Ethical Concerns Persist Over Reporting Bias in Clinical Trials
Clinicians often make prescribing decisions based solely on data from published trials. However, the creators of other unpublished trials might have found the drug to be ineffective or even harmful. “Not publishing nonpositive results, or massaging data to make trial results seem more ‘exciting,’ are ethically problematic practices,” says Mayookha Mitra-Majumdar, MPH, a research specialist in the Program on Regulation, Therapeutics, and Law at Brigham and Women’s Hospital in Boston.
Reporting bias comes in different forms. In cases of publication bias, trials showing negative or no effects are not published. In cases of outcome reporting bias, publications omit unfavorable data, include only a portion of trial data, or alter the primary outcome to show statistical significance. “What results is an inaccurate, incomplete body of evidence that can skew the perceived risk-benefit ratio of medical treatments. This can result in suboptimal clinical decisions and patient outcomes,” says Mitra-Majumdar, co-author of an article that outlines efforts to combat reporting bias over the past 20 years.1 Reporting bias is driven in part by researchers’ perceptions that journals prefer to publish studies with positive outcomes, nonzero effect sizes, and statistically significant findings. “However, it can be more insidious, such as when pharmaceutical companies are financially driven to publish positive data on their drugs to increase uptake,” Mitra-Majumdar notes.
Data suggest reporting bias is common. A meta-analysis of 4,600 papers revealed the odds of reporting outcomes supporting the study hypothesis increased 6% annually between 1990 and 2007.2 “However, studies suggest that efforts launched since then have shown some success,” Mitra-Majumdar explains. “Efforts to spur transparency and mitigate reporting bias are coming from both the research community and policymakers.”
Mitra-Majumdar calls for several crucial changes, including enforcement of penalties for delays in reporting trial results; journals prioritizing accuracy between published results and the original study protocols; and mitigating the problem of selective registration, publication, and reporting on ClinicalTrials.gov. As for IRBs, their role is primarily protecting human subjects in research, as opposed to ensuring all studies are published. “There is a natural tension between the regulatory role of IRBs and certain transparency efforts that may either risk breaches of privacy or pose additional burdens on IRBs,” Mitra-Majumdar says.
There are two ways IRBs can play a role in research transparency: require study investigators to register studies and require a data-sharing plan before IRB approval. “IRBs can then check that study results have been published transparently before ending continuing review,” Mitra-Majumdar explains.
Failure to report research findings leads to scientific bias. “It also ignores the many costs borne by patients, investigators, and funders who contributed to the research,” says William B. Feldman, MD, DPhil, MPH, an instructor at Harvard Medical School and co-chair of the ethics committee at Brigham and Women’s Hospital. “Unreported findings are an example of ‘research waste.’ We have a clear ethical responsibility in the medical community to limit research waste as best we can.”
IRBs, funding bodies, regulatory agencies, hospitals, journals, and investigators all are obligated to ensure research is publicly disseminated, according to Feldman. This is the case even if study findings show no benefit of one treatment over another or otherwise fail to reject the null hypothesis.
Trying to uncover the unpublished data is one way to combat reporting bias. “Rather than just trusting what’s in the published literature, researchers can look at the data that the company submitted to the FDA,” suggests Craig Williams, PharmD, a clinical professor at the Oregon State University.
However, this takes many hours of work, and is beyond what a typical clinician would be able achieve. For clinicians, the first step is understanding published trials might not be the whole picture. “A huge part of it is simply the awareness of it, and remembering that part of our role, whether in the clinical realm, in the IRBs, or in teaching future clinicians, is to be aware that we often don’t have all the data we think we have,” Williams explains.
Likewise, IRBs should be aware FDA package inserts may not be a complete picture of that drug. “IRBs could ask investigators submitting protocols to provide any relevant, unpublished studies they feel might impact the research,” Williams suggests.
REFERENCES
- Mitra-Majumdar M, Kesselheim AS. Reporting bias in clinical trials: Progress toward transparency and next steps. PLoS Med 2022;19:e1003894.
- Fanelli D. Negative results are disappearing from most disciplines and countries. Scientometrics 2012;90:891-904.
Several changes could be made, including enforcement of penalties for delays in reporting trial results; journals prioritizing accuracy between published results and the original study protocols; and mitigating the problem of selective registration, publication, and reporting on ClinicalTrials.gov.
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