Deprioritization of Ongoing Clinical Trials.

To be ethical, clinical trials must exhibit a favorable risk-benefit balance at the time of their initiation. However, in some cases, the expected value of a study decreases while the study is ongoing, due to developments outside of the study itself, such as findings from other studies or an otherwise shifting evidence base. While such situations are acknowledged in the research community, they have not received sufficient attention, given the high costs of uninformative studies, both in material and human capital. In addition, the Covid-19 pandemic has exposed serious shortcomings with current approaches to monitoring studies for continued relevance and value. In this article, with reference to a case study from the Covid-19 pandemic, we identify and describe the importance and challenge of ensuring that clinical trials continue to exhibit scientific relevance and value once initiated. We explore the ethical dynamics of these situations and identify unresolved issues. While more empirical work is needed to ensure that proposed solutions to the issues are evidence based, we offer some provisional considerations that amount to a framework for approaching these challenging situations.

Characterization of key information sections in informed consent forms posted on ClinicalTrials.gov.

Introduction: Recent revisions to the US Federal Common Rule governing human studies funded or conducted by the federal government require the provision of a "concise and focused" key information (KI) section in informed consent forms (ICFs). We performed a systematic study to characterize KI sections of ICFs for federally funded trials available on ClinicalTrials.gov. Methods: We downloaded ICFs posted on ClinicalTrials.gov for treatment trials initiated on or after the revised Common Rule effective date. Trial records (n = 102) were assessed by intervention type, study phase, recruitment status, and enrollment size. The ICFs and their KI sections, if present, were characterized by page length, word count, readability, topic, and formatting elements. Results: Of the 102 trial records, 76 had identifiable KI sections that were, on average, 10% of the total length of full ICF documents. KI readability grade level was not notably different from other sections of ICFs. Most KI sections were distinguished by section headers and included lists but contained few other formatting elements. Most KI sections included a subset of topics consistent with the basic elements of informed consent specified in the Common Rule. Conclusion: Many of the KI sections in the study sample aligned with practices suggested in the preamble to the revised Common Rule. Further, our results suggest that some KI sections were tailored in study-specific ways. Nevertheless, guidelines on how to write concise and comprehensible KI sections would improve the utility and readability of KI sections.

Bringing data monitoring committee charters into the sunlight.

Clinical trials investigating novel or high risk interventions, or studying vulnerable participants, often use a data monitoring committee to oversee the progress of the trial. The data monitoring committee serves both an ethical and a scientific function, by protecting the interests of trial participants while ensuring the integrity of the trial results. A data monitoring committee charter, which typically describes the procedures by which data monitoring committees operate, contains details about the data monitoring committee's organizational structure, membership, meeting frequency, sequential monitoring guidelines, and the overall contents of data monitoring committee reports for interim review. These charters, however, are generally not reviewed by outside entities and are rarely publicly available. The result is that a key component of trial oversight remains in the dark. We recommend that ClinicalTrials.gov modify its system to allow uploading of data monitoring committee charters, as is already possible for other important study documents and that clinical trialists take advantage of this opportunity to voluntarily upload the data monitoring committee charter for trials that have one. The resulting cache of publicly available data monitoring committee charters should provide important insights for those interested in a particular trial, as well as for meta-researchers who wish to understand and potentially improve how this important component of trial oversight is actually being applied.

How to limit uninformative trials: Results from a Delphi working group.

To be justifiable, clinical trials must test novel hypotheses and produce informative results. However, many trials fail on this score. A Delphi process was used to establish consensus on 35 recommendations across five domains related to the role of scientific review in preventing uninformative trials.

Comparison of Availability of Trial Results in ClinicalTrials.gov and PubMed by Data Source and Funder Type.

This study examines the dissemination of trial results by data source (ie, ClinicalTrials.gov and PubMed) and funder type (ie, industry and nonindustry).

The proportion of randomized controlled trials that inform clinical practice.

Prior studies suggest that clinical trials are often hampered by problems in design, conduct, and reporting that limit their uptake in clinical practice. We have described 'informativeness' as the ability of a trial to guide clinical, policy, or research decisions. Little is known about the proportion of initiated trials that inform clinical practice. We created a cohort of randomized interventional clinical trials in three disease areas (ischemic heart disease, diabetes mellitus, and lung cancer) that were initiated between January 1, 2009 and December 31, 2010 using ClinicalTrials.gov. We restricted inclusion to trials aimed at answering a clinical question related to the treatment or prevention of disease. Our primary outcome was the proportion of clinical trials fulfilling four conditions of informativeness: importance of the clinical question, trial design, feasibility, and reporting of results. Our study included 125 clinical trials. The proportion meeting four conditions for informativeness was 26.4% (95% CI 18.9-35.0). Sixty-seven percent of participants were enrolled in informative trials. The proportion of informative trials did not differ significantly between our three disease areas. Our results suggest that the majority of randomized interventional trials designed to guide clinical practice possess features that may compromise their ability to do so. This highlights opportunities to improve the scientific vetting of clinical research.

Approach for reporting master protocol study designs on ClinicalTrials.gov: qualitative analysis.

OBJECTIVE: To describe an approach for reporting master protocol research programs (MPRPs) that is consistent with existing good reporting practices and that uses structured information to convey the overall master protocol and design of each substudy. DESIGN: Qualitative analysis. DATA SOURCES: ClinicalTrials.gov trial registry. MAIN OUTCOME MEASURES: Established goals and related practices of the trial reporting system were outlined, examples and key characteristics of MPRPs were reviewed, and specific challenges in registering and reporting summary results to databases designed for traditional clinical trial designs that rely on a model of one study per protocol were identified. RESULTS: A reporting approach is proposed that accommodates the complex study design of MPRPs and their results. This approach involves the use of separate registration records for each substudy within one MPRP protocol (with potential exceptions noted). CONCLUSIONS: How the proposed approach allows for clear, descriptive, structured information about each substudy's prespecified design and supports timely reporting of results after completion of each substudy is described and illustrated. Although the focus is on reporting to ClinicalTrials.gov, the approach supports broader application across trial registries and results databases. This paper is intended to stimulate further discussion of this approach among stakeholders, build awareness about the need to improve reporting of MPRPs, and encourage harmonization across trial registries globally.

Completeness of clinical evidence citation in trial protocols: A cross-sectional analysis.

BACKGROUND: Human protection policies require assessment of how proposed clinical trials relate to prior and ongoing studies testing similar hypotheses. We assessed the extent to which clinical trial protocols cited relevant published and ongoing clinical trials that would have been easily accessible with reference searches. METHODS: We created a random sample of trial protocols using ClinicalTrials.gov, stratifying by industry and non-industry-sponsored studies. We then conducted reference searches to determine the extent to which protocols cited clinical trials with identical intervention-indication pairings that were accessible in PubMed and ClinicalTrials.gov at the time of trial initiation. FINDINGS: Of the 101 trial protocols evaluated, 73 had at least one identified citable trial. None contained statements suggesting a systematic search for relevant clinical evidence. Of industry-sponsored trial protocols with at least one identified citable trial, 7 of 23 (30.4%) did not cite any published clinical trials and 10 of 33 (30.3%) did not cite any ongoing relevant trials. Of the non-industry-sponsored trial protocols with at least one identified citable trial, 5 of 28 (17.9%) did not cite any published clinical trials and 14 of 19 (73.7%) did not cite any ongoing trials. CONCLUSIONS: Clinical trial protocols undercite accessible, relevant trials and do not document systematic searches for relevant clinical trials. Consequently, ethics review committees often receive an incomplete picture of the research landscape if they review protocols similar to those deposited on ClinicalTrials.gov. FUNDING: This study was funded by the Canadian Institutes of Health Research and the Greenwall Foundation.