Sample size adaptation designs and efficiency comparison with group sequential designs.

This study is to give a systematic account of sample size adaptation designs (SSADs) and to provide direct proof of the efficiency advantage of general SSADs over group sequential designs (GSDs) from a different perspective. For this purpose, a class of sample size mapping functions to define SSADs is introduced. Under the two-stage adaptive clinical trial setting, theorems are developed to describe the properties of SSADs. Sufficient conditions are derived and used to prove analytically that SSADs based on the weighted combination test can be uniformly more efficient than GSDs in a range of likely values of the true treatment difference δ $$ \delta $$ . As shown in various scenarios, given a GSD, a fully adaptive SSAD can be obtained that has sufficient statistical power similar to that of the GSD but has a smaller average sample size for all δ $$ \delta $$ in the range. The associated sample size savings can be substantial. A practical design example and suggestions on the steps to find efficient SSADs are also provided.

A systematic survey of adaptive trials shows substantial improvement in methods is needed.

OBJECTIVES: To investigate the design, conduct, and analysis of adaptive trials through a systematic survey and provide recommendations for future adaptive trials. STUDY DESIGN AND SETTING: We systematically searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases up to January 2020. We included trials that were self-described as adaptive trials or applied adaptive designs. We identified three frequently used adaptive designs and summarized their methodological details in terms of design, conduct, and analysis. Lastly, we provided recommendations for future adaptive trials. RESULTS: We included a total of 128 trials in this study. The primary motivations for using adaptive design were to speed up the trials and facilitate decision-making (n = 29, 31.5%). The three most frequently used methods were group sequential design (GSD) (n = 71, 55.5%), adaptive dose-finding design (ADFD) (n = 35, 27.3%), and adaptive randomization design (ARD) (n = 26, 20.3%). The timing and frequency of interim analysis were detailed in three-fourths of the GSD trials (n = 55, 77.5%) and in half of the ADFD trials (n = 19, 54.3%); however, more than half of the ARD trials (n = 15, 57.7%) did not provide this information. Some trials selected a different outcome than the primary outcome for interim analysis (GSD: n = 7, 12.7%; ADFD: n = 8, 27.6%; ARD: n = 7, 50.0%), but the majority of these trials did not provide explicit reasons for this choice (GSD: n = 7, 100.0%; ADFD: n = 7, 87.5%; ARD: n = 5, 71.4%). More than half (n = 76, 59.4%) of trials did not mention the accessibility of supporting documents, and two-thirds (n = 86, 67.2%) did not state the establishment of independent data monitoring committees (IDMCs). Moreover, unplanned adjustments were observed during the conduct of one-sixth adaptive trials (n = 22, 17.2%). Based on our findings, we provide 14 recommendations for improving adaptive trials in the future. CONCLUSION: Substantial improvements were needed in methods of adaptive trials, particularly in the areas of interim analysis, the establishment of independent data monitoring committees, and unplanned adjustments. In this study, we offer recommendations from both general and specific aspects for researchers to carefully design, conduct, and analyze adaptive trials.

Expansão global dos ensaios clínicos: inovação e interação / Global expansion of clinical trials: innovation and interaction / Expansión global de los ensayos clínicos: innovación e interacción

A inovação em saúde é caracterizada por uma forte interação com o setor de ciência e tecnologia. O crescente interesse pela internacionalização das atividades de pesquisa e desenvolvimento conduz ao questionamento sobre as oportunidades em função das interações com outros países, como mecanismo para a construção de capacidades nacionais de inovação. Conforme os ensaios clínicos atravessaram as fronteiras nacionais, alcançando uma expressão global, as redes de relações entre os atores envolvidos tornaram-se cada vez mais complexas e apresentam-se como uma possibilidade para a caracterização da interação dos sistemas nacionais de inovação no plano global, particularmente pelo ponto de vista da produção de atividades de ciência, tecnologia e inovação em saúde. O objetivo deste trabalho foi estudar a expansão global de ensaios clínicos a fim de se discutir possíveis fatores relacionados com a interação dos sistemas nacionais de inovação dos países envolvidos. Os métodos empregados incluíram pesquisa bibliográfica e análise de dados secundários. Constata-se uma crescente interdependência dos sistemas nacionais de inovação, requerendo novas estruturas internacionais de inovação. Surgem novas oportunidades para a produção e a difusão internacional do conhecimento. Os ensaios clínicos promovem e requerem interação entre empresas, universidades e instâncias governamentais, revelando-se como elemento estratégico para a estruturação dos sistemas nacionais de inovação em saúde no contexto global.

Innovation in health is characterized by strong interaction with the science and technology sector. Growing interest in the internationalization of research and development leads to questions on opportunities as a function of interactions with other countries, as a mechanism for national capacity-building in innovation. As clinical trials cross national borders and achieve global relevance, networks of relations between the actors become increasingly complex and present themselves as a possibility for characterizing interaction of national innovation systems at the global level, particularly from the point of view of producing activities in science, technology, and innovation in health. This study aimed to analyze the global expansion of clinical trials in order to discuss possible factors related to the interaction between national innovation systems in the countries involved. The methods included literature searches and analysis of secondary data. There is a growing interdependence between national innovation systems, requiring new international innovation structures. New opportunities emerge for the production and international dissemination of knowledge. Clinical trials promote and require interaction between companies, universities and government agencies, proving strategic for structuring national innovation systems in health in the global context.

La innovación en salud está caracterizada por una fuerte interacción con el sector de ciencia y tecnología. El creciente interés por la internacionalización de las actividades de investigación y desarrollo conduce al cuestionamiento acerca de oportunidades, en función de las interacciones con otros países, como mecanismo para la construcción de capacidades nacionales de innovación. A medida que los ensayos clínicos atravesaron las fronteras nacionales, tuvieron un alcance global, las redes de relaciones entre los actores implicados se hicieron cada vez más complejas y se presentan como una posibilidad para la caracterización de la interacción de los sistemas nacionales de innovación mundialmente, particularmente, desde el punto de vista de la producción de actividades de ciencia, tecnología e innovación en salud. El objetivo de este trabajo fue estudiar la expansión global de ensayos clínicos, a fin de discutir posibles factores relacionados con la interacción de los sistemas nacionales de innovación de los países implicados. Los métodos empleados incluyeron: investigación bibliográfica y el análisis de datos secundarios. Se constata una creciente interdependencia de los sistemas nacionales de innovación, requiriendo nuevas estructuras internacionales de innovación. Surgen nuevas oportunidades para la producción y la difusión internacional del conocimiento. Los ensayos clínicos promueven y requieren la interacción entre empresas, universidades e instancias gubernamentales, revelándose como un elemento estratégico para la estructuración de los sistemas nacionales de innovación en salud dentro del contexto global.