This section entails;

• Understanding the Importance of Informed Consent in clinical trials and in General
• Informed Consent for Clinical Trials
• What is Informed Consent
• What are the Four Elements of Informed Consent
• What are the Five Components that Healthcare Providers Must Discuss With Me Regarding Treatment
• What Methods Can or Should they use to Communicate the Necessary Information
• Is my signed consent the last word on the subject?
• What are the exceptions to the rule of Informed Consent?
• Ethics in Clinical Research
• Social and Clinical Value
• Scientific Validity
• Fair Subject Selection
• Favorable Risk-benefit Ratio
• Independent Review
• Informed Consent
• Respect for Potential and Enrolled Subjects
• Sources

There are important viewpoints on ethics in clinical trials involving African-Americans and Latinos. Ethics offers a sense of assurance needed to encourage participation within these clinical trials, particularly given historical malpractices for African-Americans and other traditionally underrepresented groups. Included is a video that provides contextual perspectives on historical malpractices.

As new medical products are being developed, no one knows for sure how well they will work or what risks will be found. Clinical trials are used to answer questions such as:

• Are new medical products safe enough to outweigh the risks related to the underlying condition?
• How should the product be used? For example, what is the best dose, frequency, or any special precautions needed to avoid problems?
• How effective is the medical product at relieving symptoms, treating, or curing a condition?

The main purpose of clinical trials is to “study” new medical products in people. Because of the newness of the products, it is important for people who are considering participation in a clinical trial to understand their role as a “subject of research” and not as a patient.

While research subjects may get personal treatment benefit from participating in a clinical trial, they must understand that they:

• may not benefit from the clinical trial;
• may be exposed to unknown risks; and
• are entering into a study that may be very different from the standard medical practices that they currently know.

To make an informed decision about whether to participate or not in a clinical trial, people need to be informed about:

• what will be done to them;
• how the protocol (plan of research) works;
• what risks or discomforts they may experience; and
• what does voluntary participation and decision-making involve on their part.

This information is provided to potential participants through the informed consent process. Informed consent means that the purpose of the research is explained to them, including what their role would be and how the trial will work.

Additional information regarding clinical trials is included on the website. Below are areas related to consent:

• WHAT IS INFORMED CONSENT
• WHAT YOU NEED TO KNOW BEFORE ENROLLING IN A CLINICAL TRIAL

WHAT IS INFORMED CONSENT

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Informed Consent for Clinical Trials

The term "informed consent" is mistakenly viewed as the same as getting a research participant's signature on the consent form. FDA believes that obtaining a research participant's verbal or written informed consent is only part of the process.

Informed consent involves providing a potential participant with:

• adequate information to allow for an informed decision about participation in the clinical investigation.
• facilitating the potential participant's understanding of the information.
• an appropriate amount of time to ask questions and to discuss with family and friends the research protocol and whether you should participate.
• obtaining the potential participant's voluntary agreement to participate.
• continuing to provide information as the clinical investigation progresses or as the subject or situation requires.

To be effective, the process must provide sufficient opportunity for the participant to consider whether to participate. (21 CFR 50.20.) FDA considers this to include allowing sufficient time for participants to consider the information and providing time and opportunity for the participant to ask questions and have those questions answered. The investigator (or other study staff who are conducting the informed consent interview) and the participant should exchange information and discuss the contents of the informed consent document. This process must occur under circumstances that minimize the possibility of coercion or undue influence. (21 CFR 50.20.)

https://www.ncbi.nlm.nih.gov/books/NBK430827/

A central part of the informed consent process is the informed consent document. The Food and Drug Administration (FDA) does not dictate the specific language required for the informed consent document, but does require certain basic elements of consent be included.

Before enrolling in a clinical trial, the following information must be given to each potential research subject:

• A statement explaining that the study involves research;
• An explanation of the purposes of the research;
• The expected length of time for participation;
• A description of all the procedures that will be completed during enrollment on the clinical trial;
• Information about all experimental procedures that will be completed during the clinical trial;
• A description of any predictable risks;
• Any possible discomforts (e.g., injections, frequency of blood test etc.) that could occur as a result of the research;
• Any possible benefits that may be expected from the research;
• Information about any alternative procedures or treatment (if any) that might benefit the research subjects;
• A statement describing the following: the confidentiality of information collected during the clinical trial, how records that identify the subject will be kept, the possibility that the FDA may inspect the records for research involving more than minimal risk information including an explanation as to whether any compensation or medical treatments are available if injury occurs, what they consist of, or where more information may be found. questions about the research, research subjects' rights, and injury related to the clinical trial.
• Research subject participation is voluntary;
• Research subjects have the right to refuse treatment and will not lose any benefits for which they are entitled; and
• Research subjects may choose to stop participation in the clinical trial at any time without losing the benefits for which they are entitled.

Contact information will be provided for answers to a statement that, when appropriate, one or more of the following elements of information must also be provided in the informed consent document:

• A statement that the research treatment or procedure may involve unexpected risks (to the subject, unborn baby, if the subject is or may become pregnant).
• Any reasons why the research subject participation may be ended by the clinical trial investigator (e.g., failing to follow the requirements of the trial or changes in lab values that fall outside of the clinical trial limits).
• Added costs to the research subject that may result from participating in the trial.
• The consequence of leaving a trial before it is completed (e.g. if the research and procedures require a slow and organized end of participation).
• A statement that important findings discovered during the clinical trial will be provided to the research subject.
• The approximate number of research subjects that will be enrolled in the study.

A potential research subject must have an opportunity to:

• read the consent document,
• ask questions about anything they do not understand.

Usually, if one is considering participating in a clinical trial, he or she may take the consent document home to discuss with family, friends, or an advocate. An investigator should only get consent from a potential research subject if:

• enough time was given to the research subject to consider whether or not to participate; and
• the investigator has not persuaded or influenced the potential research subject.

The information must be in a language that is understandable to the research subject. Informed consent may not include language that:

• the research subject is made to ignore or appear to ignore any of the research subject's legal rights; and
• releases or appears to release the investigator, the sponsor, the institution, or its agents from their liability for negligence.

Participating in clinical trials is voluntary. You have the right not to participate, or to end your participation in the clinical trial at any time. Read the informed consent document carefully. Ask questions about any information you do not understand or find confusing.

Draft Guidance: Informed Consent Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors

What are the four elements of informed consent?

Stakeholders generally agree that informed consent requires these four conditions:

1. The healthcare provider must verify that you (the patient) have the capacity to understand and make decisions about your healthcare. If you can’t, they must appoint someone to make decisions in your place (a surrogate).
2. The healthcare provider must disclose enough information for the decision-maker to make an informed choice. (More on what constitutes “enough for an informed choice” below.)
3. The healthcare provider must judge that the decision-maker understands the information.
4. The decision-maker must freely authorize the treatment plan, usually with their signature.

What are the five components that healthcare providers must discuss with me regarding treatment?

In order for you to make an “informed choice,” your healthcare provider must disclose:

• Your diagnosis. Even if you have appointed a surrogate to make decisions for you, healthcare providers must tell you the name and the nature of your condition. Informed consent laws prevent them from withholding this information, even at the request of your family or surrogate.
• The proposed treatment plan. Your healthcare provider must explain the treatment or treatments they want you to consider. They may have a clear recommendation or there may be no single “best” option. You may also get different recommendations from different specialists.
• The risks and benefits of the plan. When healthcare providers recommend treatment, they must disclose what the potential risks are, how likely those risks are, what the potential benefits are and how likely it is to succeed. However, they may leave out very remote risks, risks related to factors they couldn’t have known about or risks that are considered common knowledge.
• Alternative options. Even if your provider has a clear recommendation for your treatment plan, they should mention any medically recognized alternatives that you might want to consider. This discussion should also include the risks and benefits of alternative treatments.
• What happens if you do nothing. You have the right to refuse or delay treatment, but your healthcare provider must make sure that you understand the risks and benefits if you do.

WHAT YOU NEED TO KNOW BEFORE ENROLLING IN A CLINICAL TRIAL

There is important information you need know before enrolling in a clinical trial. Following below are various questions that offer insight into those areas.

What methods can or should they use to communicate the necessary information?

Your healthcare provider may use a variety of media to communicate about your condition, including oral communication, written pamphlets, infographics and videos. They should ensure that the wording is accessible for non-medical people to understand. If you aren’t fluent in the same language, they must provide a qualified translator to communicate with you and obtain your informed consent.

Is my signed consent the last word on the subject?

No. A signed document may be one required part of the informed consent process. But it’s not the beginning or the end. Healthcare providers must also document the full communication process leading up to it, including allowing time for you to ask questions and to think about it. You can also change your mind at any time. Signing your consent doesn’t obligate you to continue with the original plan.

What are the exceptions to the rule of informed consent?

Informed consent as described above isn’t practical or appropriate in every situation. Some of the recognized exceptions to the rule include:

• When you are incapacitated. What happens if a medical condition interferes with your ability to understand information and make decisions? Maybe it’s a condition you’ve had for some time, or maybe it’s a temporary condition affecting you at a moment when you need medical care. Your healthcare provider will have to identify an appropriate surrogate to make decisions for you in this case. You may have already designated one, or they may need to refer to a family member, friend or partner, according to the local laws. If you have any ability to participate in the informed consent process, your provider should try to involve you as much as possible. If your provider is unsure of your mental capacity, they may need to have you evaluated first.
• When it’s an emergency. Sometimes you need urgent care, and delaying that care to get informed consent first could put your life at risk. When time is of the essence, your provider may not discuss all the possible treatment alternatives in order to get on with the treatment they believe you need. Emergency conditions also commonly cause temporary incapacitation. You may be able to give your informed consent after treatment has begun, but you may not recover that ability before treatment begins. When this is the case, healthcare providers presume your consent to save your life. They will attempt to obtain your explicit consent as soon as you are able to give it, and they will strive to keep you informed going forward.
• When you’re a child. If you’re a legal minor, your parent or legal guardian is your default surrogate, responsible for giving informed consent to your care. However, some states accept that minors of a certain age may be mature enough to consider and make decisions about their own care. This is called the “mature minor” exception, and it works differently in different situations. A different type of law called “medical emancipation” can release a minor from involving their parent or guardian in their medical care. In this case, though, minors aren’t necessarily granted autonomy. The court may assign a different surrogate to decide medical matters for them. But the parent or guardian won’t be entitled to that information or consent.

Ethics in Clinical Research

Ethical Guidelines

The goal of clinical research is to develop generalizable knowledge that improves human health or increases understanding of human biology. People who participate in clinical research make it possible to secure that knowledge. The path to finding out if a new drug or treatment is safe or effective, for example, is to test it on patient volunteers. But by placing some people at risk of harm for the good of others, clinical research has the potential to exploit patient volunteers. The purpose of ethical guidelines is both to protect patient volunteers and to preserve the integrity of the science.

The ethical guidelines in place today were primarily a response to past abuses, the most notorious of which in America was an experiment in Tuskegee, Alabama, in which treatment was withheld from 400 African-American men with syphilis so that scientists could study the course of the disease. Various ethical guidelines were developed in the 20th century in response to such studies.

Some of the influential codes of ethics and regulations that guide ethical clinical research include:

• Nuremberg Code (1947)
• Declaration of Helsinki (2000)
• Belmont Report (1979)
• CIOMS (2002)
• U.S. Common Rule (1991)

Using these sources of guidance and others, seven main principles have been described as guiding the conduct of ethical research:

• Social and clinical value
• Scientific validity
• Fair subject selection
• Favorable risk-benefit ratio
• Independent review
• Informed consent
• Respect for potential and enrolled subjects

Social and clinical value

Every research study is designed to answer a specific question. Answering certain questions will have significant value for society or for present or future patients with a particular illness. An answer to the research question should be important or valuable enough to justify asking people to accept some risk or inconvenience for others. In other words, answers to the research question should contribute to scientific understanding of health or improve our ways of preventing, treating, or caring for people with a given disease. Only if society will gain useful knowledge — which requires sharing results, both negative and positive — can exposing human subjects to the risk and burden of research be justified.

Scientific Validity

A study should be designed in a way that will get an understandable answer to the valuable research question. This includes considering whether the question researchers are asking is answerable, whether the research methods are valid and feasible, and whether the study is designed with a clear scientific objective and using accepted principles, methods, and reliable practices. It is also important that statistical plans be of sufficient power to definitively test the objective, for example, and for data analysis. Invalid research is unethical because it is a waste of resources and exposes people to risk for no purpose

Fair Subject Selection

Who does the study need to include, to answer the question it is asking? The primary basis for recruiting and enrolling groups and individuals should be the scientific goals of the study — not vulnerability, privilege, or other factors unrelated to the purposes of the study. Consistent with the scientific purpose, people should be chosen in a way that minimizes risks and enhances benefits to individuals and society. Groups and individuals who accept the risks and burdens of research should be in a position to enjoy its benefits, and those who may benefit should share some of the risks and burdens. Specific groups or individuals (for example, women or children) should not be excluded from the opportunity to participate in research without a good scientific reason or a particular susceptibility to risk.

Favorable Risk-Benefit Ratio

Uncertainty about the degree of risks and benefits associated with a drug, device, or procedure being tested is inherent in clinical research — otherwise there would be little point on doing the research. And by definition, there is more uncertainty about risks and benefits in early-phase research than in later research. Depending on the particulars of a study, research risks might be trivial or serious, might cause transient discomfort or long-term changes. Risks can be physical (death, disability, infection), psychological (depression, anxiety), economic (job loss), or social (for example, discrimination or stigma from participating in a certain trial). Has everything been done to minimize the risks and inconvenience to research subjects, to maximize the potential benefits, and to determine that the potential benefits to individuals and society are proportionate to, or outweigh, the risks? Research volunteers often receive some health services and benefits in the course of participating, yet the purpose of clinical research is not to provide health services.

Independent Review

To minimize potential conflicts of interest and make sure a study is ethically acceptable before it even starts, an independent review panel with no vested interest in the particular study should review the proposal and ask important questions, including: Are those conducting the trial sufficiently free of bias? Is the study doing all it can to protect research volunteers? Has the trial been ethically designed and is the risk–benefit ratio favorable? In the United States, independent evaluation of research projects is done through granting agencies, local institutional review boards (IRBs), and data and safety monitoring boards. These groups also monitor a study while it is ongoing.

Informed consent

For research to be ethical, most agree that individuals should make their own decision about whether they want to participate or continue participating in research. This is done through a process of informed consent in which individuals (1) are accurately informed of the purpose, methods, risks, benefits, and alternatives to the research, (2) understand this information and how it relates to their own clinical situation or interests, and (3) make a voluntary decision about whether to participate.

There are exceptions to the need for informed consent from the individual — for example, in the case of a child, of an adult with severe Alzheimer’s, of an adult unconscious by head trauma, or of someone with limited mental capacity. Ensuring that the individual’s research participation is consistent with his or her values and interests usually entails empowering a proxy decision maker to decide about participation, usually based on what research decision the subject would have made, if doing so were possible.

Respect for potential and enrolled subjects

Individuals should be treated with respect from the time they are approached for possible participation—even if they refuse enrollment in a study—throughout their participation and after their participation ends. This includes:

1. Respecting their privacy and keeping their private information confidential.
2. Respecting their right to change their mind, to decide that the research does not match their interests, and to withdraw without penalty.
3. Informing them of new information that might emerge in the course of research, which might change their assessment of the risks and benefits of participating.
4. Monitoring their welfare and, if they experience adverse reactions, untoward events, or changes in clinical status, ensuring appropriate treatment and, when necessary, removal from the study.
5. Informing them about what was learned from the research. Most researchers do a good job of monitoring the volunteers’ welfare and making sure they are okay. They are not always so good about distributing the study results. If they don’t tell you, ask

Sources:

For more information about what makes clinical research, we refer you to:

Ezekiel J. Emanuel, MD, PhD; David Wendler, PhD, and Christine Grady, PhD. "What Makes Clinical Research Ethical?" Journal of the American Medical Association, Vol. 283, No. 20, May 24, 2000, pp. 2701-2711.

Copy on this website is based largely on this article, on an interview with Dr. Grady, and on Dr. Emanuel's PowerPoint presentation, "What makes research ethical," available online: http://www.bioethics.nih.gov/slides/10-29-03-Emmanuel.pdf

Dr. Grady is acting chief of the Bioethics Department and head of the Section on Human Subjects Research. Dr. Wendler heads the Unit on Vulnerable Populations. Dr. Emanuel was chief of the CC Bioethics Department 1996-20