Genetic Testing or Analysis

IRB Member Fact Sheet--Version Date: 11/30/2008

Human Subjects Protocols involving Genetic Testing or Analysis
The following guidelines have been adopted to facilitate review of research involving genetic testing or collection of information that has genetic implications (e.g., pedigree publication, construction of family histories) and intended to assist both IRBs and research teams. The chapter on Human Genetic Research in the IRB Guidebook produced by the Office for Human Research Protections and the National Bioethics Advisory Commission’s report,  Research involving human biological materials: ethical issues and policy guidance,  Vol. 1, served as the primary bases for these guidelines and is an additional source of guidance.

Definition
Genetic research involves the analysis of any of the following: DNA, RNA, chromosomes, proteins, or certain metabolites which might act as or identify markers associated with a known or suspected predisposition to disease or behavior.  Usually genetic research involves the collection of human biological material such as blood, skin or other tissues, nail clippings or hair.  Genetic research also may include the construction of pedigrees (maps of the distribution of a particular trait or condition among related individuals) or family medical histories.   Although gene transfer, sometimes known as gene therapy, is another form of genetic research, these studies are not covered in this document.  Please see the Gene Transfer Guidance.

Information Researchers are Required to Provide the IRB for Review
Regardless of whether the research involves a genetic component, UW-Madison IRBs are required to assess whether research studies meet the criteria for IRB approval outlined under the Common Rule and, if applicable, FDA regulations. 

In order for research studies to be approved, the IRB must ensure that the research study meets the criteria specified under the federal regulations for IRB approval (45 CFR 46.111).  These criteria are outlined below and followed by a description of how IRBs and research teams can ensure these are met for genetic research.

Identification and Assessment of Genetic Research Risks
The risks to research participants from genetic research generally are not the risks from the procedures used to extract the biological sample or the genetic information from the biological sample.  Instead, the risks relate to the potential social, psychological, and economic impact if information from genetic testing or the creation of a pedigree is shared with the research subjects or others. 

Genetic research poses special challenges for IRBs because it is often difficult to assess the nature and degree of risks posed by it and how to minimize these risks, especially as techniques improve to allow easy analysis of a wide range of genes and our knowledge of the function of genes increases. This has been complicated by the requirement that genotyping information derived any NIH-funded genome-wide association studies must be submitted to a federal database (dbGAP) so that it can be shared with other researchers. It is unclear whether these data will be available to law enforcement agencies or others unrelated to research interests. Thus, assurances cannot be confidently made about the identfiability of genetic information submitted to dbGaP. .  Consent processes and documents should be clear about these risks, and should state that all the risks of genetic research are not known at this time.

Identification of Risks
When research teams are preparing applications to the IRB, they should keep in mind what the risks of genetic research are and address proactively in their submissions how these will be minimized.  The risks of genetic research include:
If the research team plans on disclosing information to individuals, additional risks include:
Determining Level of Risk
Generally research studies involving genetic testing or the construction of pedigrees cannot be classified as minimal risk studies.  Consequently, initial review of such research cannot be reviewed under expedited procedures. 

It can be especially challenging for IRBs to determine what category genetic research can be approved under when it involves children.  The federal regulations outline 4 categories under which research involving children can be approved.  One category, research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children, can only be approved by the Secretary of the Department of Health and Human Services.  Otherwise, the research must be able to meet one of the following categories:
  1. Research not involving greater than minimal risk
  2. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects
  3. Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subject's disorder or condition
    • NOTE: Under this category, the risk must represent a minor increase over minimal risk; the intervention or procedure must present experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; and the intervention or procedure must be likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition.
When a protocol involves genetic testing, the IRB will consider the following factors in determining the level of risk presented by the research:
Disclosure of the Results of Genetic Analyses
Disclosure of results from tests that have not been validated are unlikely to be approved by the IRB.  Whether the results of genetic analyses should be provided to the individuals undergoing the testing should be considered carefully because of the psychosocial risks of associated with disclosure, including confusion, emotional upset, damage to family relationships, or adverse effects on self image.  When the tests conducted in the research study have been validated and are available outside of the study, the IRB would not require the disclosure of results to subjects or their representatives unless the tests are part of their clinical care.  If results will be shared with subjects or others, the research team should describe the following in the application:
IRBs and research teams should keep in mind that some subjects or their representatives may not wish to receive results and should ensure that the consent form allows participants to indicate their choice regarding disclosure.

Genetic testing may be done to with the intent to confirm a diagnosis.  Researchers and IRBs need to consider the consequences should a diagnosis not be confirmed.  If subjects or their representatives will be informed if their diagnosis is not confirmed, the research team should have procedures in place to handle this finding, such as genetic counseling, and disclose this possibility in the consent form.  If the researcher does not plan to disclose failure to confirm a diagnosis to subjects or their representatives, the researcher will need to describe how this information will be handled and whether it will be apparent to subjects (e.g., if a confirmation of diagnosis is needed to determine subjects’ eligibility for a research study will they wonder if this has occurred if they are ineligible to participate).

Implications for Family Members
Genetic family studies pose special issues because of the relationship between the individuals and the fact that the research has implications beyond the individual undergoing the genetic testing.  IRBs must determine when individuals other than those being tested become research subjects.  As the OHRP IRB Guidebook notes, in making this decision IRB should consider whether the information about others provided by a subject is also available to the investigator through public sources (e.g., family names and addresses) and other personal information that is not available through public sources (e.g., information about medical conditions or adoptions).  IRBs also should make certain measures are in place for family-based research that help ensure individuals are not pressured to recruit other family members for the research or confidential information is not shared amongst family members without explicit consent. 

Pedigree Research
Publication of pedigrees may result in the identification of individuals to family members and others.  Research teams and IRBs must consider what measures should be in place to protect subject confidentiality and what level of informed consent is required prior to publication.  Please see the following article that succinctly and cogently outlines issues related to recruitment for familial research – Beskow LM, Botkin JR, Daly M, Juengst ET, Lehmann LS, et al (2004). Ethical issues in identifying and recruiting participants for familial genetic research. American Journal of Medical Genetics, 130A, pp. 424-31.

References

William W. Lowrance and Francis S. Collins. Identifiability in Genomic Research.
SCIENCE VOL 317 3 AUGUST 2007

NIH Factsheet: Genome - Wide Association Studies (GWAS) Policy
https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=28

NIH Policy and Guidance on Genome-Wide Association Studies (GWAS). http://grants.nih.gov/grants/gwas/

GenomeWide Association Studies (GWAS). NIH Points to Consider
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 Genome-Wide Association Studies (GWAS)
http://grants.nih.gov/grants/gwas/gwas_ptc.pdf