Research Involving Genetic, Genomic, and/or DNA Collection or Analysis

• Genomics refers to the study of the entire genome of an organism, where the genome is the entire set of genetic instructions found in a cell.
• Large-scale genomic data (a term from the 2014 NIH GDS Policy) includes genome-wide association studies (GWAS), single nucleotide polymorphisms (SNP) arrays, and genome sequence, transcriptomic, metagenomic, epigenomic, and gene expression data. Analyzing two or more genes can count as “large-scale genomic data” if done in more than 1000 human subjects.
• Epigenetics involves the study of changes caused by the activation and deactivation of genes without any change in the underlying DNA sequence of the organism. Epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable.

Among other regulatory and ethical considerations, the Protocol Document and related sections in the eResearch smartform should adequately describe plans for each of the following.

eResearch smartform sections: 01-1.2 or 07, 20

• Answer ‘yes’ to the ‘trigger’ question for genetic analysis at 7.1.1 or (for secondary use only studies) 01-1.2, question 1.2 if
  • study analysis will generate genetic/genomic information, whether novel or confirmation of known genetic information, including secondary analysis of biospecimens collected previously or for other purposes
  • and/or
  • biospecimens collected during the study will be retained for future unspecified use, which may include genetic analysis (e.g. the standard ‘future unspecified use’ terms in IRBMED Standard Informed Consent template)

Note:  If the study procedures add genetic analysis during the course of completing the research, Section 01-1.2 or 07, 20 will be required as part of the amendment.

• 20.2 and 20.3 – use key words so reviewers can quickly identify the type of genetic analysis, e.g. genomic, epigenetic, SNP.
• 20.4 – see section II.B immediately below for additional considerations when data/biospecimens are shared.
• 20.5 – see section IV below for considerations in identifying what must be included in the consent document(s).
• 20.6 and 20.7 – see section II.C below for considerations in deciding when and whether to share results of genetic testing.

eResearch smartform sections: 11, 18, 24; or linked Repository (REP) application

1. Confidentiality of biospecimens and data
   1. Stored specimens and data files should be coded and labeled without direct identifiers. The ‘key’ to the code should be stored in a secure manner.
   2. Refer to HRPP Data Security Guidelines and ITS Safe Computing resources.
   3. eResearch application section 11 (and sub-sections) should reflect actual study team practices.
2. Determine if the NIH Genomic Data Sharing (GDS) Policy (2014) applies
   1. The policy applies to NIH-funded research generating large-scale genomic data. “Large-scale” depends both on number of genes sequenced and on number of human participants.  Examples: Genome Wide Association Studies (GWAS), Single Nucleotide Polymorphism (SNP) arrays, genome sequences, expression data (e.g., transcriptomic, epigenomic, genetic)
   2. If the policy applies, preferably, obtain Institutional Certification for GDS as part of the initial eResearch application.
3. Sharing outside the University (to external collaborators on the study, or for future unrelated ‘secondary use’ studies) requires a Data Use Agreement/Materials Transfer Agreement and may require a separate review.
4. Re-use of data/biospecimens for future separate studies
   1. NIH Data Management and Sharing Policy (published 2020, effective date 2023) expects that “researchers will maximize the appropriate sharing of scientific data.”
   2. Unless necessary for the new analysis, provide ‘secondary use’ investigators only deidentified and coded information without the ‘key’ to the code. This generally does not require a separate IRB application.
5. When the study ends or the PI leaves the institution.
   1. The University retains ownership of research biospecimens and derivatives, unless stipulated otherwise by the terms of specific research agreements for which the specimens were collected. (UMMS Research Biorepositories Policy – level-2 login required)
   2. Investigators preparing to leave the University should consult
      1. UMMS Regulatory Affairs Office (level-1 login required) “Exit Checklist” (U-M Resources for Researchers – level-1 login required)
      2. Michigan Medicine Corporate Compliance Office (level-2 login required) Data Use and Sharing webpage
   3. Submit Amendments and/or Terminations to the IRB for ongoing studies (HUM) or repositories (REP) from the PI, including
      1. who takes on responsibility for any future contact with participants
      2. efforts to notify participants, if any

1. Which of the following will be returned to participants?
   1. 1. General study results
      2. Individual study results
      3. Incidental findings
      4. Secondary findings
   2. How quickly will results be returned? By whom? Can the return of results continue after the participant’s involvement, or the study, ends?
   3. May participants “opt out” of receiving certain kinds of findings?
2. Explain the basis for returning (or not) each type of finding. Factors affecting the decision include:
   1. Whether individual research results are likely to be of clinical significance
      1. Can the genetic tests be repeated by a commercial CLIA certified lab (i.e. can commercially available tests provide the same information)?
      2. Laboratories providing research findings for medical use (e.g., affected patients will be recommended for surgery, drug therapy or the research result will be used to guide other aspects of medical management) should be encouraged to obtain CLIA certification for the test.
      3. Diagnostic test devices may be required to obtain an FDA IDE (contact MICHR-MIAP with questions).
   2. Potential psychological or emotional ramifications of learning the information
      1. Who will provide any relevant genetic or other counseling (e.g. helping participants decide whether to seek additional testing) and who will cover the costs?
   3. Ethical considerations of allowing participants to opt out of receiving clinically significant, actionable, and lifesaving findings
3. If research findings are not routinely returned to participants, plan for the case of unanticipated information that could be medically compelling to the participant. Certain incidental and secondary findings are predictably associated with a particular modality or type of research, and researchers have a duty to anticipate such incidental findings—whether common or rare—to the extent possible.
   1. Submit an ORIO to IRBMED when any actual medically compelling case is discovered.
   2. Indicate who will evaluate the relevance of the information

Related eResearch smartform sections: 10-1, 10-2

1. Informing other family members of the research
   1. Researchers should not request the names and contact information of relatives from primary participants, without their relatives’ consent or knowledge.
   2. Primary participants may be asked to share information about the study to relatives who can then contact the study team if interested in participating or return a “permission to be contacted” card.
   3. Researchers who request participants act as go-betweens between the study team and other family members should educate the participants on how to present study information and the contact process in a non-coercive manner.
2. Research contact with other family members
   1. Avoid enrolling or collecting specimens at family reunions or other family gatherings where privacy is compromised and time for education and informed discussion/consent is limited. Regulations require that researchers seek informed consent only under circumstances that allow the prospective participant sufficient opportunity to discuss and consider whether or not to participate, and that minimize the possibility of coercion or undue influence.
3. The privacy of participants and families must be protected when information is published or publicly presented.
   1. Avoid publication or presentation of a pedigree that may easily identify a family with a rare disorder or uniquely structured family unit.
   2. Collect family history only as needed for study objectives. Additional identifiable information might pose harm or embarrassment to nonparticipating family members.
   3. Seek informed consent from the individual the information pertains to (i.e., the family member), unless appropriately waived by the IRB.

It may not be appropriate to involve child participants in research on genetic diseases or conditions that present in adulthood or can be asymptomatic, because the child’s best interest is to protect their future autonomy whether to receive information. On the other hand, if the research may reveal genetic propensities for conditions with known behavioral or environmental risk factors, this may be relevant to parents’ decisions about the health care and well-being of the child participant, current or future other children in the family, or of the parents themselves. The relevance of the information depends also, though, on whether the research results are clinically verifiable.

Among other regulatory and ethical requirements, the consent document(s) should adequately describe the elements below that have special significance for genetic information. Template sentences/paragraphs relating to most of these are available in the IRBMED Standard Informed Consent Template.

1. Sharing of DNA sample or genetic information for future research. Participants can be invited to choose between different levels of access, but researchers should limit the number of choices to avoid participant confusion and later administrative complexity.
   1. When a biobank or data repository is the main intent of the project, it is common to request upfront consent for any and all future re-use.
   2. When the genetic information is generated as part of a treatment study, more restrictive options may be appropriate. Participants enrolling in clinical trials that include collection/storage of tissue or DNA samples for ancillary or future research purposes should have the option to withhold consent for that aspect, while still participating in the clinical research trial.
2. Plans for disclosure or purposeful non-disclosure of research results (45 CFR 46.116(c)(8))
   1. When and how general or individual study results, incidental or secondary findings, and clinically significant individual results may returned, and the basis for this decision
   2. Sharing of information related to adult onset diseases if the participants are children
   3. Risks of learning the information (e.g. parentage issues, knowledge of a previously unknown condition)
   4. Whether participants may “opt out” of receiving certain kinds of findings.
3. Risks (and mitigations thereof) particular to knowledge/sharing of genetic information
   1. Genetic information may impact insurability or employability, or may cause other potential forms of discrimination (e.g. stigmatization). Researchers should consider, and should prompt the participants to consider, these risks and the mitigation of the risks, including in the case of unintentional or accidental release of research information.
   2. Genetic Information Non-Discrimination Act (GINA) protects against misuse of an individual’s genetic information (genetic tests of the individual or family members, and the manifestation of a disease or disorder in the individual’s family members).
      1. By GINA definition, “genetic test” means only an analysis
         1. of human DNA, RNA, chromosomes, proteins, or metabolites
         2. that detects genotypes, mutations, or chromosomal changes
      2. GINA protections are not relevant to, and should not be in consent documents for, studies with genetic analyses related only to microbiome, gene expression, and epigenetics (i.e. not also generating results related to heritable variants).
   3. A federal Certificate of Confidentiality (CoC) protects against forced disclosure of information from a research context.
      1. CoC is included as a term/condition of grant for funding from NIH, CDC, SAMHSA, HRSA and FDA.
      2. Investigators are encouraged to obtain a CoC from the NIH for non-NIH funded studies. Researchers may apply for an NIH CoC if a primary focus of the research is within the NIH mission (i.e., health/mental health-related). Individual level genomic data are generally considered sensitive data warranting CoC protection.
4. The extent to which primary participants’ family members may be involved. (See heading ‘Participant Selection’ above.)
5. The options for participant withdrawal from the study. Investigators should keep sufficient identifiers to accommodate participants’ withdrawal of permission for further use of their data. Commonly, information/biospecimens cannot be ‘recalled’ if shared with collaborators, but disposal of the data and any remaining specimens stored with the study team is possible.  Any time limits for withdrawal must be specified in the consent.
6. Costs associated with participation in the research for the participant or family, such as
   1. Genetic or other counseling when results are returned
   2. Retesting by a commercial CLIA certified lab
7. As a best practice, the components specific to informed consent for genetic testing under Michigan law (MCL 333.17020 and 333.17520), outlined at HRPP Operations Manual Part 11.II.A.2.b. (This is a best practice, albeit the laws do not apply to procedures performed as a component of biomedical research subject to FDA and OHRP oversight).

If the study continues throughout the time when child participants may have reached the age of majority, the study must seek reconsent from the now-adult participants themselves. This includes ongoing use of data or biospecimens collected for a research repository.

A legally authorized representative must consent to research participation on behalf of adults with cognitive impairment or otherwise impaired decision making (“incapacitated individuals”); and on behalf of children. HRPP Operations Manual Part 11.II.A.1 defines “age of majority,” “incapacitated Individual,” and individuals who can serve as legally authorized representative, with references to the Michigan Code of Law. See also IRBMED guidance Who May Consent for Participation in Research Studies (Michigan).

A complete (every page) copy of signed consent forms should be placed in the U-M medical record of participants (Michigan Medicine Policy 01-04-310, level-2 login required), particularly when the research intervention may affect other treatment or care (in most cases this means scanning the document into MiChart (level-2 login or VPN required)). However, doing so may not be appropriate in all cases (for example if identification of the participant might put them at risk of criminal prosecution or harm to reputation).

U-M IRBs are responsible for evaluating the risks of a research study, weighing the probability of each risk coming to pass, and assessing the magnitude of harm that may result. Harm to research participants and their families based on genetic information can be both higher probability and higher magnitude than most other kinds of personally identifiable information, so genetic analysis studies may be considered to pose greater than minimal risk even when physical and/or psychological risks are minimal.

Expedited review is permitted for genetic research studies if the IRB application is otherwise eligible for expedited review. Genetic research alone is usually not a trigger for a convened board review. IRBMED no longer requires annual continuing review for these studies if the IRB application is otherwise eligible for No Continuing Review.

• IRBMED Standard Informed Consent Template, “Genomic Data Sharing” blue help sections
• IRBMED Biorepository Informed Consent Template and Informational Sheet
• National Human Genome Research Institute
  • Required Elements of the Consent Form (with sample language for each element)
  • Informed Consent for Genomics Research Resource
  • Clinical Research FAQ  
•  “Tailoring the process of informed consent in genetic and genomic research,” Rotimi CM and Marshall PA, PMCID: PMC2873798

• “Privacy and Progress in Whole Genome Sequencing” (2012) at Presidential Commission on the Study of Bioethical Issues
• NIH Office of Science & Policy Genomic Data Sharing

• NHGRI Return of Research Results guidance
• SACHRP Recommendations on Reporting Incidental Findings (2017)
• SACHRP Recommendations on Return of Individual Research Results (2019)
• “Anticipate and Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts” (2013) at Presidential Commission on the Study of Bioethical Issues
• Digest and Comment from Am J Epidemiol on “Anticipate and Communicate” PMID: 25150271

• “Does family always matter? Public genomes and their effect on relatives” Bloss, CS 2013 PMCID: PMC3978598
• “Protecting Third Parties in Human Subjects Research” Resnick, DB and Sharp, RR. 2006 PMCID: PMC3951397
• “The Interface Between the Practice of Medical Genetics and Human Genetic Research: What Every Genetic Counselor Needs to Know” Yashar BM and Markel DS. 2004 PMID: 15604636
• “Protecting the Privacy of Family Members in Survey and Pedigree Research” Botkin J. 2001 PMID: 11176815