In a notice of proposed rulemaking (NPRM) released September 2, 2015, the U.S. Department of Health and Human Services (HHS), through the Office for Human Research Protections (OHRP) and 15 other federal departments and agencies, issued long-awaited proposed amendments to the Federal Policy for the Protection of Human Subjects (the Common Rule). HHS’ stated goal of these significant and extensive amendments is to align the Common Rule with changes to the research and privacy landscape since the original Common Rule was promulgated in 1991, and to otherwise strengthen and modernize the Common Rule.

As proposed, the NPRM would materially alter how research is designed and conducted, and would meaningfully change how genomic and tissue-related research is structured. In addition, the Common Rule currently only applies to federally funded or supported research (unless an institution has made an election in its Federalwide Assurance to conduct human subjects research in accordance with the Common Rule regardless of funding). In a meaningful expansion of its jurisdictional scope the NPRM proposes to subject all non-FDA regulated, non-exempted and non-excluded human subjects research, irrespective of funding source for a particular research study, conducted at a U.S. institution that receives federal support for human subjects research generally to the Common Rule. The proposed changes in the NPRM may also have a significant impact on current research and quality assurance practices.

Given the NPRM’s proposal to significantly expand the scope of the Common Rule and the other extensive changes it proposes, the NPRM is of interest to a wide array of stakeholders who need to be aware of HHS’ trajectory on these proposed changes and who should consider participating in submitting public comments regarding the proposed changes. Such comments are due December 7, 2015.

History and Overview of the NPRM

On July 26, 2011, the Office of the Secretary of HHS, in coordination with the Executive Office of the President’s Office of Science and Technology Policy (OSTP), published an advanced notice of proposed rulemaking (ANPRM) that solicited comments regarding modernizing and revising current human subjects protections. 76 Fed. Reg. 44,512 (July 26, 2011). The ANPRM’s proposals for significant changes to the Common Rule prompted strong reactions. Many of the striking proposals discussed in the ANPRM have carried over to the NPRM, and comments submitted in response to the ANPRM and subsequent guidance in related areas have prompted additional new proposals in the NPRM.

The NPRM proposes a series of major changes to the Common Rule, including changes to its overall jurisdictional scope; requirements relating to secondary use of biospecimens and individually identifiable information; and the research review and oversight process. Key changes are summarized below.

• Jurisdiction. As proposed in the ANPRM, the NPRM would extend the Common Rule’s jurisdiction to trials conducted at U.S. institutions receiving federal support for non-FDA (Food and Drug Administration), “non-exempt and non-excluded human subjects research, regardless of the funding source of the specific clinical trial” (emphasis added).

• Regulating biospecimens under the Common Rule. Although the NPRM notes that a majority of the commenters to the ANPRM opposed such a change, the NPRM proposes to include biospecimens in the definition of a “human subject” regardless of whether the biospecimens contain identifiable information, except under very limited circumstances. This requirement would apply only prospectively, and would be delayed in its implementation until three years after the publication of the final rule. Under the current regulations, a biospecimen constitutes a “human subject” if the data annotating that sample is determined to be individually identifiable. The role of identifiability in determining whether use of data or tissue constitutes research involving a human subject is a foundational definitional divide that finds residence not just in the Common Rule, but also in the Health Insurance Portability and Accountability Act (HIPAA) and many state laws. The NPRM’s proposal is a significant departure from this historical mainstay. In describing the change, OHRP suggests that it will balance public preferences for autonomy and will “avoid[] codifying any given interpretation of the quickly evolving debates regarding whether certain analytical results (e.g., decoding the whole genome) should be considered to yield identifiable data.”

  • Alternative proposals for regulating biospecimens. Although the NPRM proposes to define all biospecimen research as human subjects research under the Common Rule, the NPRM also solicits comments on two alternative proposals for how to extend the scope of the Common Rule with respect to biospecimens.

    • One alternative is to change the definition of a “human subject” to specifically include individuals from whom data is generated from whole genome sequencing (WGS). Under this alternative proposal, the Common Rule would apply to any research that would generate WGS data and the use of any of the data generated from WGS, and to secondary research uses of any part of the WGS data (this is referred to as “Alternative A” in the NPRM).

    • Another proposal would classify biospecimens, and certain information generated from biospecimens used in particular technologies (referred to in the NPRM as “bio-unique information”), as relating to a “human subject” for purposes of the Common Rule. Only information derived from specific technologies listed on a newly created “Secretary’s List” would meet the definition of “bio-unique information.” For example, the NPRM notes that if WGS is a technology listed on the Secretary’s List, then WGS research using biospecimens would be subject to the Common Rule as human subjects research, regardless of the researcher’s ability to identify the biospecimen’s source (this is referred to as “Alternative B” in the NPRM). HHS solicits comments regarding the above options for how it would expand the definition of a “human subject.”

• Secondary use of biospecimens and private information. Regulating the secondary research use of biospecimens and private information is also a central focus of the NPRM. “Secondary use” means the use of data or biospecimens for a purpose different from the purpose for which the data or biospecimen was originally created or collected (e.g., using for research tissue samples that were collected for and left over from clinical care). The NPRM points to recent studies showing that most people prefer to have control over secondary uses of their biospecimens and data, and considers “continuing to allow secondary research with biospecimens collected without consent” an “untenable position” that is out of line with most individuals’ wishes.

  • Because, as described above, the NPRM would expand the scope of the Common Rule to include all biospecimens, the NPRM also proposes changes designed to continue to facilitate biospecimen research. In particular, the NPRM proposes to allow researchers to obtain a one-time broad consent for the storage or maintenance of biospecimens (as well as identifiable private information) for secondary research use and for the use of such stored material for subsequent individual research studies. Nonetheless, this consent requirement will likely present a number of operational and record keeping challenges, especially if individuals wish to give consent for some but not all use cases

  • In addition, though the NPRM proposes to consider secondary uses of biospecimens as human subjects research, it also proposes an exclusion applicable to the secondary use of non-identifiable biospecimens for research that generates information already known about the individual. This would include validation tests and research to develop specific diagnostic tests. The NPRM proposes an exemption for the storage or maintenance for secondary research use of properly obtained biospecimens or identifiable private information. This exemption would still be subject to certain requirements, such as certain recordkeeping requirements and compliance with the new proposed privacy requirements. The NPRM also proposes an exemption for research involving the use of biospecimens or identifiable private information that have been specifically stored or maintained to allow for potential future secondary research uses. The NPRM includes another exemption for the secondary research use of some identifiable private information acquired for non-research purposes.

• Informed consent requirements. The NPRM proposes changes to the organization and presentation of information to subjects and the elements of informed consent. The NPRM also adds new elements of consent, which are required for certain types of research. Notably, for research involving the collection of identifiable private information, subjects must be notified if their non-identified information could be used for future research without additional consent. The NPRM would also create a “Secretary’s Template” that researchers could use to collect broad consent from subjects for the secondary research use of biospecimens and identifiable private information. If researchers choose not to use the template, such broad consent must include certain specific elements proposed in the NPRM. Another notable proposal would require consent documents for trials conducted or supported by a Common Rule department or agency to be posted on a publicly available federal website within 60 days after the close of the trial’s recruitment.

• Informed consent waiver criteria. The NPRM proposes a number of changes relating to the requirements for institutional review board (IRB) waiver of the informed consent requirements.

  • Because, as described above, the NPRM would require researchers to obtain informed consent to bank biospecimens for secondary research use (even if the biospecimens are annotated with only de-identified information), the NPRM proposes to impose a new waiver prohibition for IRBs. If an individual was asked and specifically refused to sign a broad consent to allow the storage or maintenance of his/her biospecimens (or identifiable private information) for secondary research uses, IRBs would not be permitted to waive this consent requirement for either the storage or maintenance or for the secondary research use as a way to circumvent that refusal.

  • The NPRM proposes additional new waiver criteria for research involving biospecimens. These criteria would permit IRBs to waive or amend the consent requirement for biospecimen research only in “extremely rare” circumstances, such as when the research “could not be conducted with other biospecimens for which informed consent was or could be obtained.”

  • The NPRM establishes new waiver criteria modeled after the HIPAA Privacy Rule requirements for studies that use identifiable biospecimens or identifiable information in particular. Specifically, the NPRM proposes a requirement that the research “could not be practicably carried out without accessing or using identifiers” (emphasis added). The NPRM also clarifies how HHS interprets the term “practicably” in waiving informed consent for all other research studies (i.e., when the research cannot be practicably carried out without the waiver of consent).

• New exclusion regulations. The NPRM proposes to include a new list of 11 specific activities that would be “excluded” from the Common Rule’s requirements. Such activities include but are not limited to: (i) certain quality assurance or improvement activities involving the implementation of an accepted practice to improve the quality or delivery of health care; (ii) certain activities covered by the HIPAA Privacy Rule; (iii) the secondary research use of non-identifiable biospecimens designed only to generate information about an individual that is already known; and (iv) certain collection and analysis of data and biospecimens for an institution’s own internal operational monitoring and program improvement purposes. In order to qualify as an excluded activity under (iv) above, the data or biospecimen collection and analysis must be either be: (a) limited to the use of data or biospecimens originally collected for a purpose other than the current proposed activity, or (b) obtained through oral or written communications, like surveys or interviews, with individuals.

  • The proposed exclusions are notable for their scope and nature and raise a number of questions. Proposed exclusion category (iv) above is unusual in its incorporation of biospecimen use in activities that otherwise appear to be similar to health care operations activities. This category also appears to cover activities similar to those covered by the quality assurance and improvement exclusion (exclusion (i) above). The quality assurance exclusion, in turn, would not cover the evaluation of the accepted quality assurance or quality improvement practice itself, even if the purpose of the evaluation arguably is not to develop “generalizable knowledge” (i.e., the purpose is not research). It is unclear whether proposed exclusion (iv) is intended to encompass some or all of the evaluation activities that the NPRM carves out of the quality assurance exclusion. Another source of potential confusion is the NPRM’s discussion of the HIPAA Privacy Rule exclusion (exclusion (ii) above), which explicitly references only covered entities and is silent on activities of business associates.

• New exemption regulations and a new exemption tool. The NPRM also proposes to exempt eight categories of research from certain Common Rule requirements and to make available a determination tool to assist researchers in determining whether their trial is exempt. This tool would act as a “safe harbor mechanism”—assuming researchers included correct and accurate information, federal regulators would consider the tool’s determination of exempt status to be appropriate.

• Data security and information protection standards. The NPRM proposes to generally require researchers to “implement reasonable safeguards for protecting against risks to the security or integrity of biospecimens or identifiable private information.” The NPRM proposes several options from which researchers and institutions may choose to satisfy this obligation, including a list of specific measures published by the HHS Secretary, complying with HIPAA as otherwise required of the institution or investigator, and the requirements of other statutes such as the Family Educational Rights and Privacy Act (FERPA). Specific to biospecimens and identifiable private information, OHRP proposes to limit the re-disclosure of biospecimens and identifiable private information that were obtained for research purposes to four specific purposes (such as research regulated under the Common Rule).

• Single IRB / changes to IRB review. Under the proposed rules, all U.S. institutions engaged in cooperative research must rely on a single IRB as their reviewing IRB for that study, with limited exceptions. The NPRM also changes the default for expedited review for minimum risk studies, requiring expedited review unless the reviewers determine the study is more than minimal risk (in contrast with the current requirement, where an IRB may use expedited review only if the reviewer determines the study is no more than minimal risk). The NPRM would also eliminate continuing review for minimal risk studies unless the reviewer documents why continuing review should take place, and for research involving certain secondary research with information and biospecimens.

• Harmonization. The NPRM notes that the FDA intends to modify its separate human subjects protection regulations in light of the NPRM, as appropriate. As seen above, the NPRM also attempts to cross-walk to certain HIPAA standards and concepts. These attempts, however, fall far short of harmonizing the Common Rule with HIPAA’s research-related requirements, and leave many unanswered questions regarding the interaction between these two rules moving forward.