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July 27, 2011

HHS and OSTP Publish ANPR to Improve Rules Protecting Human Health Research Subjects

The ACTA Group

On July 26, 2011, the Office of the Secretary of the Department of Health and Human Services (HHS), in coordination with the Office of Science and Technology Policy (OSTP), issued an advance notice of proposed rulemaking (ANPR) to request comment on how current regulations for protecting human subjects who participate in research might be modernized and revised to be more effective. The ANPR seeks comment on how to protect better human subjects who are involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. Comments are due September 26, 2011. More information about the ANPR is available online.

In 1991, HHS and 14 other federal departments and agencies adopted a uniform set of rules for the protection of human subjects, the “Common Rule,” identical to Subpart A of 45 C.F.R. Part 46. The Common Rule requires that federally funded investigators in most instances obtain and document the informed consent of research subjects, and describes requirements for institutional review board (IRB) membership, function, operations, research review, and recordkeeping. The regulations also delineate criteria for, and levels of, IRB review. Currently, except for human subjects research that is determined to be exempt from the regulations, federally funded research involving human subjects is reviewed by an IRB in one of two ways: (1) by a convened IRB; or (2) through an expedited review process.

The ANPR notes that the Common Rule was developed when research was predominantly conducted at universities, colleges, and medical institutions, and each study generally took place at only a single site. Although the regulations have been amended over the years, they have not kept pace with the evolving human research enterprise, the proliferation of multi-site clinical trials and observational studies, the expansion of health services research, research in the social and behavioral sciences, and research involving databases, the Internet, and biological specimen repositories, and the use of advanced technologies, such as genomics. The National Bioethics Advisory Commission (NBAC) published a 2001 concluding report that made 30 recommendations addressing areas including the scope and structure of the oversight system, the level of review applied to research, emphasizing the informed consent process, documentation and waiver of informed consent, protecting privacy and confidentiality, adverse event reporting, and review of cooperative or multi-site research studies. According to the ANPR, NBAC’s recommendations are one source for the revisions currently being considered.

HHS and OSTP propose changes to the following seven aspects of the current regulatory framework. According to the ANPR, the fundamental goal is to enhance the effectiveness of the research oversight system by improving the protections for human subjects while also reducing burdens, delays, and ambiguity for investigators and research subjects. The ANPR requests comment on 74 specific questions concerning:

  1. Refinement of the existing risk-based regulatory framework;
  2. Utilization of a single IRB review of record for domestic sites of multi-site studies;
  3. Improvement of consent forms and the consent process;
  4. Establishment of mandatory data security and information protection standards for all studies that involve identifiable or potentially identifiable data;
  5. Establishment of an improved, more systematic approach for the collection and analysis of data on unanticipated problems and adverse events;
  6. Extension of federal regulatory protections to all research, regardless of funding source, conducted at institutions in the U.S. that receive some federal funding from a Common Rule agency for research with human subjects; and
  7. Improvement in the harmonization of regulations and related agency guidance.

HHS and OSTP recognize that the ANPR “is both lengthy and detailed,” but the level of detail “reflects the importance and types of changes that have been proposed by the Institute of Medicine (IOM), NBAC, and other commentators and are now being considered for adoption.” HHS and OSTP seek comment on these proposals and on the broader question of how to modernize, simplify, and enhance the current system. HHS and OSTP intend to revise the Common Rule, recognizing that other laws and regulations, such as the other subparts of the HHS human subjects protection regulations (Subparts B, C, and D, which deal with particular populations of vulnerable subjects, and Subpart E of 45 C.F.R. Part 46), Food and Drug Administration regulations, and the Health Insurance Portability and Accountability Act Privacy Rule most likely will be affected and will need to be harmonized, as appropriate, with any regulatory changes made to the Common Rule.

HHS and OSTP state they will take into account the deliberations of the Presidential Commission for the Study of Bioethical Issues, as well as consider public comments received on the request for information that the Commission issued on March 2, 2011, that sought public comment on the current federal and international standards for protecting the health and well-being of participants in scientific studies supported by the federal government.


At first glance, the notice seems daunting as it asks for comments on 74 questions related to human research studies. The most benign observation is that the notice, as it states, is an attempt to modernize, coordinate, and to some extent unify the rules of engagement for conducting human subjects research. A less generous assessment might view asking for comment on 74 questions in an ANPR as an indication that the Agency in question is aiming a wide range of questions to engender extensive and detailed comments with the hope that something resembling consensus and guidance on complex issues might emerge.

The attempt to modernize the requirements and have a more “uniform” set of procedures across research activities also runs some risk that uniformity will cause unintended consequences. “One size fits all” requirements may not always capture all future needs while eliminating some elements of flexibility, perhaps presently unrecognized, allowed under current requirements. EPA’s pesticide program imposed new requirements for research involving human subjects, and while it was originally designed to focus on a relatively narrow set of research activities, it now confounds attempts to gather research on a wide range of studies which in some cases are far removed from the kinds of research which were the original controversy. In that case, the original controversy involved research where humans were fed calibrated doses of pesticides; the resulting regulations now apply to consumer preference studies where consumers might be asked about their fragrance preference to a toilet bowl cleaning and disinfectant product. Observational studies of pesticides, once thought of as non-controversial, are now subject to extensive and newly imposed requirements.

The HHS ANPR invites comments on, among other things, how to exempt research from certain procedures and how to define minimum risk studies — topics presumably searching for comment to avoid similar pitfalls. At the same time, the reach of the federal government is wide, and blanket requirements at a minimum may impose new and formal procedures on some areas of research which before now has not seemed to need much additional scrutiny or formal review procedures. So here again, unintended consequences could be imposed on areas of research not seen as needing much current review, including raising the cost of testing, extensive administrative record-keeping requirements, or muddling of how to apply new requirements when assessing past studies — as it was in the case of EPA’s pesticide program.