In 1972, Jean Heller of the Associated Press reported on a 40-year-old research study that had followed black Alabama sharecroppers, some of whom had syphilis. The revelation of deception, withholding of appropriate treatment, and other unethical practices exploded into the Tuskegee scandal. Tuskegee led to the National Research Act of 1974, which authorized the Department of Health, Education, and Welfare (now the Department of Health and Human Services [HHS]) to augment government policies for protecting human research subjects.1 The protections, ultimately codified as 45 Code of Federal Regulations 46 (45 CFR 46), specify requirements for valid institutional review board (IRB) assessment of most human-subjects research and informed consent by research participants.2
In the decade after 1974, specific safeguards were added for pregnant women, fetuses, neonates, children, and prisoners. For instance, research involving prisoners, such as commonly conducted early-phase drug studies, was severely restricted; only research on “possible causes, effects, and processes of incarceration, and of criminal behavior, prisoners as incarcerated persons, [and] . . . conditions particularly affecting prisoners as a class” was permitted. In 1991, many other (though not all) federal departments and agencies adopted the main part of 45 CFR 46 for their human-subjects research, which became known as the Common Rule.
Despite deaths of research participants (including well-publicized cases such as Jesse Gelsinger’s death in a University of Pennsylvania gene-therapy trial), the changing nature of research (e.g., more multisite trials, genetic research, research involving biospecimens), and problems with the regulations and their application, the rules have changed little since 1991.3 Informed-consent documents grow ever longer and consistently exceed the eighth-grade reading level, with wide variation in participants’ comprehension. Researchers have documented unjustified variation in assessments of studies’ risks and benefits. And the review system is inefficient, with numerous IRB reviews for multicenter studies delaying initiation of research for months or years, despite little evidence that multiple reviews enhance protections.
Simply documenting problems, however, is insufficient to catalyze changes in laws or regulations. Concrete solutions must be developed, and then an event such as a scandal or an election can force political action. As health care reform attests, this combination rarely coalesces to generate actual reform.4 Fortunately, in November 2009, while working at the White House Office of Management and Budget, I was able to convene representatives of HHS and other departments to develop reforms to enhance participant protections and make the oversight process more efficient. Those meetings led to an Advance Notice of Proposed Rulemaking in 2011 and release of a Notice of Proposed Rulemaking (NPRM) this September.5 The end of this long process is now in sight.
Proposed Changes to the Common Rule
The proposed changes, though imperfect, are a significant step forward. Six aspects deserve special attention; some would enhance protections, while others would improve efficiency — and in turn enhance protections by focusing resources and attention on studies posing the most serious risks and ethical challenges.
- The proposal applies protections to all clinical trials conducted at U.S. institutions receiving federal funding for human-subjects research.
- Currently, protections apply only to research funded by departments and agencies that have adopted the Common Rule.
- The regulations aim to enhance and streamline the informed-consent process, in part by shortening and focusing informed-consent documents on “essential information that a reasonable person would want to know,” with additional details provided in an appendix.
- Secondary research on biospecimens and identifiable private information originally collected for research, clinical, or other purposes would require informed consent.
- In keeping with extensive empirical research, one-time, general, open-ended consent could be obtained at the time of collection. This approach allows people to decide whether they want their specimens and data used for research but obviates the need for subsequent consent for each project.
- The proposal defines four types of regulatory oversight — delineating the types of research that are excluded (a new category) or exempt, types qualifying for expedited review by a single IRB member because they pose minimal risk, and types requiring full-IRB review.
- Continuing-review requirements would change.
- Excluded and exempt research would still require no continuing review.
- The default for expedited research would be no continuing review — a change — but a study’s reviewer could make a case for continuing review.
- For greater-than-minimal-risk research, a change would mean continuing review could cease once recruitment and experimental interventions were completed and only clinical monitoring of participants and analysis and reporting of research results remained.
- Instead of protocols for multicenter projects being reviewed by each institution’s IRB, all participating U.S. sites would rely on a single IRB review.
- The only exceptions would be for multicenter projects that require multiple IRB reviews by law (e.g., for FDA-regulated device research), research at non-U.S. sites, and cases in which a funding agency chooses to require multiple reviews.