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Two unusual circumstances arose in the conduct, review, and publication of the VICTAS randomized clinical trial.1 First, the funder reportedly withdrew financial support for the study after enrollment of only 25% of the planned study sample, resulting in early termination of the study; and second, a member of the data and safety monitoring board (DSMB) is an author of the article.
The National Institutes of Health (NIH; which was not a funder of the VICTAS trial) is the largest single funder of biomedical research in the world. Clinical research is generally supported by grants or contracts, and it is very unusual for the NIH to withhold or withdraw funds for a study if appropriate documented progress is being made and no ethical or other scientific issues have arisen. However, in the past few decades, patient advocacy groups and new foundations, often with the active engagement of the individual(s) who created the foundation, have begun to fund biomedical research. It is important for investigators, and the offices of sponsored programs at the investigators’ institutions, who are usually responsible for the contractual relationship between an investigator (or institution) and the funder, to be aware of the details governing and ensuring the ongoing support of a study.
According to the authors of the VICTAS study, “[a]fter 501 participants were enrolled, additional funding for the trial was withheld due to a change in the funder’s priorities, and no further enrollments occurred, leading to administrative termination of the trial prior to meeting any prespecified stopping criterion. Aside from the knowledge that the trial had not yet stopped at an earlier interim analysis, the funder had no information regarding unblinded trial results at the time funding was terminated.”1
In general, it is inappropriate for a funder to withdraw, withhold, or discontinue funding for an ongoing study for reasons other than prespecified issues related to the scientific conduct of the study. Although the funder of the VICTAS trial may have had business reasons, philosophical priorities, or other factors that were considered in its decision, the withdrawal of funding and resultant termination of the trial compromised the integrity of the study, precluded the study from definitively answering an important clinical question, and represented a serious violation of the implicit pact with the study participants who volunteered for the trial.
Another important element to help ensure scientific standards, safety, and integrity in the conduct of clinical trials is to have an appropriately constituted and functioning independent DSMB. The DSMB has numerous responsibilities, of which 2 of the most important are to oversee the conduct of the study, ensuring the safety of study participants; and to advise the investigators about early termination of the study, generally based on prespecified stopping rules. In some studies, an individual who has specific expertise in study design and may have been involved in the initial planning and design of the study also might serve as a member of the DSMB. However, the DSMB should be composed of an independent group of experts, and some guidelines recommend that “no member of the DSMB should have direct involvement in the conduct of the study” and “no member should have financial, proprietary, professional, or other interests that may affect impartial, independent decision-making by the DSMB.”2 Moreover, once the study begins, the DSMB should be entirely “independent” from the conduct and analysis of the study.
In the VICTAS trial, the individual who served as chair of the DSMB also was involved with the initial design of the study, participated in the statistical analysis and interpretation of the data, and is listed as an author of the article. This type of involvement in multiple capacities in a clinical trial should be discouraged and has the potential to compromise the conduct and oversight of the study and the analysis and interpretation of study results.
Given these concerns, why has JAMA decided to publish the study? First, the VICTAS trial is among the largest studies conducted that focused on an important clinical question—does the use of vitamin C, thiamine, and corticosteroids reduce mortality in patients who are critically ill? Second, the design of the study was sophisticated and the trial was rigorously conducted, except for the early termination. Third, the study was stopped early because the sponsor withdrew support, and the DSMB reportedly was not involved with the recommendation; thus, the individual who served as both DSMB chair and author had no role in this decision. Fourth, there appears to be no commercial interest in these products, and none of the authors reported having financial conflicts of interest related to the drugs used in the study. Fifth, and perhaps most important, publication of the data from the VICTAS trial recognizes and acknowledges the 501 patients with sepsis-induced respiratory or cardiovascular dysfunction who participated in this trial and whose contributions were intended to provide important information to advance the care of other critically ill patients.
Even though some aspects of the VICTAS trial are unusual and do not reflect standard practice, these issues illustrate that the design, conduct, oversight, reporting, and funding of randomized clinical trials continue to evolve.3 Among the key lessons from the VICTAS trial are that (1) organizations that fund clinical research must honor their commitment to investigators and patients who participate in clinical trials and (2) individuals involved in the design, conduct, or oversight of clinical trials should only participate to the extent that performing their roles and responsibilities will ensure the necessary independence and checks and balances in trial conduct and oversight, and must not be perceived as potentially compromising the integrity of the trial. It is important that these fundamental yet at times complex issues be discussed and debated because of the importance of randomized clinical trials in contributing to the evidence that ultimately is used to improve clinical care.
Corresponding Author: Howard Bauchner, MD, JAMA, 330 N Wabash Ave, Chicago, IL 60611 (firstname.lastname@example.org).
Conflict of Interest Disclosures: None reported.
Bauchner H, Fontanarosa PB, Golub RM. Funding and DSMB Membership in the VICTAS Clinical Trial. JAMA. 2021;325(8):751–752. doi:10.1001/jama.2020.25952
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