Inadequate Dissemination of Phase I Trials: A Retrospective Cohort Study

Decullier, Évelyne; Chan, An‐Wen; Chapuis, François

doi:10.1371/journal.pmed.1000034

Cited by 38 publications

(32 citation statements)

References 21 publications

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“…This has been shown before [8]. However, the percentage of phase 1 trials that was published in our cohort was substantially higher (35%) than the previous study (17%) [8], suggesting that progress has also been made in the field of phase 1 trials, but still not sufficient. Publication of phase 1 trials may be considered less interesting because their direct impact for clinical practice is limited when the drug is still far from marketing approval.…”

Section: Discussionsupporting

confidence: 55%

“…The publication rate approximated their plateau at the time of our final search, suggesting that only a few more publications can be expected. The observed publication rate of 42% is relatively high compared with other studies investigating older cohorts [3,6,7,8,9,11,12,13,14,16,35,36]. This suggests that the publication rate of clinical trials has somewhat improved, but is still far from ideal.…”

Section: Discussionmentioning

confidence: 78%

“…The waste and bias implicated in clinical research caused by non-publication over the past years [3,6,7,8,9,10,11,12,13,14,15,16,17,18] has strengthened the view of several organizations and governments that all clinical trials must be published [19,20,21,22,23]. Previous studies specifically focused on publication of randomized controlled trials (RCTs) [24], covered only trials within one medical specialty [25], examined a limited selection of determinants, or used incomplete trial cohorts depending on public registrations [26,27] or interview response rates [10].…”

Section: Introductionmentioning

confidence: 99%

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Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials

Bogert

Souverein

Brekelmans³

et al. 2016

PLoS ONE

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The objective of this study was to investigate the occurrence and determinants of non-publication of clinical drug trials in the Netherlands.All clinical drug trials reviewed by the 28 Institutional Review Boards (IRBs) in the Netherlands in 2007 were followed-up from approval to publication. Candidate determinants were the sponsor, phase, applicant, centers, therapeutic effect expected, type of trial, approval status of the drug(s), drug type, participant category, oncology or other disease area, prospective registration, and early termination. The main outcome was publication as peer reviewed article. The percentage of trials that were published, crude and adjusted odds ratio (OR), and 95% confidence interval (CI) were used to quantify the associations between determinants and publication. In 2007, 622 clinical drug trials were reviewed by IRBs in the Netherlands. By the end of follow-up, 19 of these were rejected by the IRB, another 19 never started inclusion, and 10 were still running. Of the 574 trials remaining in the analysis, 334 (58%) were published as peer-reviewed article. The multivariable logistic regression model identified the following determinants with a robust, statistically significant association with publication: phase 2 (60% published; adjusted OR 2.6, 95% CI 1.1–5.9), phase 3 (73% published; adjusted OR 4.1, 95% CI 1.7–10.0), and trials not belonging to phase 1–4 (60% published; adjusted OR 3.2, 95% CI 1.5 to 6.5) compared to phase 1 trials (35% published); trials with a company or investigator as applicant (63% published) compared to trials with a Contract Research Organization (CRO) as applicant (50% published; adjusted OR 1.7; 95% CI 1.1–2.8); and multicenter trials also conducted in other EU countries (68% published; adjusted OR 2.2, 95% CI 1.1–4.4) or also outside the European Union (72% published; adjusted OR 2.0, 95% CI 1.0–4.0) compared to single-center trials (45% published). Trials that were not prospectively registered (48% published) had a lower likelihood of publication compared to prospectively registered trials (75% published; adjusted OR 0.5, 95% CI 0.3–0.8), as well as trials that were terminated early (33% published) compared to trials that were completed as planned (64% published; adjusted OR 0.2, 95% CI 0.1–0.3). The non-publication rate of clinical trials seems to have improved compared to previous inception cohorts, but is still far from optimal, in particular among phase 1, single-center, not prospectively registered, and early terminated trials.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials

Bogert

Souverein

Brekelmans³

et al. 2016

PLoS ONE

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“…This is especially the case since phase I trials may experience especially low rates of publication: one study of French clinical trials shows a 17% publication rate for phase I trials compared to an average of 43% for the other phases. 42 Second, for the 19% of compounds that are approved, sponsors may withhold publication of unfavorable results. Third, for trials that are published, the published article may present the trial data in a way that minimizes harms.…”

Section: Discussionmentioning

confidence: 99%

Risks of phase I research with healthy participants: A systematic review

et al. 2015

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Background/Aims Tragedies suggest that phase I trials in healthy participants may be highly risky. This possibility raises concern that phase I trials may exploit healthy participants to develop new therapies, making the translation of scientific discoveries ethically worrisome. Yet, few systematic data evaluate this concern. The present paper systematically reviews the risks of published phase I trials in healthy participants and evaluates trial features associated with increased risks. Methods Data on adverse events and trial characteristics were extracted from all phase I trials published in PubMed, Embase, Cochrane, Scopus, and PsycINFO (1 January 2008 through 1 October 2012). Inclusion criteria were phase I studies that enrolled healthy participants of any age, provided quantitative adverse event (AE) data, and documented the number of participants enrolled. Exclusion criteria included 1) AE data not in English, 2) a “challenge” study in which participants were administered a pathogen, and 3) no quantitative information about serious AE’s. Data on the incidence of adverse events, duration of AE monitoring, trial agent tested, participant demographics, and trial location were extracted. Results In 475 trials enrolling 27,185 participants, there was a median of zero serious adverse events (interquartile range, 0-0) and a median of zero severe adverse events (interquartile range, 0-0) per 1000 treatment group participants/day of monitoring. The rate of mild and moderate adverse events was a median of 1147.19 per 1000 participants (interquartile range, 651.52 – 1730.9) and 46.07 per 1000 participants/AE monitoring day (interquartile range, 17.80 – 77.19). Conclusions We conclude that phase I trials do cause mild and moderate harms but pose low risks of severe harm. To ensure that this conclusion also applies to unpublished trials, it is important to increase trial transparency.

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“…While the majority of such studies are tumor agnostic (enroll a variety of tumor types), there is an increasing trend to conduct phase I trials (or phase I expansion cohorts[12]) in one or a few malignancies. At a registry level, the challenge in relying too heavily on the phase I data reported here is that many phase I trials may not be registered in clinicaltrials.gov[13,14]. Nevertheless, we feel that this limitation is unlikely to be systematic among the malignancies described.…”

Section: Discussionmentioning

confidence: 96%

Clinical trial spots for cancer patients by tumour type: The cancer trials portfolio at clinicaltrials.gov

Prasad

Goldstein

2015

European Journal of Cancer

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Background Although participation in cancer clinical trials is low, little is known about the number of available clinical trials, and open spots for patients. Moreover, it is unclear what the relationship is between clinical trial openings and the incidence and mortality of cancer subtypes. Methodology We identified the number of phase I, phase II, and phase III registered at clinicaltrials.gov by cancer (tumor) type. All counts were over the preceding 5 years (2008 to 2013). We compared these counts against the incidence and prevalence of disease reported by Surveillance, Epidemiology, and End Results (SEER) database for 32 common cancers Results From 2008 to 2013, 3879 phase I trials, 4982 phase II trials and 1379 phase III trials concerning a cancer subtype were registered in clinicaltrials.gov. These trials had a cumulative proposed recruitment of 203396, 421502, and 697787 patients, respectively. Trial enrollment varied by tumor type, with both over and under-representation occurring. Conclusion Opportunities to enroll in clinical trials vary by phase and tumor type. Oncologists must remain committed to clinical trials.

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Inadequate Dissemination of Phase I Trials: A Retrospective Cohort Study

Cited by 38 publications

References 21 publications

Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials

Non-Publication Is Common among Phase 1, Single-Center, Not Prospectively Registered, or Early Terminated Clinical Drug Trials

Risks of phase I research with healthy participants: A systematic review

Clinical trial spots for cancer patients by tumour type: The cancer trials portfolio at clinicaltrials.gov

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