The Code of Federal Regulations is a compendium of the general and permanent rules and regulations published in the Federal Register by the federal executive departments and agencies. The CFR is divided into 50 titles that represent broad areas subject to Federal regulations. Title 45 CFR encompasses regulation of Public Welfare. Title 21 CFR is administered by the FDA and covers regulations of Food and Drugs. Title 45 CFR 46 (The Common Rule) is a core set of regulations defining protection of Human Subjects in clinical research. 45 CFR part 46 includes four subparts:
- Subpart A, also known as the Federal Policy or the “Common Rule”
- Subpart B, additional protections for pregnant women, human fetuses and neonates
- Subpart C, additional protections for prisoners
- Subpart D, additional protections for children
Through a system of IRB registration and assurances, HHS regulations require institutions to commit to compliance with 45 CFR 46 before initiating participation in HHS-conducted or -supported research involving human subjects. The main elements of the Common Rule include: What human research issues are addressed in 45 CFR part 46? HHS regulations at 45 CFR part 46 stipulate substantive and procedural requirements for investigators and institutions engaged in HHS-supported or -conducted research. Specifically, in addition to providing definitions and information about application of the regulations, specific sections of the regulations address the following topics:
- Assuring compliance with the regulations (46.103)
- Institutional Review Board (IRB) membership (46.107)
- IRB functions and operations (46.108)
- IRB review of research (46.109)
- Expedited review procedures for certain kinds of research involving no more than minimal risk, and for minor changes in approved research (46.110)
- Criteria for IRB approval of research, including minimizing risk, ensuring confidentiality, and protecting vulnerable populations, (46.111)
- Review by institution (46.112)
- Suspension or termination of IRB approval of research (46.113)
- Cooperative research (46.114)
- IRB records (46.115)
- General requirements for informed consent (46.116)
- Documentation of informed consent (46.117)
- Applications and proposals lacking definite plans for involvement of human subjects (46.118)
- Research undertaken without the intention of involving human subjects (46.119)
- Evaluation and disposition of applications and proposals for research to be conducted or supported by a Federal Department or Agency (46.120)
- Use of Federal funds (46.122)
- Early termination of research support: Evaluation of applications and proposals (46.123)
- Conditions (46.124)
Additional protections for specific populations have been adopted by HHS (and other departments and agencies to a lesser extent), as follows:
- Subpart B, Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research
- Subpart C, Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as Subjects
- Subpart D, Additional Protections for Children Involved as Subjects in Research
Since 1991, 45 CFR 46 was formally adopted by more than a dozen other Departments and Agencies that conduct or fund research involving human subjects. The Department of Veterans Affairs promulgated this same rule at 38 CFR 16. Today, this Federal Policy is shared by 17 Departments and Agencies, representing most, but not all, of the federal Departments and Agencies sponsoring human-subjects research.
Title 21 CFR: The FDA regulations (Title 21 CFRs) are applicable when research is being conducted to develop a medical product that will be licensed for sale in the United States. Certain federally sponsored and privately sponsored research is subject to the regulations of the FDA according to 21 CFR 50 and 56. Title 21 CFR 50 defines regulations for informed consent and 21 CFR 56 defines regulations for IRBs. These regulations largely overlap but are not identical with the Common Rule. Investigators need to know both sets of regulations to apply them appropriately. Title 21 CFR 312 details the regulations for human research done with investigational drugs. This Title includes, but is not limited to, the regulations for applying to FDA to conduct research under an Investigational New Drug (IND) application (21 CFR 312 Subpart B), responsibilities of Sponsors and Investigators under an IND (21 CFR 312 Subpart D), and expanded access to Investigational Drugs (21 CFR 312 Subpart I). The IND and IDE Submissions section of this guidebook discusses the drug development process in more detail. Title 21 CFR 812 details the regulations for human research with investigational devices. The regulations lay out the framework for applying to FDA to conduct human subjects research with Investigational Devices (21 CFR 812 Subpart B), responsibilities of Sponsors (21 CFR 812 Subpart C) and Investigators (21 CFR 812 Subpart E), and IRB approval 21 CFR 812 Subpart D). The IND and IDE Submissions section of this guidebook discusses the drug development process in more detail.