After the London tragedy, is it still possible to consider Phase I is safe?

Sibille, M.; Donazzolo, Yves; Lecoz, Franck; Krupka, E.

doi:10.1111/j.1365-2125.2006.02740.x

Cited by 32 publications

(25 citation statements)

References 5 publications

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“…The most rare adverse events in past research were one drug-related, clinically serious adverse event per 5,000 participants. 13 Therefore, the almost five year coverage period was intended to capture a sufficient number of trials to detect rare but serious harms.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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“…Subjects who volunteer for phase I trials get no therapeutic benefit from the IMP, so appropriate and rigorous risk assessments are required, before the trial, to minimize the risk of harming the subjects. The overall safety of Phase I trials is good, with an incidence of 0.02% of serious adverse events related to the investigational drug [4]; however, there is paucity of safety data on nonchemical investigational drugs such as proteins, cytokines, and monoclonal antibodies. There are several guidelines on calculating a safe starting dose on the IMP in Phase I trials [5,6].…”

Section: Phase I Studiesmentioning

confidence: 97%

“…Typically, this randomizes between two or more experimental arms without a control arm [3,4,8]. Usually, there will be a test for the activity of each arm, using standard criteria for single-arm studies, and a rule for selecting the "best" of the active arms for further testing.…”

Section: Phase II Studiesmentioning

confidence: 99%

Clinical Trials in Pharmacogenomics and Stratified Medicine

Padmanabhan

2014

Handbook of Pharmacogenomics and Stratified Medicine

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“…In spite of—or perhaps because of—these sensational cases of phase I trials gone awry, phase I investigators are keen to demonstrate evidence of the low probability of harm to healthy volunteers. For example, meta-analyses of published phase I trials consistently indicate that fewer than 1 percent of healthy volunteers experience serious drug-related adverse effects (Kumagai et al 2006; Sibille et al 2006), and investigators routinely frame participation as safer than many blue-collar professions (Kupetsky-Rincon and Kraft 2012). …”

Section: Conceptual Framework and Backgroundmentioning

confidence: 99%

Feeding and Bleeding

Fisher

2014

Science, Technology, & Human Values

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Phase I clinical trials are the first stage of testing new pharmaceuticals in humans. The majority of these studies are conducted under controlled, inpatient conditions using healthy volunteers who are paid for their participation. This article draws on an ethnographic study of six phase I clinics in the United States, including 268 semistructured interviews with research staff and healthy volunteers. In it, I argue that an institutional banalization of risk structures the perceptions of research staff and healthy volunteers participating in the studies. For research staff, there are three mechanisms by which risk becomes banal: a perceived homogeneity of studies, Fordist work regimes, and data-centric discourse. For healthy volunteers, repeat study participation contributes to the institutional banalization of risk both through the process of desensitization to risk and the formation of trust in the clinics. I argue that the institutional banalization of risk also renders invisible ethical concerns about exploitation of underprivileged groups in pharmaceutical research.

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After the London tragedy, is it still possible to consider Phase I is safe?

Cited by 32 publications

References 5 publications

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

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

Clinical Trials in Pharmacogenomics and Stratified Medicine

Feeding and Bleeding

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