High quality protocols facilitate proper conduct, reporting, and external review
 of clinical trials. However, the completeness of trial protocols is often
 inadequate. To help improve the content and quality of protocols, an
 international group of stakeholders developed the SPIRIT 2013 Statement
 (Standard Protocol Items: Recommendations for Interventional Trials). The SPIRIT
 Statement provides guidance in the form of a checklist of recommended items to
 include in a clinical trial protocol. This SPIRIT 2013 Explanation and Elaboration paper provides important
 information to promote full understanding of the checklist recommendations. For
 each checklist item, we provide a rationale and detailed description; a model
 example from an actual protocol; and relevant references supporting its
 importance. We strongly recommend that this explanatory paper be used in
 conjunction with the SPIRIT Statement. A website of resources is also available
 (www.spirit-statement.org). The SPIRIT 2013 Explanation and Elaboration paper, together with the Statement,
 should help with the drafting of trial protocols. Complete documentation of key
 trial elements can facilitate transparency and protocol review for the benefit
 of all stakeholders.

https://www.bmj.com/content/bmj/346/bmj.e7586.full.pdf

SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials

The core mission of National Institute of Neurological Disorders and Stroke (NINDS) is twofold. First, NINDS seeks fundamental knowledge about the brain and nervous system. Second, NINDS aims to use that knowledge to reduce the burden of neurological diseases. In support of its mission, NINDS performs and funds basic, translational, and clinical neuroscience research on more than 600 neurological diseases, including genetic diseases (e.g. Huntington’s disease; muscular dystrophy), developmental disorders (e.g. cerebral palsy), neurodegenerative diseases (e.g. Parkinson’s disease; Alzheimer’s disease; multiple sclerosis), metabolic diseases (e.g. Gaucher’s disease), cerebrovascular diseases (e.g. stroke; vascular dementia), trauma (e.g. spinal cord and head injury), convulsive disorders (e.g. epilepsy), infectious diseases (e.g. AIDS dementia) and brain tumors. Common marmosets (Callithrix jacchus) offer unique, powerful advantages to both components of the NINDS mission. In support of the first component, marmosets are particularly well suited for neuroanatomical and functional brain studies, as their brains retain the typical anatomical and functional organization of the primate brain. A major advantage is that the marmoset is a lissencephalic primate, which greatly facilitates the mapping of functional brain areas by neuroimaging techniques, such as fMRI and optical imaging, as well as by electrophysiology, with high spatial resolution. In support of the second component, marmosets are excellent models of neurological disorders. Unlike rodents, marmosets are outbred and every individual is genetically different. Further, the marmoset brain has a gray-to-white matter ratio comparable to humans, which strongly facilitates modeling diseases such as multiple sclerosis and small vessel disease. The species also exhibits the breadth of cognitive sophistication that distinguishes primates from other taxonomic groups. Finally, geneedited marmosets can be generated with an intergeneration time and establishment of transgenic lines 2-3 times faster than other primate species, which makes marmosets be the ideal primate species for the development of genetically engineered lines. For all of the above reasons, marmosets are poised to be a central player to advance the core mission of the NINDS.

National Institute of Neurological Disorders and Stroke

Sepsis, a common and potentially fatal systemic illness, is triggered by microbial infection and often leads to impaired function of the lungs, kidneys or other vital organs. Since the early 1980s, a large number of therapeutic agents for the treatment of sepsis have been evaluated in randomized controlled clinical trials. With few exceptions, the results from these trials have been disappointing, and no specific therapeutic agent is currently approved for the treatment of sepsis. To improve upon this dismal record, investigators will need to identify more suitable therapeutic targets, improve their approaches for selecting candidate compounds for clinical development and adopt better designs for clinical trials.

Strategies to improve drug development for sepsis.

Objectives: Designing studies with an internal pilot phase may optimise the use of pilot work to inform more efficient randomised controlled trials (RCTs). Careful selection of preagreed decision or 'progression' criteria at the juncture between the internal pilot and main trial phases provides a valuable opportunity to evaluate the likely success of the main trial and optimise its design or, if necessary, to make the decision not to proceed with the main trial. Guidance on the appropriate selection and application of progression criteria is, however, lacking. This paper outlines the key issues to consider in the optimal development and review of operational progression criteria for RCTs with an internal pilot phase. Design: A structured literature review and exploration of stakeholders' opinions at a Medical Research Council (MRC) Hubs for Trials Methodology Research workshop. Key stakeholders included triallists, methodologists, statisticians and funders. Results: There is considerable variation in the use of progression criteria for RCTs with an internal pilot phase, although 3 common issues predominate: trial recruitment, protocol adherence and outcome data. Detailed and systematic reporting around the decisionmaking process for stopping, amending or proceeding to a main trial is uncommon, which may hamper understanding in the research community about the appropriate and optimal use of RCTs with an internal pilot phase. 10 top tips for the development, use and reporting of progression criteria for internal pilot studies are presented. Conclusions: Systematic and transparent reporting of the design, results and evaluation of internal pilot trials in the literature should be encouraged in order to facilitate understanding in the research community and to inform future trials.

https://bmjopen.bmj.com/content/bmjopen/7/2/e013537.full.pdf

Informing efficient randomised controlled trials: exploration of challenges in developing progression criteria for internal pilot studies.

Cardiovascular drug development: is it dead or just hibernating?

Adaptive designs allow planned modifications based on data accumulating within a study. The promise of greater flexibility and efficiency stimulates increasing interest in adaptive designs from clinical, academic, and regulatory parties. When adaptive designs are used properly, efficiencies can include a smaller sample size, a more efficient treatment development process, and an increased chance of correctly answering the clinical question of interest. However, improper adaptations can lead to biased studies. A broad definition of adaptive designs allows for countless variations, which creates confusion as to the statistical validity and practical feasibility of many designs. Determining properties of a particular adaptive design requires careful consideration of the scientific context and statistical assumptions. We first review several adaptive designs that garner the most current interest. We focus on the design principles and research issues that lead to particular designs being appealing or unappealing in particular applications. We separately discuss exploratory and confirmatory stage designs in order to account for the differences in regulatory concerns. We include adaptive seamless designs, which combine stages in a unified approach. We also highlight a number of applied areas, such as comparative effectiveness research, that would benefit from the use of adaptive designs. Finally, we describe a number of current barriers and provide initial suggestions for overcoming them in order to promote wider use of appropriate adaptive designs. Given the breadth of the coverage all mathematical and most implementation details are omitted for the sake of brevity. However, the interested reader will find that we provide current references to focused reviews and original theoretical sources which lead to details of the current state of the art in theory and practice.

/pdf/adaptive-trial-designs-a-review-of-barriers-and-4fhz3upovt.pdf

Adaptive trial designs: a review of barriers and opportunities

Medical and health policy decision-makers require improved design and analysis methods for comparative effectiveness research (CER) trials. In CER trials, there may be limited information to guide initial design choices. In general settings, adaptive designs (ADs) have effectively overcome limits on initial information. However, CER trials have fundamental differences from standard clinical trials including population heterogeneity and a vaguer concept of a “minimum clinically meaningful difference”. The objective of this article is to explore the use of a particular form of ADs for comparing treatments within the CER trial context. To achieve this, the authors review the current state of clinical CER. They also identify areas of CER as particularly strong candidates for application of novel AD and illustrate the potential usefulness of the designs and methods for two group comparisons. The authors found that ADs can stabilize power. Furthermore, the designs ensure adequate power for true effects ...

/pdf/adaptive-designs-for-comparative-effectiveness-research-29qmx890gq.pdf

Mitchell A. Thomann

Papers

Adaptive trial designs: a review of barriers and opportunities

Adaptive designs for comparative effectiveness research trials