Related Pages Protecting Participants in Clinical Trials 1 A collection of material about the ways in which clinical trials participants are protected before and during the conduct of a study. Protecting Human Research Participants 2 A free, on-line tutorial offered by the National Institutes of Health (NIH) Office of Extramural Research, for physicians, nurses, and other members of clinical research teams. This online course satisfies the NIH human subjects training requirement for extramural researchers obtaining Federal funds.

Introduction

Safeguards

History

What to Expect

Questions to Ask

More Information

A Guide to Understanding Informed Consent

If you and your physician have found a clinical trial that is of interest to you and for which you are eligible (that is, you meet requirements such as type and stage of cancer, age, treatment history, overall health, and others), you will need information in order to make a decision about whether to participate in the trial. Making a decision about participating in a research study involves understanding the potential risks and benefits as well as your rights and responsibilities. The presentation and discussion of these important issues are part of the process called informed consent. This guide will tell you what to expect during the informed consent process, explain its importance to clinical research participants, and describe how it fits into a larger system that protects the welfare of people who take part in clinical trials.



Introduction

A Definition of Informed Consent

You may already have experience with signing consent forms for other kinds of medical procedures, such as surgery, or for cancer treatments such as radiation or chemotherapy. However, informed consent for a clinical trial involves much more than just reading and signing a piece of paper. Rather, it involves two essential parts: a document and a process.

The informed consent document provides a summary of the clinical trial (including its purpose, the treatment procedures and schedule, potential risks and benefits, alternatives to participation, etc.) and explains your rights as a participant. It is designed to begin the informed consent process, which consists of conversations between you and the research team. If you then decide to enter the trial, you give your official consent by signing the document. You can keep a copy and use it as an information resource throughout the course of the trial.

The informed consent process provides you with ongoing explanations that will help you make educated decisions about whether to begin or continue participating in a trial. Researchers and health professionals know that a written document alone may not ensure that you fully understand what participation means. Therefore, before you make your decision, the research team will discuss with you the trial’s purpose, procedures, risks and potential benefits, and your rights as a participant. If you decide to participate, the team will continue to update you on any new information that may affect your situation. Before, during, and even after the trial, you will have the opportunity to ask questions and raise concerns. Thus, informed consent is an ongoing, interactive process, rather than a one-time information session.

Myth and Reality

Before you start exploring this section of the site, you may find it helpful to confront some of the most common misperceptions about informed consent and clinical trials. Even if these do not represent your thinking about informed consent, they can serve as a helpful reminder of what the process is really about before you go through it.

Myth: Informed consent is designed primarily to protect the legal interests of the research team.

Reality: The purpose of the process is to protect you and other participants by providing access to information that can help you make an informed choice. It also is designed to make you aware of your rights as a participant.

Myth: The most important part of this process is signing the informed consent document.

Reality: Actually, the heart of this process is your ongoing interaction and discussions with the research team and other medical personnel–before, during, and after the trial. The document is designed to get this conversation started.

Myth: My doctor knows best; he or she can tell me whether or not I should consent to participate.

Reality: Your doctor is likely to be a valuable source of advice and information, but only you can make this decision. No one–not even medical experts–can predict whether a treatment, screening, prevention, or supportive care method under evaluation in a trial will prove successful. The informed consent process is designed to help you weigh all of the information and make the right choice for you or your child.

Myth: Once I sign the consent form, I have to enroll and stay enrolled in the trial.

Reality: That's not true. Even after you sign the form, you are free to change your mind and decide not to participate. You also have the right to leave a clinical trial at any time for any reason, without forfeiting access to other treatment.

Myth: Medical personnel are busy, so I can't really expect them to keep me informed as the trial progresses or listen to my questions.

Reality: The research team has a duty to keep you informed, make sure that you understand the information they provide, and answer your questions. If you ever feel that you are not getting what you need, do not hesitate to speak up. You will be given the name and phone number of a key contact person who can answer your questions throughout the course of the trial. Keep in mind that people like you are making this research possible through their willingness to participate.

Safeguards

Informed Consent and the Larger System of Protections

Informed consent for clinical trials is just one part of a larger system in place to safeguard people who want to help researchers evaluate new practices that may improve treatment, supportive care, screening, and prevention, while perhaps benefiting from these new methods. This system ensures that clinical trials are conducted ethically, without undue risk to participants. What follows are links to some of the resources that contribute to this system of protections.

Simplification of informed consent documents

The informed consent process can be effective only if patients understand the study information presented by the medical team. After both participants and investigators voiced concerns that informed consent documents for clinical trials were becoming too long, complicated, and difficult to understand, the National Cancer Institute issued recommendations and other guidance for the documents' developments (see Simplification of Informed Consent Documents ³). The recommendations had three goals in mind:

• to make the forms more useful and understandable to people who want to participate in clinical trials;
• to aid investigators in developing better informed consent documents; and
• to assist Institutional Review Boards (IRBs) in reviewing the documents and ensuring their quality.

Office of Human Research Protections (OHRP)

This OHRP ⁴, which is part of the U.S. Department of Health and Human Services (DHHS), is responsible for:

• guiding the medical community on ethical issues in biomedical or behavioral research, and
  
  
• implementing DHHS's Regulations for the Protection of Human Subjects ⁵ (Title 45, Part 46 of the Code of Federal Regulations, Protection of Human Subjects; also referred to as 45 CFR 46).

These federal regulations set standards for the informed consent process; the formation and function of Institutional Review Boards (see below); the involvement of prisoners, children, and other vulnerable groups in research; and many other protective measures.

The regulations apply to any federally funded research that involves people (which includes NCI-sponsored clinical trials). Participating institutions must provide OHRP with a written assurance that they will comply with the regulations. In addition, many research institutions conducting independent (i.e., not federally funded) trials have volunteered to adhere to these regulations.

Human Subject Protection Program, FDA

The U.S. Food and Drug Administration (FDA), through its Office of Health Affairs, has developed its own set of regulations on the protection of human subjects (Title 21, Parts 50 and 56 of the Code of Federal Regulations; also referred to as 21 CFR 50, 56).

The regulations apply to any clinical trial that involves an investigational drug, biological product, or other device that is regulated by the FDA under the Food, Drug, and Cosmetics Act -- regardless of whether or not the trial receives Federal funding. If a trial is supported by the Department of Health and Human Services and involves an FDA-regulated drug or device, then it is subject to both organizations' regulations. (For more information, see Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors ⁶).

The American Hospital Association and "The Patient Care Partnership"

The American Hospital Association (AHA) first adopted a "patient's bill of rights" in 1973, which was later revised into a brochure called The Patient Care Partnership: Understanding Expectations, Rights and Responsiblities ⁷. This brochure (available in multiple languages) lists a patient's rights to considerate and respectful care, privacy, confidentiality, information about options, and access to medical records, among others. The AHA expects hospitals to use the brochure to ensure quality care and encourages them to adapt its contents to meet the needs of the communities they serve.

Institutional Review Boards

Institutions have an Institutional Review Board (IRB) made up of medical specialists, nurses, social workers, medical ethicists, and patient advocates. The IRB reviews all clinical trial protocols and approves only those that address medically important questions in a scientifically and ethically responsible manner. It also reviews all informed consent documents to make sure that they provide clear and complete information for those who may wish to take part.

You might be interested in taking a look at the IRB Guidebook ⁸ issued by the NIH's Office of Human Research Protections.

Peer review

Before a clinical trial gets under way, it also may be reviewed by experts chosen by the sponsoring organization (such as the National Cancer Institute, the Food and Drug Administration, or pharmaceutical company) for scientific merit, patient safety, and ethical considerations.

For more information about peer review at the National Institutes of Health (NIH), including NCI, see the Office of Extramural Research: Peer Review Policy and Issues ⁹ or the NIH Center for Scientific Review ¹⁰.

Patient representatives

Many hospitals and clinical centers employ patient representatives, who work to make sure that those who receive care (including clinical trial participants) are informed of and understand their rights and responsibilities.

Other organizations

Groups such as Public Responsibility in Medicine and Research (PRIM&R) ¹¹ help to educate medical personnel and the public about the ethical, legal, and policy issues involved in clinical research.

History

The History of Informed Consent and the System of Protections

Over the past half-century, the international and U.S. medical communities have taken numerous steps to protect people who take part in clinical research. The following timeline provides an overview of some of the key events that have contributed to the development of the current system.

1947 — The Nuremberg Code

Developed in response to the Nuremberg Trials of Nazi doctors who performed unethical experimentation during World War II, the Code was the first major international document to provide guidelines on research ethics. It made voluntary consent a requirement in clinical research studies, emphasizing that consent can be voluntary only if:

• participants are able to consent;
• they are free from coercion (i.e., outside pressure); and
• they comprehend the risks and benefits involved.

The Code also states that researchers should minimize risk and harm, make sure that risks do not significantly outweigh potential benefits, use appropriate study designs, and guarantee participants' freedom to withdraw at any time. The Nuremberg Code was adopted by the United Nations General Assembly in 1948.

1964 — Declaration of Helsinki

At the 18th World Medical Assembly in Helsinki, Finland, the World Medical Association adopted 12 principles to guide physicians on ethical considerations related to biomedical research. It emphasizes the distinction between medical care that directly benefits the patient and research that may or may not provide direct benefit. These guidelines were revised at subsequent meetings in 1975 (Tokyo, Japan), 1983 (Venice, Italy), and 1989 (Hong Kong).

1974 — The National Research Act

The U.S. Congress signed this act into law, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission was charged with:

1. identifying the basic ethical principles that should govern medical research involving people, and then
2. recommending steps to improve the Regulations for the Protection of Human Subjects.

1979 — The Belmont Report ¹²

After four years of work, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued "The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research." The report sets forth three principles underlying the ethical conduct of research:

1. respect for persons: recognizing the autonomy and dignity of individuals, and the need to protect those with diminished autonomy (i.e., impaired decision-making skills), such as children, the aged, and the disabled;
2. beneficence: an obligation to protect persons from harm by maximizing benefits and minimizing risks;
3. justice: fair distribution of the benefits and burdens of research.

The Belmont Report explains how these apply to research practices; for example, it identifies informed consent as a process that is essential to the principle of respect. In response to the report, both the U.S. Department of Health and Human Services and the U.S. Food and Drug Administration revised their regulations on research studies that involve people.

1991 — Federal Policy for the Protection of Human Subjects ⁵

This policy was adopted to ensure a uniform system of protections in all federal agencies and departments that conduct research.

What to Expect

What Should I Expect During the Informed Consent Process?

According to The Belmont Report ¹², the informed consent process relies on three principles:

• adequate information is provided (generally, what a "reasonable person" would want to know to make a decision);
  
  
• participants comprehend the information; and
  
  
• consent is given voluntarily.

While this process varies among different research institutions and clinical centers, you generally should expect the following:

• An initial meeting during which a member (or members) of the research team provides you with the informed consent document and explains its content to you. This discussion may also include your oncologist (cancer specialist) and primary care doctor, as well as a nurse, social worker, patient representative, and/or staff psychologist. You may wish to bring along a family member or friend for support, and to help you keep track of the information presented. This information should be given logically and at a comfortable pace, with plenty of time allowed for you to consider it and ask questions. You may be given a video, audiotape, or even an interactive computer program to help you better understand the information in the consent document.

If your child (under age 18) is the one who will participate in the clinical trial, you will go through this process on his or her behalf. More and more frequently, children over the age of 6 are being asked to give their "assent" to participation as well. If this is the case, you will be asked to give permission for your child to take part in the assent process. During this process, a child or teenager is provided with a form that explains, in concrete and age-appropriate terms, the purpose of the research, what they will be asked to do, and what procedures they will undergo. Usually, a nurse or other heath professional also explains the information and gives the child a chance to ask questions. Then they are asked to indicate their assent either by signing the form or making a mark in a specific place.

The following example gives you an idea of what a child participant assent form might look like:

• Time to digest the information. It can be very difficult to absorb this information in one sitting, especially at a time of emotional distress. You should be given a copy of the document so that that you can take it home, review it as many times as you need, and discuss it with family, friends, social workers, clergy, a patient representative, or other trusted advisors.
  
  
• Assessment of your understanding. The research team should take some steps to ensure that you comprehend the information, either by having you fill out a questionnaire, asking you questions orally, or having you explain certain aspects of the trial in your own words. You also should alert team members to anything you do not understand. If you find that the document is written in words that are too difficult for you, don't hesitate to let them know that.
  
  
• Opportunities to ask questions. Both during the initial meeting and in follow-up discussion(s), you should be given the chance to ask questions and raise concerns. Keep asking questions until you have all the information you need to make your decision.
  
  
• Continuing updates on new information. As the trial proceeds, the research team may discover new information that could affect your health, welfare, or willingness to remain in the study. They will share this with you and may ask you to sign a new informed consent document. Of course, you are free to leave the study if this information leads you to have doubts about continuing to participate.

What Will I Find in the Informed Consent Document?

In 1998 the National Cancer Institute Working Group on Informed Consent issued recommendations ³ designed to help research institutions and clinical centers write comprehensive, user-friendly informed consent documents. The group also developed a template and sample forms that provide models for covering all of the information that federal regulations require for informed consent documents.

You may wish to print out the template ¹³ or a sample form ¹⁴ and use it as a model of what to look for in the document that you receive.

While informed consent documents do vary from place to place, they should communicate all of the information described below in language that you can understand, with some help from the research team (if needed). Even if your trial is not federally funded and therefore not governed by these regulations, you should know that any scientifically valid trial will provide an informed consent document that supplies such information

The information covered should include:

• TITLE
• PURPOSE [Why is this clinical trial being done?]

In this section, researchers explain why they are conducting the trial. Their reasons will depend on the type of cancer and the trial type (i.e., whether they are investigating new prevention, screening, supportive care, or treatment methods). Researchers conduct treatment trials either because they have not found an effective treatment for a certain type of cancer, or they are not sure which treatment method works best.

In these trials, Phase I tests the safety and effectiveness of a new treatment, or aims to find out what dosage of a new drug can be given safely. Phase II treatment trials evaluate the effects (good and bad) that a treatment may have on people with a certain type of cancer. Phase III treatment trials compare the effectiveness of a new treatment or treatment combination with that of standard treatment. Researchers use prevention, screening, and supportive care trials to evaluate new strategies for preventing cancer, detecting it more accurately and effectively, and alleviating treatment side effects.

• DESCRIPTION OF PROCEDURES [What is involved in the trial?]

This section describes the procedures that you will undergo, how frequently you will have them, and where they will take place (at home, in the hospital or clinical center, or in an outpatient setting). For treatment trials, this section should include:

• procedures that are part of regular cancer care and may be done even if you do not join the trial;
  
  
• standard procedures being done because you are in the trial; and
  
  
• procedures that are being tested or evaluated by the trial.

If this is a "randomized" trial, then you will be assigned at random (by computer) into one of two or more study groups. People in the different groups will receive different treatments or treatment combinations, so that researchers can evaluate which is most effective. If this is the case, the document should make clear what procedures each group will undergo. It should also indicate what your chances are of being placed in any one group.

• DURATION [How long will I be in the trial?]

This section indicates how long the trial will last and whether it involves followup, and if so, for how long. It also includes information about any circumstances under which the researcher might remove you from the trial (for example, if your condition worsens or new information indicates you shouldn't continue). The document should make clear that you have the right to stop participating at any time, and it should describe any possible medical consequences of sudden withdrawal.

• RISKS [What are the risks of the trial?]

This section includes the foreseeable physical and nonphysical risks of participating in the trial. A nonphysical risk might be time away from work, while physical risks might include side effects such as nausea, vomiting, pain, or susceptibility to infection, among others. The document should indicate the likelihood of these risks occurring, how serious they may be, and whether they are more likely to be short-term (last only during the trial or shortly afterward) or long-term (last weeks, months, or even years after the trial is over). The document should make clear which risks are related to the investigational aspects of the trial. It also should include specific information about reproductive risks (Could participating make you infertile? Should you not get pregnant or father a child while on the trial? Can you nurse a child during the trial?).

• BENEFITS [Are there benefits to taking part?]

The document describes any benefits to you or to others which may reasonably be expected. A trial may or may not involve direct medical benefits to you, but it might lead to new knowledge that can help others in the future.

• ALTERNATIVES TO PARTICIPATION [What are my options if I don't participate?]

For treatment trials, this section describes what care options you have besides participating in the trial, such as other commonly-used therapies or no treatment at all.

• CONFIDENTIALITY

This statement tells you the extent to which your information will be kept confidential. It should inform you about any groups or organizations that may have access to your records for quality assurance and data analysis (such as the National Cancer Institute, the Food and Drug Administration, or other trial sponsor).

• COSTS/ ADDITIONAL EXPENSES [What are the costs?]

This section indicates whether participating in the trial will result in added costs to you or your insurance company (see Clinical Trials and Insurance Coverage - A Resource Guide ¹⁵ for more information on this topic). It also covers other cost issues, such as who will pay for emergency medical treatment in case of injury or illness, whether you will have to pay for drugs that become commercially available during the trial (if this is a drug trial), and whether or not you will receive payment for participating.

• PARTICIPANT'S RIGHTS [What are my rights as a participant?]

The document should specify that:

1. your participation is voluntary;
   
   
2. you can choose not to take part or leave at any time without penalty or loss of benefits; and
   
   
3. any new information that might affect your participation will be shared with you.

• CONTACT INFORMATION [Whom do I call if I have questions or problems?]

You should have a contact name and phone number (usually of a member of the research team) for getting answers to questions about the study or a research-related injury. You also should be given a phone number for the Institutional Review Board or a patient representative, in case you have questions about your rights as a research participant.

• SUPPLEMENTAL INFORMATION [Where can I get more information?]

This section lists additional resources that may prove useful as you make your decision, such as NCI's Cancer Information Service, informational booklets, community organizations, and Web resources.

• THE SIGNATURE

Your signature represents your legal consent to participate in the trial.

If any of these sections appears to be incomplete or missing from the informed consent document, don't hesitate to ask for the information.

Other Useful Tips

• Keep a copy of the informed consent document as a helpful resource for the duration of the trial. Ask for a copy if one isn't offered to you. You may also request a copy of the protocol (full study plan).
  
  
• According to Federal regulations, no informed consent document may include any language that asks or appears to ask you to waive your legal rights, or that releases or appears to release the investigator, the sponsor, or the institution from liability for negligence.
  
  
• If you cannot understand the forms you are signing, don't be afraid to let someone know that you are having trouble. If you have difficulties reading the document at first, try not to get upset. Many people feel anxious about reading and signing documents and communicating with physicians. Just take your time and ask for help when you need it.

Questions to Ask

A Checklist of Questions to Ask the Research Team

The following questions deal with many of the areas that should be covered in the informed consent document (see previous section). To double-check that you have all the information you need, consider printing out this checklist and bringing it to a meeting with the research team. You also may wish to fill it out as you read the informed consent document, both to ensure your own understanding of the trial and to create a ready reference written in your own words. Many of these questions are specific to treatment trials, but the checklist still should prove useful if you are considering a prevention, screening, or supportive care trial.

The Study

1. What is the purpose of the study?
2. Why do researchers think the approach may be effective?
3. Who will sponsor the study?
4. Who has reviewed and approved the study?
5. How are study results and safety of participants being checked?
6. How long will the study last?
7. What will my responsibilities be if I participate?
8. Whom can I speak with about questions I have during and after the trial? to find out the study results?
9. What steps will be taken to protect my privacy and the confidentiality of my medical records?

Possible Risks and Benefits

1. What are my possible short -term benefits?
2. What are my possible long -term benefits?
3. What are my short - term risks, such as side effects?
4. What are my possible long -term risks?
5. What other options do people with my risk of cancer or type of cancer have?
6. How do the possible risks and benefits of this trial compare with those options?

Participation and Care

1. What kinds of therapies, procedures and /or tests will I have during the trial?
2. Will they hurt, and if so, how long?
3. How do the tests in the study compare with those I would have outside of the trial?
4. Will I be able to take my regular medications while in the clinical trial?
5. Where will I have my medical care?
6. Will I have to be hospitalized? If so, how often and for how long?
7. Who will be in charge of my care?
8. What type of follow-up care is part of the study?

Personal Issues

1. How could being in the study affect my daily life?
2. Can I talk to other people in the study?

Cost Issues

1. Will I have to pay for any part of the trial such as tests or the study drug?
2. If so, what will the charges likely be?
3. What is my health insurance likely to cover?
4. Who can help answer any questions from my insurance company or health plan?
5. Will there be many travel or child care costs that I need to consider while I am in the trial?

Resources for Understanding Informed Consent

You may find that the informed consent process and conversations with your medical team are sufficient in helping you arrive at a decision. Or you may wish to gather more outside information before making up your mind. Other good sources of information include:

• local hospitals
  
  
• Institutional Review Boards
  
  
• patient advocacy and support groups
  
  
• health plans
  
  
• NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615
  
  
• library and Internet research

You can also search the National Library of Medicine's PubMed database ¹⁶ for additional articles on informed consent and clinical trials.

Keep in mind that everyone's information needs are different. You should do whatever makes you feel most comfortable as you make this important decision.

Bibliography

Includes sources used in this Guide as well as background reading:

Broome M. "Consent (Assent) for Research with Pediatric Patients." Working manuscript.

Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for the National Cancer Institute. "Recommendations for the Development of Informed Consent Documents for Cancer Clinical Trials." August 1998.

Davis T et. al. "Informed Consent for Clinical Trials: A Comparative Study of Standard versus Simplified Forms." Journal of the National Cancer Institute 1998 May 6; 90 (9): 668-74.

Faden R, Beauchamp T. A History and Theory of Informed Consent (New York: Oxford UP, 1986). Chapter 8, "The Concepts of Informed Consent and Competence," and Chapter 9, "Understanding."

Grossman SA et. al."Are Informed Consent Forms that Describe Clinical Oncology Research Protocols Readable by Most Patients and Their Families?" Journal of Clinical Oncology 1994 Oct; 12 (10): 2211-5.

Jimison HB et. al. "The Use of Multimedia in the Informed Consent Process." Journal of the American Medical Information Association 1998 May-Jun; 5 (3): 245-56.

Kodish E et. al. "Informed Consent in the Childrens Cancer Group: Results of Preliminary Research." Cancer 1998 June 15; 82 (12): 2467-81.

National Cancer Institute. "Informed Consent: New Recommendations to Simplify, Improve Quality." Fact sheet, 11/98.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. "The Belmont Report ¹²: Ethical Principles and Guidelines for the Protection of Human Subjects of Research." April 18, 1979

Office of Human Research Protections, Department of Health and Human Services. "IRB Guidebook ⁸."

Porter JP. "Basic Considerations in Informed Consent in Research." Clinical Research and Regulatory Affairs 1995; 12 (2): 95-109.

Warren Grant Magnuson Clinical Center, National Institutes of Health. "Partners in Research: Volunteer Patients and the NIH Clinical Center ¹⁷."

University of Minnesota Institutional Review Board. "Informed Consent Overview ¹⁸."