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 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.
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.
Related human-subjects protection topics on CASRAI
Beyond the subpart-by-subpart pages above, these cover the surrounding compliance mechanics in more depth:
- IRB (Institutional Review Board) — the reviewing body itself
- IRB/REC Approval Process: What Needs Review and What Doesn’t
- IRB Application and IRB Approval Cost
- IRB Noncompliance & Unanticipated Problem Reporting
- IRB Certification: Training vs. CIP vs. AAHRPP and CITI Human Subjects Research Training
- Vulnerable Populations Under the Common Rule and Undue Influence & Vulnerable Populations in Research Ethics
- Quality Improvement vs. Human Subjects Research: The IRB Determination
- The Honest Broker Role in De-Identified Data and Secondary Use of Identifiable Data and Biospecimens
- Citizen Science and Human-Subjects Regulation
- NIH Human Subjects Section: A Worked Example and PHS Human Subjects and Clinical Trials Information Form
- Informed Consent in Research, 4 Principles of Informed Consent, Components of Informed Consent, and When Should Informed Consent Be Obtained?
- IRB vs. Ethics Committee: What’s the Difference?
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.
