Historical information is always relevant for clinical trial design. Additionally, if incorporated in the analysis of a new trial, historical data allow to reduce the number of subjects. This decreases costs and trial duration, facilitates recruitment, and may be more ethical. Yet, under prior-data conflict, a too optimistic use of historical data may be inappropriate. We address this challenge by deriving a Bayesian meta-analytic-predictive prior from historical data, which is then combined with the new data. This prospective approach is equivalent to a meta-analytic-combined analysis of historical and new data if parameters are exchangeable across trials. The prospective Bayesian version requires a good approximation of the meta-analytic-predictive prior, which is not available analytically. We propose two- or three-component mixtures of standard priors, which allow for good approximations and, for the one-parameter exponential family, straightforward posterior calculations. Moreover, since one of the mixture components is usually vague, mixture priors will often be heavy-tailed and therefore robust. Further robustness and a more rapid reaction to prior-data conflicts can be achieved by adding an extra weakly-informative mixture component. Use of historical prior information is particularly attractive for adaptive trials, as the randomization ratio can then be changed in case of prior-data conflict. Both frequentist operating characteristics and posterior summaries for various data scenarios show that these designs have desirable properties. We illustrate the methodology for a phase II proof-of-concept trial with historical controls from four studies. Robust meta-analytic-predictive priors alleviate prior-data conflicts ' they should encourage better and more frequent use of historical data in clinical trials.

Traditional drug development consists of a sequence of independent trials organized in different phases. Full development typically involves (i) a learning phase II trial and (ii) one or two confirmatory phase III trial(s). For example, in the phase II trials several doses of the new compound might be compared to a control and/or placebo with the goal of deciding whether to stop or continue development and, in the latter case, selecting one or two "best" doses to carry forward into the confirmatory phase. The phase III trials are then conducted as stand-alone confirmatory studies, not incorporating in their statistical analyses data collected in the previous phases. Seamless phase II/III designs are aimed at interweaving the two phases of full development by combining them into one single, uninterrupted study conducted in two stages. In the dose-finding example above, one (or more) dose(s) are selected after the first stage based on the available data at interim, and are then observed further in the second stage. The final analysis of the selected dose(s) includes patients from both stages and is performed such that the overall type I error rate is controlled at a prespecified level regardless of the dose selection rule used at interim. The adequacy of the dose selection at interim is obviously a critical step for the success of a seamless phase II/III trial. In this paper we focus on the description of flexible test procedures allowing for adaptively selecting hypotheses at interim and thus allowing the combination of learning and confirming in a single seamless trial. We review the statistical background, introduce different test procedures and compare them in a power study. In a subsequent paper (Schmidli et al., 2006) we give several applications from our daily practice and discuss related implementation issues in conducting adaptive seamless designs.

The normal‐normal hierarchical model (NNHM) constitutes a simple and widely used framework for meta‐analysis. In the common case of only few studies contributing to the meta‐analysis, standard approaches to inference tend to perform poorly, and Bayesian meta‐analysis has been suggested as a potential solution. The Bayesian approach, however, requires the sensible specification of prior distributions. While noninformative priors are commonly used for the overall mean effect, the use of weakly informative priors has been suggested for the heterogeneity parameter, in particular in the setting of (very) few studies. To date, however, a consensus on how to generally specify a weakly informative heterogeneity prior is lacking. Here we investigate the problem more closely and provide some guidance on prior specification.

Sample size estimation in clinical trials depends critically on nuisance parameters, such as variances or overall event rates, which have to be guessed or estimated from previous studies in the planning phase of a trial. Blinded sample size reestimation estimates these nuisance parameters based on blinded data from the ongoing trial, and allows to adjust the sample size based on the acquired information. In the present paper, this methodology is developed for clinical trials with count data as the primary endpoint. In multiple sclerosis such endpoints are commonly used in phase 2 trials (lesion counts in magnetic resonance imaging (MRI)) and phase 3 trials (relapse counts). Sample size adjustment formulas are presented for both Poisson-distributed data and for overdispersed Poisson-distributed data. The latter arise from sometimes considerable between-patient heterogeneity, which can be observed in particular in MRI lesion counts. The operation characteristics of the procedure are evaluated by simulations and recommendations on how to choose the size of the internal pilot study are given. The results suggest that blinded sample size reestimation for count data maintains the required power without an increase in the type I error.

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A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).

Adaptive seamless phase II/III designs combine a phase II and a phase III study into one single confirmatory clinical trial. Several examples of such designs are presented, where the primary endpoint is binary, time-to-event or continuous. The interim adaptations considered include the selection of treatments and the selection of hypotheses related to a pre-specified subgroup of patients. Practical aspects concerning the planning and implementation of adaptive seamless confirmatory studies are also discussed.

Randomized controlled trials are the gold standard to investigate efficacy and safety of new treatments. In certain settings, however, randomizing patients to control may be difficult for ethical or feasibility reasons. Borrowing strength using relevant individual patient data on control from external trials or real‐world data (RWD) sources may then allow us to reduce, or even eliminate, the concurrent control group. Naive direct use of external control data is not valid due to differences in patient characteristics and other confounding factors. Instead, we suggest the rigorous application of meta‐analytic and propensity score methods to use external controls in a principled way. We illustrate these methods with two case studies: (i) a single‐arm trial in a rare cancer disease, using propensity score matching to construct an external control from RWD; (ii) a randomized trial in children with multiple sclerosis, borrowing strength from past trials using a Bayesian meta‐analytic approach.