2.1 FDA vs. HHS Governance & 45 CFR Part 46

2.1 FDA vs. HHS Governance & 45 CFR Part 46

Introduction to Federal Governance in Clinical Research

The oversight of human subjects research in the United States is structured around federal executive departments and their specific administrative codes. At the cabinet level, the Department of Health and Human Services (HHS) serves as the principal agency for protecting the health of all Americans and providing essential human services. The Food and Drug Administration (FDA) is an operating division under HHS. However, despite sharing the same parent department, the FDA and other HHS agencies operate under distinct statutory frameworks and administrative regulations.

HHS-funded or HHS-conducted research is governed by the Office for Human Research Protections (OHRP) under Title 45 of the Code of Federal Regulations, Part 46 (45 CFR Part 46). In contrast, clinical investigations involving products regulated by the FDA—regardless of funding source—are governed by the FDA under Title 21 of the Code of Federal Regulations (specifically 21 CFR Part 50 for Informed Consent and 21 CFR Part 56 for Institutional Review Boards). Understanding the overlapping jurisdictions, regulatory differences, and historical foundations of these two frameworks is a core requirement for the Certified Clinical Research Professional (CCRP) exam.

The Common Rule (45 CFR Part 46 Subpart A)

The Common Rule is the popular term for the Federal Policy for the Protection of Human Subjects, codified under 45 CFR Part 46 Subpart A. Originally adopted in 1991 and substantially revised in 2018 (often referred to as the Revised Common Rule), it represents a baseline ethical and administrative standard that has been adopted by approximately 20 federal departments and agencies (including the Department of Defense, Department of Veterans Affairs, and National Science Foundation). The Common Rule outlines requirements for:

1. The establishment, composition, and operations of Institutional Review Boards (IRBs).
2. The mandatory elements and process of obtaining Informed Consent.
3. Categories of research that are exempt from the regulation.
4. Requirements for institutional compliance, through the Federalwide Assurance (FWA) agreement.

While the FDA is an agency under HHS, it has historically not been a full signatory to the Common Rule because its statutory authority derives from the Federal Food, Drug, and Cosmetic Act (FD&C Act), which imposes unique requirements on product-safety trials. Nevertheless, the 21st Century Cures Act of 2016 mandated that the FDA harmonize its regulations with the Common Rule to the extent possible, reducing administrative burdens while maintaining subject protections.

Structure and Subparts of 45 CFR Part 46

45 CFR Part 46 is divided into five distinct subparts, each providing protections for specific populations or establishing administrative requirements:

• Subpart A (The Common Rule): Establishes the core requirements for IRB review, informed consent, and institutional assurance that apply to all human subjects research funded or conducted by HHS.
• Subpart B (Pregnant Women, Human Fetuses, and Neonates): Provides additional safeguards for research involving pregnant women, fetuses, and neonates. It requires that research first be conducted on animals and non-pregnant humans whenever possible, and mandates that the risk to the fetus be minimized. Consent requirements are highly specific: if the research holds the prospect of direct benefit to the pregnant woman and fetus, or if the risk to the fetus is minimal, maternal consent alone is sufficient. However, if the research holds the prospect of direct benefit solely to the fetus, then the consent of both the mother and the father must be obtained, unless the father is unavailable, incompetent, or in cases of rape or incest.
• Subpart C (Prisoners): Establishes strict protections for prisoners due to their vulnerability to coercion or undue influence in a closed environment. Under Subpart C, the IRB must include at least one member who is a prisoner representative (someone with appropriate background and experience to represent the interests of prisoners). Furthermore, the IRB can only approve research in one of four highly narrow categories: (1) study of the possible causes, effects, and processes of incarceration; (2) study of prisons as institutional structures or prisoners as incarcerated persons; (3) research on conditions particularly affecting prisoners as a class; or (4) research on practices that have the intent and reasonable likelihood of improving the health or well-being of the subjects.
• Subpart D (Children): Outlines additional safeguards for research involving children. It establishes four categories of permissible research based on the level of risk and prospect of direct benefit:
  1. Section 46.404: Research not involving greater than minimal risk. Requires the permission of at least one parent and the assent of the child.
  2. Section 46.405: Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects. Requires the permission of at least one parent and child assent.
  3. Section 46.406: Research involving greater than minimal risk and no prospect of direct benefit, but likely to yield generalizable knowledge about the subject's disorder or condition. Requires the permission of both parents (unless one is deceased, unknown, incompetent, or not reasonably available) and child assent.
  4. Section 46.407: Research not otherwise approvable but presenting an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children. Requires review by an HHS panel of experts and the permission of both parents.
• Subpart E (IRB Registration): Establishes the requirement for all IRBs reviewing HHS-supported human subjects research to register with HHS through the OHRP system.

Key Differences: 21 CFR (FDA) vs. 45 CFR (HHS)

While both sets of regulations aim to protect human subjects, their differences stem from their differing regulatory scopes. HHS regulations apply based on the funding source (research conducted or supported by HHS), while FDA regulations apply based on the use of a regulated product (investigational drugs, biological products, or medical devices in human subjects), regardless of funding.

Informed Consent Waivers and Harmonization

A primary historic distinction between 45 CFR 46 and 21 CFR 50 is the ability to waive or alter informed consent.

• HHS (45 CFR 46.116): Allows an IRB to waive or alter elements of informed consent for research that involves no more than minimal risk, cannot practicably be carried out without the waiver, will not adversely affect the rights and welfare of subjects, and provides subjects with additional pertinent information after participation when appropriate.
• FDA (21 CFR 50): For decades, the FDA did not allow IRBs to waive informed consent for minimal risk research, except in highly restricted circumstances: emergency use (21 CFR 50.23) and emergency research where consent is not possible (21 CFR 50.24). However, in December 2023, the FDA issued a final rule (effective January 22, 2024), adding 21 CFR 50.22. This section aligns with the Common Rule, allowing an IRB to waive or alter informed consent for clinical investigations that present no more than minimal risk to the human subjects, provided the investigation could not practicably be carried out without the waiver and the waiver does not adversely affect the rights and welfare of the subjects. This represents a significant step in regulatory harmonization.

IRB Composition and Emergency Research

Under 45 CFR 46, an IRB must evaluate research within its institutional scope, and there are no requirements for emergency treatment use since HHS does not regulate product marketing. The FDA, under 21 CFR Part 56, allows for emergency IRB reviews under specific circumstances and has detailed regulations regarding the clinical investigator's control of investigational products.

Detailed Comparison Table

Clinical research coordinators and monitors must be vigilant in identifying which regulations apply to a study. If a clinical trial is evaluating an investigational drug (FDA-regulated) and is funded by the National Institutes of Health (NIH, an HHS agency), both 21 CFR and 45 CFR apply. In cases of conflict, the regulation that is more protective of the human subjects must be followed.