A meta-analysis of threats to valid clinical inference in preclinical research of sunitinib

Henderson, Valerie C.; Demko, Nadine; Hakala, Amanda; MacKinnon, Nathalie; Federico, Carole A; Fergusson, Dean; Kimmelman, Jonathan

doi:10.7554/elife.08351

Cited by 34 publications

(39 citation statements)

References 51 publications

(60 reference statements)

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“…If all malignancies respond to sorafenib, the value for trial planning of the type of in vivo testing used in experiments analyzed here is doubtful. Third, our trim and fill analysis suggested an overestimation of effect size due to publication bias across malignancies that is similar to what we observed for sunitinib (5). Our analysis did not find a strong dose-response relationship for pooled malignancies-nor for one of the malignancies currently approved for monotherapy.…”

Section: Discussionsupporting

confidence: 57%

“…Similarly, we found limited attention to internal validity threats, as indicated by the general nonimplementation and reporting of design elements such as concealed allocation, blinded outcome assessment, and animal attrition. With respect to construct validity, researchers generally relied on young, immunocompromised, and female mice, as they had for sunitinib (5). In this study and in the previous one, however, we did not detect exaggerated effect sizes in studies harboring internal or construct validity threats, as others have (40,41).…”

Section: Discussioncontrasting

confidence: 52%

“…Statistical significance was set at a P value of 0.05; because of multiplicities, all testing was exploratory. We did not prospectively register a protocol for this meta-analysis; however, except where noted, hypothesis testing was prespecified, and we followed the methods used in our previous meta-analysis of the anticancer drug, sunitinib (5).…”

Section: Meta-analysismentioning

confidence: 99%

“…In a previous report, we investigated design, reporting, and outcomes for tumor volume experiments contained within preclinical studies of the anticancer drug, sunitinib (5). We found that design practices that reduce the threat of bias and random variation, such as outcome assessment blinding, were rarely implemented.…”

Section: Introductionmentioning

confidence: 99%

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Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy

et al. 2016

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The validity of preclinical studies of candidate therapeutic agents has been questioned given their limited ability to predict their fate in clinical development, including due to design flaws and reporting bias. In this study, we examined this issue in depth by conducting a meta-analysis of animal studies investigating the efficacy of the clinically approved kinase inhibitor, sorafenib. MEDLINE, Embase, and BIOSIS databases were searched for all animal experiments testing tumor volume response to sorafenib monotherapy in any cancer published until April 20, 2012. We estimated effect sizes from experiments assessing changes in tumor volume and conducted subgroup analyses based on prespecified experimental design elements associated with internal, construct, and external validity. The meta-analysis included 97 experiments involving 1,761 animals. We excluded 94 experiments due to inadequate reporting of data. Design elements aimed at reducing internal validity threats were implemented only sporadically, with 66% reporting animal attrition and none reporting blinded outcome assessment or concealed allocation. Anticancer activity against various malignancies was typically tested in only a small number of model systems. Effect sizes were significantly smaller when sorafenib was tested against either a different active agent or combination arm. Trim and fill suggested a 37% overestimation of effect sizes across all malignancies due to publication bias. We detected a moderate dose-response in one clinically approved indication, hepatocellular carcinoma, but not in another approved malignancy, renal cell carcinoma, or when data were pooled across all malignancies tested. In support of other reports, we found that few preclinical cancer studies addressed important internal, construct, and external validity threats, limiting their clinical generalizability. Our findings reinforce the need to improve guidelines for the design and reporting of preclinical cancer studies.

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Section: Discussionsupporting

confidence: 57%

Section: Discussioncontrasting

confidence: 52%

Section: Meta-analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy

et al. 2016

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“…[31][32][33][34][35] In comparison, venetoclax alone had a ,25% enhanced effect above DMSO for most patients ( Figure 3B colored bar at the bottom).…”

Section: Sensitivity Of Cll Cells To Venetoclax Depends On Microenvirmentioning

confidence: 99%

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

Oppermann

Ylanko

Shi

et al. 2016

Blood

105

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How well are Phase 2 cancer trial publications supported by preclinical efficacy evidence?

Pratte

Ganeshamoorthy

Carlisle

et al. 2019

Intl Journal of Cancer

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Major ethics policies require that human studies be preceded by animal experiments. We probed the extent to which trials testing efficacy of cancer drugs cited preclinical efficacy studies testing the same drug and disease indication. Using a sample of Phase 2 trial publications for novel cancer monotherapies approved by Food and Drug Administration 2005–2007, we conducted a systematic analysis of citations to preclinical efficacy evidence within trial publications. Citations were classified based on whether they “matched” the drug and indication of the trial. Our sample included 179 Phase 2 publications published 2004–2016. At least one preclinical study was cited for 113 of 179 publications (63%); 56 (31%) cited matching preclinical studies, and 74 (41%) did not cite either matching preclinical or matching clinical trial evidence. When excluding evidence that would likely not have been available to investigators before trial launch, 45 trials (25%) cited matching preclinical studies; 91 (51%) did not cite any matched preclinical or clinical, preceding evidence. No relationship between citation of matching and preceding preclinical evidence and trial outcomes was observed (28.4% of nonpositive trials vs. 26.9% of positive trials, p ~ 1). This suggests that many Phase 2 trial publications do not cite matching preclinical efficacy studies. Limited citation either suggests its absence or its exclusion from a publication. To ensure trials rest on a sound ethical basis and that publications support valid inference, journal editors and referees might encourage more complete descriptions of preclinical evidence or, where appropriate, active disclosure of its absence.

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A meta-analysis of threats to valid clinical inference in preclinical research of sunitinib

Cited by 34 publications

References 51 publications

Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy

Design and Reporting of Targeted Anticancer Preclinical Studies: A Meta-Analysis of Animal Studies Investigating Sorafenib Antitumor Efficacy

High-content screening identifies kinase inhibitors that overcome venetoclax resistance in activated CLL cells

How well are Phase 2 cancer trial publications supported by preclinical efficacy evidence?

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