The Literature Isn’t Just Biased, It’s Also Late to the Party

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Animal studies of drug efficacy are an important resource for designing and performing clinical trials. They provide evidence of a drug’s potential clinical utility, inform the design of trials, and establish the ethical basis for testing drugs in human. Several recent studies suggest that many preclinical investigations are withheld from publication. Such nonreporting likely reflects that private drug developers have little incentive to publish preclinical studies. However, it potentially deprives stakeholders of complete evidence for making risk/benefit judgments and frustrates the search for explanations when drugs fail to recapitulate the promise shown in animals.

In a future issue of The British Journal of Pharmacology, my co-authors and I investigate how much preclinical evidence is actually available in the published literature, and when it makes an appearance, if at all.

Although we identified a large number of preclinical studies, the vast majority was reported only after publication of the first trial. In fact, for 17% of the drugs in our sample, no efficacy studies were published before the first trial report. And when a similar analysis was performed looking at preclinical studies and clinical trials matched by disease area, the numbers were more dismal. For more than a third of indications tested in trials, we were unable to identify any published efficacy studies in models of the same indication.

There are two possible explanations for this observation, both of which have troubling implications. Research teams might not be performing efficacy studies until after trials are initiated and/or published. Though this would seem surprising and inconsistent with ethics policies, FDA regulations do not emphasize the review of animal efficacy data when approving the conduct of phase 1 trials. Another explanation is that drug developers precede trials with animal studies, but withhold them or publish them only after trials are complete. This interpretation also raises concerns, as delay of publication circumvents mechanisms—like peer review and replication—that promote systematic and valid risk/benefit assessment for trials.

The take home message is this: animal efficacy studies supporting specific trials are often published long after the trial itself is published, if at all. This represents a threat to human protections, animal ethics, and scientific integrity. We suggest that animal care committees, ethics review boards, and biomedical journals should take measures to correct these practices, such as requiring the prospective registration of preclinical studies or by creating publication incentives that are meaningful for private drug developers.

BibTeX

@Manual{stream2014-542,
    title = {The Literature Isn’t Just Biased, It’s Also Late to the Party},
    journal = {STREAM research},
    author = {Carole Federico},
    address = {Montreal, Canada},
    date = 2014,
    month = jun,
    day = 30,
    url = {http://www.translationalethics.com/2014/06/30/the-literature-isnt-just-biased-its-also-late-to-the-party/}
}

MLA

Carole Federico. "The Literature Isn’t Just Biased, It’s Also Late to the Party" Web blog post. STREAM research. 30 Jun 2014. Web. 21 Jul 2017. <http://www.translationalethics.com/2014/06/30/the-literature-isnt-just-biased-its-also-late-to-the-party/>

APA

Carole Federico. (2014, Jun 30). The Literature Isn’t Just Biased, It’s Also Late to the Party [Web log post]. Retrieved from http://www.translationalethics.com/2014/06/30/the-literature-isnt-just-biased-its-also-late-to-the-party/


Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research

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Much has already been said about Filing Cabinet syndrome in medical research: the tendency of researchers to publish exciting results from clinical trials, and to stash null or negative findings safely away from public view in a filing cabinet. Nonpublication distorts the medical literature, because it prevents medical practitioners from accessing negative information about drugs. Recall that, back in 2004, attorney-general Eliot Spitzer sued Glaxo Smithkline for suppressing trial results that showed elevated risk of suicide for adolescents taking the antidepressant drug Paxil; this and several similar episodes led FDA, major medical journals, World Health Organization, World Medical Association, and others to require researchers to register clinical trials before they enroll any patients.


Yet important gaps remain. In the March 2010 issue of PLoS Biology, Emily S. Sena and coauthors provide the most detailed analysis yet of one of these gaps: nonpublication of preclinical (animal) studies. They aggregated results of 16 systematic reviews of preclinical studies involving acute ischaemic stroke, and used statistical methods to estimate the degree of publication bias, and the likely effect of publication bias on measured disease responses. Among other things, they found that 16% of animal experiments were not published, leading to a 31% overstatement of efficacy. The authors note: “we estimate that for the interventions described here, experiments involving some 3,600 animals have remained unpublished. We consider this practice to be unethical.”

The authors urge that central registries of preclinical studies be established and maintained– a call that is not likely to go heeded anytime soon by companies that have much at stake in the secrecy in preclinical research. But their proposal ought to be taken seriously by anyone committed not only to respecting animals used in medical research, but also protecting the welfare of human beings who might enroll in possibly unwarranted clinical research. (photo credit: amy allcock 2009)

BibTeX

@Manual{stream2010-66,
    title = {Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research},
    journal = {STREAM research},
    author = {Jonathan Kimmelman},
    address = {Montreal, Canada},
    date = 2010,
    month = may,
    day = 11,
    url = {http://www.translationalethics.com/2010/05/11/filing-cabinet-syndrome-the-effect-of-nonpublication-of-preclinical-research/}
}

MLA

Jonathan Kimmelman. "Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research" Web blog post. STREAM research. 11 May 2010. Web. 21 Jul 2017. <http://www.translationalethics.com/2010/05/11/filing-cabinet-syndrome-the-effect-of-nonpublication-of-preclinical-research/>

APA

Jonathan Kimmelman. (2010, May 11). Filing Cabinet Syndrome: The Effect of Nonpublication of Preclinical Research [Web log post]. Retrieved from http://www.translationalethics.com/2010/05/11/filing-cabinet-syndrome-the-effect-of-nonpublication-of-preclinical-research/


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