3. Participant Protection in Clinical Trials
History of Participant Protection
The Informed Consent Process
Review Committees
Many people think that participant rights are
not protected in clinical trials because of past abuses
of research participants. Today, Federal regulations help
ensure that clinical trials are run in an ethical manner.
Participant rights and safety are protected
through:
Informed consent, a process through which
potential participants learn the purpose, the risks, and
the benefits of a clinical trial before deciding whether
to participate. This process continues throughout the
study.
Two review panels, which approve a clinical
trial protocol before it begins:
Monitoring, which continues during the trial,
by:
IRBs, which monitor participant safety
Data and safety monitoring boards (DSMBs) for
phase 3 trials, which perform periodic reviews of the
conduct of the clinical trials and participant
safety
Required reports to Federal agencies, which
oversee the conduct of the trial
Learning Objectives
By reading this section and completing the exercise, you
will be able to:
Review key historical events regarding participant
protection
Describe how participants are protected through
the informed consent process
Explain how review boards and panels protect
participants
Demonstrate familiarity with Government
regulations and agencies
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Although we now have strong safeguards for protecting those who
participate in research, these protections have resulted from
notorious abuses of human rights in the past. The first formal
statement of protection for individuals in research emerged from the
Nuremberg trials in Germany, where Nazi scientists and physicians who
had conducted experiments on World War II concentration camp victims
were convicted. 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, several controversial research studies
highlighted the critical need for protection for those participating
in clinical trials. None of these studies sought to inform the
participants about the research or gain their consent.
From 1932 to 1972, the infamous Tuskegee syphilis study followed
low-income African American men with syphilis but did not treat them.
During the study, the men were offered free medical care and were
told that they would be treated for "bad blood."
In the 1960s, two other research studies received major public
attention. The first was a series of experiments with mentally
retarded children; another involved debilitated elderly
participants.
In response to these tragedies, regulations and policies were
developed to ensure that people are told about the benefits, risks,
and purpose of research for which they volunteer.
In 1976, the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research developed three basic
principles governing research involving human subjects that were
published in the Belmont Report. These principles, which today form
the basis for human subject protection regulations in the United
States are:
Respect for persons-recognition of personal dignity and
autonomy of individuals, and special protection of persons with
diminished autonomy
Beneficence-obligation to protect persons from harm by
maximizing unanticipated benefits and minimizing possible risk of
harm
Justice-fairness in the distribution of research benefits
and burdens
Informed consent is a critical part of ensuring participant safety
in research. Informed consent is an ongoing process during which
potential participants learn important information about a clinical
trial. This information helps them decide whether to participate.
The research team, which is made up of doctors and nurses, first
explains the trial to potential participants in understandable
language. The team explains the trial's:
Before agreeing to take part in a trial, people have the right
to:
Learn about all their treatment options
Learn all that is involved in the trial - including all
details about treatment, tests, and possible risks and
benefits
Discuss the trial with the principal investigator and
other members of the research team
Both hear and read the information in language they can
understand
Informed Consent Form
After discussing all aspects of the study with a potential
participant, the team gives the person an informed consent form to
read. The form includes written details about the information that
was discussed and also describes the confidentiality of the
participant's records. If a person agrees to take part in the study,
he or she signs the form.
Although informed consent documents can vary in their length and
complexity, they should all contain information on:*
The clinical trial's nature, purpose, and duration; the
procedures to be followed; and which procedures are experimental
Reasonable, foreseeable risks and discomforts
Benefits to the participants and to others
Alternative procedures or treatments
Confidentiality of records
Procedures if the trial involves more than minimal risk
(e.g., compensation, availability of medical treatment)
Contact for questions
Voluntary participation-that there will be no loss of
benefits on withdrawal and that participants may stop participating
at any time
All Government-funded trials must contain this information by
law.
* These informed consent requirements are listed in Title 45 CFR Part
46, Sub part A.
Informed Consent Forms: Making Them Easy to
Understand
The informed consent process can be effective only if
potential participants understand the information given to
them. In recent years, both participants and investigators
have voiced concerns that informed consent documents for
clinical trials were becoming too long, complicated, and
difficult to understand.
NCI has issued recommendations designed to help research
institutions and clinical centers write user-friendly
informed consent documents. Sample templates can be found
online in both English and Spanish in the clinical trials
section of www.cancer.gov.
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An Ongoing Process
The informed consent process does not end once the form is signed.
If new benefits, risks, or side effects are discovered during a
trial, the researchers must inform study participants. In addition,
participants are encouraged to ask questions at any time about what
is happening during the trial. This information helps participants
make educated decisions about whether to continue participating in a
clinical trial.
Pediatric Assent to Participate in Trials
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 using visual aids. Parents or guardians are asked to give informed permission for their child to participate in a trial. Assent must be obtained from 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 research" (in other words, if the trial offers a treatment that is thought to be better than those currently avaialable 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.
Weighing Decisions About Participating
People thinking about taking part in a trial should ask
researchers the following questions to help with their
decision-making:
Why is this trial taking place?
Why do the doctors who designed the trial believe that
the treatment being studied may be better than the one being used
now? Why may it not be any better?
How long will I be in the trial?
What kinds of tests and treatments are involved?
What are the possible side effects or risks of the new
treatment?
What are the possible benefits?
How could the trial affect my daily life?
Will I have to travel long distances?
Will I have to pay for any of the treatments or
tests?
Does the trial include long-term followup care?
What are my other treatment choices, including standard
treatments?
How does the treatment I would receive in this trial
compare with the other treatment choices in terms of possible
outcomes, possible side effects, time involved, costs to me, and
quality of my life?
Most clinical trials are subject to different types of review that
are designed to protect all participants. Clinical trials that are
sponsored by NCI - whether funded by a grant, run by a cooperative
group, or run through a cancer center - 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 scientific and technical merit of their trial
protocols. In addition, all federally-funded clinical trials must be
reviewed by groups called institutional review boards (IRBs).
Institutional Review Boards (IRBs)
IRBs are made up of people who are qualified to evaluate new and
ongoing clinical trials on the basis of scientific, legal, and
ethical merit. The board members determine whether the risks involved
in a trial are reasonable with respect to the potential benefits.
IRBs also monitor the ongoing progress of trials from beginning to
end.
Federal regulations require that each IRB be made up of at least
five people; one member must be from outside the institution
conducting the trial. IRBs are usually made up of a mix of medical
specialists and lay members of the community, and many include
members from diverse occupations and backgrounds. In most cases, IRBs
are located where the trial is to take place. Many institutions that
carry out clinical trials have their own IRBs.
Federal law requires IRB approval for clinical trials that
are:
A number of institutions require that all clinical trials,
regardless of funding, be approved and reviewed by local IRBs.
Potential participants considering a clinical trial should ask if it
has been approved by an IRB.
During the Trial: IRB Monitoring
If the IRB grants approval for a trial, it also must decide how
frequently the trial should be reviewed once it is underway.
Frequency is usually determined according to the degree of risk the
trial involves.
At least once a year, the IRB must review a progress report
provided by the clinical researcher in charge of the trial. The
report features information about how many people are enrolled and
how many have withdrawn, a description of participants' experiences,
including benefits and adverse effects, and the progress to date.
Based on this information, the IRB decides whether the trial
should continue as described in the original research plan, and, if
not, what changes need to be made. An IRB can decide to stop a
clinical trial at any time if the researcher is not following
requirements or if the trial appears to be causing unexpected harm to
participants.
Data and Safety Monitoring Boards (DSMBs)
For phase 3 trials, DSMBs are appointed to help ensure
participants' safety. A DSMB may also be appropriate and necessary
for certain phase 1 and 2 clinical trials.
The DSMB is an independent committee made up of statisticians,
physicians, and other expert scientists.
The data and safety monitoring board must:
Ensure that any risks associated with
participation are minimized to the extent practical and possible
Avoid exposing participants to excessive risk
Ensure the integrity of data
Stop a trial if safety concerns arise or as soon as its
objectives have been met
DSMBs also monitor all trial results. If early results show clear
advantages of a new drug, the sponsor of the study may choose to end
the trial early and establish a protocol allowing wider use of the
drug before final approval for marketing. If a drug is shown to have
a strongly negative effect, the trial is stopped immediately.
In 1995, a trial of the drug tamoxifen (tamoxifen citrate) showed
that the drug dramatically reduced the short-term risk of breast
cancer. The DMSB and the researchers assessed the data and halted the
trial so that the results could be made widely available and all
women in the trial could have the opportunity to take the drug.
Researchers submitted a new application to FDA, which expedited its
review status. The new application was the basis for FDA approval of
tamoxifen for reducing breast cancer risk.
All federally-sponsored trials are subject to two sets of similar
regulations enforced by HHS's Office for Human Research Protections
(OHRP) and the FDA to ensure the protection of people who
participate. If a trial is supported by the Government and it
involves an FDA-regulated drug or device, then it is subject to both
sets of regulations.
People thinking about taking part in a clinical trial
should ask researchers the following questions to be sure a
trial is reputable:
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 the study data and participant safety
being monitored?
What happens with the results of the trial?
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OHRP Regulations
OHRP protects those participating in research and provides
leadership for all Federal agencies that carry out research involving
people.
The OHRP enforces important regulations for participant protection
in clinical trials called the Common Rule.4 These
regulations set standards regarding the:
Informed consent process
Formation and function of IRBs
Involvement of prisoners, children, and other vulnerable
groups in research
FDA Regulations
FDA enforces another set of regulations on participant protection
in clinical trials.5 They concern any clinical trial that
involves an FDA-regulated drug or device, regardless of whether the
trial receives Federal funding. FDA periodically inspects IRB records
and operations to certify the adequacy of approvals, participant
safeguards, and conduct of business.
Strengthening Government Oversight
Although breaches in participant protection seldom occur,
recent discoveries of inadequate participant protection have
taken place. Beginning in 2000, HHS began to take additional
steps to:
Strengthen regulations concerning participant
safety
Strengthen Government oversight of medical
research
Reinforce clinical researchers' responsibilities
to follow Federal research guidelines
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4 Title 45 CFR Part 46, Sub Part A
5 Title 21 CFR Part 50, 56.
Participant Protection
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How would you respond to the following questions? You may wish to print
them for a reference.
A. Aren't people who join clinical trials just "guinea pigs" for
research without protections?
__________________________________________________________
__________________________________________________________
__________________________________________________________
B. Can a person be put on a clinical trial without his or her
knowledge?
__________________________________________________________
__________________________________________________________
__________________________________________________________
C. If someone is in a phase 3 trial and it is found that there is
a clear advantage for the participants in the other group, what
happens?
__________________________________________________________
__________________________________________________________
__________________________________________________________
D. What happens if someone wants to stop participating in a
trial?
__________________________________________________________
__________________________________________________________
__________________________________________________________
Answers to Exercise 3
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