Table 1 Research guidelines: return of IRRs and IFs to participants

Network of Applied Genetic Medicine, Statement of Principles on the Return of Research Results and Incidental Findings (2013) (Summary) [7].

Principle 2: Individual Results And Incidental Findings That Should Be Offered

Individual results and incidental findings should be offered to participants when:

  1) they are material, i.e. when the following conditions are met:

    1.1) they meet generally accepted criteria of scientific and clinical validity (criteria which are widely recognised by the medical community);

    1.2) they have clinical utility for the participant, i.e.:

      - the benefits associated with the communication of the results outweigh the risks;

      - prevention or treatment is available; and

      - individual, familial and social factors were considered;

  2) exceptions and additional considerations related to the research context have been weighed;

  3) REB approval has been obtained;

  4) the participant has consented to the return of results; and

  5) the research result has been confirmed.

Principle 3: Individual Results And Incidental Findings That May Be Offered

Individual results and incidental findings that are not compliant with the criteria set out in Principle 2 may be offered to participants (i.e. at the researcher’s discretion) when:

  1) they meet generally accepted criteria of scientific and clinical validity;

  2) the benefits of return surpasses the risks;

  3) REB approval has been obtained;

  4) the participant consented to the return; and

  5) the research result has been confirmed.

Principle 4: Individual Results And Incidental Findings That Have Implications For Family Members

It is possible that individual results and incidental findings have implications for the participant’s BIOLOGICAL RELATIVES. Under certain circumstances, these results may be returned (i.e. at the researcher’s discretion) to family members when:

  1) they meet the generally accepted criteria of scientific and clinical validity;

  2) the benefits of the return outweigh the risks;

  3) REB approval has been obtained;

  4) the research result has been confirmed;

  5) the participant agrees to share the result with biological relatives; and

  6) the biological relatives concerned agree to receive the results.

Public Population Project in Genomics and Society, Population Studies: Return of Research Results and Incidental Findings Policy Statement (2012) [5].

Return of IRRs and IFs to Participants: Conditions and Modalities

No Return of IRRs and IFs

There may be population studies where the policy is not to return individual results or findings, and this was consented to by participants at recruitment. This remains a viable option where appropriate. Researchers accessing the study population and their local Ethics Review Committee should be made aware of this policy.

For population studies with a no-return policy or where participants did not consent at recruitment to the return of findings but have, nonetheless, consented to recontact for updates and for further questions or collection of samples, such a period can create an opportunity to explain and introduce a return of results and IFs policy and accompanying procedures, if the population study so chooses and with ethics approval. Indeed, upon recontact, participants could be provided with an option to consent (or not) to receiving such results. Moving forward, population studies with a no return policy could consider adding such an option to their consent process at recruitment.

Return of IRRs and IFs

Decision to return results: When consent to return results is present, one should consider whether the finding poses a material risk. Findings are material if they have:

  1) analytical validity;

  2) clinical significance; and

  3) actionability.

Researchers, in collaboration with their local Ethics Review Committee, should consider returning IRRs and IFs to participants when they determine that the following criteria are met:

  1) the participant has consented thereto in the initial consent form or at a later time;

  2) the findings are analytically valid (ie, confirmed independently);

  3) they reveal a significant risk of a serious health condition; and,

  4) they are actionable.

Researchers, in collaboration with their local Ethics Review Committee, may consider returning IRRs and IFs when the above criteria are not satisfied, but when the following criteria are met:

  1) the participant has consented thereto in the initial consent form or at a later time;

  2) the findings are analytically valid (ie, confirmed independently);

  3) they reveal an established risk of likely health importance to the participant; and

  3) they have a likely therapeutic benefit.

The decision to return IRRs and IFs remains the responsibility of the researchers and the local Ethics Review Committee. Resources should be available for this decision-making process.

Communication of results. Contacting participants for the communication of material findings remains the responsibility of the population study. The population study should ensure the quality of the results, as well as the timeliness and appropriateness of the information returned to a given participant (including considerations related to the number of recontacts).

Procedures

Population studies should put in place policies and procedures that clarify and circumscribe the obligations and procedures arising from their return of results policy. These should be reflected in any material-transfer agreements and access policies for researchers. These policies should include the length of duration of any return of results policy and the degree of involvement of researchers. Attention should be paid to issues of feasibility and reasonability. Procedures should be in place in the population study for the communication of such results by a health professional.

National Bioethics Advisory Commission, Research Involving Human Biological Materials: Ethical Issues and Policy Guidance, Vol. 1. (1999) [8].

Return results only if

  a. “the findings are scientifically valid and confirmed”

  b. “the findings have significant implications for the subjects’ health concerns” and

  c. “a course of action to ameliorate or treat these concerns is readily available.”

National Heart, Lung, and Blood Institute:

Recommendation 1: IRRs “should be offered to study participants in a timely manner if they meet all of the following criteria:

Fabsitz RR, McGuire A, Sharp RR, et al., Practical Guidelines for Reporting Genetic Research Results to Study Participants: Updated Guidelines from an NHLBI Working Group (2010) [9].

  a. The genetic finding has important health implications for the participant and the associated risks are established and substantial.

  b. The genetic finding is actionable, that is, there are established therapeutic or preventive interventions or other available actions that have the potential to change the clinical course of the disease.

  c. The test is analytically valid and the disclosure plan complies with all applicable laws.

  d. During the informed consent process or subsequently, the study participant has opted to receive his/her individual genetic results.”

Recommendation 4 “Investigators may choose to return individual genetic results to study participants if the criteria for an obligation to return results are not satisfied (see Recommendation 1) but all of the following apply:

  a. The investigator has concluded that the potential benefits of disclosure outweigh the risks from the participant’s perspective.

  b. The investigator’s Institutional Review Board (IRB) has approved the disclosure plan.

  c. The test is analytically valid and the disclosure plan complies with all applicable laws.

  d. During the informed consent process or subsequently, the study participant has opted to receive his/her individual genetic results.”

Canadian College of Medical Geneticists and the Canadian Association of Genetic Counsellors, Joint Statement on the Process of Informed Consent for Genetic Research (2008) [10].

7(vii). Disclosure of results

Research participants should be informed at the outset if the results from the study will be disclosed and, if so, in what manner (e.g. individually to each participant or collectively as a study group through publication or another means). […] As indicated in section 7(v) above, researchers must take care to protect the privacy and confidentiality of individual participants in the course of results disclosure. Researchers should ensure that participants do not have unrealistic expectations with respect to disclosure of results. For example, a realistic estimate of the timeframe should be communicated to the participant. Ideally, participants should have the option to decline to be informed of study results at the time of enrollment or at any time during the study. It is recommended that for all studies in which results will be disclosed, genetic counselling should be a component of the informed consent process. The counselling provided should be appropriate to the clinical impact of the study. It should be provided at a level of depth and by staff with a level of training and expertise that is appropriate for the complexity of the information being explained.

Clinically Significant Results: It is recommended that any clinically-significant laboratory results ascertained through a research laboratory and disclosed to the research participant be validated in an accredited clinical diagnostic laboratory to ensure that appropriate quality assurance measures have been followed. Accredited clinical diagnostic laboratories that offer confirmation of research findings can be identified using online databases such as GeneTests.org.

Unexpected Results: Genetic research is unique in that there is the potential to obtain information about individuals or families that was unanticipated. In addition, it is possible that in the course of studying one disease, a researcher may discover that an individual, family or community is at increased risk for another, possibly unrelated, disorder. If individual results are to be disclosed, research participants should be made aware of the possibility that unexpected results could be obtained and should be informed of policy with regards to disclosure of such results in the context of significant health implications for the individual and/or his family. Prior consent should be obtained with regard to the research participant’s wish to be informed of these unanticipated results

Wolf SM, Lawrenz FP, Nelson CA, et al. Managing Incidental Findings in Human Subjects Research: Analysis and Recommendations (2008) [11].

Researcher should disclose IFs likely to offer strong net benefit from participant’s perspective: (a) genetic information revealing significant risk of a condition likely to be life-threatening; (b) genetic information that can be used to avoid or ameliorate a condition likely to be grave; and (c) genetic information that can be used in reproductive decision-making: (1) to avoid significant risk for offspring of a condition likely to be life-threatening or grave or (2) to ameliorate a condition likely to be life-threatening or grave.

Researcher may disclose IFs offering possible net benefit from participant’s perspective: (a) genetic information revealing significant risk of a condition likely to be grave or serious, when that risk cannot be modified but a research participant is likely to deem that information important; and (b) genetic information that is likely to be deemed important by a research participant and can be used in reproductive decision-making: (1) to avoid significant risk for offspring of a condition likely to be serious or (2) to ameliorate a condition likely to be serious.

Researcher should not disclose IFs offering unlikely net benefit from the participant’s perspective, including information whose likely health or reproductive importance cannot be ascertained.

Zawati HZ et al. Reporting Results from Whole-genome and Whole-exome Sequencing in Clinical Practice: a Proposal for Canada? [12] (endorsed by the Canadian College of Medical Geneticists)

Prior to using [Whole Genome or Whole Exome Sequencing], physicians need to explain to their patients the nature of the results that could arise, so as to allow them to make informed choices over whether to take the test and which results they wish to receive.

Results revealing a clinically significant condition that is actionable during childhood should be reported to the parents. Parents cannot refuse to receive such results.

The child’s views should be solicited and given due weight and consideration in accordance with his or her age and maturity.