Covariate-adjusted value-guided subgroup identification via boosting.

It is widely recognized that treatment effects could differ across subgroups of patients. Subgroup analysis, which assesses such heterogeneity, provides valuable information in developing personalized therapies. There has been extensive research developing novel statistical methods for subgroup identification.

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer.

Background: Concurrent chemoradiotherapy is a standard therapy for patients with stage III non-small-cell lung cancer (NSCLC). Durvalumab is an approved treatment option following concurrent chemoradiotherapy in the absence of disease progression. The multicenter, phase III, randomized, placebo- and active-controlled, double-blind KEYLYNK-012 study evaluates whether initiation of immunotherapy with pembrolizumab concurrently with chemoradiotherapy, followed by post-chemoradiotherapy pembrolizumab with or without olaparib improves outcomes for participants with stage III NSCLC.

Estimands for overall survival in clinical trials with treatment switching in oncology.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology.

Principal stratum strategy: Potential role in drug development.

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called intercurrent events in the ICH E9(R1) guideline.

Independent drug action and its statistical implications for development of combination therapies.

Researchers have long sought to find combinations of cancer drugs that might achieve synergy. However, while observed in some preclinical tumor models, synergistic effects are rarely seen in clinical trials. In fact, growing evidence in clinical trial data shows that the treatment effect of most approved combination therapies can be largely explained by the independent drug action model at the patient level.

A nonparametric method for value function guided subgroup identification via gradient tree boosting for censored survival data.

In randomized clinical trials with survival outcome, there has been an increasing interest in subgroup identification based on baseline genomic, proteomic markers, or clinical characteristics. Some of the existing methods identify subgroups that benefit substantially from the experimental treatment by directly modeling outcomes or treatment effect. When the goal is to find an optimal treatment for a given patient rather than finding the right patient for a given treatment, methods under the individualized treatment regime framework estimate an individualized treatment rule that would lead to the best expected clinical outcome as measured by a value function.

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.

Background: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).

Methods: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression.

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.

Background: Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer.

Methods: We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries.

A randomized clinical trial evaluating the safety and efficacy of sitagliptin added to the combination of sulfonylurea and metformin in patients with type 2 diabetes mellitus and inadequate glycemic control.

Background: Type 2 diabetes mellitus (T2DM) treatment generally requires multiple antihyperglycemic agents. When diet, exercise, and treatment with sulfonylurea and metformin do not achieve glycemic goals, several options are available. The present study evaluated the efficacy and tolerability of sitagliptin 100 mg/day added to therapy with sulfonylurea and metformin.

Efficacy and Tolerability of Sitagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control: A Randomized, Double-Blind, Non-Inferiority Trial.

Objective: The aim of this study was to evaluate the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control with diet and exercise alone.

Methods: This was a randomized, parallel-group, multinational, non-inferiority clinical trial with an active-controlled, double-blind treatment period in which patients ≥ 65 and ≤ 85 years of age with T2DM were screened at 85 sites. Patients were randomized to once-daily sitagliptin (100 or 50 mg, depending on renal function) or glimepiride (in titrated doses) for 30 weeks.

Early Clinical Development Planning via Biomarkers, Clinical Endpoints, and Simulation: A Case Study to Optimize for Phase 3 Dose Selection.

Background: This study investigated a framework that leverages the relationship between biomarkers and a target clinical endpoint to optimize an early development plan.

Methods: Different biomarker designs were assessed for proof of concept (PoC) and dose finding (DF) to improve phase 2b (Ph2b) design as well as phase 3 (Ph3) dose choice. A case study using a Bayesian trivariate normal distribution model for 2 biomarkers and a clinically relevant endpoint was utilized with simulation to assess performance characteristics.

Information-based sample size re-estimation in group sequential design for longitudinal trials.

Group sequential design has become more popular in clinical trials because it allows for trials to stop early for futility or efficacy to save time and resources. However, this approach is less well-known for longitudinal analysis. We have observed repeated cases of studies with longitudinal data where there is an interest in early stopping for a lack of treatment effect or in adapting sample size to correct for inappropriate variance assumptions.

Consistency assessment with global and bridging development strategies in emerging markets.

Global trial strategy with the participation of all major regions including countries from emerging markets surely increases new drug development efficiency. Nevertheless, there are circumstances in which some countries in emerging markets cannot join the original global trial. To evaluate the extrapolability of the original trial results to a new country, a bridging trial in the country has to be conducted.

Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes.

Aims: To assess efficacy and safety of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in combination therapy with metformin (≥1500 mg/day) and pioglitazone (≥30 mg/day) in patients with type 2 diabetes (T2DM) with inadequate glycemic control (hemoglobin A1c [HbA1c] ≥7.5% and ≤11%).

Methods: This placebo-controlled, double-blind study included 313 patients, mean baseline HbA1c=8.

The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes.

Background:   The present study was conducted to evaluate the efficacy, safety and tolerability of sitagliptin added to ongoing metformin therapy in Chinese patients with type 2 diabetes (T2DM) who failed to achieve adequate glycemic control with metformin monotherapy.

Methods:   After a metformin titration/stabilization period and a 2-week, single-blind, placebo run-in period, 395 Chinese patients with T2DM aged 25-77 years (baseline HbA1c 8.5%) were randomized (1:1) to double-blind placebo or sitagliptin 100 mg q.

Effects of MK-0941, a novel glucokinase activator, on glycemic control in insulin-treated patients with type 2 diabetes.

Objective: To assess the efficacy and safety of MK-0941, a glucokinase activator (GKA), when added to stable-dose insulin glargine in patients with type 2 diabetes.

Research Design And Methods: In this double-blind study, 587 patients taking stable-dose insulin glargine (±metformin ≥1,500 mg/day) were randomized (1:1:1:1:1) to MK-0941 10, 20, 30, or 40 mg or matching placebo t.i.

A note on dichotomization of continuous response variable in the presence of contamination and model misspecification.

The purpose of this note is to raise awareness of the complexity of the practice involving dichotomization. It is well known that the regular regression models are effective tools for analyzing Gaussian-type response variables, and researchers are often told that it is a 'bad idea' to practice dichotomization if continuous measurements are available. We demonstrate through special cases, however, that there is another side of the story if the response variable is contaminated.

Genetic structures of copy number variants revealed by genotyping single sperm.

Background: Copy number variants (CNVs) occupy a significant portion of the human genome and may have important roles in meiotic recombination, human genome evolution and gene expression. Many genetic diseases may be underlain by CNVs. However, because of the presence of their multiple copies, variability in copy numbers and the diploidy of the human genome, detailed genetic structure of CNVs cannot be readily studied by available techniques.