I served for a number of years on an IRB at a teaching and research hospital. A recent note about the discontinuance of a clinical trial (see: Merck Shares Drop After Anti-Clotting Drug Trials Curtailed) called attention to the work of a Data Monitoring and Safety Board (DMSB) (see: What’s a Data and Safety Monitoring Board, Anyway?). Below is an excerpt from the note:
Merck’s recent announcement that it halted one study of an experimental anti-clotting drug and reduced the number of patients in another has highlighted the role of data and safety monitoring boards, which keep tabs on the progress of clinical trials to watch for safety issues and effectiveness. For now, it appears members of the DSMB, ...overseeing the trials of vorapaxar, are the only people who know what happened with the trials. Merck said it didn’t yet know what went wrong, if anything, and the investigators said the same. The entire point of a DSMB is that it’s independent. It’s made up of...experts in the disease area being studied, and also in areas that might present safety problems....Members of the DSMB make scheduled periodic checks of the trial as it progresses, and are the only people with access to the unblinded results; investigators and patients must be kept in the dark to avoid biasing the findings. But the DSMB has access to the raw data so it can step in to protect patients if something appears to go awry. There are a few reasons why a DSMB would recommend stopping or altering a trial. It could be because interim data suggest the drug is effective — and would almost certainly show the same trend if the trial continued — so it would be unethical to deny treatment to patients in the placebo group. Or a trial could be stopped if the data available to the DSMB show it would be very unlikely for the drug to show any benefit even if the trial continued. Before a trial starts, the sponsor will determine what level of data would trigger such an intervention. Safety is different....Board members rely more on their discretion when they look at data on adverse effects or patient deaths, since some problems might be anticipated and others completely out of the blue. If their collective judgment is that there’s a problem, they will recommend to the study sponsor that the trial be stopped.
Here's more details about when a research study requires DSMB oversight (see: What is a DSMB; Regulatory considerations)
Though it is not required, the FDA generally expects the use of DSMBs for randomized trials with mortality or major morbidity as primary endpoints. The only mention of DSMBs in the Code of Federal Regulations is found in 21 CFR 50.24 (a)(7)(iv)....This regulation mandates that the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation for studies where human subjects are in a life-threatening situation and the investigation meets the criteria in 21 CFR 50.24.
By way of contrast, the function of IRBs at research institutions is to review all research involving human subjects to ensure that their rights are being protected. Here is a summary statement about IRBs from the FDA (see: Institutional Review Boards Frequently Asked Questions - Information Sheet):
Under FDA regulations, an IRB is an appropriately constituted group that has been formally designated to review and monitor biomedical research involving human subjects. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. This group review serves an important role in the protection of the rights and welfare of human research subjects....To accomplish this purpose, IRBs use a group process to review research protocols and related materials (e.g., informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects of research.
In summary, the IRBs provide an institutional review a priori of all research studies involving human subjects. In addition, DSMBs are required for research "with mortality or major morbidity as primary endpoints." The members of these latter groups also review raw study data "so [the DSMB] can step in to protect patients if something appears to go awry." A clinical trial can also be stopped by the DSMB if the drug in question is deemed to be proved effective. The two groups work independently but do communicate with each other within an institution.
What’s a Data and Safety Monitoring Board, Anyway?
By Katherine Hobson
Merck’s recent announcement that it halted one study of an experimental anti-clotting drug and reduced the number of patients in another has highlighted the role of data and safety monitoring boards, which keep tabs on the progress of clinical trials to watch for safety issues and effectiveness.
For now, it appears members of the DSMB — also called a data monitoring committee — overseeing the trials of vorapaxar are the only people who know what happened with the trials. Merck said it didn’t yet know what went wrong, if anything, and the investigators said the same.
The entire point of a DSMB is that it’s independent. It’s made up of a handful (as many as about seven) experts in the disease area being studied, and also in areas that might present safety problems. For example, if animal studies have suggested a drug may have nervous-system side effects, there’s likely to be a neurologist on the DSMB, Rita Basu, a researcher at the Mayo Clinic who chairs one of its institutional review boards, tells the Health Blog. (IRBs, which are also independent, are set up by an institution to oversee all the research conducted within its walls.) DSMBs also include a statistician.
Members of the DSMB make scheduled periodic checks of the trial as it progresses, and are the only people with access to the unblinded results; investigators and patients must be kept in the dark to avoid biasing the findings. But the DSMB has access to the raw data so it can step in to protect patients if something appears to go awry.
There are a few reasons why a DSMB would recommend stopping or altering a trial. It could be because interim data suggest the drug is effective — and would almost certainly show the same trend if the trial continued — so it would be unethical to deny treatment to patients in the placebo group. Or a trial could be stopped if the data available to the DSMB show it would be very unlikely for the drug to show any benefit even if the trial continued. Before a trial starts, the sponsor will determine what level of data would trigger such an intervention.
Safety is different, Susan Ellenberg, a professor of biostatistics at the Hospital of the University of Pennsylvania, tells the Health Blog. Board members rely more on their discretion when they look at data on adverse effects or patient deaths, since some problems might be anticipated and others completely out of the blue. If their collective judgment is that there’s a problem, they will recommend to the study sponsor that the trial be stopped.
We don’t yet know what happened in the vorapaxar trials. The DSMB was simultaneously overseeing both trials — one for people with acute coronary syndrome, and one for people with a history of heart attack, stroke or peripheral artery disease. The board recommended closing the first trial shortly before it was scheduled to finish and also recommended that patients with a history of stroke be removed from the second trial. (We asked Merck to put us in touch with a member of the trials’ DSMB, but a company spokesman declined to do so.)
If a trial is stopped completely, information about the exact problem is usually released as soon as possible.
But if a trial is continuing in all or part, a DSMB “would want to give out as little information as possible” so as not to “compromise the integrity of the trial,” says Ellenberg.
It would be unethical to refuse treatment to patients in the placebo group. Or a trial could be interrupted if the data available to the DSMB indicated that it would be very unlikely for the drug to show any benefit, even if the trial continued.
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