FDA Releases Guidance on Informed Consent

This article reviews the FDA’s recent guidance for informed consent, and what should be included.

In August 2023, the FDA released guidance intended to assist institutional review boards (IRBs), clinical investigators, and sponsors in complying with FDA’s informed consent regulations for clinical investigations. The FDA also states that future changes to the guidance on informed consent maybe coming as FDA is currently in the rulemaking process of seeking to harmonize FDA regulations  with the 2018 Common Rule.

The guidance starts with a reminder that “informed consent” is much more than obtaining a patient’s signature on a legal document. Informed consent is a process that involves ensuring that patients, or their representatives, have adequate information to make an informed decision regarding their voluntary participation in clinical research. The FDA considers advertising to recruit participants as the start of the informed consent process. A good consent process  also includes ongoing communication with participants throughout the study.

The guidance reviews general requirements for informed consent found in 21 CFR 50.20, as well as the basic elements of informed consent required by 21 CFR 50.25(a). Specifically, the guidance reviews provisions regarding:

  • Obtaining legally effective signed consent, with some exceptions
  • Minimizing the opportunity for undue influence or coercion
  • Providing information in understandable language
  • Omitting any exculpatory language that waives the legal rights of the participant

Exceptions to Informed Consent

Informed consent is required for participation in FDA-regulated clinical investigations. Some exceptions include:

  • Life-threatening situations, such as emergency research
  • Military operations
  • Public health emergencies

FDA issued a proposed rule that, if finalized, would allow IRBs to approve an informed consent procedure that waives or alters certain informed consent elements or that waives the requirement to obtain informed consent for certain minimal risk clinical investigations.

Coercion and Undue Influence

According to the Belmont Report, “Coercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance.” Undue influence occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance.

The guidance provides examples in which coercion or undue influence may occur when recruiting potential research participants. For example, if an employer seeks to enroll employees in a clinical investigation sponsored or conducted by the employer, the informed consent process should contain safeguards to ensure that participation is voluntary and that the possibility of undue influence or coercion by supervisors, peers, or others is minimized.

The FDA also cautions the potential conflict of interest when the investigator is also the patient’s physician. Informed consent should include assurance that a decision to forgo enrollment will not adversely affect their medical care.

Undue influence may also occur with statements about the safety or efficacy of the investigational drug or device. Such statements are prohibited, as are any statements that may suggest or overstate a clinical benefit to the participant. For example, wording that refers to the clinical investigation as a “therapeutic trial” could contribute to a prospective subject’s misunderstanding that the trial will offer a direct benefit for their disease or condition.

The FDA also forbids any language that suggests that the agency endorses the investigation.

Renumeration or reimbursement for expenses such as travel expenses to and from the clinical research site, including hotel stays or parking, are not included as a potential source of undue influence when deemed reasonable and commensurate with incurred expenses. . Reimbursement for other expenses may be considered by an IRB on a case-by-case basis, and IRBs should consider whether the proposed remuneration could be an undue influence.

An IRB should consider how much money research subjects should receive, and for what subjects should receive payment. IRBs should review both the amount of payment and the proposed method and timing of disbursement to assure that they are not coercive and do not present undue influence.

Understandable Language

Information, both oral and written, must be in language understandable to the prospective subject or legal representative. Medical and scientific terminology must be explained.

Exculpatory Language

The consent process must not include exculpatory language through which a subject, or the LAR, is made to waive or appear to waive any of their legal rights, or release or appear to release the investigator, the sponsor, the institution, or its agents from liability for negligence (21 CFR 50.20). FDA considers exculpatory language to be language that has the general effect of freeing or appearing to free an individual or an entity from malpractice, negligence, blame, fault, or guilt.

General Elements of Informed Consent

FDA regulations identify eight basic elements of informed consent to be provided to the subject:

  • Description of the study, including the purpose and duration of the study
  • Risks and discomforts, including risks or discomforts of tests, interventions and procedures required by the protocol
  • Potential benefits, both to the patient and society
  • Alternative procedures and treatments, including a description of the care they would be likely to receive if they choose not to participate in the research
  • Confidentiality, including how records will be maintained and which parties may have access to the information (the study sponsor, the research team, regulatory agencies, IRB members, etc.)
  • Compensation and medical treatment in case of injury, including an explanation to subjects of where they may obtain further information
  • Contacts, in case the participant has further questions or needs to report an issue or study-related injury. This information should include contact names (or offices), email addresses, and their telephone numbers. FDA recommends that the individual or office named for questions about subjects’ rights not be part of the investigational team, because subjects may be hesitant to report specific concerns or identify possible problems to someone who is part of the investigational team.
  • Emphasis that participation is voluntary, including information that the patient may stop participation at any time without penalty or loss of benefits to which subjects are entitled

In some cases, the IRB may decide to include additional elements, such as:

  • Unforeseeable risks, for example, a statement that the particular test or procedure may involve risks to subjects (or to the embryo or fetus, if the subject is or may become pregnant) that are currently unforeseeable
  • Involuntary termination of the subject’s participation, including the circumstances under which that may occur
  • Additional costs to the subject, particularly if insurance or other reimbursement mechanisms might not fund the medical care they receive as a result of participating in a clinical investigation
  • Consequences of a subject’s decision to withdraw, including withdrawal procedures if there may be adverse impact on the participant
  • Significant new information should be provided in the case that significant new findings may influence the subject’s willingness to continue participation, such as new risk information
  • Number of participants, because a patient’s decision to participate in the study may be influenced by knowledge that the clinical investigation is a small initial trial of the product

Before research activities occur, a person knowledgeable about the clinical investigation and capable of answering questions raised by the prospective subject should conduct a consent discussion. The consent discussion and the consent form must contain information to allow prospective subjects to make an informed decision about participation in a clinical investigation and provide an opportunity for prospective subjects to ask questions about the clinical investigation and the information in the consent document.

Part two of this series will highlight the FDA’s guidance on documentation of the informed consent process.