Human Subjects Protection and Cancer Surveillance Research: Revised Regulations, Expanded Opportunities

Abstract

On January 19, 2017, the United States federal government issued revisions to the Common Rule under which scientists who receive federal funding conduct research involving human subjects. The revised Common Rule expressly addresses public health surveillance in relation to scientific research and the protection of human subjects, and its impacts are anticipated to contribute to the efficiency of activities, including cancer registration and surveillance, and research that uses cancer registry data.

On January 19, 2017, the United States federal government issued revisions to the Common Rule under which scientists who receive federal funding conduct research involving human subjects. The revised Common Rule expressly addresses public health surveillance in relation to scientific research and the protection of human subjects (1). It is designed to contribute to the efficiency of activities, including cancer registration and surveillance, as well as research that uses cancer registry data.

Cancer registration, a response to the demands of the citizenry that cancers be counted (2), enables a range of scientific endeavors, including surveillance research and studies involving patient contact through registry data. As a discipline, surveillance research depends on the systematic collection of data on cancer patients and populations to “examine and test hypotheses about cancer predictors, incidence, and outcomes in geographically defined populations over time” (3). Registry data thus inform findings ranging from the personal and the molecular—the identification of genetic susceptibilities to cancer—to broad, common factors in cancer incidence such as harmful environmental exposures (4). Such findings are made possible through research conducted in accordance with regulations for the protection of the human subjects who are involved or about whom identifiable data are accessed and used. Since the publication of the Belmont Report in 1979, the adoption of regulations, and the expansion of these regulations as the Common Rule in 1991, compliance has increasingly compelled researchers to work with many local institutional review boards (IRB) and to navigate the requirements of medical privacy laws in regard to the use of individual-level data in human subjects’ research. As cancer research has become multidisciplinary and often involves multiple institutions, IRB approvals for surveillance research and cancer research in general have become more burdensome.

With the intent to modernize and strengthen the regulations embodied in the Common Rule, the government has issued revisions that resonate with the core aims of public health, with the goal of ultimately better facilitating productive, scientific outcomes. Herein, we highlight three changes of interest to researchers, research participants, and other stakeholders in cancer research:

1. The recognition and exclusion from IRB oversight of public health surveillance activities, including the collection and testing of biospecimens;

2. The requirement that a research study in which more than one institution located in the United States is engaged be reviewed by a single IRB with the others entering a relationship of reliance; and

3. The expansion of exemption categories to include many research studies involving the collection of identifiable human subjects’ data through survey and interview procedures.

Linking Public Health Ethics and Human Subjects Protection

A range of core conditions support the ethics of public health activities. These conditions, a “rough conceptual map to the terrain of public health ethics” include: (i) public justification that includes transparency and public accountability, (ii) least infringement on individual autonomy through selection of methods and procedures, (iii) effectiveness, (iv) necessity, and (v) proportionality in that benefits outweigh infringed interests (5). Consistent with these conditions, the revised Common Rule defines and distinguishes public health surveillance activities from research activities and excludes public health surveillance activities from IRB oversight.

The revisions indicate that a legislative mandate can provide a satisfactory, ethical basis for engagement in scientific activities and reflects meaningful engagement with issues of individual autonomy in accordance with individual legal rights. Legislative mandates typically also support the condition of necessity such as the necessity underlying population-based registration of all cancer cases. Furthermore, in recognition of the value of genetic and molecular science to public health, the definition of these activities extends to “the collection and testing of biospecimens, conducted, supported, requested, ordered, required, or authorized by a public health authority. Such activities are limited to those necessary to allow a public health authority to identify, monitor, assess, or investigate potential public health signals, onsets of disease outbreaks, or conditions of public health importance (including trends, signals, risk factors, patterns in diseases, or increases in injuries from using consumer products)…” (6).

The definition of public health surveillance activities is also limited to avoid creating a parallel, unregulated track of human subjects’ research activities. The explanation of the final rule anticipates continued IRB oversight of “exploratory studies designed to better understand risk factors for chronic diseases, including genetic predisposition, for chronic diseases; exploratory studies designed elucidate the relationships between biomarkers of exposure and biomarkers of disease; and exploratory studies of potential relationships between behavioral factors (e.g., diet) and indicators of environmental exposures” (6). These types of activities would be considered research, and thus subject to the revised Common Rule, even if conducted by a federal agency with a public health mandate. The definition of public health surveillance activities is, nevertheless, broadly consistent with the data collection and analyses performed by state cancer registries and the activities of registries that participate in federal cancer surveillance programs, such as database linkages.

Facilitating Efficient Research

The most notable structural change for research and institutional programs to protect human subjects will be the implementation of the single IRB requirement. With a compliance date set for January 20, 2020, any institution “located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States. The reviewing IRB will be identified by the Federal department or agency supporting or conducting the research or proposed by the lead institution subject to the acceptance of the Federal department or agency supporting the research” (7). This single IRB requirement is echoed in a policy notice issued by the National Institutes of Health (NIH) that will apply to new NIH awards with an effective date of September 25, 2017 (8). The Common Rule requirement mandates elevated coordination among institutions engaged in multisited research. The dominant models for this cooperation include the use of a “central” or “independent” IRB that reviews the research in which institutions are mutually engaged, and the use of an existing, IRB as a single or lead IRB among the engaged institutions (9).

For institutions that provide human subjects protection oversight through reliance on a central or single IRB, research studies are generally expected to proceed more efficiently. For research involving cancer registry data, especially when data are needed from more than one registry, the efficiency will be realized to the extent that data access and release procedures can also be harmonized. In California, for example, regional registries operating with state and federal support currently use similar but separate data request procedures to screen for human subjects’ protection approval or exemption, and to ensure that data release activities comply with state law (10). These procedures could be consolidated into a model application procedure, tested in California, and developed into a common application useful in many jurisdictions. The benefits of a common application would be responsive to the increasingly multiregional, comparative, and statistically rich character of cancer research. These benefits would include establishing a community of practice among researchers, in which applications are better and more uniformly prepared, and more easily filled across registries and jurisdictions in which cancer data are collected. The North American Association of Central Cancer Registries has launched its Virtual Pooled Registry Working Group with similar objectives and a charge to develop “a voluntary process to combine limited data from multiple registries to facilitate record linkage research” (11).

In addition to single IRB review, modified criteria for continuing review will offer researchers efficiency. Pursuant to the revised Common Rule, continuing review is no longer required for a study reviewed under an expedited category in absence of a local determination of a specific need for such review. Similarly, continuing review is no longer required for a study that has “progressed to the point that it involves only … [d]ata analysis, including analysis of identifiable private information or identifiable biospecimens, or [a]ccessing follow-up clinical data from procedures that subjects would undergo as part of clinical care”(12).

Expanding Exemptions and Reflecting on Risks

With respect to changes regarding research methods and the relationships between methods and risks to human subjects, the revised Common Rule enhances and expands categories of research subject to exemption from IRB review. Cancer researchers who use registry data beyond public health surveillance activities will benefit from, for example, the accommodation through exemption of research that “involves only information collection and analysis involving the investigator’s use of identifiable health information when that use is regulated under 45 CFR parts 160 and 164, subparts A and E, for the purposes of “health care operations” or “research” as those terms are defined at 45 CFR 164.501 or for “public health activities and purposes” as described under 45 CFR 164.512(b)” (13).

The breadth of changes to the categories of exemption offers an opportunity to reflect on the risks associated with research involving cancer registry data and the adequacy of human subjects’ protections. A subset of these studies, research about cancer survivorship is conducted among a growing population more than 15 million survivors and persons living with cancer in the United States alone (14). The size of this population has shifted social perceptions of cancer itself. Stigma and shame are substantially reduced by a cultural shift underway as clinicians anticipate rendering some cancers curable and others more like chronic rather than acute disease, and as surviving cancer becomes an attainable achievement and an everyday experience (15). Some of the vulnerability associated with cancer has been reduced or eliminated as evidenced by the willingness of cancer patients to participate in research that is unlikely to present direct benefits (16). Risks of informational harms, however, are more specifically defined in law, and elevated by the increasing use of information technologies in medicine and research (17, 18). Through consent documents and other study materials, researchers routinely describe the potential impacts of loss of privacy and breach of confidentiality, discrimination in relation to medical insurance and employment, reputational harms, and the implications of discovering genetic information, the sharing of which can impact not only individual research participants but also biological family members who may be unrelated to or nonparticipants in research. IRBs are also attuned to risks that affect participant experiences; they may require researchers to signal risks such as recollection of trauma or distress, depression, or misperception of a disorder or other personal condition on the basis of implications of questions or inferences from one’s own responses to research questions. Broadly, these risks may be characterized as risks of informational harms. The revised Common Rule indicates that when these risks are appropriately conveyed and mitigated through data management and security procedures, many research activities present minimal risk and may be efficiently approved or granted exemption.

Researchers who seek to combine cancer registry data with biospecimen data in their research will find new instructions and requirements in the revised Common Rule. Biospecimens are given elevated attention in the definition of research and in the classification of levels of review. They are treated as a form of property that may be lawfully alienated from the human body, consistent with the nascent case law of biospecimens in research (19, 20). The revised Common Rule does not otherwise resolve cultural questions about how biospecimens are regarded in relation to the body nor does it specify consensus about interpreting the biological, philosophical, and legal relationships between person, body, and specimen. Rather, the revised Common Rule emphasizes informed consent in the provision of biospecimens, describes “broad consent” for the “storage, maintenance, and secondary research use of identifiable biospecimens,” and recognizes the value of biorepositories in support of molecular and genetic science. Although critical commentaries responding to draft text of the revised Common Rule (21–23) suggested that some existing samples and modes of specimen access may be compromised, there are also examples of large cohort studies such as the NCI’s Breast Cancer Family Registry that presently function as the revised Common Rule contemplates use of broad consent for the collection and use of biospecimen samples (24).

Conclusion

Notwithstanding the challenges of navigating the proposed regulations for research involving human biospecimen samples, cancer researchers, their research participants, and other stakeholders in research involving cancer registry data will find the changes to human subjects’ protection a welcome support. The changes productively recognize the role of public health surveillance activities, direct an efficient consolidation of the oversight of research provided by IRBs, and deliver a thoughtfully revised and expanded set of categories accounting for research that may be exempt from review or accommodated as presenting minimal risk to human subjects. In these respects, the changes match important criteria of justification for public health interventions, including transparency and accountability, minimal infringement on individual autonomy, effectiveness, necessity, and proportionality in benefits relative to risks and compromise of private interests. The proposed regulations will, on balance, serve the advancement of cancer science.