Estimating treatment effect in randomized trial after control to treatment crossover using external controls.

In clinical trials, it is common to design a study that permits the administration of an experimental treatment to participants in the placebo or standard of care group post primary endpoint. This is often seen in the open-label extension phase of a phase III, pivotal study of the new medicine, where the focus is on assessing long-term safety and efficacy. With the availability of external controls, proper estimation and inference of long-term treatment effect during the open-label extension phase in the absence of placebo-controlled patients are now feasible.

Opportunities and challenges with decentralized trials in Neuroscience.

Decentralized clinical trials (DCTs), that is, studies integrating elements of telemedicine and mobile/local healthcare providers allowing for home-based assessments, are an important concept to make studies more resilient and more patient-centric by taking into consideration participant's views and shifting trial activities to better meet the needs of trial participants. There are however, not only advantages but also challenges associated with DCTs. An area to be addressed by appropriate statistical methodology is the integration of data resulting from a possible mix of home and clinic assessments at different visits for the same variable, especially in adjusting for sources of possible systematic differences.

The use of external controls: To what extent can it currently be recommended?

With more and better clinical data being captured outside of clinical studies and greater data sharing of clinical studies, external controls may become a more attractive alternative to randomized clinical trials (RCTs). Both industry and regulators recognize that in situations where a randomized study cannot be performed, external controls can provide the needed contextualization to allow a better interpretation of studies without a randomized control. It is also agreed that external controls will not fully replace RCTs as the gold standard for formal proof of efficacy in drug development and the yardstick of clinical research.

A multistate model for early decision-making in oncology.

The development of oncology drugs progresses through multiple phases, where after each phase, a decision is made about whether to move a molecule forward. Early phase efficacy decisions are often made on the basis of single-arm studies based on a set of rules to define whether the tumor improves ("responds"), remains stable, or progresses (response evaluation criteria in solid tumors [RECIST]). These decision rules are implicitly assuming some form of surrogacy between tumor response and long-term endpoints like progression-free survival (PFS) or overall survival (OS).

Nonparametric adaptive enrichment designs using categorical surrogate data.

Adaptive survival trials are particularly important for enrichment designs in oncology and other life-threatening diseases. Current statistical methodology for adaptive survival trials provide type I error rate control only under restrictions. For instance, if we use stage-wise P values based on increments of the log-rank test, then the information used for the interim decisions need to be restricted to the primary survival endpoint.

Comparison of design strategies for a three-arm clinical trial with time-to-event endpoint: Power, time-to-analysis, and operational aspects.

To optimize resources, randomized clinical trials with multiple arms can be an attractive option to simultaneously test various treatment regimens in pharmaceutical drug development. The motivation for this work was the successful conduct and positive final outcome of a three-arm randomized clinical trial primarily assessing whether obinutuzumab plus chlorambucil in patients with chronic lympocytic lymphoma and coexisting conditions is superior to chlorambucil alone based on a time-to-event endpoint. The inference strategy of this trial was based on a closed testing procedure.

Bayesian predictive power: choice of prior and some recommendations for its use as probability of success in drug development.

Bayesian predictive power, the expectation of the power function with respect to a prior distribution for the true underlying effect size, is routinely used in drug development to quantify the probability of success of a clinical trial. Choosing the prior is crucial for the properties and interpretability of Bayesian predictive power. We review recommendations on the choice of prior for Bayesian predictive power and explore its features as a function of the prior.

Data sharing and the evolving role of statisticians.

Background: Greater transparency and, in particular, sharing of clinical study reports and patient level data for further research is an increasingly important topic for the pharmaceutical and biotechnology industry and other organisations who sponsor and conduct clinical research as well as academic researchers and patient advocacy groups. Statisticians are ambassadors for data sharing and are central to its success. They play an integral role in data sharing discussions within their companies and also externally helping to shape policy and processes while providing input into practical solutions to aid data sharing.

Statistical and data reporting guidelines for the European Journal of Cardio-Thoracic Surgery and the Interactive CardioVascular and Thoracic Surgery.

As part of the peer review process for the European Journal of Cardio-Thoracic Surgery (EJCTS) and the Interactive CardioVascular and Thoracic Surgery (ICVTS), a statistician reviews any manuscript that includes a statistical analysis. To facilitate authors considering submitting a manuscript and to make it clearer about the expectations of the statistical reviewers, we present up-to-date guidelines for authors on statistical and data reporting specifically in these journals. The number of statistical methods used in the cardiothoracic literature is vast, as are the ways in which data are presented.

The use of phase 2 interim analysis to expedite drug development decisions.

Purpose: To expedite drug development, we propose a two-step decision-making process that utilizes interim efficacy results from a comparative phase 2 trial to determine whether to accelerate subsequent phase 3 preparations, and final analysis to ultimately determine whether to conduct phase 3 testing.

Methods: The operational characteristics of this process were evaluated by modeling simulated data of oncology trials and retrospectively analyzing data from historical comparative phase 2 trials. Progression-free survival (PFS) was used as the primary endpoint; the estimated PFS hazard ratios (HRs) of ≤0.

European Federation of Statisticians in the Pharmaceutical Industry's position on access to clinical trial data.

The European Federation of Statisticians in the Pharmaceutical Industry (EFSPI) believes access to clinical trial data should be implemented in a way that supports good research, avoids misuse of such data, lies within the scope of the original informed consent and fully protects patient confidentiality. In principle, EFSPI supports responsible data sharing. EFSPI acknowledges it is in the interest of patients that their data are handled in a strictly confidential manner to avoid misuse under all possible circumstances.

Comments on the draft guidance on "adaptive design clinical trials for drugs and biologics" of the U.S. Food and Drug Administration.

The U.S. FDA has published a draft guidance on "Adaptive Design Clinical Trials for Drugs and Biologics", which gives regulatory guidance on methodological issues in exploratory and confirmatory clinical trials planned with an adaptive design.

Left ventricular geometry predicts cardiovascular outcomes associated with anemia correction in CKD.

Partial correction of anemia in patients with chronic kidney disease (CKD) reduces left ventricular hypertrophy (LVH), which is a risk factor for cardiovascular (CV) morbidity, but complete correction of anemia does not improve CV outcomes. Whether LV geometry associates with CV events in patients who are treated to different hemoglobin (Hb) targets is unknown. One of the larger trials to study the effects of complete correction of anemia in stages 3 to 4 CKD was the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial.

Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors.