3.2 Informed Consent Core Elements & Process (21 CFR Part 50)

3.2 Informed Consent Core Elements & Process (21 CFR Part 50)

Informed consent is the cornerstone of clinical research ethics, grounded in the principle of Respect for Persons from the Belmont Report. Under 21 CFR Part 50, informed consent is defined not merely as the act of signing a form, but as an ongoing communication process between the clinical investigator (or their delegated research staff) and the subject. This process must ensure that the subject is fully informed, understands the research, and exercises free power of choice without any element of force, fraud, deceit, duress, coercion, or undue influence.

The 8 Basic Elements of Informed Consent (21 CFR 50.25(a))

Any informed consent document used in an FDA-regulated study must contain the following eight basic elements:

1. Research Statement: A statement that the study involves research, an explanation of the purposes of the research, the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
2. Foreseeable Risks: A description of any reasonably foreseeable risks or discomforts to the subject. This must be written in lay terms and describe the likelihood, severity, and reversibility of potential side effects.
3. Expected Benefits: A description of any benefits to the subject or to others which may reasonably be expected from the research. If there is no direct therapeutic benefit expected, this must be explicitly stated. Financial compensation for participation must not be listed as a benefit.
4. Alternative Treatments: A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject. This includes standard-of-care treatments, other clinical trials, or supportive/palliative care options.
5. Confidentiality and FDA Access: 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 Food and Drug Administration (FDA) may inspect the records. The consent must notify subjects that the FDA has direct access to their medical records.
6. Compensation and Medical Treatment for Injury: 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. The text must clarify who pays for the treatment (e.g., the sponsor, the subject's insurance, or the subject).
7. Contact Information: An explanation of whom to contact for answers to pertinent questions about the research (usually the principal investigator) and research subjects' rights (usually the IRB), and whom to contact in the event of a research-related injury to the subject.
8. Voluntary Participation and Withdrawal: A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

The 6 Additional Elements of Informed Consent (21 CFR 50.25(b))

The following six elements must be included in the consent form when appropriate or applicable to the clinical trial:

1. Unforeseeable Risks: 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. This is mandatory for trials involving investigational products with unknown safety profiles.
2. Investigator-Initiated Termination: Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent. Examples include a subject's failure to follow study procedures, safety concerns, or sponsor cancellation of the trial.
3. Additional Costs: Any additional costs to the subject that may result from participation in the research. This includes costs for study-related tests, parking, or co-pays that are not covered by the research sponsor.
4. Consequences and Procedures for Withdrawal: The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject (e.g., a safety follow-up visit, tapering off study medication).
5. Significant New Findings: 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. If new safety data emerges, the subject must sign an updated, IRB-approved consent form to continue.
6. Approximate Number of Subjects: The approximate number of subjects involved in the study, which helps the subject understand the scope of the trial.

Verbatim ClinicalTrials.gov Statement (21 CFR 50.25(c))

For all "applicable clinical trials" (which includes most controlled clinical trials of FDA-regulated drugs, biologics, and devices), the FDA requires that the informed consent form include the following statement, word-for-word:

"A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time."

This statement must be reproduced exactly. Clinical research coordinators must verify that this exact paragraph is included during their consent form template reviews.

The Informed Consent Process

Informed consent is a process, not just a signature on a paper. Key compliance steps in this process include:

• Timing: Informed consent must be obtained prior to initiating any study-related procedures. This includes screening tests, blood draws, washout periods of current medications, or pre-study imaging. Any study procedure performed before consent is signed constitutes a major protocol violation.
• Language and Literacy: The consent form must be written in language that is understandable to the subject or their representative. IRBs generally require consent forms to be written at an 8th-grade reading level or lower. Technical medical terms must be translated into lay terms (e.g., "myocardial infarction" becomes "heart attack," and "venipuncture" becomes "blood draw from a vein").
• No Coercion or Undue Influence: The consent process must occur under circumstances that provide the prospective subject or their representative sufficient opportunity to consider whether or not to participate, minimizing the possibility of coercion or undue influence. The investigator or coordinator must allow the subject to ask questions, discuss the study with family members or their primary care physician, and must never pressure the subject to sign.
• Exculpatory Language Prohibition (21 CFR 50.20): No informed consent, whether oral or written, may include any exculpatory language through which the subject or their representative is made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

Documentation and Signatures (21 CFR 50.27)

To document that the consent process took place, the following rules must be followed:

• Signatures and Dates: The consent form must be signed and personally dated by the subject or the subject's Legally Authorized Representative (LAR). Note that FDA regulations require the subject or LAR to write the date themselves; pre-printing the date or having the coordinator write the date is a compliance violation.
• Copies: A copy of the signed and dated consent form must be given to the person signing the form (the subject or LAR). The original signed document must be retained in the investigator's study records (often referred to as the Investigator Site File [ISF]).
• FDA vs. ICH GCP Differences:
  • Under FDA regulations (21 CFR 50.27), only the subject or their LAR is required to sign and date the consent form.
  • Under ICH GCP E6(R3) (and previously E6(R2)), the person who conducted the informed consent discussion must also sign and personally date the consent form.
  • Because most clinical trials follow both FDA and ICH GCP standards, clinical research sites must follow local IRB standard operating procedures, which almost always require the signature of both the subject and the person obtaining consent.
• Impartial Witness: An impartial witness is required in specific circumstances, such as when the subject is unable to read or write (illiterate) or if a short form consent process is used. The witness must be present during the entire consent discussion, verify that the information was accurately explained, that the subject understood, and that consent was voluntary. The witness then signs and dates the consent form.