Continual Reassessment and Related Dose-Finding Designs

During the last twenty years there have been considerable methodological developments in the design and analysis of Phase 1, Phase 2 and Phase 1/2 dose-finding studies. Many of these developments are related to the continual reassessment method (CRM), first introduced by O'Quigley, Pepe and Fisher (\citeyearQPF1990). CRM models have proven themselves to be of practical use and, in this discussion, we investigate the basic approach, some connections to other methods, some generalizations, as well as further applications of the model. We obtain some new results which can provide guidance in practice.Comment: Published in at http://dx.doi.org/10.1214/10-STS332 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

The 1913 and 1914 white workers' strikes

African Studies Seminar series. Paper presented October 1978The gold mining industry on the Rand began in the 1880's and by 1913 there were 63 mines employing about 21 000 white workers and 200 000 black workers. Gold, the international money commodity, had a fixed price. This meant there was a certain constraint with regard to the costs of production because increases could not be passed on to the buyers. The gold bearing ore on the Rand was deep lying and of a consistent low grade throughout the Reef. Because of its depth large amounts of capital investment were required for its exploitation. This was provided by finance houses in Europe through whom groups of gold mining companies were controlled. The profitability of the industry was constrained by the fixed price, the low grade of the ore and the need for large scale capital investment. Because of this the industry depended on cheap labour. The problem of finding and maintaining a supply of cheap labour dominated the policies of the industry. In the early years the great majority of blacks lived in the rural areas subsisting as independent farmers or on white owned land as squatters, share croppers and wage labourers…. As far as the gold mining industry was concerned in the early years some blacks came voluntarily in order to obtain cash to buy European produced goods such as guns. But increasingly black labour was obtained by recruiters who worked for the gold mining industry…. The black labour force thus obtained was lacking in any experience of industrial life and was restricted to unskilled work. In order to develop the mines and carry out certain skilled mining operations the gold companies also needed a supply of skilled workers. These were not available in South Africa. Skilled miners from overseas were induced £o come to the. Witwatersrand because of the relatively high wages. Most of them originated in Britain. Skilled miners tended to be nomadic and some had experience of work in Australia, America and other gold fields throughout the world. These miners' brought to South Africa their trade union experience and soon established branches of British craft unions and an autonomous miners union. As blacks became experienced in gold mining operations the TCM wanted to be able to substitute this labour for the more expensive white workers. Skilled whites were still necessary but where skills could be fragmented blacks could carry out some of the operations…. This is largely an empirical study of the 1913 miners' strike and the 1914 railway strike. I concentrate on events rather than analysis and would be glad of any help from people in the seminar. Although it is impossible to exhaustively state the causes for the 1913 strike I outline some of the factors I see as important. These include the insecurity of white miners because of their fear of being replaced by black and their reaction to general labour condition including their insecurity of tenure and the occupational disease phthisis. The strike itself revolved around the question of the recognition of trade unions which the TCM refused to do

A Hierarchical Bayesian Design for Phase I Trials of Novel Combinations of Cancer Therapeutic Agents

We propose a hierarchical model for the probability of dose-limiting toxicity (DLT) for combinations of doses of two therapeutic agents. We apply this model to an adaptive Bayesian trial algorithm whose goal is to identify combinations with DLT rates close to a prespecified target rate. We describe methods for generating prior distributions for the parameters in our model from a basic set of information elicited from clinical investigators. We survey the performance of our algorithm in a series of simulations of a hypothetical trial that examines combinations of four doses of two agents. We also compare the performance of our approach to two existing methods and assess the sensitivity of our approach to the chosen prior distribution.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78700/1/j.1541-0420.2009.01363.x.pd

Parametric non-mixture cure models for schedule finding of therapeutic agents

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75664/1/j.1467-9876.2008.00660.x.pd

Experimental designs for phase I and phase I/II dose-finding studies

We review the rationale behind the statistical design of dose-finding studies as used in phase I and phase I/II clinical trials. We underline what the objectives of such dose-finding studies should be and why the widely used standard design fails to meet any of these objectives. The standard design is a ‘memoryless' design and we discuss how this impacts on practical behaviour. Designs introduced over the last two decades can be viewed as designs with memory and we discuss how these designs are superior to memoryless designs. By superior we mean that they require less patients overall, less patients to attain the maximum tolerated dose (MTD), and concentrate a higher percentage of patients at and near to the MTD. We reanalyse some recently published studies in order to provide support to our contention that markedly better results could have been achieved had a design with memory been used instead of a memoryless design

Controlled backfill in oncology dose-finding trials

The use of backfill in early phase dose-finding trials is a relatively recent practice. It consists of assigning patients to dose levels below the level where the study is at. The main reason for backfilling is to collect additional pharmacokinetic, pharmacodynamic and response data, in order to assess whether a plateau may exist on the dose-efficacy curve. This is a possibility in oncology with molecularly targeted agents or immunotherapy. Recommending for further study a dose level lower than the maximum tolerated dose could be supported in such situations. How to best allocate backfill patients to dose levels is not yet established. In this paper we propose to randomise backfill patients below the dose level where the study is at. A refinement of this would be to stop backfilling to lower dose levels when these show insufficient efficacy compared to higher levels, starting at dose level 1 and repeating this process sequentially. At study completion, data from all patients (both backfill patients and dose-finding patients) is used to estimate the dose-response curve. The fit from a change point model is compared to the fit of a monotonic model to identify a potential plateau. Using simulations, we show that this approach can identify the plateau on the dose-response curve when such a plateau exists, allowing the recommendation of a dose level lower than the maximum tolerated dose for future studies. This contribution provides a methodological framework for backfilling, from the perspective of both design and analysis in early phase oncology trials

Generalizing the TITE-CRM to adapt for early- and late-onset toxicities

Due to the staggered entry of subjects in phase I trials, some subjects will only be partially through the study when others are ready to be enrolled. Nonetheless, many phase I designs focus solely upon whether or not subjects experience toxicity, thereby determining the maximum tolerated dose (MTD) with a binomial likelihood using data from fully observed subjects. The time-to-event continual reassessment method (TITE-CRM) was the first attempt to incorporate information from partially observed subjects by using a weighted binomial likelihood in which the weights are based upon the actual toxicity time distribution. Unfortunately, it is difficult to accurately estimate the toxicity time distribution because only a small proportion of enrolled subjects will experience toxicity. Creators of the TITE-CRM propose the simple alternative of weighting subjects by the proportion of time observed, as well as two adaptive weights to adjust for late-onset toxicities. As a alternative to these approaches, we suggest assuming the toxicity times, as a proportion of the total time under observation, have a Beta distribution with parameters 1.0 and θ ; we also allow θ to vary by dose. The value of θ allows us to reflect the occurrence of early- or late-onset toxicities without correctly specifying the actual distribution of toxicity times. Through this model, we do not necessarily expect to improve identification of the MTD, but rather hope to reduce the exposure of subjects to overly toxic doses. Through simulation, we examine how well our model identifies the MTD and allocates dose assignments in three scenarios investigated by previous publications. Copyright © 2005 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34864/1/2337_ftp.pd

Screen printed electrochemical sensors for real-time sodium monitoring in sweat

We report on the preparation of disposable potentiometric sensor strips for monitoring sodium in sweat. We also present their integration in a microfluidic chip used to harvest sweat in-situ during exercise. The sensor-chip is integrated with a miniaturized electronic platform able to transmit data wirelessly in real time during a stationary cycling session in a controlled environment