The Elements of Informed Consent: What 21 CFR 50.25 Actually Requires

At a glance

• 21 CFR 50.25 contains two lists, not one. The eight basic elements in 50.25(a) are required in every consent. The six additional elements in 50.25(b) are required only “when appropriate.”
• Treating the second list as optional boilerplate, or as universally required, is the most common way a consent form goes wrong.
• 50.25(c) adds a third requirement that is easy to miss: a specific ClinicalTrials.gov statement, quoted verbatim in the regulation, for applicable clinical trials.
• Documentation is a separate obligation under 50.27, with two permitted forms: a full written consent document, or a short form with a witness and an IRB-approved written summary.
• The exceptions in 50.23 and 50.24 are narrow and heavily conditioned. Neither is a general-purpose waiver.

Two lists, not one

Most consent-form problems trace to a single misreading. 21 CFR 50.25 does not set out one list of things a consent must say. It sets out two, and they carry different force.

Section 50.25(a) opens: “In seeking informed consent, the following information shall be provided to each subject.” Eight items follow. There is no qualifier. Every one applies to every subject in every study covered by the part.

Section 50.25(b) opens differently: “When appropriate, one or more of the following elements of information shall also be provided to each subject.” Six items follow. The qualifier is doing real work, and it cuts both ways. A form that omits an additional element which is appropriate to the study is deficient. A form that mechanically includes all six regardless of relevance has padded the document without improving anyone’s understanding.

The judgment about which additional elements apply belongs to the study and its review, not to a template.

The conditions consent must be obtained under

Before the elements themselves, 50.20 sets the conditions. No investigator may involve a human being as a subject in covered research unless the investigator has obtained the legally effective informed consent of the subject or the subject’s legally authorized representative, except as provided in 50.22, 50.23 and 50.24.

Four constraints sit in that section, and each is separately checkable:

• Consent may be sought only under circumstances that give the prospective subject or representative sufficient opportunity to consider whether to participate.
• Those circumstances must minimize the possibility of coercion or undue influence. This is where recruitment practice and consent practice meet, and it is worth reading alongside how a study advertises, compensates, and pre-screens.
• The information given must be in language understandable to the subject or the representative.
• No consent, oral or written, may include exculpatory language through which the subject waives or appears to waive any legal rights, or releases or appears to release the investigator, the sponsor, the institution, or its agents from liability for negligence.

That last one is absolute. It is not softened by a “to the extent permitted by law” clause, and it applies to oral consent as much as to the signed form.

The eight basic elements: 50.25(a)

Each of these must be provided to each subject.

1. (a)(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.
2. (a)(2) A description of any reasonably foreseeable risks or discomforts to the subject.
3. (a)(3) A description of any benefits to the subject or to others which may reasonably be expected from the research.
4. (a)(4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
5. (a)(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 Food and Drug Administration may inspect the records.
6. (a)(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.
7. (a)(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 a research-related injury to the subject.
8. (a)(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.

Two of these are more often thinned out than the others. Element (a)(5) requires the consent to name the possibility of FDA inspection of records, which is a different statement from a general confidentiality assurance, and a form that promises confidentiality without it is incomplete. Element (a)(1) requires identification of which procedures are experimental, not merely a description of what will happen; a subject who cannot tell the research procedures from the clinical ones has not been given what the section requires.

The six additional elements: 50.25(b)

These apply when appropriate to the particular study.

1. (b)(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.
2. (b)(2) Anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent.
3. (b)(3) Any additional costs to the subject that may result from participation in the research.
4. (b)(4) The consequences of a subject’s decision to withdraw from the research, and procedures for orderly termination of participation by the subject.
5. (b)(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.
6. (b)(6) The approximate number of subjects involved in the study.

Note what (b)(2) and (b)(4) do together. One covers the investigator ending a subject’s participation, the other covers the subject ending it themselves. They are separate elements because they answer different questions, and a form that addresses only withdrawal has covered half the ground.

The statement most forms forget: 50.25(c)

For applicable clinical trials, as defined in 42 U.S.C. 282(j)(1)(A), 50.25(c) requires a specific statement in informed consent documents and processes, notifying the subject that trial information has been or will be submitted to the clinical trial registry databank. The regulation quotes the required wording:

“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 is one of the few places where the regulation supplies exact text rather than a description of content.

Two further provisions round out the section. Under 50.25(d), the informed consent requirements are not intended to preempt applicable Federal, State, or local laws requiring additional information to be disclosed. Under 50.25(e), nothing in the regulations limits a physician’s authority to provide emergency medical care as permitted by applicable law.

Documentation is a separate obligation: 50.27

Having the right content is one requirement. Documenting consent is another, and it lives in its own section.

Under 50.27(a), except as provided in 56.109(c), informed consent shall be documented by the use of a written consent form approved by the IRB and signed and dated by the subject or the subject’s legally authorized representative at the time of consent. A copy shall be given to the person signing the form.

Three conditions travel together there, and exam-style questions about consent documentation usually turn on whether all three are present: IRB approval of the form, signature and date by the subject or representative at the time of consent, and a copy provided to the signer. The IRB approval element is why consent documentation and IRB review are not separable processes; if your study runs under a central board, see central vs local IRB.

Under 50.27(b), the consent form may take either of two shapes:

• The long form. A written consent document that embodies the elements of informed consent required by 50.25. It may be read to the subject or the representative, but the investigator shall in any event give them adequate opportunity to read it before it is signed.
• The short form. A short written document stating that the elements required by 50.25 have been presented orally. This route carries extra machinery: there shall be a witness to the oral presentation, the IRB shall approve a written summary of what is to be said, only the short form itself is signed by the subject or representative, the witness shall sign both the short form and a copy of the summary, and the person actually obtaining consent shall sign a copy of the summary. A copy of the summary is given to the subject or representative in addition to a copy of the short form.

The short form is not a shortcut. It substitutes a witnessed oral presentation and an approved summary for a document the subject reads, and it adds signatures rather than removing them.

The exceptions are narrow

Two sections permit research to proceed without consent obtained in the ordinary way. Both are tightly conditioned, and neither functions as a general waiver.

50.23: exception from general requirements

Obtaining informed consent is deemed feasible unless, before use of the test article, both the investigator and a physician who is not otherwise participating in the clinical investigation certify in writing all four of the following:

1. The human subject is confronted by a life-threatening situation necessitating use of the test article.
2. Informed consent cannot be obtained from the subject because of an inability to communicate with, or obtain legally effective consent from, the subject.
3. Time is not sufficient to obtain consent from the subject’s legal representative.
4. There is available no alternative method of approved or generally recognized therapy that provides an equal or greater likelihood of saving the life of the subject.

All four, certified in writing, by two people, one of whom is independent of the investigation.

Where immediate use is required to preserve the subject’s life and there is not time to obtain the independent determination in advance, 50.23(b) permits the clinical investigator to make the determinations alone, with review and written evaluation by a non-participating physician within 5 working days after use. Under 50.23(c), the documentation goes to the IRB within 5 working days after use of the test article.

50.24: emergency research

This is a different instrument and should not be confused with 50.23. It allows an IRB responsible for review of the investigation, with the concurrence of a licensed physician who is a member of or consultant to the IRB and not otherwise participating in the investigation, to approve an investigation without requiring consent from all subjects, where the IRB finds and documents a set of conditions. Those begin with:

• Subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and collection of valid scientific evidence is necessary to determine safety and effectiveness of particular interventions.
• Obtaining informed consent is not feasible because subjects will not be able to consent as a result of their medical condition, and the intervention must be administered before consent from the subjects’ legally authorized representatives is feasible.

50.23 is a certification made about an individual subject in front of them. 50.24 is a prospective IRB approval covering a class of subjects in a planned emergency study. Using the language of one while operating under the other is a recurring source of confusion.

What ICH E6(R3) adds

ICH E6(R3) and 21 CFR Part 50 are not interchangeable, and it is worth being precise about where the guideline goes further than FDA’s text.

Principle 2.1 states that freely given informed consent should be obtained and documented from every participant prior to participation, that legally acceptable representatives acting in the participant’s best interest should provide consent where a participant cannot, and that where a minor is a participant, assent should be collected from that minor, as appropriate and in accordance with local regulatory requirements.

Principle 2.2 supplies something Part 50 never states: the objective of the process. The process and information should be designed to enable potential participants to evaluate the benefits, risks and burden of participating and to make an informed decision, and the information should be clear and concise so as to be understandable. Part 50 requires understandable language; E6(R3) says what the understanding is for. A form can satisfy the first and still fail the second, and that gap is where most genuinely poor consent documents sit.

Principle 2.3 directs that the process take into account relevant aspects of the trial, including the characteristics of participants, the trial design, the setting, and the potential use of technology to inform participants and obtain consent. Part 50’s text does not address electronic consent at all, so a study using eConsent is working against a guideline expectation that has no counterpart in the regulation.

A difference worth naming rather than smoothing over

Principle 2.4 addresses emergency situations by saying that where consent cannot be obtained prior to participation, consent should be obtained from the participant or their legally acceptable representative as soon as possible, in accordance with applicable regulatory requirements and the processes approved by the IRB/IEC.

21 CFR 50.24 approaches the same situation from a different direction. It permits an IRB to approve an investigation without requiring that informed consent of all subjects be obtained, subject to the findings listed above.

These are not the same mechanism. E6(R3) frames deferred consent as the expectation; 50.24 establishes a prospective exception granted by an IRB. A US study under an IND conducted in emergency settings has to satisfy 50.24 on its own terms, and an investigator who reads Principle 2.4 as describing what FDA requires will have the wrong model of the obligation. Where a study is run to both, the two need to be reconciled deliberately by the sponsor and the IRB, not assumed to align.

Sources

• 21 CFR Part 50, Protection of Human Subjects (2024 edition) — govinfo.gov
• ICH E6(R3) Good Clinical Practice — ich.org