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Quantifying the risks of non-oncology phase I research in healthy volunteers: meta-analysis of phase I studies

BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h3271 (Published 26 June 2015) Cite this as: BMJ 2015;350:h3271
  1. Ezekiel J Emanuel, chair, vice provost for global initiatives12,
  2. Gabriella Bedarida, medical director3,
  3. Kristy Macci, project manager3,
  4. Nicole B Gabler, associate scholar4,
  5. Annette Rid, senior lecturer5,
  6. David Wendler, senior investigator6
  1. 1Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, PA, USA
  2. 2Office of the Provost, University of Pennsylvania, PA, USA
  3. 3New Haven Clinical Research Unit, Pfizer, New Haven, CT, USA
  4. 4Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania
  5. 5Department of Social Science, Health & Medicine, King’s College London, London, UK
  6. 6Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA
  1. Correspondence to: E J Emanuel vp-global{at}upenn.edu
  • Accepted 28 May 2015

Abstract

Objective To quantify the frequency and seriousness of adverse events in non-oncology phase I studies with healthy participants.

Design Meta-analysis of individual, healthy volunteer level data.

Setting 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.

Participants 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.

Main outcome measures 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).

Conclusion 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.

Footnotes

  • We thank Jean Paul Hoffman for data extraction.

  • Contributors: EJE, AR, and DW conceived and designed the study and are the guarantors. GB, KM, and NBG acquired and analysed the data. EJE, NBG, AR, and DW interpreted the data. EJE drafted the manuscript. GB, KM, NBG, AR, and DW critically reviewed the manuscript. All authors approved the final version of the manuscript. The views expressed are those of the authors. They do not represent the position or policy of the NIH, DHHS, US government, or Pfizer. AR received funding from the Swiss National Science Foundation (PA00B-117505/1 and PA0033-117502/2). Pfizer made the data available, provided guidance on how the data were collected, provided insights into the conduct of phase I research, and covered the salaries of the employees involved in each trial and in this project. Pfizer had an opportunity to review the manuscript but made no changes to the data interpretation.

  • Funding: This study was funded, in part by NIH intramural research funds and in part by funds from the Department of Medical Ethics and Health Policy of the Perelman School of Medicine, University of Pennsylvania. The researchers from NIH, University of Pennsylvania, and King’s College London were independent of Pfizer and had no financial compensation from Pfizer. NBG was awarded a Pfizer grant that ended in 2009. The two Pfizer employees were paid by Pfizer. AR received funding from the Swiss National Science Foundation (PA00B-117505/1 and PA0033-117502/2). Pfizer provided no specific financial support for this study.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare: GB and KM are employees of Pfizer. NBG was awarded a Pfizer grant that ended in 2009; the non-Pfizer researchers have no financial ties—past or present—to Pfizer except for the statistician (NG) who participated in one Pfizer funded study that ended in 2009; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was deemed exempt from institutional review by the NIH because it involved the analysis of existing, stored, and deidentified data.

  • Data sharing: Data are available on request from the corresponding author at vp-global{at}upenn.edu.

  • Transparency: The lead author (EJE) affirms that the manuscript is an honest, accurate and transparent account of the study being reported. No important aspect of the study has been omitted. No discrepancies are withheld.

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