A Generalization of the Two Trials Paradigm.

The two trials paradigm plays a prominent role in drug development and has been widely and controversially discussed. Its purpose is to ensure replicability or substantiation of study results. This note investigates a simple generalization of the paradigm to more than two trials that preserves the project wise type-I error rate and power.

Replicability of studies following a dual-criterion design.

Replicability of results is regarded as the corner stone of science. Recent research seems to raise doubts about whether this requirement is generally fulfilled. Often, replicability of results is defined as repeating a statistically significant result.

Subgroup analysis and interpretation for phase 3 confirmatory trials: White paper of the EFSPI/PSI working group on subgroup analysis.

Subgroup by treatment interaction assessments are routinely performed when analysing clinical trials and are particularly important for phase 3 trials where the results may affect regulatory labelling. Interpretation of such interactions is particularly difficult, as on one hand the subgroup finding can be due to chance, but equally such analyses are known to have a low chance of detecting differential treatment effects across subgroup levels, so may overlook important differences in therapeutic efficacy. EMA have therefore issued draft guidance on the use of subgroup analyses in this setting.

Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents.

Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions.

Applicability and added value of novel methods to improve drug development in rare diseases.

Background: The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports.

Methods: The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters.

Subgroup identification in clinical trials via the predicted individual treatment effect.

Identifying subgroups of treatment responders through the different phases of clinical trials has the potential to increase success in drug development. Recent developments in subgroup analysis consider subgroups that are defined in terms of the predicted individual treatment effect, i.e.

Relationship Between Maximal Dynamic Force in the Deep Back Squat and Sprinting Performance in Consecutive Segments Up to 30 m.

Möck, S, Hartmann, R, Wirth, K, Rosenkranz, G, and Mickel, C. Relationship between maximal dynamic force in the deep back squat and sprinting performance in consecutive segments up to 30 m. J Strength Cond Res 35(4): 1039-1043, 2021-The sprint (in track and field athletics) is characterized by a fluent transition from predominantly knee extending musculature during the initial acceleration phase toward dominance of the hamstring muscle group thereafter.

Methods for the analysis of multiple endpoints in small populations: A review.

While current guidelines generally recommend single endpoints for primary analyses of confirmatory clinical trials, it is recognized that certain settings require inference on multiple endpoints for comprehensive conclusions on treatment effects. Furthermore, combining treatment effect estimates from several outcome measures can increase the statistical power of tests. Such an efficient use of resources is of special relevance for trials in small populations.

Correlation of dynamic strength in the standing calf raise with sprinting performance in consecutive sections up to 30 meters.

Sprinting represents a result-relevant task in many sports. The correlation of sprinting performance and one-repetition maximum (1RM) in a squat has been assumed as assured. Results of the correlation with 1RM of the plantar flexors are still pending.

Statistical analysis of Goal Attainment Scaling endpoints in randomised trials.

Goal Attainment Scaling is an assessment instrument to evaluate interventions on the basis of individual, patient-specific goals. The attainment of these goals is mapped in a pre-specified way to attainment levels on an ordinal scale, which is common to all goals. This approach is patient-centred and allows one to integrate the outcomes of patients with very heterogeneous symptoms.

Exploratory subgroup analysis in clinical trials by model selection.

The interest in individualized medicines and upcoming or renewed regulatory requests to assess treatment effects in subgroups of confirmatory trials requires statistical methods that account for selection uncertainty and selection bias after having performed the search for meaningful subgroups. The challenge is to judge the strength of the apparent findings after mining the same data to discover them. In this paper, we describe a resampling approach that allows to replicate the subgroup finding process many times.

Mavoglurant in adolescents with fragile X syndrome: analysis of Clinical Global Impression-Improvement source data from a double-blind therapeutic study followed by an open-label, long-term extension study.

Background: A phase II randomized, placebo-controlled, double-blind study and subsequent open-label extension study evaluated the efficacy, safety, and tolerability of mavoglurant (AFQ056), a selective metabotropic glutamate receptor subtype-5 antagonist, in treating behavioral symptoms in adolescent patients with fragile X syndrome (FXS). A novel method was applied to analyze changes in symptom domains in patients with FXS using the narratives associated with the clinician-rated Clinical Global Impression-Improvement (CGI-I) scale.

Methods: In the core study, patients were randomized to receive mavoglurant (25, 50, or 100 mg BID) or placebo over 12 weeks.

Remarks on designs enriching for placebo non-responders.

Background: High response under placebo constitutes a concern in clinical studies, particularly in psychiatry. Discontinuation of placebo responders identified during a placebo run-in is often recommended to avoid failures of clinical trials in the presence of high placebo effects. Evidence for the benefit of this approach is ambiguous.

Bayesian Design of Proof-of-Concept Trials.

The proof-of-concept (PoC) decision is a key milestone in the clinical development of an experimental treatment. A decision is taken on whether the experimental treatment is further developed (GO), whether its development is stopped (NO-GO), or whether further information is needed to make a decision. The PoC decision is typically based on a PoC clinical trial in patients comparing the experimental treatment with a control treatment.

Analysis of cross-over studies with missing data.

This paper addresses some aspects of the analysis of cross-over trials with missing or incomplete data. A literature review on the topic reveals that many proposals provide correct results under the missing completely at random assumption while only some consider the more general missing at random situation. It is argued that mixed-effects models have a role in this context to recover some of the missing intra-subject from the inter-subject information, in particular when missingness is ignorable.

Analysis Sets and Inference in Clinical Trials.

The debate about what constitutes a valid analysis of clinical trial data is longstanding. While the intention-to-treat (ITT) principle seems to be widely accepted in the context of controlled clinical trials aiming to show superiority of an experimental treatment over a control, the best choice for a noninferiority trial is still under discussion. In this article, it is argued that the definition of analysis sets and the purpose of ITT and per-protocol analyses proposed in the International Conference on Harmonisation biostatistics guideline E9 should be revised to allow for more appropriate analyses, given that statistical methodology has been developed since the guideline was issued.

The impact of randomization on the analysis of clinical trials.

The design of a comparative clinical trial involves a method of allocating treatments to patients. Usually, this assignment is performed to achieve several objectives: to minimize selection and accidental bias, to achieve balanced treatment assignment in order to maximize the power of the comparison, and most importantly, to obtain the basis for a valid statistical inference. In this paper, we are concerned exclusively with the last point.

Another view on the analysis of cardiovascular morbidity/mortality trials.

In many morbidity/mortality studies, composite endpoints are considered. Although the primary interest is to demonstrate that an invention delays death, the expected death rate is often that low that studies focussing on survival exclusively are not feasible. Components of the composite endpoint are chosen such that their occurrence is predictive for time to death.

Joint modeling of outcome, observation time, and missingness.

A modeling framework is described for the specific setting of clinical trials in which there is only a single post-randomization response measurement, which may itself be missing, or, for clinical reasons, may be measured before the trial end. Such settings have three simultaneous processes: the outcome itself, the time to measurement, and the occurrence of missing values. A simple latent variable structure within a multivariate Gaussian distribution is used to model them.

A note on the Hodges-Lehmann estimator.

The Hodges-Lehmann estimator was originally developed as a non-parametric estimator of a shift parameter. As it is widely used in statistical applications, the question is investigated what it is estimating if the shift model does not hold. It is shown that for data whose distributions are symmetric about their median the Hodges-Lehmann estimator based on the Wilcoxon Rank Sum test estimates the difference between the medians of the distributions.

A note on ethnic sensitivity studies.

In this article, we propose a similarity criterion for ethnic sensitivity studies in pharmacokinetic variables. We present how this criterion can be used in the context of different dose-exposure models and how sample size and power calculations can be done. Examples for the planning and analysis of ethnic sensitivity studies are provided.

Dose-finding study of valspodar (PSC 833) with daunorubicin and cytarabine to reverse multidrug resistance in elderly patients with previously untreated acute myeloid leukemia.

Introduction: This trial was designed to determine the maximum tolerated dose of intravenous daunorubicin (DNR) in combination with valspodar and to test the feasibility of P-glycoprotein modulation using valspodar in elderly patients with previously untreated acute myelogenous leukemia receiving standard induction chemotherapy.

Methods: Patients > or =60 years of age with previously untreated AML received valspodar (10 mg/kg/24 h by continuous intravenous infusion [CIV] on days 1-4 with a 2-mg/kg loading dose on day 1) in conjunction with two cycles of induction chemotherapy consisting of cytarabine (200 mg/m(2) CIV on days 1-7), and DNR (35 mg/m(2) [cohort 1] or 45 mg/m(2) [cohort 2] on days 1-3, intravenous bolus). Patients were assessed for dose-limiting toxicities (DLT), response rate, event-free and overall survival, and pharmacokinetics of valspodar and DNR.