Related Pages Protecting Participants in Clinical Trials A collection of material about the ways in which clinical trials participants are protected before and during the conduct of a study. Monitoring NCI-Sponsored Clinical Trials Protections for patients in cancer studies come into play at various times before and during a clinical trial. Before a trial can start enrolling patients, for example, it must be approved by an Institutional Review Board (IRB), located at the hospital or other site where the study will be conducted.

The Role of Institutional Review Boards and Data Safety Monitoring Boards
Quality Assurance Monitoring
Ending Trials Early: Protecting the Interests of Participants and the Public
The Ongoing Informed Consent Process

The Role of Institutional Review Boards and Data Safety Monitoring Boards

During the initial review process, the IRB will have established how often a study should be monitored -- at least yearly, but sometimes more frequently. During these review sessions, the IRB examines a progress report provided by the clinical investigator in charge of the project. The report features information about how many people are enrolled in the study and how many have withdrawn; a description of participants' experiences, including benefits and/or adverse effects; and the overall progress to date.

Based on this material, the IRB decides whether or not the project should continue as described in the original research plan, and if not, what changes need to be made. An IRB can decide to suspend or terminate approval of the clinical trial if the investigator is not following set requirements, or if the study appears to be causing unexpected serious harm to participants.

Some clinical trials -- especially large Phase III clinical trials, which often involve many institutions -- are monitored more closely and more often by Data Safety Monitoring Boards (DSMB). The DSMB is an group made up of physicians, statisticians, and patient advocates, a majority of whom are not connected with the trial. Their priority is patient safety, and they review the data periodically (at least annually, but usually more often) with the following two questions in mind:

1. Are there any unexpected or severely toxic effects?
2. What is the treatment outcome of the trial so far? DSMBs are required to produce summary reports that provide regular feedback to the IRBs at the institutions involved in the study concering the cumulative toxicities observed in trial participants.

Statisticians are key members of DSMBs, because typically many statistical tests are used to determine if there are significant differences between the groups involved in the trial. Often it is difficult to tell if a difference that appears significant early on will be carried through to the end of a trial. Therefore, DSMB members must weigh the current data and the future possibilities very carefully when making decisions.

Physicians and statisticians connected to the trial being monitored may also attend parts of the DSMB meetings, but they are not voting members. Instead, their job is to provide information about the ongoing trial results to the DSMB. In the interests of objectivity, discussion and voting take place in the absence of all professionals connected with the trial.

The National Cancer Institute (NCI) has several ways of assuring the quality of the data collected during NCI-sponsored clinical trials. Many trials, for example, have committees for central review of major elements, such as pathology, radiotherapy, surgery, and administration of investigational agents. Data quality control programs have been developed and are utilized by data management and statistical centers to help identify and correct or clarify inconsistencies and inaccuracies in submitted data.

One component of NCI's quality assurance program is on-site monitoring, or audits, of the procedures, documents, and data pertaining to a trial at a particular institution. Institutions are audited once every three years or more often. Auditors review three main categories of information:

1. conformance to Institutional Review Board and informed consent requirements,
2. shipping, storage, and use of drugs and other agents, and
3. individual patient cases.

In an ideal world, all clinical trials would run exactly as anticipated from beginning to end. Of course, that's not always the case, and there are often compelling reasons for halting a trial early. If participants are experiencing unexpected and severe side effects, or there is clear evidence that the risks are outweighing the benefits, then the IRB and the Data Safety Monitoring Board will recommend that the trial be stopped early.

In other cases, a trial might be stopped because it is going particularly well. If there is clear evidence early-on that a new treatment or intervention is effective, then the trial may be halted so that it can be made widely available right away.

The following scenarios illustrate two examples of situations like these.

• Scenario 1: Significant and Clear Advantage of the Tested Treatment

  The Breast Cancer Prevention Trial, conducted by a network of researchers who make up NCI's National Surgical Adjuvant Breast and Bowel Project, was designed to evaluate whether taking the drug tamoxifen could prevent breast cancer in women considered to be at high risk for developing it. In March 1998, interim study data showed that tamoxifen decreased the chance of getting breast cancer by almost half. Instead of continuing the trial for the full five years as planned, investigators stopped it 14 months early.

  The women in the trial who were already taking tamoxifen were offered the chance to continue the treatment for the remainder of the five-year period. Women receiving the placebo, or inactive pill, were invited to participate in the Study of Tamoxifen and Raloxifene, or STAR trial, which is designed to determine whether the osteoporosis prevention drug raloxifene is as effective as tamoxifen in reducing the chance of developing breast cancer. Their other option was to seek tamoxifen from a physician on their own, outside the context of a clinical trial.

• Scenario 2: Clear Evidence of No Additional Benefit to Tested Treatment

  Another trial involving tamoxifen called the B-14 trial, also conducted by the National Surgical Adjuvant Breast and Bowel Project, was halted early. The original trial, which started in 1982, enrolled women who had surgery for cancer that was limited to the breast. After surgery, the women took either the drug tamoxifen or a placebo to determine if tamoxifen would prevent recurrence of the cancer.

  Five years into the study, significantly more women taking tamoxifen had remained disease-free than did women taking the placebo, so the study was extended another five years. In the study extension, women who had already been taking tamoxifen were given the opportunity to re-enroll and be randomly assigned to either the tamoxifen or placebo group for another five years.

  The extended trial was cut short, however, when several interim data analyses showed that the tamoxifen group had a slightly higher rate of cancer recurrence than the placebo group. Statistical analysis showed that, even if no more of the women taking tamoxifen experienced a recurrence, the drug still would not have proven helpful in preventing cancer recurrence during that second five years. The trial was halted, and the women stopped taking tamoxifen.

In A Guide to Understanding Informed Consent, we describe the informed consent process that all participants must go through before enrolling in a clinical trial. We also note that the informed consent process does not end once the trial begins. Just as researchers are required to submit reports to the IRB, they also are required to keep participants up-to-date on any new information that may impact their decision to remain enrolled in the trial. The monitoring system that is in place ensures that such new information -- if there is any -- will be available on a regular basis.

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