Multidisciplinary considerations for implementing Bayesian borrowing in basket trials.

Drug development has historically relied on phase I-III clinical trials including participants sharing the same disease. However, drug development has evolved as the discovery of mechanistic drivers of disease demonstrated that the same therapeutic target may provide benefits across different diseases. A basket trial condenses evaluation of one therapy among multiple related diseases into a single trial and presents an opportunity to borrow information across them rather than viewing each in isolation.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the USA. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established.

Influence of Cooling duration on Efficacy in Cardiac Arrest Patients (ICECAP): study protocol for a multicenter, randomized, adaptive allocation clinical trial to identify the optimal duration of induced hypothermia for neuroprotection in comatose, adult survivors of after out-of-hospital cardiac arrest.

Background: Cardiac arrest is a common and devastating emergency of both the heart and brain. More than 380,000 patients suffer out-of-hospital cardiac arrest annually in the United States. Induced cooling of comatose patients markedly improved neurological and functional outcomes in pivotal randomized clinical trials, but the optimal duration of therapeutic hypothermia has not yet been established.

Use of Seamless Study Designs in Oncology Clinical Development- A Survey Conducted by IDSWG Oncology Sub-team.

Seamless study designs have the potential to accelerate clinical development. The use of innovative seamless designs has been increasing in the oncology area; however, while the concept of seamless designs becomes more popular and accepted, many challenges remain in both the design and conduct of these trials. This may be especially true when seamless designs are used in late phase development supporting regulatory decision-making.

A Systematic Review of Adaptive Seamless Clinical Trials for Late-Phase Oncology Development.

Introduction: Although oncology has seen large scientific and clinical advances over the last decade, it also has one of the lowest success rates for novel agents across therapeutic areas. Adaptive clinical trial design has been a popular option for increasing clinical trial efficiency and the chances of trial success. Seamless clinical trial design are studies in which two or more clinical trial phases are combined into a single study with a pre-specified transition between stages.

Unlocking the Potential: A Systematic Review of Master Protocol in Pediatrics.

The use of master protocols allows for innovative approaches to clinical trial designs, potentially enabling new approaches to operations and analytics and creating value for patients and drug developers. Pediatric research has been conducted for many decades, but the use of novel designs such as master protocols in pediatric research is not well understood. This study aims to provide a systematic review on the utilization of master protocols in pediatric drug development.

Therapeutic Hypothermia in Low-Risk Nonpumped Brain-Dead Kidney Donors: A Randomized Clinical Trial.

Importance: Delayed graft function in kidney-transplant recipients is associated with increased financial cost and patient burden. In donors with high Kidney Donor Profile Index whose kidneys are not pumped, therapeutic hypothermia has been shown to confer a protective benefit against delayed graft function.

Objective: To determine whether hypothermia is superior to normothermia in preventing delayed graft function in low-risk nonpumped kidney donors after brain death.

Hypothermia or Machine Perfusion in Kidney Donors.

Background: Therapeutic hypothermia in brain-dead organ donors has been shown to reduce delayed graft function in kidney recipients after transplantation. Data are needed on the effect of hypothermia as compared with machine perfusion on outcomes after kidney transplantation.

Methods: At six organ-procurement facilities in the United States, we randomly assigned brain-dead kidney donors to undergo therapeutic hypothermia (hypothermia group), ex situ kidney hypothermic machine perfusion (machine-perfusion group), or both (combination-therapy group).

Who wants to go first? A simulation study of accrual in a stand-alone trial versus starting a platform trial.

Others have quantified the efficiency of the platform approach as compared to a sequence of independent two-arm trials and have shown the platform approach more efficiently evaluates a set of candidate therapies. However, a practical barrier to initiating a platform trial is incentivizing the first candidate therapies to enter the platform. A platform trial is more complex and will take longer to design and operationalize than a traditional trial.

Current usage and challenges of master protocols-based on survey results by ASA BIOP oncology methodology working group master protocol sub-team.

Background: Master protocol trials, such as basket trials, umbrella trials or platform trials, have the potential of increasing efficiency in modern drug development. Meanwhile, though the concept of master protocol is getting more and more accepted, many challenges exist from design to implementation of these trials. To understand current usage and challenges of master protocol trials in action, American Statistical Association (ASA) Biopharmaceutical Section (BIOP) Oncology Methods Scientific Working Group Master Protocol Sub-team conducted a survey with the goal of providing valuable information for the community to understand the current usage of master protocol, with the goal to identify the challenges.

Comparison of Bayesian vs Frequentist Adaptive Trial Design in the Stroke Hyperglycemia Insulin Network Effort Trial.

Importance: Bayesian adaptive trial design has the potential to create more efficient clinical trials. However, a barrier to the uptake of bayesian adaptive designs for confirmatory trials is limited experience with how they may perform compared with a frequentist design.

Objective: To compare the performance of a bayesian and a frequentist adaptive clinical trial design.

Comparing Go/No-Go Decision-Making Properties Between Single Arm Phase II Trial Designs in Oncology.

Introduction: Simon's design has been widely used in oncology to conduct single arm phase II trials and to make Go/No-Go development decision. Other authors have proposed designs with decision-making frameworks that include a third, "Consider" outcome. For results in the Consider zone, a final Go/No-Go development decision must still be made; however it is typically a subjective decision based on the totality of data and the development landscape.

Practical Considerations and Recommendations for Master Protocol Framework: Basket, Umbrella and Platform Trials.

Master protocol, categorized as basket trial, umbrella trial or platform trial, is an innovative clinical trial framework that aims to expedite clinical drug development, enhance trial efficiency, and eventually bring medicines to patients faster. Despite a clear uptake on the advantages in the concepts and designs, master protocols are still yet to be widely used. Part of that may be due to the fact that the master protocol framework comes with the need for new statistical designs and considerations for analyses and operational challenges.

Bayesian adaptive design for clinical trials in Duchenne muscular dystrophy.

A Bayesian adaptive design is proposed for a clinical trial in Duchenne muscular dystrophy. The trial was designed to demonstrate treatment efficacy on an ambulatory-based clinical endpoint and to identify early success on a biomarker (dystrophin protein levels) that can serve as a basis for accelerated approval in the United States. The trial incorporates placebo augmentation using placebo data from past clinical trials.

The Design of an Adaptive Clinical Trial to Evaluate the Efficacy of Extra-Corporeal Membrane Oxygenation for Out-of-Hospital Cardiac Arrest.

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) is a promising therapy for out-of-hospital cardiac arrest (OHCA) that is refractory to standard therapy, but no multicenter randomized clinical trials have been conducted to establish its efficacy. We report the design and operating characteristics of a proposed randomized Bayesian adaptive "enrichment" clinical trial designed to determine whether ECPR is effective for refractory OHCA and, if effective, to define the interval after arrest during which patients derive benefit.

Methods: Through iterative trial simulation and trial design modification, we developed a Bayesian adaptive trial of ECPR for adults who experience non-traumatic out-of-hospital cardiac arrest.

A prospective, multi-center randomized, controlled, blinded trial of vagus nerve stimulation for difficult to treat depression: A novel design for a novel treatment.

Few treatment options exist for patients with difficult-to-treat depression (DTD). One potentially efficacious treatment is vagus nerve stimulation (VNS): chronic stimulation of the vagus nerve using an implanted stimulator. Given a series of recent VNS clinical studies, including a large, five-year naturalistic investigation, the Center for Medicare and Medicaid Services (CMS) reconsidered the previous non coverage determination and announced coverage for patients participating in a "coverage with evidence" trial.

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB.

The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) Study. Rationale and Design.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform.

Comparison of response adaptive randomization features in multiarm clinical trials with control.

We investigate multiple features of response adaptive randomization (RAR) in the context of a multiple arm randomized trial with control, where the primary goal is the identification of the best arm for use in a broader patient population. We maintain constant control allocation and vary the length of time until RAR is started, interim frequency, the underlying quantity used to calculate the randomization probabilities, and a threshold resulting in temporary arm dropping. We evaluate the designs on five metrics measuring benefit to the internal trial population, the future external population, and statistical estimation.

Comparison of methods for control allocation in multiple arm studies using response adaptive randomization.

Background/aims: Response adaptive randomization has many polarizing properties in two-arm settings comparing control to a single treatment. The generalization of these features to the multiple arm setting has been less explored, and existing comparisons in the literature reach disparate conclusions. We investigate several generalizations of two-arm response adaptive randomization methods relating to control allocation in multiple arm trials, exploring how critiques of response adaptive randomization generalize to the multiple arm setting.

The WISDOM Personalized Breast Cancer Screening Trial: Simulation Study to Assess Potential Bias and Analytic Approaches.

Background: WISDOM (Women Informed to Screen Depending on Measures of Risk) is a randomized trial to assess whether personalized breast cancer screening-where women are screened biannually, annually, biennially, or not at all depending on risk and age-can prevent as many advanced (stage IIB or higher) cancers as annual screening in women ages 40-74 years across 5 years of trial time. The short study time in combination with design choices of not requiring study entry and exit mammograms for all participants may introduce different sources of bias in favor of either the personalized or the annual arm.

Methods: We designed a simulation model and performed 5000 virtual WISDOM trials to assess potential biases.

Therapeutic Hypothermia in Organ Donors: Follow-up and Safety Analysis.

Background: In a recent trial, targeted mild hypothermia in brain-dead organ donors significantly reduced the incidence of delayed graft function after kidney transplantation. This trial was stopped early for efficacy. Here, we report long-term graft survival for all organs along with donor critical care end points.