An efficient sequential design of clinical trials

We propose an efficient group sequential monitoring rule for clinical trials. At each interim analysis both efficacy and futility are evaluated through a specified loss structure together with the predicted power. The proposed design is robust to a wide range of priors, and achieves the specified power with a saving of sample size compared to existing adaptive designs. A method is also proposed to obtain a reduced-bias estimator of treatment difference for the proposed design. The new approaches hold great potential for efficiently selecting a more effective treatment in comparative trials. Operating characteristics are evaluated and compared with other group sequential designs in empirical studies. An example is provided to illustrate the application of the method.     

Issues in blinded sample size re-estimation

The utility of blinded sample size re-estimation for clinical trials depends on the ability to estimate variability without providing information about the true treatment difference, and on some reasonable assurance that the method is not likely to cause the sample size to be increased when the treatment effect is better than anticipated. We show that violations of these properties are unlikely to occur in practice.     

Tables of the cramér-von mises distributions

Tables of the one- and two-sample unweighted Cramer-von Mises statistics are given, and compared with the limiting distribution. The two-sample statistic may be useful in (for example) clinical trials when a proportional hazards assumption (which leads to the use of the log-rank test) is unjustified: see, for example, Schumacher (1984). It is often possible to stop clinical trials early if the Cramer-von Mises test (rather than say, the log-rank test) is employed.     

A structured framework for assessing sensitivity to missing data assumptions in longitudinal clinical trials

The objective of this research was to demonstrate a framework for drawing inference from sensitivity analyses of incomplete longitudinal clinical trial data via a re‐analysis of data from a confirmatory clinical trial in depression. A likelihood‐based approach that assumed missing at random (MAR) was the primary analysis. Robustness to departure from MAR was assessed by comparing the primary result to those from a series of analyses that employed varying missing not at random (MNAR) assumptions (selection models, pattern mixture models and shared parameter models) and to MAR methods that used inclusive models. The key sensitivity analysis used multiple imputation assuming that after dropout the trajectory of drug‐treated patients was that of placebo treated patients with a similar outcome history (placebo multiple imputation). This result was used as the worst reasonable case to define the lower limit of plausible values for the treatment contrast. The endpoint contrast from the primary analysis was ? 2.79 (p = .013). In placebo multiple imputation, the result was ? 2.17. Results from the other sensitivity analyses ranged from ? 2.21 to ? 3.87 and were symmetrically distributed around the primary result. Hence, no clear evidence of bias from missing not at random data was found. In the worst reasonable case scenario, the treatment effect was 80% of the magnitude of the primary result. Therefore, it was concluded that a treatment effect existed. The structured sensitivity framework of using a worst reasonable case result based on a controlled imputation approach with transparent and debatable assumptions supplemented a series of plausible alternative models under varying assumptions was useful in this specific situation and holds promise as a generally useful framework. Copyright © 2012 John Wiley & Sons, Ltd.     

Blinded sample size re-estimation in clinical trials comparing several treatments

An important question that arises in clinical trials is how many additional observations, if any, are required beyond those originally planned. This has satisfactorily been answered in the case of two-treatment double-blind clinical experiments. However, one may be interested in comparing a new treatment with its competitors, which may be more than one. This problem is addressed in this investigation involving responses from arbitrary distributions, in which the mean and the variance are not functionally related. First, a solution in determining the initial sample size for specified level of significance and power at a specified alternative is obtained. Then it is shown that when the initial sample size is large, the nominal level of significance and the power at the pre-specified alternative are fairly robust for the proposed sample size re-estimation procedure. An application of the results is made to the blood coagulation functionality problem considered by Kropf et al. [Multiple comparisons of treatments with stable multivariate tests in a two-stage adaptive design, including a test for non-inferiority, Biom. J. 42(8) (2000), pp. 951–965].     

Using the Therapist's Inner Conversation in Teamwork with Novice Therapists

Peter Rober's work (2005a) on the therapist’s inner conversation (TIC) has been a significant contribution to understanding the therapist's 'here and now' experience that focuses on the emergence of different voices responding to what is said in the therapy session. Frediani and Rober (2016) conducted an investigation into the experience and TIC of novice therapists concerning emotions aroused and how they deal with them during family therapy. Their research prompted us to ask how this methodology could work with recent graduates and those in the last year of their undergraduate training. This was addressed in the adolescent psychotherapy team that is part of the Equipo de Trabajo y Asesoría Sistémica (Systemic Counselling and Teamwork) (eQtasis) of the Psychology Department of the University of Chile. An important characteristic has been developing an ethics for clinical practice and generating a collaborative reflexive approach as a central aspect of the clinical training. The paper aims to promote the legitimacy of the experience of novice therapists who despite limited professional experience have many stories that connect with what is said in therapy.     

Interview schedule development for a Sequential explanatory mixed method design: complementary-alternative medicine (CAM) study among Indonesian psychologists

Sequential explanatory mixed method design is the most frequently applied in both health and social sciences literature. It is denoted by ‘QUAN → qual’ which represents the quantitative study occurs first and has greater weight in addressing the study’s aims, and the qualitative study follows to explain quantitative results. Despite the extensive use of sequential explanatory design, there are limited references to this design. Therefore, this methodological paper attempts to fill the gap by providing an illustration in developing a sequential explanatory interview schedule based on complementary-alternative medicine (CAM) study among clinical psychologists in Indonesia. The most important step to develop sequential explanatory interview schedule was the construction of aspects and questions that were immensely grounded on the most notable quantitative results. In this study, eight aspects of interview schedule were constructed after analyses of the nationwide survey. The interview schedule then piloted among participants with fairly similar characteristics to the participants in the main interviews. This process enhanced the quality of questions through feedback from participants and improved the interviewer’s skills through familiarization with questions. It is expected that this reflection report could be adopted as a practical guideline in developing interview schedule for sequential explanatory mixed method design, particularly in the field of psychology.     

Bayesian sample size determination for phase IIA clinical trials using historical data and semi‐parametric prior's elicitation

The Simon's two‐stage design is the most commonly applied among multi‐stage designs in phase IIA clinical trials. It combines the sample sizes at the two stages in order to minimize either the expected or the maximum sample size. When the uncertainty about pre‐trial beliefs on the expected or desired response rate is high, a Bayesian alternative should be considered since it allows to deal with the entire distribution of the parameter of interest in a more natural way. In this setting, a crucial issue is how to construct a distribution from the available summaries to use as a clinical prior in a Bayesian design. In this work, we explore the Bayesian counterparts of the Simon's two‐stage design based on the predictive version of the single threshold design. This design requires specifying two prior distributions: the analysis prior, which is used to compute the posterior probabilities, and the design prior, which is employed to obtain the prior predictive distribution. While the usual approach is to build beta priors for carrying out a conjugate analysis, we derived both the analysis and the design distributions through linear combinations of B‐splines. The motivating example is the planning of the phase IIA two‐stage trial on anti‐HER2 DNA vaccine in breast cancer, where initial beliefs formed from elicited experts' opinions and historical data showed a high level of uncertainty. In a sample size determination problem, the impact of different priors is evaluated.     

Reflexivity,Process, and Responsibility: Itineraries in Clinical Research

From the start of the discipline, the use of sociological knowledge to produce positive changes has created theoretical/practical and neutral/normative dilemmas, which are currently a crucial point for the development of clinical research. This paper considers the implications related to these dilemmas, examining thoroughly the methodological significance of research itineraries, upon which the main structure of clinical sociological research in Italy is currently based. The importance of the concepts of process, feedback, and responsibility are discussed as the prime ingredients of sociological clinical research.     

A Parametric Estimation Procedure for Relapse Time Distributions

In a relapse clinical trial patients who have recovered from some recurrent disease (e.g.,ulcer or cancer) are examined at a number of predetermined times. A relapse can be detected either at one of these planned inspections or at a spontaneous visit initiated by the patient because of symptoms. In the first case the observations of the time to relapse, X, is interval-censored by two predetermined time-points. In the second case the upper endpoint of the interval is an observation of the time to symptoms,Y . To model the progression of the disease we use a partially observable Markov process. This approach results in a bivariate phase-type distribution for the joint distribution of (X,Y). It is a flexible model which contains several natural distributions for X, and allows the conditional distributions of the marginals to smoothly depend on each other. To estimate the distributions involved we develop an EM-algorithm. The estimation procedure is evaluated and compared with a non-parametric method in a couple of examples based on simulated data.