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

Sheng, Jacky; Feldhake, Emma; Zarin, Deborah A.; Kimmelman, Jonathan

doi:10.1016/j.medj.2022.03.002

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…To ensure that uncertainty or conflict reflect an impartial engagement with all relevant evidence, stakeholders should promote the production of comprehensive evidence synthesis through living and systematic reviews. Despite repeated calls for such reforms, a 2022 random sample of research protocols found that “none contained statements suggesting a systematic search for relevant clinical evidence.” Funding agencies and institutional review boards should require that claims relating to clinical equipoise and the importance of the knowledge gaps investigated are justified against the background of such reviews, especially for cases in which the same drug is the focus of repeated clinical investigation for similar indications.…”

Section: Managing Persistent Uncertaintymentioning

confidence: 99%

The Ethics of Clinical Research

London

Seymour

2023

JAMA

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In the face of novel pathogens, incomplete knowledge, and disagreement about the merits of medical treatments, translating the duty to care into concrete benefits for patients depends on our ability to quickly act on the duty to learn. 1 Learning is a dynamic process whose goal, in medical research, is to generate the evidence needed to reduce uncertainty and shift care toward safer, more effective, and efficient practice. It is also a social process that requires the cooperation of multiple stakeholders, including funders, researchers, health care professionals, health systems, regulatory bodies, and patients. The interests of these stakeholders can conflict, and the requirement of clinical equipoise is seen as a way to ensure that research promotes medical progress without compromising the interests of study participants. The equipoise requirement holds that (1) research that addresses uncertainty or conflicting medical judgments of conscientious and informed experts is likely to have social value and (2) allocating individuals to interventions that are subject to such conflict or uncertainty is consistent with respect for their rights or welfare. 2 But when does clinical equipoise no longer hold?The importance of this question is illustrated by the report from Naggie et al published in JAMA. 3 The authors report results from the Accelerating Covid-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial, in which 1206 participants with mild to moderate COVID-19 were randomized to receive a maximum targeted dose of 600 μg/kg of ivermectin daily for 6 days compared with placebo. This trial investigated both a higher dose and longer duration of ivermectin than prior studies. Most participants (84%) received at least 2 COVID-19 vaccine doses and 60% received the study drug within 5 days of symptom onset. The median time to recovery was 11 days in the ivermectin group compared with 11 days in the placebo group, and there was no significant benefit from ivermectin for any secondary outcomes or in subgroup analyses.These findings are consistent with previous research, including 3 other randomized trials of different doses and duration of ivermectin. However, there are currently more than 10 trials of ivermectin recruiting participants on ClinicalTrials.gov. After considering factors that can influence the persistence of clinical equipoise, we argue that decisions about what investigations to undertake must be responsive to the relative social value of continuing to reduce uncertainty around one intervention, and stakeholders must consider whether scarce time, resources, and participant effort could be better invested examining other questions.

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Section: Managing Persistent Uncertaintymentioning

confidence: 99%

The Ethics of Clinical Research

London

Seymour

2023

JAMA

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“…Representative samples of trial protocols and informed consent forms can be compared with standards to identify practice variation and areas needing improvement. 13,14…”

Section: Introductionmentioning

confidence: 99%

“…Representative samples of trial protocols and informed consent forms can be compared with standards to identify practice variation and areas needing improvement. 13,14 The importance of DMCs An important area of clinical trial functioning and oversight, however, remains out of public view: how data accumulating during a trial are monitored to protect the trial participants as well as the integrity of the data and the analyses, a responsibility often held in part by a DMC that has unique access to unblinded data while the trial is ongoing. 8,15 A well-constructed DMC charter outlines the principles by which the DMC functions for a specific trial or set of trials; it does not list a set of rules, but provides guidelines to help the DMC carry out its mission.…”

Section: Introductionmentioning

confidence: 99%

Bringing data monitoring committee charters into the sunlight

et al. 2023

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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.

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Supporting evidence in phase 2 cancer trial protocols: a content analysis

Bicer,

Nelson,

Carayannis

et al. 2024

JNCI: Journal of the National Cancer Institute

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Background Phase 2 trials are instrumental for designing definitive efficacy trials or attaining accelerated approval. However, high attrition of drug candidates in phase 2 raises questions about their supporting evidence. Methods We developed a typology of supporting evidence for phase 2 cancer trials. We also devised a scheme for capturing elements that enable an assessment of the strength of such evidence. Using this framework, we content analyzed supporting evidence provided in protocols of 50 randomly sampled phase 2 cancer monotherapy trials starting between January 2014 and January 2019, available on ClinicalTrials.gov. Results Of the 50 protocols in our sample, 52% were industry funded. Most invoked supporting evidence deriving from trials against different cancers (n = 28, 56%) or preclinical studies (n = 48, 96%), but not from clinical studies involving the target drug-indication pairing (n = 23, 46%). When presenting evidence from models, only one protocol (2%) explained their translational relevance. Instead, protocols implied translatability by describing molecular (86%) and pathophysiological (84%) processes shared by model and target systems. Protocols often provided information for assessing the magnitude, precision and risk of bias for supporting trials (n = 43, 93%, 91%, 47%, respectively). However, such information was often unavailable for preclinical studies (n = 49, 53%, 22%, 59%). Conclusion Supporting evidence is key to justifying the commitment of scientific resources and patients to a clinical hypothesis. Protocols often omit elements that would enable critical assessment of supporting evidence for phase 2 monotherapy cancer trials. These gaps suggest the promise of more structured approaches for presenting supporting evidence.

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

Cited by 3 publications

References 31 publications

The Ethics of Clinical Research

The Ethics of Clinical Research

Bringing data monitoring committee charters into the sunlight

Supporting evidence in phase 2 cancer trial protocols: a content analysis

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