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Cited by 128Antifungal resistance and susceptibilityMeta-analysis and systematic reviewsPharmaceutical industry and healthcare

Problems in the Design and Reporting of Trials of Antifungal Agents Encountered During Meta-analysis

Johansen, Helle Krogh·1999·JAMA
DOI 10.1001/jama.282.18.1752
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Abstract

Meta-analyses may become biased if the reported data in the individual trials are biased and if overlap among trials cannot be identified. We describe the unanticipated problems we encountered in collecting data for a meta-analysis comparing a new antifungal agent, fluconazole, with amphotericin B in patients with cancer complicated by neutropenia. In 3 large trials that comprised 43% of the patients identified for the meta-analysis, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is recognized as an ineffective drug in these circumstances, this approach creates a bias in favor of fluconazole. Furthermore, 79% of the patients were randomized to receive oral amphotericin B, which is poorly absorbed and not an established treatment, in contrast to intravenous amphotericin B, which was administered in 4 of 5 placebo-controlled trials, or 86% of patients. It was unclear whether there was overlap among the "polyene" trials, and it is possible that results from single-center trials were included in multicenter trial reports. We were unable to obtain information to clarify these issues from the trial authors or the manufacturer of fluconazole. Two of 11 responding authors replied that the data were with the drug manufacturer and two indicated that they did not have access to their data because of change of affiliation. In the meta-analyses, fluconazole and amphotericin B (mostly given orally) had similar effects (13 trials), whereas nystatin was no better than placebo (3 trials). Since individual trials are rarely conclusive, investigators, institutions, and pharmaceutical companies should provide essential details about their work to ensure that meta-analyses can accurately reflect the studies conducted and that patients will realize maximum benefits from treatments. We recommend that investigators keep copies of their trial data to help facilitate accurate and unbiased meta-analyses.

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  • A trial in which the comparator group receives an inappropriately high dose will lead to an underestimate of the relative harms of the study intervention.

    “conversely, an inappropriately high dose in the comparator group will lead to an underestimate of the relative harms of the study intervention.157 158”

    From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [158]

  • A trial in which the comparator group receives an inappropriately low dose of an active drug will overestimate the relative efficacy of the study intervention in clinical practice.

    “For example, a trial in which the comparator group receives an inappropriately low dose of an active drug will overestimate the relative efficacy of the study intervention in clinical practice;”

    From SPIRIT 2025 explanation and elaboration: updated guideline for protocols of randomised trials (2025) · cites this paper as [158]

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Authors
Johansen, H. K.
Affiliations
Rigshospitalet (DK)
Corresponding author
Johansen, Helle Krogh
ORCID
Johansen, Helle Krogh
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
1999-11-10
Volume
282
Issue
18
Pages
1752
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.282.18.1752
OpenAlex
W1999842431
Cited by
128
References
27
Citations by year
2025: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 1 · 2014: 8 · 2013: 5 · 2012: 3
FWCI
10.13
Type
journal article
Language
en
Open access
closed
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
  • DigitalGeorgetown (Georgetown University Library) (submittedVersion)
Topics
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Social Sciences › Decision Sciences › Statistics, Probability and Uncertainty › Meta-analysis and systematic reviews
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmaceutical industry and healthcare
Keywords
meta-analysis bias, antifungal agents, fluconazole, amphotericin B, nystatin, polyene antibiotics, neutropenia, cancer, data overlap
MeSH terms
Amphotericin B, Antifungal Agents, Humans, Mycoses, Neoplasms, Neutropenia, Nystatin, Opportunistic Infections, Research Design, Meta-Analysis as Topic, Fluconazole, Randomized Controlled Trials as Topic, Publication Bias

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