21 CFR Part 50 (Protection of Human Subjects)

21 CFR Part 50 is the FDA’s own human-subjects protection regulation. Its defining feature is its trigger: Part 50 applies because of what is being studied, not who paid for the study. Where the Common Rule reaches research supported or conducted by a federal department, Part 50 reaches clinical investigations of FDA-regulated products regardless of the source of funding — so a wholly industry-funded device trial with no federal money in it is squarely within Part 50.

Scope (21 CFR 50.1)

Part 50 applies to all clinical investigations regulated by FDA under sections 505(i) and 520(g) of the Federal Food, Drug, and Cosmetic Act, and to clinical investigations that support applications for research or marketing permits for FDA-regulated products. The regulation lists those products expressly, and the list is wider than people expect: foods (including dietary supplements) bearing a nutrient content claim or a health claim, infant formulas, food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products.

The corresponding definition at 50.3(c) makes the reach concrete. A clinical investigation is any experiment involving a test article and one or more human subjects that either requires prior submission to FDA under 505(i) or 520(g), or does not require prior submission but whose results are intended to be submitted later to, or held for inspection by, FDA as part of an application for a research or marketing permit. That second limb is the one that catches investigator-initiated studies: an intention to file the data with FDA later brings the study inside Part 50 now.

The definitions that decide edge cases (21 CFR 50.3)

• Test article — any drug (including a biological product), medical device for human use, human food additive, colour additive, electronic product, or other article subject to the FD&C Act or to sections 351 and 354-360F of the Public Health Service Act.
• Investigator — the individual who actually conducts the investigation, under whose immediate direction the test article is administered, dispensed or used; where a team conducts it, the responsible team leader.
• Sponsor versus sponsor-investigator — a sponsor initiates but does not conduct. A sponsor-investigator both initiates and actually conducts, and must be an individual: 50.3(f) states the term does not include a corporation or agency. An organisation using its own employees to run a study it initiated is a sponsor, and those employees are investigators.
• Minimal risk — probability and magnitude of harm or discomfort not greater than those ordinarily encountered in daily life or during routine physical or psychological examinations or tests.
• Legally authorized representative, assent (a child’s affirmative agreement; mere failure to object is not assent), and family member are all separately defined.

Subpart B: informed consent

The general requirement at 21 CFR 50.20 is that no investigator may involve a human being as a subject unless legally effective informed consent has been obtained from the subject or their legally authorized representative. The section then imposes four conditions that are frequently the substance of an FDA inspection finding: consent must be sought under circumstances giving sufficient opportunity to consider participation; the circumstances must minimise the possibility of coercion or undue influence; the information must be in language understandable to the subject or representative; and no consent may include exculpatory language through which the subject waives or appears to waive legal rights, or releases the investigator, sponsor, institution or its agents from liability for negligence.

Required elements (21 CFR 50.25)

Section 50.25(a) sets eight basic elements that must be provided to every subject: that the study involves research, its purpose, expected duration and procedures, with experimental procedures identified; reasonably foreseeable risks or discomforts; reasonably expected benefits to the subject or others; appropriate alternative procedures or courses of treatment; the extent of confidentiality of records, including a note that FDA may inspect the records; for more-than-minimal-risk research, whether compensation and medical treatment are available if injury occurs; whom to contact about the research, subjects’ rights, and research-related injury; and a statement that participation is voluntary and may be discontinued at any time without penalty or loss of benefits.

Section 50.25(b) adds six additional elements to be included when appropriate, including currently unforeseeable risks (with express mention of risks to an embryo or fetus), circumstances in which the investigator may terminate participation without the subject’s consent, additional costs, consequences of withdrawal, significant new findings, and the approximate number of subjects.

Section 50.25(c) requires, for applicable clinical trials as defined at 42 U.S.C. 282(j)(1)(A), a specific verbatim ClinicalTrials.gov statement in the consent document and process. Section 50.25(d) confirms the regulation does not preempt federal, state or local laws requiring additional disclosure.

Documentation (21 CFR 50.27)

Consent must be documented on a written form approved by the IRB and signed and dated by the subject or their representative at the time of consent, with a copy given to the person signing. Two forms are permitted: a full written consent document embodying the 50.25 elements, which the subject must be given adequate opportunity to read before signing; or a short form stating that the elements were presented orally, which requires a witness to the oral presentation and an IRB-approved written summary of what is to be said.

The three exceptions

• 50.22 — minimal risk waiver. Added by FDA in December 2023 (88 FR 88248), this lets an IRB waive or alter consent where the investigation is no more than minimal risk, could not practicably be carried out without the waiver, could not practicably be carried out without identifiable information or biospecimens in identifiable form where those are used, the waiver will not adversely affect subjects’ rights and welfare, and subjects are given additional pertinent information afterwards where appropriate. Before this, FDA had no general minimal-risk waiver — a long-standing divergence from the Common Rule that this section closed.
• 50.23 — life-threatening emergency. Consent is deemed feasible unless both the investigator and a physician not otherwise participating certify in writing that the subject faces a life-threatening situation, consent cannot be obtained from the subject, there is not time to reach a legal representative, and no alternative approved therapy offers an equal or greater likelihood of saving the subject’s life. Where immediate use is required and there is no time for the independent determination, the investigator may act alone, with review by an independent physician within 5 working days; the documentation goes to the IRB within 5 working days either way.
• 50.24 — emergency research. The exception for planned research in emergency settings. An IRB, with the concurrence of a licensed physician member or consultant not participating in the investigation, must find and document each of a demanding list: subjects are in a life-threatening situation with unproven or unsatisfactory available treatments; consent is not feasible because of the subjects’ condition, the intervention must be given before a representative can be reached, and eligible individuals cannot be prospectively identified; the research holds out the prospect of direct benefit supported by preclinical evidence; and the investigation could not practicably be carried out without the waiver. The plan must define the therapeutic window and commit the investigator to attempting to contact a legally authorized representative within it.

Subpart D: additional safeguards for children

Subpart D (21 CFR 50.50-50.56) governs children in FDA-regulated clinical investigations. An IRB may approve only investigations that satisfy one of three risk categories, plus the assent and permission provisions of 50.55:

• 50.51 — no greater than minimal risk.
• 50.52 — greater than minimal risk but presenting the prospect of direct benefit; the risk must be justified by the anticipated benefit, and the benefit-to-risk relation must be at least as favourable as available alternatives.
• 50.53 — greater than minimal risk with no prospect of direct benefit, but likely to yield generalizable knowledge about the subjects’ disorder or condition. This requires a minor increase over minimal risk, experiences reasonably commensurate with the child’s actual or expected situation, and knowledge of vital importance for understanding or ameliorating the condition.
• 50.54 — the escape hatch for investigations meeting none of the above. These may proceed only if the IRB finds a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting children’s health or welfare, and the Commissioner of Food and Drugs, after consulting an expert panel and allowing public review and comment, makes a specified determination.

How Part 50 relates to the other rules

Part 50 does not stand alone. Its companion is 21 CFR Part 56, FDA’s IRB regulation — Part 50 governs consent, Part 56 governs the board that reviews it, and 50.27 cross-references 56.109(c) for the circumstances in which documentation may be waived. Where a study is both federally supported and FDA-regulated, the Common Rule at 45 CFR Part 46 and Part 50 both apply and the investigator must satisfy the stricter of the two on each point. Additional sponsor and investigator obligations sit in 21 CFR Part 312 (INDs) and Part 812 (IDEs), and 21 CFR Part 54 separately governs financial disclosure by clinical investigators.

Frequently Asked Questions

What does 21 CFR Part 50 cover?

FDA’s informed-consent requirements for clinical investigations of FDA-regulated products — drugs, biologics, devices, electronic products, food and colour additives, infant formulas, and foods bearing a nutrient content or health claim. Subpart B sets the consent requirements and Subpart D adds safeguards for children.

Does Part 50 apply to studies with no federal funding?

Yes. The trigger is FDA jurisdiction over the product, not the funding source. Section 50.1 applies the part to all clinical investigations regulated by FDA under FD&C Act sections 505(i) and 520(g) and to investigations supporting applications for research or marketing permits, whoever pays for them.

How is 21 CFR Part 50 different from the Common Rule?

The Common Rule (45 CFR Part 46 and its counterparts across agencies) is triggered by federal support or conduct of the research. Part 50 is triggered by the study being FDA-regulated. Many trials fall under both, in which case the investigator must meet whichever requirement is stricter on each point.

Can informed consent be waived under Part 50?

Only in three defined situations: the minimal-risk waiver at 50.22 (added by FDA in December 2023), the life-threatening emergency exception at 50.23, and the planned emergency-research exception at 50.24. Each has its own findings that the IRB or the certifying physicians must document.

What is exculpatory language, and why does 50.20 prohibit it?

Language through which a subject waives or appears to waive legal rights, or releases the investigator, sponsor, institution or its agents from liability for negligence. Section 50.20 bars it from any consent, oral or written, because a consent that strips the subject of recourse is not a legally effective consent.

References

• 21 CFR Part 50 (Protection of Human Subjects), current edition, eCFR — 50.1, 50.3, 50.20, 50.22, 50.23, 50.24, 50.25, 50.27, 50.50-50.55
• 21 CFR Part 56 (Institutional Review Boards); 21 CFR Part 312; 21 CFR Part 812; 21 CFR Part 54
• 88 FR 88248 (21 December 2023), adding 21 CFR 50.22