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
Recognize historical events and their influence on
the development of safeguards for participants in clinical
trials
Describe current methods of participant protection
that are implemented throughout the research process
Identify Government regulations and agencies
related to patient protection
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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.
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.
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:
What is the purpose of the study or therapy?
Who has reviewed and approved it?
What are the credentials of its researchers and
personnel?
What information or results is it based on?
How are study data and patient safety being
monitored?
How will the results be shared?
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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:
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.
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