45 Cfr 46Edit

45 Cfr 46, commonly known as the Common Rule, is the cornerstone federal framework governing the protection of human subjects in research conducted or funded by the U.S. Department of Health and Human Services and many other agencies. It sets the standards for informed consent, risk assessment, and independent oversight through Institutional Review Board review. The rule covers a wide range of research activities, from university medical trials to industry-sponsored studies, and it shapes how researchers design, conduct, and report findings while aiming to prevent harm and protect participant autonomy. Over time, 45 Cfr 46 has evolved to address new research methods, such as the use of biospecimens and secondary data analysis, while seeking to keep the regulatory burden in line with the real-world risks involved.

Introductory note: the regulation is not a single barrier to innovation, but a calibrated set of protections that seeks to preserve trust in science, encourage rigorous methods, and avoid coercive or deceptive practices. Critics of overregulation argue that excessive compliance costs or bureaucratic delay can slow important medical advances, while proponents insist that robust safeguards are essential to maintain public confidence and prevent abuses. The balance between safety and progress is a recurring theme in discussions about 45 Cfr 46, and the formulation of exemptions, oversight intensity, and consent requirements remains a live area of policy debate.

History and background

The roots of the current framework lie in the Belmont Report, which articulates the ethical principles of respect for persons, beneficence, and justice. These principles form the moral core of human-subject protections. See Belmont Report.
The National Research Act of 1974 established the modern system of protections and created the institutional review structure that would later be codified in federal regulations. See National Research Act.
In 1981, the protections for human subjects were codified as 45 Cfr 46, providing a unified baseline across federal agencies for informed consent, risk assessment, and IRB oversight. See 45 CFR 46.
Subparts B, C, and D were added to address the protection of vulnerable populations—pregnant women, fetuses and neonates; prisoners; and children—so that research involving these groups would receive heightened safeguards. See Subparts B–D of 45 CFR 46.
A major modernization occurred with the 2018 Final Rule, which revised several exempt categories, clarified consent disclosures, and adjusted continuing review and other administrative requirements. The updates were designed to reduce unnecessary burdens while preserving core protections. See 2018 Common Rule amendments.
Since then, agencies have continued to implement and occasionally adjust the rule in response to evolving research methods, data practices, and privacy concerns. See Common Rule.

Structure and key provisions

Scope and definitions

45 Cfr 46 defines who and what is covered, focusing on human subjects—individuals about whom researchers obtain data through intervention or interaction, or who provide identifiable private information. The regulation also covers the conditions under which research can proceed using identifiable information or biospecimens. See human subject and identifiable private information.

Subpart A: Federal policy for the protection of human subjects

Subpart A establishes the overarching policy and basic protections applicable to most federally supported research. It sets the framework for how consent, risk assessment, and review should be performed and how protections align with the ethical principles in the Belmont Report.

Informed consent

Informed consent is central to the framework and requires that participants receive information about the research in language they can understand, along with disclosure of risks, benefits, and the voluntary nature of participation. Certain elements must be present, and under some circumstances consent can be waived or altered, or a broad consent approach may be used for future use of data or specimens. See informed consent and broad consent.

Exemptions and expedited review

The rule outlines categories under which research may be exempt from full IRB review or may undergo expedited review due to minimal risk. These exemptions are designed to avoid unnecessary regulatory burden on low-risk research while preserving protections for higher-risk activities. See Exempt research and Expedited review.

IRB review, continuing review, and records

IRBs assess research protocols, consent processes, and risk mitigation measures. They approve, require modifications, or disapprove proposed studies. Some studies require continuing review, while others are allowed to proceed with a one-time approval. See Institutional Review Board and continuing review.

Subparts B–D: Additional protections for vulnerable populations

Subpart B provides protections for pregnant women, fetuses, and neonates.
Subpart C provides protections for Prisoners.
Subpart D provides protections for Children. These sections require additional safeguards and restrictions to ensure that participation is appropriate and voluntary for populations that may be more susceptible to coercion or undue influence. See Pregnant women; Prisoners in research; Children in research.

Assurances, records, and enforcement

Institutions engaged in federally supported research typically file an Assurance (federal regulation) with the relevant federal department, establishing their commitment to comply with the protections. Compliance is overseen by the OHRP and, in many cases, violations can lead to corrective actions, funding consequences, or other enforcement measures. See Assurance and OHRP.

Privacy, data security, and data sharing

In modern research, protecting participant privacy intersects with the HIPAA and with data governance practices. Researchers must consider how de-identified data, deidentification methods, and consent for data reuse fit within 45 Cfr 46, particularly for secondary research using identifiable information or biospecimens. See HIPAA and Biospecimens.

Interplay with other laws and agencies

While 45 Cfr 46 covers a broad swath of federally funded research, other statutes and regulations—such as those governing clinical trials, biosafety, or privacy—may impose additional requirements. In practice, this means researchers often navigate a nexus of rules across federal agencies and state laws. See Common Rule and 21 CFR 50 for contrast.

Practical implications

For researchers: The rule requires careful design of consent materials, risk assessment, and documentation. It also calls for appropriate IRB oversight, training, and record-keeping. See Institutional Review Board and informed consent.
For institutions: Compliance programs, CITI training for researchers, and formal Assurance (federal regulation) processes are standard parts of the research infrastructure. See Assurance.
For participants: The protections emphasize autonomy, understanding, and voluntary participation, with mechanisms to withdraw consent and to understand potential risks. See informed consent.
For privacy and data: The rule interacts with privacy protections in HIPAA and with data governance practices, especially in studies using secondary data or biological materials. See HIPAA and Broad consent.

Controversies and debates

Balancing protection and progress: A central debate concerns whether the regulatory framework stifles innovation or sufficiently safeguards participants. Proponents insist that robust oversight builds trust, improves study quality, and prevents harm; critics argue that excessive compliance costs and administrative hurdles slow essential research, particularly in fast-moving fields like genomics or data science.
Exemptions and data use: Critics of broad data use rules fear underprotected privacy or insufficient consent for secondary analysis. Proponents argue that exemptions are a rational, risk-based tool that prevents regulatory creep for low-risk research while preserving protections for higher-risk studies. See Exempt research and Broad consent.
Consent complexity: Some observers contend that consent forms have become unwieldy and confusing, potentially undermining truly informed decisions. Others argue that clarity about risks and rights is essential, especially when dealing with identifiable information or vulnerable populations. See informed consent.
Protection of vulnerable populations: Subparts B–D aim to avoid exploitation, but debates persist about whether these protections are appropriately calibrated for modern research contexts, including community-based studies and pragmatic trials. See Prisoners in research, Children in research, and Pregnant women in research.
Widespread criticism vs practical safeguards: From a policy perspective, a defensible critique is that rules should focus on actual risk and on evidence of harm, not on symbolic protections. Advocates argue that even low-risk studies can have outsized effects on privacy and autonomy, and thus deserve protection. Critics sometimes describe such criticisms as prioritizing process over outcomes; in this view, the aim is to prevent harm while allowing research to flourish, with oversight that is proportionate to risk. See Common Rule and OHRP.