45 CFR 46 Subpart A (Basic HHS Policy for Protection of Human Research Subjects)

45 CFR 46 Subpart A is the Common Rule’s foundational text (§§46.101–46.124), setting HHS’s core definitions, institutional-assurance and IRB-registration requirements, IRB membership rules, the eight exempt research categories, and general informed-consent standards for human-subjects research. Subpart B, Subpart C, and Subpart D each add population-specific protections on top of this Subpart A baseline.

Scope and Applicability (§46.101)

§46.101 sets out which research Subpart A covers: research conducted or supported by HHS, and research otherwise covered by an institution’s Federalwide Assurance (FWA) regardless of funding source, unless a specific exclusion or exemption applies. §46.101(b) lists categories of activities that are not “research” for Common Rule purposes at all (distinct from being exempt research — see below), and §46.101(l) recognizes that some non-HHS federal departments and agencies have separately adopted the Common Rule for their own funded research, extending the same basic framework across the federal government rather than just within HHS.

Core Definitions (§46.102)

Subpart A’s definitions section does the conceptual work the rest of Part 46 depends on:

• Human subject (§46.102(e)) — a living individual about whom an investigator conducting research obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.
• Research (§46.102(l)) — a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge. Several specific activities (e.g. certain scholarly/journalistic activities, public health surveillance, and specific types of criminal-justice or intelligence activities) are excluded from this definition by §46.102(l)(1)-(4).
• Minimal risk (§46.102(j)) — risk where 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 routine physical or psychological examinations or tests. This is the baseline risk threshold used throughout Subpart A and referenced by name in Subparts B, C, and D.

Assurance and IRB Registration (§46.103)

§46.103 requires an institution engaged in covered human-subjects research to hold a written assurance of compliance approved by HHS — in practice, a Federalwide Assurance (FWA) filed with the HHS Office for Human Research Protections (OHRP) — and to register each IRB that reviews research under that assurance. The assurance is institutional, not per-study: it is the mechanism by which an institution commits to Common Rule compliance across its covered research portfolio, and it is a precondition for an IRB to have legal authority to approve research under Subpart A.

The Eight Exempt Research Categories (§46.104)

The 2018-revised Common Rule sorts certain lower-risk research into eight exempt categories at §46.104. “Exempt” does not mean unreviewed — most institutions still require some form of administrative determination that a protocol qualifies — it means the research is exempt from the rest of Subpart A’s ongoing IRB-review requirements once that determination is made:

1. Normal educational-practice research in established educational settings that doesn’t adversely affect students’ learning opportunity or educator assessment.
2. Educational tests, survey procedures, interview procedures, or observation of public behavior, where at least one identifiability/risk-limiting criterion at §46.104(d)(2) is met.
3. Benign behavioral interventions (brief, harmless, painless, non-invasive, not likely to cause lasting adverse impact) with adult subjects who prospectively agree, meeting the same identifiability/risk criteria as category 2.
4. Secondary research use of identifiable information or identifiable biospecimens already collected for another primary purpose, where consent for the secondary use is not required (identifiable biospecimens qualify only if publicly available or the research is conducted by/on behalf of a federal agency).
5. Research and demonstration projects conducted or approved by a federal department or agency head to study public benefit or service programs.
6. Taste-and-food-quality evaluation and consumer-acceptance studies meeting specific food-safety conditions.
7. Storage or maintenance of identifiable private information or biospecimens for potential future secondary research, following limited IRB review under §46.111(a)(8).
8. Secondary research use of identifiable private information or biospecimens where broad consent for that storage and secondary use was obtained and documented under §46.116/§46.117.

Categories 7 and 8 (added in the 2018 revision) both depend on a “limited IRB review” — a narrower review focused specifically on privacy and confidentiality protections, not a full §46.111 review — rather than a purely administrative determination.

IRB Membership (§46.107)

§46.107 sets minimum composition requirements for every IRB operating under Subpart A: at least five members with varying backgrounds sufficient to promote complete and adequate review of the research the institution commonly conducts; at least one member whose primary concerns are scientific and at least one whose primary concerns are nonscientific; and at least one member who is not otherwise affiliated with the institution and is not an immediate family member of anyone who is. No member may participate in initial or continuing review of a project in which they have a conflicting interest, except to provide information the IRB requests. IRBs may also invite outside experts to advise on specialized issues, but those consultants may not vote.

IRB Review Criteria and Functions (§46.108-46.111)

§46.108 requires each IRB to follow written procedures for initial and continuing review, for determining which protocols need more than minimal-risk-level scrutiny, and for reporting findings to institutional officials and, where applicable, federal departments or agencies. §46.109 gives the IRB authority to approve, require modifications to secure approval, or disapprove research, and to require progress reports and continuing review at intervals appropriate to the degree of risk (the 2018 revision eliminated mandatory continuing review for many minimal-risk protocols that qualify under §46.109(f)). §46.111 sets the substantive approval criteria — risks minimized and reasonable in relation to anticipated benefits, equitable subject selection, adequate informed consent, and, where subjects are drawn from vulnerable populations, additional safeguards under §46.111(b) — which is the specific criterion Subparts B, C, and D build population-specific conditions on top of.

Informed Consent (§46.116-46.117)

Subpart A’s informed-consent provisions require, among other elements, a statement that the activity involves research, its purposes and procedures, foreseeable risks and benefits, alternatives, confidentiality protections, and compensation/treatment information if injury occurs for more-than-minimal-risk research — organized, since the 2018 revision, behind a required concise “key information” summary at the start of the consent form. §46.117 separately governs documentation of that consent (a signed form, or a waiver of documentation in specific circumstances) — consent and its documentation are regulated separately and a waiver of one does not automatically waive the other. This is covered in more depth in CASRAI’s Informed Consent in Research guide.

How Subpart A Relates to Subparts B, C, and D

Subpart A is not one option among several — it is the mandatory baseline. An IRB applies Subpart A’s §46.111 criteria to every covered protocol first; where the subjects are pregnant women, fetuses, or neonates (Subpart B), prisoners (Subpart C), or children (Subpart D), the IRB then layers that subpart’s additional, population-specific conditions on top. None of the additional-protection subparts substitute for Subpart A review — they add to it. HHS finalized a technical/conforming update (Federal Register document 2024-24399, effective October 24, 2024) that amended Subparts B, C, and D for alignment with the 2018-revised Common Rule without changing which populations each subpart covers.

Frequently Asked Questions

Is Subpart A the same thing as “the Common Rule”?

In everyday usage, yes — Subpart A is the section most people mean when they say “the Common Rule.” Formally, 45 CFR 46 as a whole (Subparts A through D) is the HHS codification, and other federal departments/agencies that have adopted the Common Rule have their own, textually identical or near-identical, codifications of the same Subpart A language. See CASRAI’s Common Rule (45 CFR 46) entry for the broader policy history, including the 2018 revision.

Does Subpart A apply to research with no federal funding at all?

Only if the conducting institution has voluntarily extended Common Rule coverage to that research through its own policy. By its own terms, §46.101 ties Subpart A’s applicability to HHS-conducted/funded research and research otherwise covered by an institution’s FWA; institutions with an FWA commonly choose, as internal policy, to apply the same standards to some or all of their unfunded human-subjects research, but that is an institutional choice layered on top of the regulation, not a requirement of §46.101 itself.

If a protocol qualifies for one of the eight exempt categories, does it need any IRB involvement at all?

Usually some administrative determination is still required — most institutions do not let investigators self-certify exemption — and categories 7 and 8 specifically require a “limited IRB review” focused on privacy/confidentiality protections rather than a full §46.111 review. Exemption removes the protocol from Subpart A’s ongoing full-review and continuing-review requirements; it does not mean no one at the institution ever looked at it.

See also: Common Rule (45 CFR 46), the umbrella term this page’s specific citations sit under; 45 CFR 46 Subpart B and 45 CFR 46 Subpart D, the sibling population-specific subparts; Vulnerable Populations in Research; OHRP (Office for Human Research Protections), the HHS office that administers and interprets the Common Rule; Federalwide Assurance (FWA); and the IRB/REC Approval Process guide for how §46.111 review works in practice.