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Human Subjects Research in Genomics

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Introduction

The use of human subjects in biomedical, clinical and social-behavioral research can provide insights and discoveries that could not be otherwise obtained using model organisms or other methods.  The field of genomics has benefitted greatly from the use of human subjects, from the sequencing of the human genome itself to studies that identify the underlying genetic causes of human disease.  All federally-funded human subjects' research such as that supported by NIH must comply with regulations that protect the rights and welfare of human subjects, and require that researchers clarify the benefits and risks of participating in the research.  These regulations ensure that NIH research is performed ethically and responsibly. The use of human subjects in the field of genomics raises a number of key policy considerations that are being addressed at NHGRI and elsewhere.

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How Research Subjects are Protected

All human subjects research supported by the United States government, including any genomics research funded by or carried out at NIH, is subject to the Federal Policy for the Protection of Human Research Subjects, or 'Common Rule' (Code of Federal Regulations, Title 45, Part 46).  This regulation establishes rights and protections for participants in research, including an independent review of each research proposal and the active consent of participants.

The Common Rule requires informed consent, where an investigator must provide to each potential research participant a clear summary of the research study, including any risks to participants, and where each individual then needs to consent to permit the researcher to include them in the study. The Common Rule also requires that federally-funded human subjects research studies are overseen by an Institutional Review Board (IRB) to ensure the safety of research participants. 

Prior and during World War II (WWII), there were no formal regulations governing the use of human subjects in research.  Increased protections were established as a response to well-documented examples of research practices where subjects were not informed of the risks to their health of study participation, or were denied critical medical treatment (for example, see here).  Following establishment of the Nuremberg Code (1949) and Declaration of Helsinki (1964), the Common Rule (1991) was issued in response to the Belmont Report, which articulated basic ethical principles relevant for human subjects research.

On September 8, 2015, the Notice of Proposed Rulemaking (NPRM) for Revisions to the Common Rule was published in the Federal Register with the aim to "modernize, simplify, and enhance" oversight for human subjects research to address changes in the nature of research since the original publication of the Common Rule in 1991. The NPRM is open for comments through January 6, 2016. For more information about the proposed revisions as they relate to genomics research, see: Notice of Proposed Rulemaking for Proposed Revisions to the Common Rule New

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Human Participants and Genomics Research

Participating in Genomics Research

The use of human research subjects in genomics research has facilitated significant scientific discoveries and achievements, including the complete sequencing of the human genome and identification of genetic markers for human diseases.  While model organisms remain powerful research tools, the use of human subjects in genomics research enables scientists to study human genetic variation, to identify the genetic underpinnings of disease, and to research how genomics can be applied clinically. The translation of genomics discoveries from bench to bedside is ushering in the era of genomic medicine, allowing for more personalized treatments tailored to specific patients.  

NIH abides by federal regulations and guidance, including the 'Common Rule', for genomics research involving human subjects. Individuals are informed of a description of the genomics research being conducted, the ways in which their genomic information will be used, and the risks and benefits of their participation.  Given that one's genome contains personal health and other information, its analysis as part of a research study raises a number of issues that the informed consents need to address, such as the measures in place to protect participants' privacy, and under what circumstances information might be returned to patients.  

For further information and guidance, please see the Informed Consent for Genomics Research Resource.

Implications for Relatives

While genomic research may reveal new information about the research participant's health, the heritable nature of genetic information raises implications for the research participant's relatives.  Information about family members not involved in the study may be indirectly obtained through the research participant.  Furthermore, genomic research using family pedigrees can trace disease history may reveal family members that are carriers of a disease or will be affected themselves.  These indirect results pose an ethical conflict between a possible duty to warn family members of research participants and the protection of research participant privacy. 

The IRB Guidebook from the NIH Office of Protection from Research Risks provides guidance on addressing these issues.

Identifiable Populations

Identifiable populations, which include specific racial or ethnic groups, geographically-defined communities, and members of ultra-rare disease groups, present particular concerns with regard to privacy, stigmatization, and discrimination. For example, for some communities, close family relationships may make it nearly impossible to protect participants privacy. Furthermore, genetic information could raise questions around ancestry and family-ties that may disrupt the community structure.

Some communities may require the research to obtain community approval before seeking consent from potential participants and some communities have developed resources to help their members consider the major issues. For American Indian and Alaska Native communities, for example, the National Congress of American Indians Policy Research Center, in conjunction with NHGRI, has developed a resource to discuss questions and provide information about how some tribes are thinking about genetics research.

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Return of Research Results

The return of individual research results (IRRs) and incidental findings (IFs) from genomics research is an issue of interest among researchers, ethicists, funders of biomedical research, policy makers, research participants, and others.  At issue is that, when conducting clinical research studies, scientists may discover new health-related information about volunteers who have chosen to participate in the studies.  This raises the question of when and how it is appropriate for the scientists to share such research findings.  This issue is not new and it is not unique to genomics, but advances in genomic technologies have brought this issue to the forefront, and unique characteristics of genomics research have made addressing this issue particularly challenging.  NHGRI is currently funding research to examine these questions and inform future NHGRI policy. 

Individual Research Results and Incidental Findings

IRRs are the results for a specific study participant from a scientific investigation.  For example, in genomics research, an IRR could be whether a research participant possesses a particular gene variant under study.  IFs are a subset of IRRs, findings that are not related to the objectives of an investigation.  An example of an IF in genomics research would be finding that a study participant in an investigation of the genetics of heart disease possesses a gene variant related to Alzheimer's disease.

Anticipating an Increase in Individual Research Results and Incidental Findings in Genomics Research

Addressing the issue of return of IRRs and IFs is relevant for a variety of fields of human health research.  However, the volume of genomic data, the potential for its broad application, and advances in the interpretation of genomic data pose particular challenges in the field of genomic research.  As genomic technologies have advanced and the cost of sequencing has decreased, it has become feasible to produce more genomic data in research.  The greater volume of genomic data available to researchers makes the discovery of IFs more likely.

In addition, in order to maximize the usefulness of genomic data collected in research, it is often made available, with appropriate protections for study participants, to the scientific community to be used in research beyond the investigation for which the data was originally collected.  As the data is analyzed by different investigators for differing purposes, it is more likely that IRRs and IFs, beyond those from the original study, will be discovered.

Lastly, although much has been learned about the human genome, there remains much to be discovered.  Genomic information is interpreted differently over time as more is learned. Therefore, the interpretation of a result may change in the future, and new IRRs and IFs may be discovered.

Whether, When, How to Return Individual Research Results and Incidental Findings

Currently, IRRs and IFs from genomic research are not commonly returned to study participants or anyone else outside of the study team (e.g., family members, personal physicians).  However, arguments have been raised both for and against sharing this information. In addition to this lack of consensus, there are also a variety of opinions about which results and incidental findings should be returned and how, when, and to whom they should be returned.  The volume of genomic data and the potential for new findings and changing interpretations in the future makes it particularly difficult to develop recommendations and policies regarding an infrastructure and resources for returning IRRs and IFs.

Current Laws and Policies

Currently, the only federal law regarding return of genetic IRRs and IFs is the Clinical Laboratory Improvement Amendments of 1988 (CLIA), which sets quality standards for all laboratories performing clinical testing.  CLIA prohibits the return of individual research results to study subjects unless the results were obtained in a CLIA-certified laboratory.  Although some scientists have obtained CLIA certification for their laboratories, most research laboratories are not CLIA-certified, and not all research laboratories have the resources to enable re-testing in a CLIA-certified laboratory.

In the absence of laws regarding return of genetic IRRs and IFs, various groups and individuals have published recommendations and best practices, including two NIH institutes.  The National Cancer Institute has published a summary of its 2010 "Workshop on the Release of Research Results to Participants in Biospecimen Studies."  The document indicates that NCI will use the recommendations from the workshop to develop best practices.  The National Heart, Lung, and Blood Institute (NHLBI) published recommendations on reporting research results to study participants in 2006 and updated them in 2010.  In 2013, the Presidential Commission for the Study of Bioethical Issues released a report titled "Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts."  This report recommends that all practitioners should communicate with patients, research participants and consumers about the possibility of IFs and the possible benefits and risks of pursuing IFs.  Informed consent can then be obtained if the patient wishes to learn about resulting IFs, or the patient may choose to decline IF results. 

NHGRI Activity

NHGRI requires that the research that it funds comply with all applicable federal, state, and local laws, which includes CLIA.  NHGRI has awarded grants for a variety of projects that are examining return of research results and has organized the investigators involved in these projects into the Return of Results Consortium.  The consortium investigators are researching real-life applications of returning genomic results as well as legal and ethical aspects of returning results.  These grants are intended to contribute to an evidence base that may be used to inform future policy decisions.  NHGRI is also participating in discussions in the field of genomics as policy makers, funders, and researchers grapple with the issue of returning genomic research results and incidental findings, and held a workshop on the topic in 2014.

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Data Sharing and Privacy

Genomic Data Sharing Policies and Controlled Access

Technological advances in DNA sequencing have made high-throughput sequencing methods significantly faster and cheaper, allowing researchers to generate larger datasets than ever before.  These datasets can be used for genome-wide association studies (GWAS) that identify specific genomic factors associated with human health and disease.   NIH implemented the GWAS Policy in 2008, requiring data from NIH-funded GWAS to be shared with the research community in a central data repository maintained by NIH, the database of Genotypes and Phenotypes (dbGaP).  To protect research participants' privacy, access to sensitive data in dbGaP is through a controlled access policy, and NIH requires secondary usage of data to be consistent with the informed consent obtained from research participants during the initial study. 

To further expand genomic data sharing of all types, NIH released a Genomic Data Sharing policy that will be effective January 25, 2015. The policy states that NIH expects investigators to obtain consent for participants' data to be used for future research purposes and to be shared broadly through databases. NIH has the same expectations for informed consent for studies using genomic data from cell lines or clinical specimens that were created or collected after the effective date of the policy. Like the GWAS policy, the GDS policy includes numerous provisions to ensure the protection human genomic data. See http://gds.nih.gov/ for more information.

The importance of controlling data access to protect research participant privacy has been highlighted by the HeLa Genome Data Use Agreement announced by NIH in August 2013.  In collaboration with the Lacks family, NIH developed a controlled access policy through dbGaP specifically for genomic data generated from the HeLa cell line.   The HeLa Genome Data Access Working Group will review HeLa genome data requests from the research community and future HeLa genome data generated from NIH-funded research will be submitted to dbGaP.  For further information, see: "Nature Comment: Family Matters."

Genetic Information Nondiscrimination Act

The Genetic Information Nondiscrimination Act (GINA) prohibits health insurers and employers from requesting or requiring genetic information from an individual or an individual's family members, and further provides legal protection against discrimination on the basis of a person's genetic information.  HHS has issued guidance on GINA for IRBs and investigators involved with Federally-supported human subjects research.   In addition, NHGRI's Informed Consent for Genomics Research  resource contains model language for including information on GINA in informed consent forms. For further information on GINA, see: www.genome.gov/10002077/Genetic-Discrimination.

Re-identification and Privacy

DNA sequences can reveal health and other information about individuals and their families. Whether genomic information is being used for research, clinical or other uses, it is important to consider what measures are needed to ensure that individual privacy is respected. This includes issues around the use of clinical samples in research and uses in law enforcement. For more information about issues of privacy in genomics and the protections provided, please see Privacy in Genomics.

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Resources

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Last Updated: June 3, 2016

See Also:

Participating in Genomics Research

En Español:

Investigaciones genómicas en las que seres humanos se encuentran bajo estudio