Special Requirements and Guidance for Investigators
WPP #: XVII-5
Genetic (DNA) Research
Research involving genetic data and/or tissues or specimens, obtained for diagnostic or research purposes, has the potential to impact research participants’ employment, insurance, finances, education or self perception in the near and unforeseeable future should the information not be handled with considerable care. Research participants have the right to make an informed decision regarding current and future uses of their genetic information. Privacy and confidentiality related to the procurement, storage, use, and access to and use of genetic information must be carefully maintained and protected in order to prevent stigmatization, discrimination, or significant psychological harm to the subject.
A genetic test can be defined as an analysis of human DNA, RNA, chromosomes, proteins, or metabolites that can detect genotypes, mutations, or chromosomal changes. In other words, any test/assay that generates data sufficient to identify an individual by genotype (including by detection of changes in genotype in the form of mutations or polymorphisms) can be considered a genetic test. Some examples include: DNA fingerprinting, Genome Wide Association Studies (GWAS), single nucleotide polymorphism (SNP) analysis, DNA/RNA sequencing, genomics, and transcriptional profiling by PCR array or microarray formats.
Human genetic research can be divided into two very broad categories:
- Research on genetic material common to all bodily tissues and specimens, including blood. These are often described as constitutional, germ-line, or heritable studies. Such genetic research may have serious social and economic consequences if confidentiality is breached, since this type of genetic material can serve as ’fingerprint’ identification for individuals, be used to predict future diseases, or identify parentage.
- Research on the genetic information derived from the pathologic tissue (such as tumor specimens) of humans. This research involves sensitive information to the extent that research participants are associated with a particular disease or disorder. Social and economic risks related to such research are generally less serious than for germ-line research.
Human microbiome research, while not necessarily human genetic research, takes advantage of advances in DNA sequencing technologies to create a new field of metagenomics. This field allows for analysis of genetic material derived from complete microbial communities harvested from natural environments in the human body. Risks associated with such research are similar to the risks associated with inappropriate release of information contained in medical records.
Routine tests that do not detect genotypes, mutations, or chromosomal changes, such as complete blood counts, cholesterol tests, and liver enzyme tests, are not considered genetic tests under the Genetic Information Nondiscrimination Act (GINA). Also, under GINA, genetic tests do not include analyses of proteins or metabolites that are directly related to a manifested disease, disorder, or pathological condition that could reasonably be detected by a health care professional with appropriate training and expertise in the field of medicine involved.
Participant Concerns in Genetic Research
Research involving the use of genetic information has the potential to raise social and psychological risks rather than physical risks. Studies that generate information about participants’ personal health risks may provoke anxiety and confusion, damage familial relationships, and compromise participants’ insurability and employment opportunities. Even though the results of a genetic test may not provide a direct correlation to a specific risk, the test results have the potential to raise concerns, even when the results are presented in an unbiased manner that reflects the investigational or non-diagnostic nature of the result. These concerns include:
- Access to or retention of benefits or entitlements (e.g., health insurance, life or disability insurance, educational opportunity and employment);
- Stigmatization by others or the possibility of altered family relationships and interactions;
- Psychological responses to information such as an altered self-concept, possible depression, guilt, or anger; and
- Detection of biological relationships within a family such as paternity, maternity, or adoption status.
Some of these concerns, particularly as they relate to insurability, are addressed in GINA, a Federal law that prohibits discrimination in health coverage and employment based on genetic information, and thus, decreases certain types of risks. Investigators play a significant role in minimizing the risks or concerns by conducting thorough informed consent and maintaining strict confidentiality protocols when working with genetic information.
- General considerations for protocol preparation and IRB review
- Risks: It is important to thoroughly consider and describe potential risks to participants in the protocol. In most cases, the greatest risk to participants involved in genetic research is the risk associated with a breach of privacy and confidentiality. The research protocol must include a plan for protections of data and specimens during collection, storage, as well as during transit, either electronically or via over ground delivery. Refer to WPP on General Safeguards and Data Retention (VCU IRB WPP#: XII-1). The risk of psychological harm, such as feelings of depression or stigmatization, should be considered. The research plan should adequately describe the possibility of any such feelings and how the risk will be minimized.
- The Research Registry: Many genetic studies plan to maintain data for future research purposes. When this information is maintained with identifiers, this data collection is considered a research registry. The research plan must describe (1) The process for collection of specimens and/or genetic data; and (2)establishing a registry, contributing to an existing registry, and/or accessing an existing registry, at VCU or elsewhere. Refer to the WPP on Registries (VCU IRB WPP#: XVII-4).
- Certificate of Confidentiality: Consider obtaining a Certificate of Confidentiality to minimize access to research data. See VCU IRB WPP XII-2. Presence of a Certificate of Confidentiality may increase participants’ sense of security about who has access to their genetic information. In cases where the risk associated with data access is low, the PI and IRB may agree that a Certificate of Confidentiality is not indicated.
- Considerations for the Informed Consent Form and Process for Genetic Research:
- Informed Consent Template: The Informed Consent Form (ICF) template should be used if genetic research is a component of the project. Utilize sample language in the Biomedical and Social Behavioral Consent Templates for research involving: a) heritable DNA and b) HIPAA considerations, as appropriate. If data or samples will be maintained for future research in a registry or repository, information about how data will be stored and what future research may be conducted should be described in the informed consent form.
- Participant Options for Research Uses and Required Genetic Component: Consider whether the participant will be able to designate options for use of collected tissue/specimens such as designating limitations on future research to specific disease areas vs. unrestricted future use.
- If participants will have options, these should be described in the research protocol along with a description of how the registry research team will maintain a tracking system to ensure the future uses are in accordance with the specified uses selected in the individual subject’s consent.
- Indicate in the informed consent form if there are any options for how samples will be used. Refer to informed consent templates for suggested language.
- If participation in the overall research study is contingent upon participants’ permission to store data, tissues, or specimens for current or future genetic research, this should be carefully described in the protocol and the informed consent form.
- Financial and Property Aspects:
- Indicate the potential for commercial profit (if any) by the institution, investigator or sponsor from information gathered in this study.
- In most cases, the consent form should have a clear statement that the sample/data, any cell lines, profits from data etc., are the property of the University. Refer to conditions or terms in sponsor agreement/contract regarding intellectual property considerations.
- Participant Withdrawal Conditions: Consider what will be done with samples when a participant withdraws from the study.
- Participants should be clearly informed of how their samples will be handled if they wish to withdraw from the study during active participation or in the future. For example, will samples collected prior to withdrawal be removed or does withdrawal apply to future use only?
- The ability of participants to request removal of their sample and/or data from the registry is dependent on whether data will be de-identified (coded) or anonymized. Note that stripping identifiers and applying an alpha numeric code does not mean the same as anonymizing the data, such that the actual subject could never be contacted. If identifiers or a code will be maintained with a sample, the prospective subject should be informed that anonymity cannot be guaranteed.
- Disclosure of Genetic Information and Incidental Findings: Genetic testing has the potential to result in researchers becoming aware of incidental, or secondary, findings. Incidental findings are generally defined as results that are outside of the original purpose for which a test or procedure is conducted. Investigators should take time to identify incidental findings that are likely to be found and consider whether these findings can and/or should be shared with research participants. Participant should be informed of what incidental findings are likely to be sought or arise from tests/procedures being conducted. Investigators should inform participants about plans for disclosing (or not disclosing) incidental findings.
- Explain whether genetic or other incidental information will be disclosed to the participant or another party. In most cases, such information is not disclosed to participants; however consider whether the type of study and type of information may warrant such disclosure. If the research plan and/or consent form indicates that there will be no disclosure of incidental findings to participants and the investigator reconsiders, the IRB must give approval for such disclosure before it can occur.
- Participants should be informed that they have the right to decline receiving results of genetic testing.
- Information disclosed, if any, must be in a manner consistent with the recipient's level of knowledge, e.g., information would be phrased differently when disclosed to a lay person versus a scientist.
- Indicate the availability or access to genetic counseling in cases where a study may reveal genetically important information (e.g., possessing genetic defects which could be passed on to progeny).
- Genetic Information Nondiscrimination Act (GINA)
- The IRB should consider the provisions of GINA when assessing whether genetic research satisfies the criteria required for IRB approval of research, particularly whether the risks are minimized and reasonable in relation to anticipated benefits and whether there are adequate provisions in place to protect the privacy of subjects and maintain the confidentiality of their data. GINA is also relevant to informed consent. The OHRP March 2009 guidance document explains GINA: Guidance on the Genetic Information Nondiscrimination Act: Implications for Investigators and Institutional Review Boards
- Language explaining protections afforded by GINA to participant genetic data should most often appear in the informed consent document for studies involving genetic research. When investigators develop, and IRBs review, consent processes and documents for genetic research, they should consider whether and how the protections required by GINA should be reflected in the consent document's description of risks and provisions for assuring the confidentiality of the data. See OHRP guidance for suggested language about GINA protections for considered inclusion in informed consent forms.
- Involving Minors and Decisionally Impaired Adults in Genetic Research
- When samples or data originally collected from a minor or temporarily decisionally impaired individual will be maintained for future research, consider whether the subject’s informed consent to continue participation ought to be specifically obtained, or a waiver of informed consent should be sought, upon reaching the age of majority or becoming decisionally capable. This may become especially pertinent if the research will require future contact of the participant. In some cases, the inability to obtain the subject’s informed consent may preclude continued, or previous, inclusion of the subject’s data. Plans for obtaining consent in these situations should be described in the research protocol.
- Consider whether the results of any genetic analysis will, or should be, revealed to the parents or legally authorized representative. Close consideration ought to be given to disclosing information to the now adult subject, if parents had previously refused such disclosure. Investigators should consider the need for risk reducing steps such as offering counseling resources.
- Submitting Genetic Data to Public Repositories
Many funding and publication sources are increasingly requiring that genetic data be made available for future research. Repositories such as the Genome Wide Association Study (GWAS) database (dbGap) and the Gene Expression Ombnibus (GEO), both supported by the National Center for Biotechnology Information, provide examples of available repositories where genetic data may be deposited to fulfill data sharing requirements. The NIH provides a listing of common data repositories. Generally, data are submitted to such repositories in a de-identified manner; however, dbGap does have controlled access mechanisms to protect privacy when such concerns exist. Research participants should be notified through the informed consent process of any intent to share data and samples for future possible research. Consider whether participants may also be given a choice of whether to share their data.
- Research Contributing to or Obtaining Data from the NIH’s Genome Wide Association Studies (GWAS) repository (dbGap)
Investigators conducting genetic research may be directed by their NIH sponsor to contribute data and specimens to the NIH repository for genomic research. GWAS involves rapidly scanning markers across the complete sets of DNA, or genomes, of many people to find genetic variations associated with a particular disease. Such studies are particularly useful in finding genetic variations that contribute to common, complex diseases, such as asthma, cancer, diabetes, heart disease and mental illnesses. When preparing an IRB submission, investigators should be clear as to whether the research includes doing GWAS analysis and/or contributing to the NIH GWAS data repository.
- NIH accepts data into the GWAS data repository after receiving certification from the Institutional Official that the IRB has approved submission into GWAS. Further information about certification can be accessed at: Points to Consider for IRBs and Institutions. A data sharing plan addressing the following elements should be included in the research plan and reviewed and verified by the IRB:
- Data submission is consistent with all applicable laws and regulations, and VCU policies.
- Appropriate research uses of the data and the uses that are specifically excluded by the informed consent are delineated. This information is generally contained in the informed consent form in the form of choices presented to participants about the nature of current and future research they wish to allow.
- Identities of research participants will not be disclosed to the NIH GWAS data repository.
- Submission of data to the NIH GWAS repository and subsequent sharing for research purposes are consistent with the informed consent of study participants from whom the data were obtained.
- The investigator’s plan for de-identifying datasets is consistent with the standards outlined in the NIH GWAS policy.
- Risks to individuals, families, groups/populations associated with the data submitted to the NIH GWAS data repository have been considered.
- Genotype and phenotype data to be submitted were collected in a manner consistent with 45 CFR Part 46.
Some projects, such as those utilizing de-identified or anonymous secondary data, involving submission of data to GWAS may not qualify as research involving human subjects. While such a project does not require IRB approval of the research study, the institution must still certify that the data being submitted to GWAS fulfills the requirements for submission. Thus, projects of this type must be submitted to the Office of Research Subjects Protection (ORSP) for review.
Obtaining data from the NIH GWAS repository is done by submitting a Data Access Request and a Data Use Certification. The NIH requires that the Institutional Official certify that, among other things, data obtained from GWAS will be adequately secured, not be shared, and no attempts to re-identify individuals will occur. This certification is signed by the Associate Vice President for Research Administration and Compliance.
Even though data obtained from the NIH GWAS repository is de-identified and generally does not require IRB review, i.e. does not involve ‘human subjects’, some GWAS databases do require IRB review prior to releasing information. Generally, the GWAS database will indicate when IRB review is required. For more information regarding when research using anonymous or de-identified samples is ‘human subjects research’ see the OHRP guidance: Guidance on Research Involving Coded Private Information and or Biological Specimens, 2008.
Larsen, E.C. (2006) Research involving genetic testing. In, E.A.Bankert & R.J. Amdur (Eds.) Institutional Review Boards: Management and Function, 465 - 468, Boston: Jones & Bartlett.
NIH Points to Consider for IRBs and Institutions in Their Review of Data Submission Plans for Institutional Certifications under NIH’s Policy for Sharing of Data Obtained in NIH Supported or Conducted GWAS
Presidential Commission for the Study of Bioethical Issues (December 2013). Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts.