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What elements must be included in the Informed Consent Document?

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Proxima CRO Team
Stephanie Mull
Director of Project Management
Stephanie has over 20 years of clinical research experience working from the site, CRO, and sponsor perspectives.
According to 21 CFR 50.25, when seeking informed consent, the following information shall be provided to each subject:

1.      A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.

The statement that the study involves research is important because the relationship between patient-physician is different than that between subject-investigator. Any procedures relating solely to research (e.g. randomization, placebo control, additional tests) should be explained to the subjects. The procedures subjects will encounter should be outlined in the consent document, or an explanation of the procedures, such as a treatment chart, may be attached to and referenced in the consent document.

Consent documents for studies of investigational articles should include a statement that a purpose of the study includes an evaluation of the safety of the test article. Statements that test articles are safe or statements that the safety has been established in other studies are not appropriate when the purpose of the study includes determination of safety. In studies that also evaluate the effectiveness of the test article, consent documents should include that purpose, but should not contain claims of effectiveness.

2.     A description of any reasonably foreseeable risks or discomforts to the subject.

The risks of procedures relating solely to research should be explained in the consent document. The risks of the tests required in the study protocol should be explained, especially for tests that carry significant risk of morbidity/mortality. The explanation of risks should be reasonable and should not minimize reported adverse effects.

The explanation of risks of the test article should be based upon information presented in documents such as the protocol and/or investigator's brochure, package labeling, and previous research study reports. For IND studies, the IRB should assure that the clinical investigator submits the investigator's brochure (when one exists) with the other study materials for review.

3.     A description of any benefits to the subject or to others which may reasonably be expected from the research.

The description of benefits to the subject should be clear and not overstated. If no direct benefit is anticipated, that should also be stated. The IRB should be aware that this element includes a description not only of the benefits to the subject, but to "others" as well. This may be an issue when benefits accruing to the investigator, the sponsor, or others are different than normally expected to result from conducting research. Thus, if these benefits may be materially relevant to the subject's decision to participate, they should be disclosed in the informed consent document.

4.     A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

To enable a rational choice about participating in the research study, subjects should be aware of the full range of options available to them. Consent documents should briefly explain any pertinent alternatives to entering the study including,when appropriate, the alternative of supportive care with no additional disease-directed therapy. While this should be more than just a list of alternatives, a full risk/benefit explanation of alternatives may not be appropriate to include in the written document. The person(s) obtaining the subjects' consent, however, should be able to discuss available alternatives and answer questions that the subject may raise about them. As with other required elements, the consent document should contain sufficient information to ensure an informed decision.

5.      A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the FDA may inspect the records.

Study subjects should be informed of the extent to which the institution intends to maintain confidentiality of records identifying the subjects. In addition, they should be informed that FDA may inspect study records (which include individual medical records). If any other entity, such as the sponsor of the study, may gain access to the study records, the subjects should be so informed. The consent document may, at the option of the IRB, state that subjects' names are not routinely required to be divulged to FDA. When FDA requires subject names,FDA will treat such information as confidential, but on rare occasions, disclosure to third parties may be required. Therefore, absolute protection of confidentiality by FDA should not be promised or implied. Also, consent documents should not state or imply that FDA needs clearance or permission from the subject for access. When clinical investigators conduct a study for submission to FDA, they agree to allow FDA access to the study records. Informed consent documents should make it clear that, by participating in research, the subject's records automatically become part of the research database. Subjects do not have the option to keep their records from being audited/reviewed by FDA.

6.      For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.

Informed consent documents should describe any compensation or medical treatments that will be provided if injury occurs. If specific statements cannot be made (e.g. each case is likely to require a different response), the subjects should be informed where further information may be obtained. The consent should also indicate whether subjects will be billed for the cost of such medical treatments. When costs will be billed, statements such as:

  • “will be billed to you or your insurer in the ordinary manner,"
  • "the sponsor has set some funds aside for medical costs related to.... Here's how to apply for reimbursement if you think you might be eligible," or
  • "no funds have been set aside..." are preferred.

Statements such as: "will be the responsibility of you or your insurance company" or "compensation is not available," could appear to relieve the sponsor or investigator of liability for negligence, see 21 CFR 50.20.

The consent document must explain whether there is compensation available in case of injury but must not waive or appear to waive the rights of the subject or release or appear to release those conducting the study from liability for negligence. When no system has been set up to provide funds, the preferred wording is: "no funds have been set aside for," "[the cost] will be billed to you or your insurance," or similar wording that explains the provisions or the process. Wording such as: "will be your responsibility or that of your third-party payor" has been erroneously interpreted by some subjects to mean the insurance company is required to pay.

7.      An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of are search-related injury to the subject.

This requirement contains three components, each of which should be specifically addressed. The consent document should provide the name of a specific office or person and the telephone number to contact for answers to questions about: 1) the research subjects' rights; 2) a research-related injury; and 3) the research study itself. It is as important for the subject to know why an individual should be contacted as it is for the subject to know whom to contact. Although a single contact might be able to fulfill this requirement, IRBs should consider requiring that the person(s) named for questions about research subjects' rights not be part of the research team as this may tend to inhibit subjects from reporting concerns and discovering possible problems.

8.      A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

This element requires that subjects be informed that they may decline to participate or to discontinue participation at any time without penalty or loss of benefits. Language limiting the subject's right to withdraw from the study should not be permitted in consent documents. If the subjects who withdraw will be asked to permit follow-up of their condition by the researchers, the process and option should be outlined in the consent document.

In addition to the eight (8) items listed above, when appropriate, one or more of the following elements of information shall also be provided to each subject:

1.      A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable.

A statement that there may be unforeseen risks to the embryo or fetus may not be sufficient if animal data are not available to help predict the risk to a human fetus. Informed consent documents should explain that mutagenicity (the capability to induce genetic mutations) and teratogenicity (the capability to induce fetal malformations) studies have not yet been conducted/completed in animals. Subjects, both women and men, need to understand the danger of taking a drug whose effects on the fetus are unknown. If relevant animal data are available, however, the significance should be explained to potential subjects. Investigators should ensure that the potential risks that the study poses are adequately explained to subjects who are asked to enter a study. If measures to prevent pregnancy should be taken while in the study, that should be explained.

FDA guidance on the inclusion of women in clinical trials now gives IRBs broader discretion to encourage the entry of a wide range of individuals into the early phases of clinical trials. FDA urges IRBs to question any study that appears to limit enrollment based on gender and/or minority status. Statements such as, "you may not participate in this research study if you are a woman who could become pregnant" should not routinely be included in informed consent documents.

2.     Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent.

When applicable, subjects should be informed of circumstances under which their participation may be terminated by the investigator without the subject's consent. An unexplained statement that the investigator and/or sponsor may withdraw subjects at any time, does not adequately inform the subjects of anticipated circumstances for such withdrawal.

A statement that the investigator may withdraw subjects if they do not "follow study procedures" is not appropriate. Subjects are not in a position to know all the study procedures. Subjects may be informed, however, that they may be withdrawn if they do not follow the instructions given to them by the investigator.

3.     Any additional costs to the subject that may result from participation in the research.

If the subjects may incur an additional expense because they are participating in the research, the costs should be explained. IRBs should consider that some insurance and/or other reimbursement mechanisms may not fund care that is delivered in a research context.

4.     The consequences of a subjects' decision to withdraw from the research and procedures for orderly termination of participation by the subject.

When withdrawal from a research study may have deleterious effects on the subject's health or welfare, the informed consent should explain any withdrawal procedures that are necessary for the subject's safety and specifically state why they are important to the subject's welfare. An unexplained statement that the subject will be asked to submit to tests prior to withdrawal does not adequately inform the subjects why the tests are necessary for the subject's welfare.

5.      A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject.

When it is anticipated that significant new findings that would be pertinent to the subject's continued participation are likely to occur during the subject's participation in the study, the IRB should determine that a system, or a reasonable plan, exists to make such notification to subjects.

6.     The approximate number of subjects involved in the study.

If the IRB determines that the numbers of subjects in a study is material to the subjects' decision to participate, the informed consent document should state the approximate number of subjects involved in the study.

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