45 CFR 46: All Five Subparts, Explained

45 CFR 46 is the federal regulation, codified at Part 46 of Title 45 of the Code of Federal Regulations, that governs the protection of human subjects in research overseen by the U.S. Department of Health and Human Services (HHS). It is organized into five subparts (A through E), each with a different scope. “The Common Rule” is not a synonym for all of 45 CFR 46 — it refers specifically to Subpart A, the basic policy text that HHS and roughly a dozen other federal departments and agencies each separately adopted, in materially identical form, into their own sections of the CFR. This page is a map: what each subpart actually covers, how “the Common Rule” got its name and why that name is narrower than people assume, what the 2018 revision changed (and didn’t), and where to go on CASRAI for the compliance detail on each piece.

The structure of 45 CFR 46: five subparts, five different jobs

Everything in 45 CFR 46 sits under one of five subparts. They are not interchangeable, and a study can be subject to more than one at once — a pediatric trial recruiting incarcerated minors, for example, would need to satisfy Subpart A, Subpart C, and Subpart D simultaneously.

Subpart	Formal title	What it covers	CASRAI page
A	Basic HHS Policy for Protection of Human Research Subjects	The Common Rule itself — definitions of “research” and “human subject,” IRB composition and approval criteria, informed consent requirements, exemption categories	Common Rule (45 CFR 46) · Subpart A detail
B	Additional Protections for Pregnant Women, Human Fetuses, and Neonates	Extra safeguards layered on top of Subpart A when the population includes pregnant women, fetuses, or neonates	Subpart B detail
C	Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners	Restricts which research categories are permissible with incarcerated subjects and requires a prisoner representative on the reviewing IRB	Subpart C detail
D	Additional Protections for Children Involved as Subjects in Research	Requires parental/guardian permission plus, where the IRB finds the child capable, the child’s own assent (46.408) — assent is affirmative agreement, not merely the absence of objection	Subpart D detail
E	Registration of Institutional Review Boards	Requires any IRB reviewing HHS-conducted or HHS-supported human subjects research to register with OHRP (46.501–46.503) before that IRB can be designated under an institution’s Federalwide Assurance; registration runs for three years	FWA vs. IRB registration · Federalwide Assurance (FWA)

Subpart E doesn’t yet have a dedicated CASRAI reference page of its own — the comparison and FWA pages linked above cover the registration mechanics in the meantime.

Why it’s called “the Common Rule” — and why that name is narrower than people assume

“The Common Rule” refers to Subpart A specifically, not to Part 46 as a whole. The name reflects its origin: in 1991, HHS’s existing human-subjects policy was adopted, in common, by more than a dozen other federal departments and agencies, each codifying essentially the same text into its own title of the CFR (for example, the National Science Foundation’s version sits at 45 CFR 690). The point was uniformity — a study funded by two different federal agencies wouldn’t need to satisfy two different sets of substantive requirements. Subparts B, C, and D are HHS-specific additional-protection subparts that layer on top of the Common Rule for particular populations; Subpart E is an HHS-specific administrative requirement (IRB registration). Neither is what most other agencies adopted in 1991 as “the Common Rule” itself, even though many funders’ own regulations reference or incorporate similar protections for those populations.

Two definitional gates from Subpart A determine whether any of this applies at all: 45 CFR 46.102(l) defines “research,” and 46.102(e) defines “human subject” separately. Both tests have to be met before Common Rule/IRB jurisdiction attaches — meeting only one is not enough. See 45 CFR 46.102(l) — definition of research and CASRAI’s fuller walkthrough at Human Subjects Research: How the Definition Actually Works.

The three definitions in Subpart A that decide everything else

Most real disputes about 45 CFR 46 are not about the subparts at all — they are about whether a definition in § 46.102 is met. Three carry nearly all the weight, and they are quoted here from the current regulation rather than paraphrased, because the paraphrases circulating in training materials are frequently looser than the text.

Research — 45 CFR 46.102(l). The jurisdictional trigger. If an activity is not “research” as the regulation defines it, Part 46 does not apply to it at all, however sensitive the data. Full walkthrough: 45 CFR 46.102(l) — definition of research.
Human subject — 45 CFR 46.102(e). The second, independent gate. An activity can be research and still fall outside Part 46 because no human subject is involved — the classic case being analysis of genuinely de-identified data. Both tests must be met, not either one.
Minimal risk — 45 CFR 46.102(j). The threshold that determines whether a study can be reviewed by expedited procedure, whether continuing review can be waived, and whether several of the Subpart B/C/D protections are satisfied. The regulation defines it as: “that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

Two things about the minimal-risk definition trip people up in practice. It is a judgement about both probability and magnitude of harm — a very unlikely but severe harm is not minimal risk merely because it is unlikely — and the comparator written into the text is daily life or routine physical or psychological examinations, which is a general benchmark rather than one indexed to the particular subject group. Note also the paragraph letter. Minimal risk sits at 46.102(j) under the current 2018 Requirements numbering; the 2017 Federal Register final rule records that the same words sat at § __.102(i) in the pre-2018 rule. That renumbering is why older training slides and institutional SOPs cite a different subsection for identical text, and why a citation to “46.102(i)” is a reliable sign that a document has not been updated since 2019.

The eight exempt categories at 45 CFR 46.104(d)

“Exempt” is the single most-searched piece of 45 CFR 46 after the subparts themselves, and the 2018 revision expanded the list from six categories to eight. The categories are set out at § 46.104(d). Summarised faithfully, but read the regulation itself before relying on any of them:

Category	What it exempts	Conditions worth knowing
(d)(1) Normal educational practices	Research in established or commonly accepted educational settings that specifically involves normal educational practices	Only if the practices are “not likely to adversely impact students’ opportunity to learn required educational content or the assessment of educators who provide instruction”
(d)(2) Tests, surveys, interviews, observation of public behavior	Educational tests, survey or interview procedures, or observation of public behavior, including visual or auditory recording	Needs one of three criteria: subjects not readily identifiable; or disclosure would not reasonably place them at risk of criminal/civil liability or damage to financial standing, employability, educational advancement or reputation; or identifiable plus limited IRB review under 46.111(a)(7)
(d)(3) Benign behavioral interventions	Benign behavioral interventions with adult subjects, in conjunction with information collection through verbal/written response or audiovisual recording, where the subject prospectively agrees	“Benign” is defined in the regulation as brief, harmless, painless, not physically invasive, not likely to have a significant adverse lasting impact, and not something the investigator has reason to think subjects will find offensive or embarrassing. Deception disqualifies the exemption unless the subject prospectively authorised it
(d)(4) Secondary research where consent is not required	Secondary research use of identifiable private information or identifiable biospecimens	Four alternative routes, including publicly available data; recording such that subjects cannot readily be identified and the investigator neither contacts nor re-identifies them; certain HIPAA-regulated uses; and certain federal government-generated data
(d)(5) Public benefit and service programs	Federal research and demonstration projects studying or evaluating public benefit or service programs, procedures for obtaining benefits, or possible changes to them	The federal department or agency must publish the project on a publicly accessible list before the human subjects research commences
(d)(6) Taste and food quality evaluation	Taste and food quality evaluation and consumer acceptance studies	Only for wholesome foods without additives, or foods containing an ingredient/agricultural chemical/environmental contaminant at or below a level found safe by FDA, EPA or USDA’s Food Safety and Inspection Service
(d)(7) Storage or maintenance for secondary research (requires broad consent)	Storing or maintaining identifiable private information or identifiable biospecimens for potential future secondary research use	Requires broad consent plus limited IRB review making the determinations at 46.111(a)(8). New in the 2018 revision
(d)(8) Secondary research use (requires broad consent)	The secondary research use itself, of identifiable private information or identifiable biospecimens	Requires broad consent obtained under 46.116, documentation under 46.117, limited IRB review under 46.111(a)(7) including a finding that the research is within the scope of the broad consent given, and that returning individual results to subjects is not part of the study plan. New in the 2018 revision

Three structural points about the exemptions that the category list alone does not show, all set out at § 46.104(a)–(b):

Exempt is not unregulated. An exempt activity is still research involving human subjects; it is exempt from the rest of the policy “except that such activities must comply with the requirements of this section and as specified in each category”. Several categories carry conditions, and four of them — (d)(2)(iii), (d)(3)(i)(C), (d)(7) and (d)(8) — route the study back through a limited IRB review.
The exemptions interact with the other subparts. Every exemption may be applied to Subpart B research if its conditions are met. For Subpart C (prisoners) the exemptions do not apply, except for research aimed at a broader population that only incidentally includes prisoners. For Subpart D (children), categories (d)(1), (4), (5), (6), (7) and (8) may apply, (d)(2)(i) and (ii) apply only to educational tests or observation of public behavior where the investigator does not participate in what is observed, and (d)(2)(iii) may not be applied at all.
Nobody self-certifies an exemption. The determination has to be made and documented by an authorised reviewer under institutional policy, not by the research team. See Exempt Human Subjects Research.

The Common Rule vs. FDA’s human-subjects rules (21 CFR 50/56)

The single most common conflation in this space is treating the Common Rule and FDA’s own human-subjects regulations as the same thing. They aren’t, and the difference is structural, not cosmetic: the Common Rule’s trigger is federal funding or conduct (or voluntary institutional extension via a Federalwide Assurance), while FDA’s 21 CFR Part 50 (informed consent) and Part 56 (IRB requirements) are triggered by product jurisdiction — clinical investigations supporting an IND or IDE — regardless of whether any federal grant money is involved. A trial can be Common-Rule-only, FDA-only, or both at once (an NIH-funded IND study, for instance), in which case both regulatory tracks’ consent and IRB requirements apply independently and have to be reconciled. The two sets of rules run substantively parallel on many points but differ in specifics — assent requirements, waiver criteria, and continuing-review mechanics among them. CASRAI’s dedicated comparison covers this point by point rather than repeating it here: 45 CFR 46 vs. 21 CFR 50: How the Common Rule and FDA’s Human-Subjects Regulation Differ.

How 45 CFR 46 became a regulation: 1974, 1981, 1991, 2018

A recurring question — and a recurring exam item in human-subjects training — is when 45 CFR 46 was raised to regulatory status. The answer is 1974. Before that, protections for human subjects in HHS-funded research existed as departmental policy, which is a materially weaker instrument: policy binds through the terms of an award, whereas a regulation codified in the Code of Federal Regulations binds as law and carries the enforcement and rulemaking machinery that goes with it. The 2017 Federal Register final rule states the sequence plainly: “The Department of Health, Education, and Welfare first published regulations for the protection of human subjects in 1974, and the Department of Health and Human Services (HHS) revised them in the early 1980s. During the 1980s, HHS began a process that eventually led to the adoption of a revised version of the regulations by 15 U.S. federal departments and agencies in 1991.”

Four dates carry the whole history:

1974 — regulatory status. The Department of Health, Education, and Welfare (HEW, HHS’s predecessor) published the human-subjects protections as regulations at 45 CFR 46 for the first time. This is the year meant by “45 CFR 46 was raised to regulatory status.” The same year, Congress passed the National Research Act, which created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research — the body that went on to produce the Belmont Report in 1979.
1981 — the first major revision. HHS amended the basic policy in light of the National Commission’s recommendations, including the Belmont Report’s framework (46 FR 8366, 26 January 1981).
1991 — the Common Rule proper. The revised Subpart A was adopted, in materially identical form, by 15 federal departments and agencies at once (56 FR 28002, 18 June 1991). It is this simultaneous multi-agency adoption — not the 1974 or 1981 text — that earned the name “the Common Rule.”
2018 — the Revised Common Rule. The current text was published on 19 January 2017 (82 FR 7149) and reached general compliance on 21 January 2019, which is why the regulation itself calls this body of text the “2018 Requirements” and the previous text the “pre-2018 Requirements.” The regulation defines both terms at 46.101(l).

Two things follow from that chronology that matter when you are reading an older document. First, the Belmont Report (1979) came after 45 CFR 46 already existed as a regulation, not before it — Belmont supplied the ethical framework that the 1981 revision then built into the regulatory text, and 46.101(c) still points back to it as the standard against which agency heads exercise judgement about coverage. Second, section numbering has moved twice, so a citation from a pre-2019 SOP or training deck can point at the right regulation and the wrong subsection: the definitions section is the most affected, and the transition provisions themselves are set out at 46.101(l).

The 2018 Revised Common Rule: what actually changed

The most recent substantive revision to Subpart A (the “2018 Requirements,” sometimes called the Revised Common Rule) reached general compliance on January 21, 2019, though three specific burden-reducing provisions became available to institutions earlier, from July 19, 2018. It changed several concrete things:

Continuing review scaled back, not eliminated. Annual re-review is no longer required for most minimal-risk research reviewed through the expedited procedure, or for studies that have progressed to the point where the only remaining activity is analysis of already-collected identifiable data/biospecimens or obtaining follow-up clinical data. Continuing review still applies elsewhere — this is a scope reduction, not a blanket removal. See IRB Continuing Review: What It Covers and When It’s Required.
Broad consent introduced as a new pathway. Broad consent (45 CFR 46.116(d)) lets researchers obtain a single, one-time consent covering the future storage, maintenance, and secondary research use of identifiable private information or identifiable biospecimens, as an alternative to either study-specific consent or a full waiver. It did not exist as a regulatory category before this revision. See Broad Consent Under 45 CFR 46.116(d) and Waiver of Informed Consent (46.116(f)) for how the two pathways differ.
Exempt categories expanded and clarified — the regulation now enumerates eight exempt categories rather than the previous six, and two of the newer categories (7 and 8, both involving storage/secondary use of identifiable data or biospecimens) specifically require broad consent as a condition of the exemption. An exemption determination still has to be made by an authorized reviewer — it is never self-certified by the research team. See Exempt Human Subjects Research.
A single-IRB requirement for multi-site cooperative research (45 CFR 46.114) was added, requiring domestic sites in qualifying multi-site studies to rely on one IRB of record rather than each site’s own local IRB, subject to enumerated exceptions. Its compliance date (January 20, 2020) trailed the rest of the revision. This is the same general concept behind NIH’s separate, earlier single-IRB policy for its own multi-site awards. See Central IRB / Single IRB (sIRB).

What stayed the same: the core two-part “research” plus “human subject” jurisdictional test, the Subpart B/C/D population-specific protections (the 2018 revision made only technical, conforming renumbering changes there — HHS’s own summary states no substantive change to which populations each subpart covers), and the general architecture of IRB review itself.

Common misconceptions, cleared up

“The Common Rule and 45 CFR 46 are the same thing.” Not quite — the Common Rule is Subpart A. 45 CFR 46 also includes Subparts B, C, D, and E, which are HHS-specific rather than commonly adopted across agencies.
“Exempt means no oversight.” An activity that qualifies for an exempt category under 46.104 is still presumed to be research meeting the human-subjects test; it is simply exempt from full IRB review requirements. It still needs a documented exemption determination from an authorized reviewer, and two of the newer exempt categories require broad consent.
“FDA-regulated trials follow the Common Rule.” They follow 21 CFR 50/56, which runs in parallel to, not underneath, the Common Rule. See the comparison linked above.
“Continuing review was eliminated in 2018.” It was narrowed for specific categories (minimal-risk expedited research, and studies in an analysis-only or follow-up-only phase), not removed as a general requirement.

Frequently asked questions

What is 45 CFR 46?

45 CFR 46 is the HHS regulation governing protection of human subjects in research, organized into five subparts (A–E) covering the general framework plus additional protections for pregnant women/fetuses/neonates, prisoners, and children, and IRB registration requirements.

What is the Common Rule?

The Common Rule is Subpart A of 45 CFR 46 — the general human-subjects protection policy that HHS and roughly a dozen other federal departments and agencies each separately adopted, in materially identical form, in 1991.

Is the Common Rule the same as 45 CFR 46?

No. The Common Rule is specifically Subpart A. 45 CFR 46 as a whole also includes Subparts B, C, D, and E, which are HHS-specific rather than commonly adopted across agencies.

Does the Common Rule apply to FDA-regulated clinical trials?

Not by itself. FDA-regulated research follows 21 CFR Parts 50 and 56, triggered by product jurisdiction rather than federal funding. A study can be subject to the Common Rule, FDA’s rules, or both simultaneously, in which case both sets of requirements apply independently.

What changed in the 2018 Revised Common Rule?

Four substantive changes: continuing review was scaled back for certain minimal-risk/expedited and analysis-only research; broad consent was introduced as a new consent pathway for secondary use of identifiable data and biospecimens; exempt categories were expanded from six to eight, with two requiring broad consent; and a single-IRB requirement was added for multi-site cooperative research.

Who has to register an IRB under Subpart E?

Any institution operating an IRB that reviews HHS-conducted or HHS-supported human subjects research must register that IRB with OHRP before it can be designated under the institution’s Federalwide Assurance. Registration is filed by the institution and is effective for three years.

45 CFR 46 and the Common Rule: What Each Subpart Covers

Ask about 45 CFR 46 and the Common Rule: What Each Subpart Covers