Understanding Data Safety Monitoring Boards

How do DSMBs monitor ongoing clinical trials?

Several different groups oversee the ethical standards of clinical trials, including those testing AIDS vaccine candidates. These committees are set up for each new trial to ensure they are performed safely, the rights of the volunteers are protected, and that the basis of the study is scientifically credible. Before a trial begins, the overarching plans for the trial or protocol is reviewed by an independent ethics committee called an institutional review board (IRB). This group is primarily responsible for reviewing the study design and all the trial-related materials, such as informed-consent documents and informational brochures (see June 2005 Primer on Understanding Informed Consent). A clinical trial can not start without approval from the IRB.

Another external committee known as a data safety monitoring board (DSMB) is responsible for monitoring the safety and progress of the trial once it is underway. DSMBs were first established in the 1960s as a way to assist organizations sponsoring medical research with data analysis, but now their most important role is to continually assess risk and monitor safety for volunteers throughout the course of a trial. A DSMB is an independent committee that can advise the trial sponsors, funding agencies, and investigators. After analyzing the safety and efficacy data the DSMB determines if the trial should continue unchanged or with modification, or if it should be terminated. This group also monitors the scientific merit of the study in light of results from other trials or advances in the field.

The function of a DSMB

A DSMB is comprised of 3 to 10 members and usually includes researchers, clinicians, biostatisticians, and community members or advocates. Members are typically independent experts, either working in the same field or in a related discipline, who have no personal or professional ties to the intervention being tested and are therefore unbiased.

Not every clinical trial requires a DSMB and different regulatory agencies, like the US Food and Drug Administration or the European Agency for Evaluation of Medical Products (EMEA), have different standards. Generally they are utilized for double-blind studies where trial sponsors and investigators don't know who is receiving the active product or placebo, whenever there is a potential risk to the study participants, or when a trial is conducted at multiple clinical trial sites. A DSMB is especially important for large, multi-center trials that take place in different countries or on multiple continents because often the principal investigators only have access to data generated at their individual sites. The DSMB, however, can monitor the safety and efficacy data accumulated from all sites to make a decision regarding the continuation of the trial.

DSMBs have several important duties. First they periodically review the safety data from the trial and analyze the risk/benefit profile of the intervention being tested and any adverse events that occur. They also regularly examine the efficacy data that is accumulated throughout the course of the trial. For example, if the trial is testing a microbicide or an AIDS vaccine candidate that is designed to prevent HIV infection, a DSMB would review the number of volunteers who become incidentally infected with HIV through risk behaviors during the course of the study to see if more of these infections are occurring in the placebo group than in the group receiving the experimental intervention, or vice versa. This can help the DSMB determine if the experimental intervention is beneficial or possibly causing harm.

The DSMB also closely watches the progress and conduct of the trial and evaluates whether or not the study protocol is being followed. This includes reviewing the number of volunteers recruited and retained, the type of volunteers (for example women versus men), the performance of the trial sites, and the integrity of the data being reported by the sites. The progress of the trial, as well as the safety and efficacy data, are reviewed by DSMB members at pre-defined intervals and their findings are reported back to the IRB.

Altering a trial

There are several possible scenarios where a DSMB might suggest modifications to a trial protocol. For example, if the DSMB determines that there are not enough volunteers being recruited to properly determine the efficacy of the product, they might recommend that the target enrollment be increased.

In many cases the DSMB might also suggest that a trial be closed. The cost and time required to run a clinical trial are significant and it is a serious decision when one is stopped midway. However, protecting the personal safety of the volunteers and ensuring the ethical conduct of the trial are the DSMB's principal concerns. A DSMB may recommend terminating a trial when the intervention being tested appears to possibly be harmful. Recently an HIV prevention trial testing the ability of the microbicide candidate cellulose sulfate to prevent HIV infection in women was stopped early by the DSMB because more new HIV infections occurred in the volunteers using the microbicide gel than in those who received an inactive placebo gel. Evaluation is now underway to determine if the microbicide candidate was actually responsible for this increase in infection.

A DSMB may also stop a study that is in progress if the intervention offers a clear benefit and is so effective that it would be unethical to continue with a placebo group. This happened recently in two randomized, controlled trials of male circumcision. The DSMB members observed such a strikingly positive effect of male circumcision on the risk of HIV infection in men that they stopped the trial and also offered the surgical procedure to the uncircumcised men.

Another reason a DSMB may stop a trial is if it is unlikely to provide conclusive results. This is known as stopping a trial for futility and it can happen when the number of incidental HIV infections in a trial is too low to actually determine if the AIDS vaccine or microbicide candidate is effectively stopping infection.