3. Participant Protection in Clinical Trials

History of Participant Protection
The Informed Consent Process
Review Committees

Overview

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:

  • A scientific review panel

  • The institutional review board (IRB) that oversees clinical research at the local participating institution

• 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

History of Participant Protection

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

The Informed Consent Process

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:

• Purpose

• Procedures

• Risks and benefits

• Participant rights, including the rights to:

  • Make an independent decision about participating

  • Leave the study at any time without jeopardizing future treatment

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.

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?

Review Committees

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:

• Federally funded

• Evaluating a new drug, agent, or medical device subject to FDA regulation

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.

Government Regulations and Agencies

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.

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.

4 Title 45 CFR Part 46, Sub Part A
5 Title 21 CFR Part 50, 56.

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?

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B. Can a person be put on a clinical trial without his or her knowledge?

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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?

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D. What happens if someone wants to stop participating in a trial?

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Answers to Exercise 3