design 1 to 3.0, 4.3, and 3.2 for designs 2, 3, and 4, respectively.
CONCLUSION: Accelerated titration (i.e., rapid intrapatient drug dose escalation) designs appear to effectively reduce the number of patients who are under-treated, speed the completion of phase I trials, and provide a substantial increase in the information obtained.},
	language = {eng},
	number = {15},
	journal = {Journal of the National Cancer Institute},
	author = {Simon, R. and Freidlin, B. and Rubinstein, L. and Arbuck, S. G. and Collins, J. and Christian, M. C.},
	month = aug,
	year = {1997},
	pmid = {9262252},
	keywords = {Antineoplastic Agents, Neoplasms, Models, Statistical, Research Design, Humans, Clinical Trials, Phase I as Topic, Drug Administration Schedule, CITE, Quinoxalines, Sulfanilamides, READ!!!!!},
	pages = {1138--1147},
	file = {Simon et al. - 1997 - Accelerated titration designs for phase I clinical.pdf:/Users/david/zotero/storage/RSPWMWC7/Simon et al. - 1997 - Accelerated titration designs for phase I clinical.pdf:application/pdf}
}

@article{sheiner_study_1989,
	title = {Study designs for dose-ranging},
	volume = {46},
	issn = {0009-9236},
	abstract = {Premarketing dose-ranging studies of a drug are done to establish a reasonable initial dose. According to the current procedure sanctioned by the Food and Drug Administration, each patient is given one of several possible doses, including placebo, after an initial placebo run-in period. Data analysis is based on a model in which the mean response at each dose is independent of the magnitude of the dose. The initial dose is the lowest dose tested that has a response that is statistically significantly greater than the response after placebo administration. We suggest that the present conceptual approach to, and standard study design and analysis for, dose-ranging studies be changed. We believe one must begin with a parametric model for patient-specific dose-response curves. Knowledge of the distribution of these curves in a population provides a basis for choice of an initial dose (e.g., the dose that achieves a given response in a given fraction of patients) and, after observation of response to an initial dose, for choice of an incremental dose for a specific patient (by use of Bayes rule). The current parallel-dose design can provide only poor information about the distribution of dose-response curves, biased estimates of the typical curve, and little information on interpatient variability. Crossover studies provide better information. In studies in which a parametric patient-specific dose-response model is used, a dose-escalation design provides no less information than a crossover design, and it has ethical advantages that allow a more representative patient group and clinical setting to be studied.},
	language = {eng},
	number = {1},
	journal = {Clinical Pharmacology and Therapeutics},
	author = {Sheiner, L. B. and Beal, S. L. and Sambol, N. C.},
	month = jul,
	year = {1989},
	pmid = {2743708},
	keywords = {Analysis of Variance, Dose-Response Relationship, Drug, Hypertension, Antihypertensive Agents, Research Design, Humans, CITE},
	pages = {63--77},
	file = {Sheiner et al. - 1989 - Study designs for dose-ranging.pdf:/Users/david/zotero/storage/R55R2BB2/Sheiner et al. - 1989 - Study designs for dose-ranging.pdf:application/pdf}
}

@article{norris_dose_2017,
	title = {Dose {Titration} {Algorithm} {Tuning} ({DTAT}) should supersede ‘the’ {Maximum} {Tolerated} {Dose} ({MTD}) in oncology dose-finding trials},
	volume = {6},
	issn = {2046-1402},
	url = {https://f1000research.com/articles/6-112/v3},
	doi = {10.12688/f1000research.10624.3},
	language = {en},
	urldate = {2017-07-21},
	journal = {F1000Research},
	author = {Norris, David C.},
	month = jul,
	year = {2017},
	pages = {112},
	file = {Dose Titration Algorithm Tuning (DTAT) should supersede ‘the’ Maximum Tolerated Dose (MTD) in oncology dose-finding trials - F1000Research:/Users/david/zotero/storage/AGFSETEW/v3.html:text/html;Norris - 2017 - Dose Titration Algorithm Tuning (DTAT) should supe.pdf:/Users/david/zotero/storage/7PE7HN9E/Norris - 2017 - Dose Titration Algorithm Tuning (DTAT) should supe.pdf:application/pdf}
}

@article{norris_costing_2017,
	title = {Costing 'the' {MTD}},
	copyright = {© 2017, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution 4.0 International), CC BY 4.0, as described at http://creativecommons.org/licenses/by/4.0/},
	url = {https://www.biorxiv.org/content/10.1101/150821v3},
	doi = {10.1101/150821},
	abstract = {Background: Absent 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. Methods: Simulated dose titration as in (Norris F1000Research 2017;6:112) 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 individual's 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 {\textless} 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. Results: Simulated MTDi follow a gamma distribution with shape parameter α ≈ 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 drug's 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. Conclusions: The 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 drug's value to society. In a competitive environment dominated by regulatory hurdles, this may reduce the value of shareholders' investment in the drug to zero. Epilogue: The 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.},
	language = {en},
	journal = {bioRxiv},
	author = {Norris, David C.},
	month = aug,
	year = {2017},
	pages = {150821},
	file = {Norris - 2017 - Costing 'the' MTD.pdf:/Users/david/zotero/storage/USUT7LDT/Norris - 2017 - Costing 'the' MTD.pdf:application/pdf;Snapshot:/Users/david/zotero/storage/5DW2GJB5/150821.html:text/html}
}

@article{cheung_coherence_2005,
	title = {Coherence principles in dose-finding studies},
	volume = {92},
	issn = {0006-3444},
	url = {https://academic.oup.com/biomet/article/92/4/863/389425/Coherence-principles-in-dose-finding-studies},
	doi = {10.1093/biomet/92.4.863},
	abstract = {This paper studies the coherence conditions of dose-finding methods in the context of phase I clinical trials, where the objective is to estimate a targeted quantile of the unknown dose-toxicity curve. Most phase I methods are outcome-adaptive, and thus escalate or de-escalate doses for future patients based on the previous observations. An escalation for a new patient is said to be coherent only when the previous patient does not show sign of toxicity. Likewise, a de-escalation is coherent only when a toxic outcome has just been seen. The coherence conditions, motivated by ethical concerns in trial conduct, are satisfied by many statistical designs in the literature, but not by some commonly used modifications of the methods. This paper shows examples in which coherence is violated, and discusses how the coherence principles may be applied to calibrate a two-stage design and to deal with situations with delayed toxicity.},
	number = {4},
	urldate = {2017-10-05},
	journal = {Biometrika},
	author = {Cheung, Ying Kuen},
	month = dec,
	year = {2005},
	pages = {863--873},
	file = {Cheung - 2005 - Coherence principles in dose-finding studies.pdf:/Users/david/zotero/storage/CIB8Z3M4/Cheung - 2005 - Coherence principles in dose-finding studies.pdf:application/pdf;Snapshot:/Users/david/zotero/storage/YHR9CHFK/Coherence-principles-in-dose-finding-studies.html:text/html}
}

@article{norris_precautionary_2017,
	title = {Precautionary {Coherence} {Unravels} {Dose} {Escalation} {Designs}},
	copyright = {© 2017, Posted by Cold Spring Harbor Laboratory. This pre-print is available under a Creative Commons License (Attribution 4.0 International), CC BY 4.0, as described at http://creativecommons.org/licenses/by/4.0/},
	url = {https://www.biorxiv.org/content/10.1101/240846v1},
	doi = {10.1101/240846},
	abstract = {Background: Coherence 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. Methods: The 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. Results: Under 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. Conclusions: Dose 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.},
	language = {en},
	urldate = {2017-12-29},
	journal = {bioRxiv},
	author = {Norris, David C.},
	month = dec,
	year = {2017},
	pages = {240846},
	file = {Norris - 2017 - Precautionary Coherence Unravels Dose Escalation D.pdf:/Users/david/zotero/storage/NKTDTBH2/Norris - 2017 - Precautionary Coherence Unravels Dose Escalation D.pdf:application/pdf;Snapshot:/Users/david/zotero/storage/G48ZSH6A/240846.html:text/html}
}

@article{dixon_method_1948,
	title = {A {Method} for {Obtaining} and {Analyzing} {Sensitivity} {Data}},
	volume = {43},
	issn = {0162-1459},
	url = {https://amstat.tandfonline.com/doi/abs/10.1080/01621459.1948.10483254},
	doi = {10.1080/01621459.1948.10483254},
	abstract = {The standard method of dealing with sensitivity of dosage-mortality data is the probit technique developed by Bliss and Fisher. This paper provides an alternative technique based on a special system for obtaining such data. It has some advantages when observations must be taken on individuals rather than groups of individuals, and it may be preferred in certain other situations.},
	number = {241},
	urldate = {2018-06-16},
	journal = {Journal of the American Statistical Association},
	author = {Dixon, W. J. and Mood, A. M.},
	month = mar,
	year = {1948},
	keywords = {CITE},
	pages = {109--126},
	file = {Dixon and Mood - 1948 - A Method for Obtaining and Analyzing Sensitivity D.pdf:/Users/david/zotero/storage/59557VIB/Dixon and Mood - 1948 - A Method for Obtaining and Analyzing Sensitivity D.pdf:application/pdf;Snapshot:/Users/david/zotero/storage/H7W84G8I/01621459.1948.html:text/html}
}