4. Participant Protection in Clinical Trials
Evolution of Participant Protection
Government Oversight
Protecting Participants Before a Clinical Trial Begins
Protecting Participants During a Clinical Trial
Learning Objectives
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Evolution of Participant Protection
The strong national and international safeguards in place today to protect research participants evolved from notorious abuses of human rights in the past. The first formal statement of medical ethics regarding research in humans emerged from the 1946 trial and conviction in Nuremberg, Germany, of Nazi physicians and scientists who conducted experiments on concentration camp inmates during World War II. The Nuremberg Code outlined broad concepts for the protection of human subjects and forms the basis of today's international code of ethics for the conduct of research.
In the United States, three infamous clinical trials called attention to the need for participant protection:
The Tuskegee syphilis study, held from 1932 to 1972, followed - but did not treat - poor black men who had syphilis. During the trial, the men were offered "special free medical care" and were told that they would be treated for "bad blood." Instead, more than 400 men with syphilis and 200 men without the disease who served as controls were enrolled in an observational clinical trial without their knowledge or consent. By 1963, it was apparent that many more infected men than controls had developed complications, and 10 years later a report on the trial indicated that the death rate among those with syphilis was roughly double that of the controls. In the 1940s, penicillin was found to be effective in the treatment of syphilis, but researchers in the trial, which continued for almost 30 years after the discovery, neither informed nor treated subjects with the antibiotic.
From 1963 to 1966, researchers deliberately infected newly admitted "mentally defective" children at the Willowbrook School, a State school in New York, with the hepatitis virus in order to study the natural history of the disease under controlled circumstances. In some cases, parents were not allowed to admit children to the institution unless they agreed to let them participate in the trials.
In 1963, physician-investigators at the Jewish Chronic Disease Hospital in Brooklyn, New York, injected cancer cells grown in the lab into people hospitalized with various chronic diseases without informing the people or gaining their consent. In review proceedings, the Board of Regents of the State University of New York found that the trial had not been presented to the hospital's research committee; the researchers were found guilty of fraud, deceit, and unprofessional conduct.
In 1974, in response to these tragedies, the President established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. In 1979 the commission issued the Belmont Report, which delineated the ethical principles upon which today's regulations regarding research participants in the United States are based:
Respect for persons - recognition of the personal dignity and autonomy of individuals, as well as special protections for people with diminished autonomy
Beneficence - the obligation to protect people from harm by maximizing unanticipated benefits and minimizing possible risk of harm
Justice - fairness in the distribution of research benefits and burdens
In addition, the commission concluded that "a permanent board with the authority to regulate at least all federally supported research involving human subjects" should be formed.
In response, Congress passed the National Research Act, which mandated the establishment of IRBs to review all U.S. Department of Health and Human Services (DHHS)-funded research. The procedures established for IRBs were further delineated and revised in 1981.
For more details on the history of participant protection, the role of the IRB, and patient confidentiality, see http://cme.nci.nih.gov.
Two similar sets of regulations - enforced by HHS's Office for Human Research Protections (OHRP) and FDA - are in place to ensure the protection of clinical trial participants. If a trial is Government-supported and it involves an FDA-regulated drug or device, then it is subject to both sets of regulations. The basic requirements for IRBs and informed consent are congruent in the two sets of regulations.
Office for Human Research Protections
The Office for Human Research Protections (OHRP), formerly called the Office of Protection from Research Risks, safeguards participants in federally funded research and provides unity and leadership for 17 Federal departments and agencies that carry out research involving human participants. OHRP enforces an important regulation called the Common Rule (Title 45 CFR Part 46, Subpart A). The Common Rule sets standards for:
Informed consent process
Formation and function of IRBs
Involvement of prisoners, children, and other vulnerable groups in research
Many other protective measures
Researchers must provide written statements describing the organization of the IRB, its procedures for approving trials, and how clinical trial participants are protected.
Although breaches in participant protection seldom occur, recent discoveries of inadequate protection have prompted the restatement of oversight goals and the addition of some new requirements by OHRP and the National Institutes of Health (NIH) to strengthen enforcement of the Common Rule, including:
Aggressive efforts to improve the education and training of clinical research staff, IRB members, and staff research administrators regarding protection
Guidelines to reaffirm the need to audit informed consent records for evidence of full compliance and confirmation of consent by investigators
Submission of monitoring plans for all phase 1 and 2 clinical trials and the presence of a data and safety monitoring board for phase 3 trials
Additional information to clarify regulations regarding conflict of interest
For a detailed proposal of the Government oversight goals set forth by former HHS Secretary Donna Shalala, see "Protecting Research Subjects - What Must Be Done" in the September 14, 2000, issue of the New England Journal of Medicine (343:808-810).
Food and Drug Administration
FDA has its own regulations and policies on IRB review, informed consent, and participant protection (Title 21 CFR Parts 50 and 56). The regulations apply to any clinical trial that involves an investigational drug, biological product, or other device regulated by FDA, regardless of whether the trial receives Federal funding. FDA periodically inspects IRB records and operations to certify the adequacy of approvals, human subject safeguards, and the conduct of business.
Protecting Participants Before a Clinical Trial Begins
Scientific Review by Sponsor
Clinical trials that are sponsored by NCI are reviewed through different types of panels, including experts who review the scientific and technical merit of the proposed research. Many other clinical trial sponsors, such as pharmaceutical companies, also seek expert advice on the merits of their studies. Typical issues addressed by members of expert panels include:
Significance: Does the trial address an important problem? If its aims are achieved, how will scientific knowledge be advanced? What effect will the trial have on current concepts or methods in the field?
Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate? Does the applicant acknowledge potential problem areas and consider alternative tactics?
Innovation: Does the project employ novel concepts, approaches, or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies?
Investigator: Do the principal investigator and other researchers have sufficient training and experience to carry out the project?
Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?
Institutional Review Board (IRB) Approval
An IRB functions as both a clearinghouse and a monitor of clinical trials. It determines whether the risks involved in a clinical trial are reasonable with respect to the potential benefits, and it must approve any clinical trial before it begins. The IRB also monitors the ongoing progress of the research.
Federal regulations require that an IRB include at least five people from diverse occupations and backgrounds. In addition, one member must be outside the sponsoring institution - that is, not connected to it by employment or relatives. To meet these requirements, IRBs are usually made up of a mix of medical specialists, nurses, other health care professionals, ethicists, and lay members from the community.
Most institutions that carry out clinical trials have their own review boards (there are roughly 3,000 IRBs in the United States). In some cases, a small institution might arrange for its research to be reviewed by another IRB rather than set up its own. All trials that are federally funded or evaluate a new drug or medical device regulated by FDA must be submitted to an IRB. However, many institutions require that all clinical trials conducted in their facilities, regardless of funding source, be IRB-approved. Before a trial can begin, the principal investigator submits an application to an IRB. The board reviews it on the basis of the following criteria:
Risks to participants are minimized as much as possible through sound research design
Risks to participants are reasonable in relation to the anticipated benefits and the knowledge that may result
Participant selection is equitable
Informed consent is sought in accordance with 45 CFR Part 46.116
Informed consent is documented in accordance with 45 CFR Part 46.116
Provisions are made for monitoring the data collected to ensure the safety of participants
Provisions are made to protect the privacy of participants and the confidentiality of data collected during the trial
Additional safeguards are in place if any participants are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, people with mental disabilities, or people with low income or education levels)
The IRB decides whether to approve the clinical trial and notifies the researcher and the institution in writing. The IRB may specify changes the researcher must make in order to gain approval.
After approving a trial, the IRB must decide how frequently to monitor it - usually on the basis of the risk involved. At the very least, the trial's progress must be reviewed yearly.
Informed Consent
Informed consent, as a legal, regulatory, and ethical concept, is an integral part of research. In clinical trials, informed consent is the process of providing all relevant information about the trial's purpose, risks, benefits, alternatives, and procedures to a potential participant, who then, consistent with his or her own interests and circumstances, makes an informed decision about whether or not to participate. Before agreeing to take part in a clinical trial, participants have the right to:
Learn everything that is involved in the trial - including all details about treatment, tests, and possible risks and benefits
Both hear and read the information in language they can understand
Informed Consent Documents
The informed consent form or document provides a summary of the clinical trial and explains a participant's rights. It is designed to begin the informed consent process. The participant acknowledges that he or she is entering a study, has been told what it involves, and understands the potential risks and benefits of participating.
Although reputable researchers do not try to fool people or sign them up against their will, individuals sometimes have difficulty understanding the information about a trial before agreeing to participate. Individuals may not understand the medical terminology and/or clinical requirements of a study, and they should be encouraged to ask questions until they understand all aspects of treatment. For many people it is important to ask a friend or family member to come with them when they receive information about medical options to be sure all important questions are raised. Some people may want to take notes or bring a tape recorder to assist them with questions and recall.
The following elements of informed consent are required under the Common Rule (Title 45 CFR Part 46, Subpart A):
Statement that the trial involves research
Explanation and description of the nature of the trial, purpose of the trial, duration of participation, procedures to be followed, and which procedures are experimental
Description of foreseeable risks and discomforts
Benefits to the participant and others
Alternative procedures or treatments
Description of the confidentiality of records
Explanation of procedures if the project involves more than minimal risk (e.g., compensation, availability of medical treatment)
Contact person for questions
Statement that participation is voluntary, that there will be no loss of benefits on withdrawal, and that the participant may withdraw at any time
Statement that the participant's signature indicates a decision to participate, having read and discussed the information presented
Any research trial, regardless of whether it is federally funded, should provide this information to participants in an informed consent document.
NCI has issued recommendations designed to help research institutions and clinical centers write comprehensive, user-friendly informed consent documents. Its Working Group on Informed Consent also developed a template and sample forms that serve as models for covering all of the information that Federal regulations require. To view the template or other documents related to informed consent, see the clinical trials section of www.cancer.gov.
Pediatric Assent to Participate
Children and adolescents are not deemed capable of giving true informed consent, so they are asked for their assent to (or dissent from) participation in a clinical trial. The trial must be explained in age-appropriate language or visual aids. Parents or guardians are asked to give informed permission for their child to participate in a trial.
Assent must be obtained from all children and young people over age 7 unless:
The child is found to be incapable of assenting
The clinical trial offers a treatment or procedure that "holds out a prospect of direct benefit that is important to the health or well-being of the child and is available only in the context of the research" (in other words, if the trial offers a treatment that is thought to be better than those currently available or if it offers the only alternative to those available)
Even in these cases, permission from the parent or guardian is required. For more information, see the clinical trials section of www.cancer.gov.
Protecting Participants During a Clinical Trial
Informed Consent Process
The informed consent process provides people with ongoing explanations that will help them make educated decisions about whether to begin or to continue participation in a clinical trial. The process does not end with the signing of informed consent documents. If new benefits, risks, or side effects are discovered during the trial, researchers must inform participants. Participants are encouraged to ask questions at any time.
Institutional Review Board Role
During the initial review process, the IRB establishes how often a clinical trial should be monitored. Monitoring occurs at least yearly but sometimes more frequently. During these review sessions, the IRB examines a progress report provided by the clinical researcher in charge of the project. The report describes:
How many people are enrolled in the trial
How many have withdrawn
Participants' experiences, including benefits and adverse effects
Progress to date
Based on this information, the IRB decides whether 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 a clinical trial if the researcher is not following requirements or if the trial appears to be causing serious harm to participants.
Data and Safety Monitoring Board (DSMB) Role
NIH requires that all phase 3 clinical trials undergo monitoring by a DSMB, and that all phase 1 and 2 clinical trials have a data and safety monitoring plan. A DSMB may also be appropriate and necessary for phase 1 and 2 clinical trials that are blinded, take place at multiple clinical sites, or employ particularly high-risk interventions or vulnerable populations.
The DSMB is an independent committee whose membership includes, at a minimum, a statistician and a clinical expert in the area being studied. Other members are experts in all scientific disciplines needed to interpret the data and ensure participant safety. Members may also be clinical trial experts, statisticians, bioethicists, or other clinicians knowledgeable about the trial's subject matter.
The objectives of data and safety monitoring plans are to:
Ensure that risks associated with participation are minimized to the extent practical and possible
Ensure the integrity of data
Stop a trial if safety concerns arise or if its objectives are met
Ending Trials Early
There can be compelling reasons for halting a trial early. If participants experience severe side effects, or if there is clear evidence that risks outweigh benefits, the IRB and DSMB will recommend that the trial be stopped early. A trial might also be stopped if there is clear evidence that the new intervention is effective - in order to make it widely available.
Breast Cancer Prevention Trial
The Breast Cancer Prevention Trial, conducted by 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 of developing the disease. In March 1998, interim data showed that tamoxifen cut the chance of getting breast cancer almost in half. Instead of continuing the trial for the full 5 years, as planned, researchers stopped the trial after about 4 years.
Women in the trial who were taking tamoxifen were offered the opportunity to continue treatment for the remaining 14 months of the trial. Women receiving the placebo were invited to participate in the Study of Tamoxifen and Raloxifene, or STAR trial, designed to determine whether the osteoporosis prevention drug raloxifene is as effective as tamoxifen in reducing the chance of developing breast cancer. The women's other option was to seek tamoxifen from a physician on their own, outside a clinical trial.
B-14 Trial
Another trial involving tamoxifen and conducted by the National Surgical Adjuvant Breast and Bowel Project, the B-14 trial, was also halted early - but for a different reason. This trial, which started in 1982, enrolled women who had had surgery for cancer that was limited to the breast. After surgery, the women took either tamoxifen or a placebo for 5 years to determine whether tamoxifen would prevent recurrence of the cancer. Five years into the trial, significantly more of the women taking tamoxifen remained disease-free, so the trial was extended another 5 years. Women who had been taking tamoxifen were given the opportunity to reenroll in the trial and be randomly assigned to take tamoxifen or placebo for an additional 5 years.
The extended trial was cut short 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 no additional benefit was to be gained by continuing tamoxifen for more than 5 years. The trial was halted, and the women stopped taking tamoxifen beyond 5 years.
Before taking part in any clinical trial, health care professionals and their patients should make sure it is reputable by getting answers to these important questions:
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Quality Assurance Monitoring
NCI has several ways of ensuring the quality of data collected during clinical trials. Many trials, for example, have committees that review major elements of the study for accuracy, such as:
Pathology
Radiotherapy
Surgery
Administration of investigational drugs
In addition, data management and statistical centers use quality control measures to help identify and correct or clarify inconsistencies and inaccuracies in submitted data.
Another part of NCI's quality assurance program is onsite monitoring, or audits, of trial procedures, documents, and data. Institutions are audited at least once every 3 years. Auditors review three main areas:
Conformance to IRB and informed consent requirements
Shipping, storage, and use of drugs and other agents
Individual participants' cases
Adverse Event Reporting
An adverse event is any unanticipated problem involving risks to clinical trial participants or others. For more information on adverse event reporting, see cancer.gov/clinicaltrials.
Refer to the case study for a review and summary of content covered in this workbook.
