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On September 8, 2015, the Department of Health and Human Services proposed significant revisions to the Federal Policy for the Protection of Human Subjects (“Common Rule”’ Background of NPRM
In 1991, HHS developed’s research and medical data. In addition, the number of biospecimen repositories and large clinical databases has risen dramatically. Research is also expanding in geographic scope, with studies often conducted at multiple domestic and international sites and across research networks. Further, new technologies, including genomic sequencing, are rapidly increasing the data to which investigators have access.
As the nature of research has evolved, so have the types of risks and benefits associated with such research. Large numbers of studies no longer involve direct interaction with research subjects themselves, and instead analyze information obtained from medical records, administrative claims data, existing biospecimens stored in repositories, and other data sources. As a result, the risks related to these types of research studies are largely related to privacy and confidentiality, not physical harm.
’s Office of Science and Technology Policy, published an advanced notice of public rulemaking (ANPRM) to request comment on how current regulations for protecting human subjects who participate in research might be modernized and revised to be more effective. HHS received considerable comments on the ANPRM, as discussed in the NPRM, and revised the proposal based, in part, on public input.
The NPRM aims to “better protect human subjects involved in research, ” Significant Proposed Changes to the Common Rule I. Expanding “” to Cover Non-Identified Biospecimens
Currently, the Common Rule applies to the secondary research use of a biospecimen only if the biospecimen is identifiable. The NPRM would expand the Common Rule’s definition of “human subject” so that it covers all research uses of biospecimens, irrespective of whether the biospecimens are identifiable. Consent for the secondary research use of biospecimens could be waived in extremely limited circumstances, but otherwise would have to be study-specific or broadly applicable to future, unspecified research (“”). This particular proposed revision, which was proposed in the 2011 ANPRM, has already elicited strong opposition from many researchers and research associations.
For public comment, the NPRM identifies two alternative approaches, which would expand the definition of “ to include the following: Whole genome sequencing data, or any part of the data generated as a consequence of whole genome sequencing, regardless of the individual identifiability of the biospecimens used to generate such data; or Research use of information produced using a technology applied to a biospecimen that generates information unique to an individual such that it is foreseeable that, when used in combination with publicly available information, the individual could be identified (“). II. Excluded Activities
The NPRM proposes to create a new section of the regulation for research that would be excluded from the Common Rule. The NPRM identifies 11 specific types of excluded activities, some of which are “exempt” under the current Common Rule. Unlike exempt research, “excluded” activities would not be expected to undergo any institutional, administrative or IRB review to determine whether the activity is excluded. Rather, investigators would be responsible for self-determining whether their research is excluded. Even though a research activity may be excluded, the NPRM articulates an expectation that such research still be conducted consistent with the principles outlined in the Belmont Report. The following categories of activities, among others, would be considered “ Activities not considered
Program improvement activities
This category includes data collection and analysis, including the use of biospecimens, for an institution
Public health surveillance
“health care operations,” “public health activities,” or
“do not meaningfully diminish subject autonomy
y to generate information about the person that is already known. This exclusion would include the development and validation of certain tests and assays (such as research to develop a diagnostic test for a condition using specimens from individuals known to have the condition and those known not to have the condition) and quality assurance and control activities. III. Exempt Research
The current Common Rule’s exemption categories continue in the NPRM, either as exemptions or exclusions (and thus not subject to administrative or IRB review). The NPRM proposes an important modification to the exemption regulations to assist investigators and institutions in making timely and accurate exemption determinations – namely, the development by federal departments and agencies of a voluntary “exemption determination tool” or algorithm. If a person puts accurate information about the study into the tool, the tool would indicate whether the study is exempt. Institutions would be able to rely on the use of the federally developed tool as a safe harbor
Low-risk interventions subject only to documentation requirements
The NPRM proposes a new class of exempt research involving benign interventions in conjunction with the collection of data from an adult subject. “Benign interventions” would be brief in duration, harmless, painless, not physically invasive, and not likely to have a significant adverse lasting impact on the subjects. In addition, the investigator would have to have no reason to think the subjects would find the interventions offensive or embarrassing. As examples, the NPRM mentions research activities in which a subject is asked to read materials, review pictures or videos, play online games, solve puzzles, or perform cognitive tasks. The subject would have to prospectively agree to the intervention and data collection, and: (a) the information obtained would have to be recorded in such a manner that human subjects could not be identified directly or through identifiers linked to the subjects; or (b) any disclosure of the human subjects
New basic element of informed consent
Under the NPRM, research with non-identified data would continue to be regarded as not involving “human subjects.” The NPRM thus proposes that a new element of informed consent be required to ensure that subjects are informed of the possibility that identifiers could be removed from collected data, and then the non-identified data could be used for secondary research studies without the Common Rule protections. The new basic element of consent would apply to all research collecting identifiable private information. Based on the investigator
The NPRM also proposes three additional elements of consent that would require that prospective subjects (1) be informed that their biospecimens may be used for commercial profit and whether the subject will or will not share in this commercial profit; (2) be informed whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions; and (3) be provided with an option to consent, or refuse to consent, to investigators recontacting the subject to seek additional information or biospecimens or to discuss participation in another research study. V. Broad Consent to the Storage, Maintenance, and Secondary Research Use of Biospecimens and Identifiable Private Information
Ability to withdraw consent
Public posting of non-identifiable data
To facilitate the use of broad consent, the NPRM proposes that the Secretary of HHS will publish in the Federal Register broad consent templates that would contain all of the required elements of consent. The NPRM notes that at least two broad consent templates would be developed: one for information and biospecimens originally collected in the research context, and another for information and biospecimens originally collected in the non-research context.
While the NPRM regulatory text does not propose to modify “practicably,
Waiver for research involving biospecimens
Additional, more stringent waiver conditions would apply to research involving biospecimens. Specifically, the NPRM proposes that (1) there be compelling scientific reasons” for the research use of the biospecimens; and (2) the research could not be conducted with other biospecimens for which informed consent was or could be obtained. The NPRM proposes that the Common Rule prohibit IRBs from waiving informed consent if individuals were asked and refused to provide broad consent to the storage and maintenance for secondary research use of biospecimens and identifiable private information.
The NPRM also clarifies that waivers of informed consent might not be permitted for research subject to FDA regulation. However, as described in our Ropes
Posting of consent forms
As an additional means of increasing transparency and facilitating the development of more informative informed consent forms, the NPRM proposes that a copy of the final version of the consent form for clinical trials conducted or supported by a Common Rule department or agency would need to be posted on a publicly available Federal website. Within 60 days after the trial closes to recruitment, the awardee or the federal department or agency conducting the clinical trial would be required to post the consent document, the name of the clinical trial and information about whom to contact for additional details about the trial. As the NPRM explains, “[t]he primary purpose of this provision is to improve the quality of consent forms in federally funded research by assuring that—contrary to current practices, under which it is often very difficult to ever obtain a copy of these documents—they eventually would become subject to public scrutiny.
obtained, the requirement to obtain a signed consent form may be waived. The study documents must include a description as to why signing forms is not the norm for the distinct cultural group or community. VII. Cooperative Research
One of the most significant changes proposed by the NPRM is the mandate that all institutions located in the United States engaged in cooperative research rely on a single IRB as their reviewing IRB for that study. The reviewing IRB would be selected by the federal department or agency supporting or conducting the research, or by the lead institution if there is no such funding agency or department. This requirement would not apply to (1) cooperative research for which more than single IRB review is required by law (e.g., FDA-regulated devices); or (2) research for which the federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular study.
The NPRM clarifies that this proposal would not relieve any site of its other obligations under the regulations to protect human subjects. Although a local IRB may conduct its own additional internal review, such a review would not be binding on the local site if not adopted by the single IRB, nor would its terms be enforced by OHRP.
and institutions to implement either: a list published by the Secretary of HHS of specific measures that an institution or investigator can use to meet the requirements, or safeguards that meet the standards in the HIPAA rules. IX. Harmonization of Agency Guidance
The NPRM includes a provision that would require that federal guidance on the requirements of the Common Rule be issued only after consultation, to the extent appropriate, with other Common Rule departments and agencies, if feasible. While FDA is not a Common Rule agency, the preamble specifies that FDA intends to modify its regulations in light of this NPRM, to the extent appropriate, considering its unique statutory framework and regulatory mission. The preamble further states that FDA and OHRP will continue to work together in developing guidance on their respective regulatory requirements that are found both in FDA regulations and in the Common Rule, to the extent feasible. X. Cover Unaffiliated IRBs Not Operated by an Institution Holding a Federalwide Assurance
The NPRM proposes to add a new provision that would authorize Common Rule departments and agencies to enforce compliance directly against unaffiliated IRBs that are not operated by an assured institution. This would address concerns about OHRPs current practice of enforcing compliance with the Common Rule through the institutions that are engaged in human subjects research, even in circumstances when the regulatory violation is directly related to the actions of an external IRB. The NPRM also proposes that the institution and the IRB should establish and follow written procedures identifying the compliance responsibilities of each entity.
uld not be required, unless specifically mandated by the IRB, after the study reaches the stage when it involves either (a) analyzing data (including identifiable private information), or (2) accessing follow-up clinical data from procedures that subjects would undergo as part of standard care for their medical condition or disease. XII. Expedited Review Procedures
The NPRM would allow expedited review to occur for studies on the Secretarys list unless the IRB reviewer(s) determine(s) that the study involves more than minimal risk. This is in contrast to the current Common Rule, which requires that an IRB use the expedited review procedure only if the IRB reviewer determines that the research involves no more than minimal risk. Therefore, this proposed change represents a change in the default position: research included on the Secretarys list only involves minimal risk, unless the IRB makes a determination that the research is actually greater than minimal risk. XIII. IRB Review of Research Plan for Returning Results
As a new criterion for IRB approval, the NPRM provides that if an investigator proposes a research plan for returning clinically relevant results to subjects, the IRB must determine that the plan is appropriate. IRBs do not need to determine whether there should be a plan for returning individual research results. The NPRM recognizes that challenges can arise regarding return of individual research results when it is not clear if the findings have clinical validity or utility, or when the knowledge imparted may cause psychological distress or social harm. XIV. Extend the Common Rule to All Clinical Trials
The NPRM would extend the scope of the policy to cover all “clinical trials,” regardless of funding source, conducted at a U.S. institution that receives federal funding for non-exempt human subjects research. The NPRM defines “” to be a research study in which one or more hum
The NPRM states that the effective date of the final rule will be one year after publication in the Federal Register. The compliance date of the new rules generally would also be one year from the publication of the Final Rule, except for the new rules covering all biospecimens and the mandate of a single reviewing IRB, for which the compliance date would be three years. XVI. Transition Provisions: Use of Prior Collections of Biospecimens
The NPRM states that research involving the use of prior collections of biospecimens is permitted if the biospecimens were collected for either research or non-research purposes before the effective date of the final rule, and the individually identifiable information associated with the biospecimens has been removed. “Legally Authorized Representative”
The preamble of the NPRM seeks comment on the definition of a “legally authorized representative”’ a clinical or a research context. In the absence of such a law, generally community or other standards (such as institutional policies) define hierarchies or identify individuals who may provide legally effective consent, for clinical (non-research) purposes, on behalf of others who cannot consent for themselves. The NPRM seeks comment on whether a revision that would expand the current definition to also permit an LAR to be defined by an accepted common practice standard that is used in a state for determining who can legally consent to clinical care would be consistent with the ethical principles underlying the Common Rule. Benefits and Costs
As stated above, the goals of the NPRM include facilitating research and reducing regulatory burden. Researchers have expressed concern, however, with the compliance costs associated with obtaining consent for secondary research of biospecimens and identifiable private information. HHS recognizes there are approximately 9 million individuals biospecimens collected for research annually and that the compliance costs associated with the NPRM would be considerable, but asserts that these costs are outweighed by other cost savings in the proposal as well as non-quantifiable benefits from improved human subjects protections and regulatory uniformity.