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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.
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Monitoring the Safety of Clinical Trials
Who's Responsible?
What Are IRBs?
The Approval Process
The Monitoring Process
Monitoring the Safety of Clinical Trials
If you are thinking about participating in a clinical trial, you probably have a few important questions weighing on your mind: Is there a system in place to make sure this is a worthwhile study that does not subject people to unnecessary risks? In other words, who is checking up on the research team? What if things don't turn out the way that investigators are expecting they will? Who is watching out for any unexpected problems? Who is making sure that participants are protected? This guide is designed to answer those questions.
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Who's Responsible?
The central guardian of participants' safety and welfare in clinical trials that are federally funded (which includes NCI-sponsored trials) is the Office for Human Research Protections (OHRP), a part of the U.S. Department of Health and Human Services). OHRP is responsible for enforcing the Protection of Human Subjects part of the Code of Federal Regulations (Title 45, Part 46). If the trial is evaluating a new drug, medical device or other product that is subject to approval by the U.S. Food and Drug Administration (FDA), then the FDA's Office of Human Affairs is responsible for ensuring that it meets the Code of Federal Regulations (see the FDA's A Guide to Informed Consent).
If the trial falls into both categories, then it is subject to both sets of regulations, which actually are quite similar. Both include guidelines regarding the role of local Institutional Review Boards (IRBs), the formal body in the community charged with overseeing medical research involving people. Understanding the work of IRBs will help you see that there are outside panels of experts monitoring the investigators who conduct clinical trials -- and representing the interests of those who participate.
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What Are IRBs?
An Institutional Review Board functions as both a clinical trials clearinghouse and monitor -- in other words, it must give approval before any clinical trial can begin, and then keep close tabs on the progress of the research. Most institutions that carry out clinical trials have their own IRBs; in fact, there are roughly 3,000 of them in the U.S. In selected cases, a small research institution might arrange for their research to be reviewed by another IRB, rather than setting up their own.
While the specific make-up of an IRB varies from place to place, it always includes people who are qualified to evaluate new and ongoing clinical trials on the basis of scientific, legal, and ethical merit. Federal regulations require that an IRB include at least five people of diverse occupations and backgrounds; for instance, an IRB could not be made up of five physicians or five nurses. At least one member must have primarily scientific interests, and another member must have primarily non-scientific interests.
In addition, one member must be an institution outsider, not connected by a job or relatives to the institution. To meet these requirements, IRBs usually are made up of a mix of medical specialists, ethicists, and patient advocates.
If the trial you are considering is federally funded or is evaluating a new drug or medical device regulated by the FDA, then it is definitely subject to review by an IRB. However, many institutions also require that all clinical trials conducted there be approved and reviewed by the IRB.
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The Approval Process
Before a proposed research study can even start enrolling people, the investigator must submit a detailed application to the IRB. The IRB carefully reviews the application with the following criteria in mind:
- The risks to participants are minimized as much as possible, through sound research design and the use of procedures that are not unnecessarily risky.
- The risks are reasonable in relation to the anticipated benefits and the importance of the knowledge that may result.
- Participants will be selected fairly.
- There is a plan in place for seeking and documenting participants' informed consent (see Simplification of Informed Consent Documents). The informed consent document is both legally and ethically sound.
- If necessary, provisions have been made for monitoring the data collected to ensure the safety of participants as the trial progresses.
- Provisions have been made to protect the privacy of participants and the confidentiality of data collected during the study.
Based on these considerations, the IRB either approves or refuses to approve the clinical trial and notifies the investigator and the institution of its decision in writing. In some cases, the IRB may specify certain changes the investigator must make in order to secure approval for the study. If the IRB grants approval, it also must decide how frequently the trial should be reviewed once it is under way.
Usually this is determined according to the degree of risk the trial involves. At the very least, its progress must be reviewed yearly. For certain trials, especially large multi-site Phase III trials, a Data Safety Monitoring Board may be appointed to keep track of the data in order to ensure participants' safety, to ensure that evaluation of interim results are made completely, and to ensure that the results and ethics of the trial are above reproach.
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The Monitoring Process
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:
- Are there any unexpected or severely toxic effects?
- 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:
- conformance to Institutional Review Board and informed consent requirements,
- shipping, storage, and use of drugs and other agents, and
- 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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