Modelling and simulation to improve decision‐making in clinical development

Modelling and simulation are buzz words in clinical drug development. But is clinical trial simulation (CTS) really a revolutionary technique? There is not much more to CTS than applying standard methods of modelling, statistics and decision theory. However, doing this in a systematic way can mean a significant improvement in pharmaceutical research. This paper describes in simple examples how modelling could be used in clinical development. Four steps are identified: gathering relevant information about a drug and the disease; building a mathematical model; predicting the results of potential future trials; and optimizing clinical trials and the entire clinical programme. We discuss these steps and give a number of examples of model components, demonstrating that relatively unsophisticated models may also prove useful. We stress that modelling and simulation are decision tools and point out the benefits of integrating them with decision analysis. Copyright © 2005 John Wiley & Sons, Ltd.     

Decision‐making in early clinical drug development

This paper illustrates an approach to setting the decision framework for a study in early clinical drug development. It shows how the criteria for a go and a stop decision are calculated based on pre‐specified target and lower reference values. The framework can lead to a three‐outcome approach by including a consider zone; this could enable smaller studies to be performed in early development, with other information either external to or within the study used to reach a go or stop decision. In this way, Phase I/II trials can be geared towards providing actionable decision‐making rather than the traditional focus on statistical significance. The example provided illustrates how the decision criteria were calculated for a Phase II study, including an interim analysis, and how the operating characteristics were assessed to ensure the decision criteria were robust. Copyright © 2016 John Wiley & Sons, Ltd.     

Decision‐making in drug development using a composite definition of success

Evidence‐based quantitative methodologies have been proposed to inform decision‐making in drug development, such as metrics to make go/no‐go decisions or predictions of success, identified with statistical significance of future clinical trials. While these methodologies appropriately address some critical questions on the potential of a drug, they either consider the past evidence without predicting the outcome of the future trials or focus only on efficacy, failing to account for the multifaceted aspects of a successful drug development. As quantitative benefit‐risk assessments could enhance decision‐making, we propose a more comprehensive approach using a composite definition of success based not only on the statistical significance of the treatment effect on the primary endpoint but also on its clinical relevance and on a favorable benefit‐risk balance in the next pivotal studies. For one drug, we can thus study several development strategies before starting the pivotal trials by comparing their predictive probability of success. The predictions are based on the available evidence from the previous trials, to which new hypotheses on the future development could be added. The resulting predictive probability of composite success provides a useful summary to support the discussions of the decision‐makers. We present a fictive, but realistic, example in major depressive disorder inspired by a real decision‐making case.     

Penalized regression with model‐based penalties

Nonparametric regression techniques such as spline smoothing and local fitting depend implicitly on a parametric model. For instance, the cubic smoothing spline estimate of a regression function ∫ μ based on observations ti, Yi is the minimizer of Σ{Yi ‐ μ(ti)}² + λ∫(μ′′)². Since ∫(μ″)² is zero when μ is a line, the cubic smoothing spline estimate favors the parametric model μ(t) = α_o + α₁t. Here the authors consider replacing ∫(μ″)² with the more general expression ∫(Lμ)² where L is a linear differential operator with possibly nonconstant coefficients. The resulting estimate of μ performs well, particularly if Lμ is small. They present an O(n) algorithm for the computation of μ. This algorithm is applicable to a wide class of L's. They also suggest a method for the estimation of L. They study their estimates via simulation and apply them to several data sets.     

Learning from a lot: Empirical Bayes for high‐dimensional model‐based prediction

Empirical Bayes is a versatile approach to “learn from a lot” in two ways: first, from a large number of variables and, second, from a potentially large amount of prior information, for example, stored in public repositories. We review applications of a variety of empirical Bayes methods to several well‐known model‐based prediction methods, including penalized regression, linear discriminant analysis, and Bayesian models with sparse or dense priors. We discuss “formal” empirical Bayes methods that maximize the marginal likelihood but also more informal approaches based on other data summaries. We contrast empirical Bayes to cross‐validation and full Bayes and discuss hybrid approaches. To study the relation between the quality of an empirical Bayes estimator and p, the number of variables, we consider a simple empirical Bayes estimator in a linear model setting. We argue that empirical Bayes is particularly useful when the prior contains multiple parameters, which model a priori information on variables termed “co‐data”. In particular, we present two novel examples that allow for co‐data: first, a Bayesian spike‐and‐slab setting that facilitates inclusion of multiple co‐data sources and types and, second, a hybrid empirical Bayes–full Bayes ridge regression approach for estimation of the posterior predictive interval.     

Automated selection of post‐strata using a model‐assisted regression tree estimator

Despite having desirable properties, model‐assisted estimators are rarely used in anything but their simplest form to produce official statistics. This is due to the fact that the more complicated models are often ill suited to the available auxiliary data. Under a model‐assisted framework, we propose a regression tree estimator for a finite‐population total. Regression tree models are adept at handling the type of auxiliary data usually available in the sampling frame and provide a model that is easy to explain and justify. The estimator can be viewed as a post‐stratification estimator where the post‐strata are automatically selected by the recursive partitioning algorithm of the regression tree. We establish consistency of the regression tree estimator and a variance estimator, along with asymptotic normality of the regression tree estimator. We compare the performance of our estimator to other survey estimators using the United States Bureau of Labor Statistics Occupational Employment Statistics Survey data.     

Gaining acceptability for the Bayesian decision‐theoretic approach in dose‐escalation studies

There has recently been increasing demand for better designs to conduct first‐into‐man dose‐escalation studies more efficiently, more accurately and more quickly. The authors look into the Bayesian decision‐theoretic approach and use simulation as a tool to investigate the impact of compromises with conventional practice that might make the procedures more acceptable for implementation. Copyright © 2005 John Wiley & Sons, Ltd.     

Assessing interactions for fixed‐dose drug combinations in subcutaneous tumor xenograft studies

Drug combinations in preclinical tumor xenograft studies are often assessed using fixed doses. Assessing the joint action of drug combinations with fixed doses has not been well developed in the literature. Here, an interaction index is proposed for fixed‐dose drug combinations in a subcutaneous tumor xenograft model. Furthermore, a bootstrap percentile interval of the interaction index is also developed. The joint action of two drugs can be assessed on the basis of confidence limits of the interaction index. Tumor xenograft data from actual two‐drug combination studies are analyzed to illustrate the proposed method. Copyright © 2013 John Wiley & Sons, Ltd.     

Sample size determination in fixed‐dose combination drug studies

In this paper, the application of the intersection–union test method in fixed‐dose combination drug studies is discussed. An approximate sample size formula for the problem of testing the efficacy of a combination drug using intersection–union tests is proposed. The sample sizes obtained from the formula are found to be reasonably accurate in terms of attaining the target power 1?β for a specified β. Copyright © 2003 John Wiley & Sons, Ltd.     

Coherence principles in interval‐based dose finding

This paper studies the notion of coherence in interval‐based dose‐finding methods. An incoherent decision is either (a) a recommendation to escalate the dose following an observed dose‐limiting toxicity or (b) a recommendation to deescalate the dose following a non–dose‐limiting toxicity. In a simulated example, we illustrate that the Bayesian optimal interval method and the Keyboard method are not coherent. We generated dose‐limiting toxicity outcomes under an assumed set of true probabilities for a trial of n=36 patients in cohorts of size 1, and we counted the number of incoherent dosing decisions that were made throughout this simulated trial. Each of the methods studied resulted in 13/36 (36%) incoherent decisions in the simulated trial. Additionally, for two different target dose‐limiting toxicity rates, 20% and 30%, and a sample size of n=30 patients, we randomly generated 100 dose‐toxicity curves and tabulated the number of incoherent decisions made by each method in 1000 simulated trials under each curve. For each method studied, the probability of incurring at least one incoherent decision during the conduct of a single trial is greater than 75%. Coherency is an important principle in the conduct of dose‐finding trials. Interval‐based methods violate this principle for cohorts of size 1 and require additional modifications to overcome this shortcoming. Researchers need to take a closer look at the dose assignment behavior of interval‐based methods when using them to plan dose‐finding studies.     

Interval estimation for the breakpoint in segmented regression: a smoothed score‐based approach

This paper is concerned with interval estimation for the breakpoint parameter in segmented regression. We present score‐type confidence intervals derived from the score statistic itself and from the recently proposed gradient statistic. Due to lack of regularity conditions of the score, non‐smoothness and non‐monotonicity, naive application of the score‐based statistics is unfeasible and we propose to exploit the smoothed score obtained via induced smoothing. We compare our proposals with the traditional methods based on the Wald and the likelihood ratio statistics via simulations and an analysis of a real dataset: results show that the smoothed score‐like statistics perform in practice somewhat better than competitors, even when the model is not correctly specified.     

Idle thoughts of a ‘well‐calibrated’ Bayesian in clinical drug development

The use of Bayesian approaches in the regulated world of pharmaceutical drug development has not been without its difficulties or its critics. The recent Food and Drug Administration regulatory guidance on the use of Bayesian approaches in device submissions has mandated an investigation into the operating characteristics of Bayesian approaches and has suggested how to make adjustments in order that the proposed approaches are in a sense calibrated. In this paper, I present examples of frequentist calibration of Bayesian procedures and argue that we need not necessarily aim for perfect calibration but should be allowed to use procedures, which are well‐calibrated, a position supported by the guidance. Copyright © 2016 John Wiley & Sons, Ltd.     

Efficient estimation for case‐cohort studies

The author considers time‐to‐event data from case‐cohort designs. As existing methods are either inefficient or based on restrictive assumptions concerning the censoring mechanism, he proposes a semi‐parametrically efficient estimator under the usual assumptions for Cox regression models. The estimator in question is obtained by a one‐step Newton‐Raphson approximation that solves the efficient score equations with initial value obtained from an existing method. The author proves that the estimator is consistent, asymptotically efficient and normally distributed in the limit. He also resorts to simulations to show that the proposed estimator performs well in finite samples and that it considerably improves the efficiency of existing pseudo‐likelihood estimators when a correlate of the missing covariate is available. Although he focuses on the situation where covariates are discrete, the author also explores how the method can be applied to models with continuous covariates.     

Analysis of band‐recovery data in a multistate capture‐recapture framework

Dead recoveries of marked animals are commonly used to estimate survival probabilities. Band‐recovery models can be parameterized either by r (the probability of recovering a band conditional on death of the animal) or by f (the probability that an animal will be killed, retrieved, and have its band reported). The T parametrization can be implemented in a capture‐recapture framework with two states (alive and newly dead), mortality being the transition probability between the two states. The authors show here that the f parametrization can also be implemented in a multistate framework by imposing simple constraints on some parameters. They illustrate it using data on the mallard and the snow goose. However, they mention that because it does not entirely separate the individual survival and encounter processes, the f parametrization must be used with care on reduced models, or in the presence of estimates at the boundary of the parameter space. As they show, a multistate framework allows the use of powerful software for model fitting or testing the goodness‐of‐fit of models; it also affords the implementation of complex models such as those based on mixture of information or uncertain states     

Minimax A‐ and D‐optimal integer‐valued wavelet designs for estimation

The author discusses integer‐valued designs for wavelet estimation of nonparametric response curves in the possible presence of heteroscedastic noise using a modified wavelet version of the Gasser‐Müller kernel estimator or weighted least squares estimation. The designs are constructed using a minimax treatment and the simulated annealing algorithm. The author presents designs for three case studies in experiments for investigating Gompertz's theory on mortality rates, nitrite utilization in bush beans and the impact of crash helmets in motorcycle accidents.