Curtis L. Meinert’s research while affiliated with Johns Hopkins University and other places

Background The clinical trial landscape has evolved over the last two decades, shaped by advances in therapeutics and drug development and innovation in trial design and methods. The tracking of such changes became possible with trial registration, providing the public with a window into the massive clinical research enterprise. The ClinicalTrials.gov website was launched in 2000 by the NIH National Library of Medicine and is the largest clinical trial registry worldwide. The purpose of this analysis is to describe the composition and methodologic features of clinical trials as registered on ClinicalTrials.gov and to identify trends over time. Methods We analyzed data from the publicly available Clinical Trials Transformation Initiative Aggregate Analysis of ClinicalTrials.gov (AACT) database, focusing on trials (interventional studies) started between 1 January 2000 through 31 December 2020. Characteristics of design (e.g., phase, randomization, use of masking, number of treatment groups, sample size), eligibility criteria (age groups, gender), interventions, conditions, and funders (primary sponsor) were tabulated over time, by year trial started. Results There were 274,043 registered interventional studies (trials) included in the analysis. Most trials were reported as randomized (65%); single site (60%); parallel-group (56%); funded by other sources (e.g., individuals, universities, and community-based organizations) (65%); and involving drug interventions (55%). Notable trends include an increase in the proportion of registered trials without FDA-defined phases (“Phase N/A”) over time, a decrease in proportion of trials that involve drugs or report treatment as a primary purpose, declining sample size and time to complete trials, and an increase in proportion of trials reporting results among completed trials. The proportion of missing registration fields has also decreased over time and more trials make protocols and other documents available. There is a current need to expand the registration fields in ClinicalTrials.gov to adapt to the evolving trial designs and reduce the number of trials categorized as “other.” Observed trends may be explained by changes in trial regulations as well as expanding and evolving trial designs, interventions, and outcome types. Conclusions Clinical trial registration has transformed how trial information is accessed, disseminated, and used. As clinical trials evolve and regulations change, trial registries, including ClinicalTrials.gov, will continue to provide a means to access and follow trials over time, thus informing future trial design and highlighting the value of this tremendous resource.

Trials are not for the faint of heart. As noted by Donald Fredrickson (Director of the NIH: 1 July 1975 to 30 June 1981), “they lack glamor, they strain our resources and patience, and they protract the moment of truth to excruciating limits” (Fredrickson 1968). This chapter addresses issues in design and conduct of trials including who to study, choice of treatments to be tested, choice of outcome measures, and issues in monitoring and governance of the trial.

This chapter deals with names and acronyms for trials, whose name goes in mastheads of publications from the trial, how papers are titled, and credit listings in manuscripts. The issue of whose names goes on publications is reasonably straight forward when only a few people are involved in a work but becomes progressively more complicated as the size of the investigator group increases. Should attribution be to the entire research group without any persons listed in the publication masthead, or should it be to named persons? If the format is to list names, then who should be listed and in what order? How should results papers from the trial be titled? Titling is important because title is what is used to attract readers. What should it be? Should it be headline style announcing results of the trial, or should it be descriptive indicating the nature of the trial producing the results? Credits serve to inform readers who were involved and provide insights into how the trial was done. What goes in the credits sections of papers and in what format?

An archive, in the context of a trial, is a collection of documents and records relevant to the design and conduct of the trial maintained as a historical repository. Archiving is a process that starts before the first person is enrolled and continues to the end of the trial when all analyses are complete and the investigator group disbands. So, when a trial is finished, money has run out, and investigators have dispersed, what do you have archived and where? The answer to the first question is “everything you may need later,” and the answer to the second is “someplace readily accessible far into the foreseeable future.” Both answers are correct but not helpful because the first question requires a crystal ball of what might be needed and the second requires a place like the Smithsonian and there are no Smithsonians for archiving records of clinical trials. This chapter is about the process of archiving and about what to archive.

Publication is the sine qua non of trials. In the societal sense, there is no lasting information generated from trials, absent publication. Investigators are not finished until they have published their results and have done so regardless of the nature or direction of the results. One might think that paper writing starts when the trial ends and is finished when the results are published but the reality is that it should start early in the course of the trial and continue long after the trial is finished. This chapter is about the paper writing process.

Background: The clinical trials landscape has evolved over the last two decades, shaped by advances in therapeutics and drug development, the emerging role of technology in trials, innovation in trial design and methods, and increased access to clinical trial information and data through registration. The ClinicalTrials.gov website was launched in 2000 by the NIH National Library of Medicine and is the largest clinical trials registry worldwide. The purpose of this cross-sectional analysis is to describe the composition and methodologic features of clinical trials as registered on ClinicalTrials.gov, and to identify key trends over time. Methods: We analyzed data from the publicly available CTTI AACT database, focusing on trials (interventional studies) started between 1 January, 2000 through 31 December, 2020. Characteristics of trial design (e.g., randomization, use of masking, sample size), eligibility criteria, outcome types, interventions, conditions, and results reporting were summarized over time. Results: There were 271,272 trials included in the analysis, of which 57% were completed. Most trials were randomized (66%), single site (68.7%), funded by other sources (69.0%) and had sample sizes less than 100 participants (62%). There was a significant increase in trials without FDA-defined phases ("Phase N/A") observed over time as a result of evolving trial designs, interventions and outcome types. Over 3,000 trials related to COVID-19 started in 2020 alone. Conclusions: ClinicalTrials.gov is a powerful tool that provides a window into the past, present, and future of the clinical research enterprise. Understanding characteristics and trends of trials can inform future trial design and clinical decision making.

Importance ClinicalTrials.gov is a valuable resource that can be used to trace the state and nature of trials. Since its launch in 2000, more than 345 000 trials have been registered. Little is known about the characteristics and trends in clinical trials over time and how they differ by sponsor type. Objective To assess trends in clinical trials registered in ClinicalTrials.gov over time and by sponsor type. Design, Setting, and Participants This cross-sectional study included clinical trials (interventional studies) registered in ClinicalTrials.gov from January 1, 2000, through December 31, 2019. The trials were grouped by lead sponsor: National Institutes of Health (NIH) and other US government agencies, industry, and other sources (foundations, universities, hospitals, clinics, and others). A static version of the Clinical Trials Transformation Initiative Aggregate Analysis of ClinicalTrials.gov database was downloaded on January 1, 2020, for analysis. Main Outcomes and Measures ClinicalTrials.gov registration fields, including overall status, phase, intervention, number of sites, use of masking and randomization, sample size, and time to study completion by start year and lead sponsor (organization that provided funding or support for a clinical study). Results A total of 245 999 clinical trials (interventional studies) were started between 2000 and 2019, of which 135 144 (54.9%) were completed. Among completed trials, 5113 (3.8%) were sponsored by the NIH or a US government agency, 48 668 (36.0%) by industry, and 81 363 (60.2%) by other sources. Most trials were single center (61.3%), randomized (65.6%), and phase 1 to 2 (35.5%) or did not have a US Food and Drug Administration–defined phase (38.4%), with fewer drug trials being conducted over time. Sample sizes were small (median, 60; interquartile range [IQR], 30-160) and diminished over time. Trial median completion times varied by lead sponsor: 3.4 years (IQR, 1.9-5.0 years) for NIH- and US government–sponsored trials, 1.2 years (IQR, 0.5-2.4 years) for industry trials, and 2.1 years (IQR, 1.1-3.7) for trials sponsored by other sources. Conclusions and Relevance The findings suggest that the composition and design of trials changed from 2000 to 2019 and differed substantially by sponsor type. Increased funding toward larger randomized clinical trials may be warranted to inform clinical decision-making and guide future research.