title: Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies.
abstract: OBJECTIVE
  To quantify the frequency and seriousness of adverse events in non-oncology phase I studies with healthy participants.
  
  
  METHODS
  Meta-analysis of individual, healthy volunteer level data.
  
  
  METHODS
  Phase I studies with healthy volunteers conducted between September 2004 and March 2011 at Pfizer's three dedicated phase I testing sites in Belgium, Singapore, and the United States. These included studies in which drug development was terminated.
  
  
  METHODS
  11,028 participants who received the study drug in 394 distinct non-oncology phase I studies, which involved 4620 unique individuals. A total of 2460 (53.2%) participants were involved in only one study, whereas others participated in two or more studies.
  
  
  METHODS
  Adverse events classified as mild, moderate, and severe as well as serious adverse events-defined by the Food and Drug Administration as events that result in death, a life threatening event, admission to hospital, prolongation of existing hospital stay, a persistent or major disability, or a congenital anomaly or birth defect. Pfizer researchers of phase I trials determined adverse events, and serious adverse events were those filed with the FDA.
  
  
  RESULTS
  Overall, 4000 (36.3%) participants who received the study drug experienced no adverse events and 7028 (63.7%) experienced 24,643 adverse events. Overall, 84.6% (n=20,840) of adverse events were mild and 1.0% (n=255) were severe. 34 (0.31%) serious adverse events occurred among the 11,028 participants who received the study agent, with no deaths or life threatening events. Of the 34 serious adverse events, 11 were related to the study drug and seven to study procedures, whereas 16 were unrelated to a study drug or procedure, including four that occurred when the participant was receiving a placebo. Overall, 24.1% (n=5947) of adverse events were deemed to be unrelated to the study drug. With a total of 143 (36%) studies involving placebo, 10.3% (n=2528) of all adverse events occurred among participants receiving placebo. The most common adverse events were headache (12.2%, n=3017), drowsiness (9.8%, n=2410), and diarrhea (6.9%, n=1698). Research on drugs for neuropsychiatric indications had the highest frequency of adverse events (3015 per 1000 participants).
  
  
  CONCLUSIONS
  Among 11,028 healthy participants who received study drug in non-oncology phase I studies, the majority (85%) of adverse events were mild. 34 (0.31%) serious adverse events occurred, with no life threatening events or deaths. Half of all adverse events were related to the study drug or to procedures. Extrapolation of these data to other types of phase I studies, especially with biological agents, may not be warranted.
authors.affiliation: Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, PA, USA Office of the Provost, University of Pennsylvania, PA, USA vp-global@upenn.edu.
authors.forename: Ezekiel J
authors.initials: EJ
authors.lastname: Emanuel
authors.affiliation: New Haven Clinical Research Unit, Pfizer, New Haven, CT, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bedarida
authors.affiliation: New Haven Clinical Research Unit, Pfizer, New Haven, CT, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Macci
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania.
authors.forename: Nicole B
authors.initials: NB
authors.lastname: Gabler
authors.affiliation: Department of Social Science, Health & Medicine, King's College London, London, UK.
authors.forename: Annette
authors.initials: A
authors.lastname: Rid
authors.affiliation: Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wendler
mesh_terms: D001530:Belgium; D017321:Clinical Trials, Phase I as Topic; D064420:Drug-Related Side Effects and Adverse Reactions; D064368:Healthy Volunteers; D006801:Humans; D018570:Risk Assessment; D012846:Singapore; D014481:United States