7.3.5 Informing Study Participants of Research Results
Conrad Fernandez, MD, FRCPC
*Updated December 1, 2016 by Dr Conrad Fernandez MD, FRCPC
- To examine the moral rationale for the offer of return of aggregate or individual research results
- To examine the potential benefits and harms of returning aggregate or individual research results
- To understand the current practice and attitudes of researchers and participants to the return of research results
- To understand some of the logistical challenges that arise in offering to provide research results
Natalie, a 13-year-old girl in Grade 8, presents to her family doctor with a one-month history of low-grade fevers, a 10-pound weight loss and a slowly growing lump in her neck. Further history reveals that she also has had recent night sweats and difficulty in lying flat when trying to sleep. Workup at a tertiary care pediatric hospital demonstrates a stage II B Hodgkin's disease with bulky mediastinal mass. She and her parents, who are divorced, consent to her participation in a Children's Cancer Group clinical trial. This trial examines the role of response-based therapy involving the elimination of exposure to radiotherapy for those patients with rapid early responses. There is a voluntary concurrent biology study, which is intended to examine epigenetic changes that predispose patients to chemotherapy-induced toxicity and late effects. She and her family also agree to participate in this correlative biology study.
Natalie has a slow response to chemotherapy and, by protocol, receives radiation to her chest. Her Hodgkin's disease remains in remission, and she and her family move to Alberta. Her care is transferred to a pediatric centre, and she faithfully attends clinic until she moves to Winnipeg to study fine arts. She sees a new family doctor but has no specific oncology follow-up. At 26 years of age, she has her first daughter, and, as part of the postnatal care, is found to have a breast mass. Workup demonstrates a localized but large breast carcinoma.
As part of her discussion with her breast cancer specialist, she learns that several manuscripts have been published as a result of the study she took part in describing both clinical outcomes and novel genetic risk factors for second malignancy. The study identified that radiation therapy in adolescent girls predisposes them to breast cancer and that all such patients should have mammograms or breast MRI beginning eight years after radiation. It also identified that a novel polymorphism in a DNA repair gene, which she carries, doubles the risk of breast cancer .She begins to angrily wonder what else she hasn't been told, and what the risk may be to her daughter.
- Is there a moral imperative to offer aggregate or individual research results to research participants?
- What are the potential benefits or harms of offering aggregate or individual research results?
- Who should receive results of research if the participant is no longer a minor? Does the person (parent in this case) have the right to receive research results of his or her child?
- Who is responsible for retaining contact?
- Should participants be offered individualized results of biology (including genetic) research?
- What if she had died prior to the results being available. Does her daughter have a right to be told of the genetic polymorphism predisposing her to breast cancer?
Aggregate Results. Offering a summary of research results acknowledges the ethical principle of respect for persons, avoids treating research participants as a means to an end and may have direct positive consequences for the participant and indirect benefits to research as a whole.1 Based on supporting this principle of respect for the dignity of the person, there is increasing recognition of a moral responsibility incumbent on researchers to offer a summary of research results to participants, in almost all cases.2 Unfortunately, there is good evidence to suggest that this practice has been relatively uncommon and inconsistent, with less than a third of researchers in some series providing results to participants.3,4
There are clear potential benefits, which must be balanced against the harms of returning research results.1 These benefits include direct benefits to the participant of providing information that may enhance the quality of life or lead to investigations that will reduce future harms. There are less direct benefits of reducing a feeling of exploitation by the participant, emphasizing the central nature of the participant to the research and disseminating accurate results in a different means than is traditionally available. Indirect benefits may include an overall support to scientific endeavours as research participants understand their contribution to the understanding of disease and therapy. There is also the potential to build greater trust in researchers and thus future support or participation in research.
In contrast to the benefits enumerated above, harms may accrue to the participant including distress5,6 about increased future risks (such as breast cancer), possible discrimination related to insurance or employment opportunities, and incorrect or even harmful medical decisions based on invalidated results. Several authors have taken the stance that the sharing of research results should be restricted to participants who request them, restricted to only situations in which there is clear medical benefit or restricted to when the researcher/clinician believes there may be harm to the participant in learning the results.7,8 Beyond the participants themselves, there may be distress among family members in revisiting the research setting (especially if the participant has died). Despite these harms, participants have consistently indicated that they wish results to be offered — thus exercising their right to self-determination.9,10
Concerns about logistical challenges also have been expressed by researchers, including the maintenance of contact follow-up with participants,11 the ability of researchers to express their findings in appropriate lay language and the potential costs of return of results, which are predicted to escalate with the anticipated potential for negative consequences to the participant.12 These incremental costs are based on the expectation and desire of participants to receive distressing results in a face-to-face manner in the context of a well-organized program designed and equipped to support participants. It is felt that simply providing results without informed consent of the participant is neither respectful of the participant nor supportive of the overall moral responsibility to offer results in a way that will address harms. It should be noted that, while an offer of results is morally obligatory, participants are not obliged to receive them, as the autonomy of the individual should be respected. Some evidence suggests that most participants wish to own the responsibility of retaining contact,13 thus alleviating a major concern of researchers.
A further logistical issue is when and to whom the results should be offered. We believe that a climate of expectation should be created such that participants know their rights and anticipate the offer of results. This climate can be created by regulatory revisions, research ethics board policies and guidelines and regular reinforcement with participants at such times as the original consent and the completion of the study.14 It would seem appropriate that participants receive results only after peer review, as one would expect the same high degree of standards to be set for the dissemination of results to participants as in the medical literature. The likelihood is that most participants would allow for the sharing of results with erstwhile proxy decision-makers, but respect for privacy should allow now competent participants to make that decision.
Individual results. While the literature originally focused on clarifying the need for a summary of valid and reliable data to be shared with participants in a usable lay format, there has been an explosion of literature exploring the concept and practice of returning individualized results, especially in the setting of genetic results.15-20 The risks and benefits cited above for the return of aggregate results remain but are potentially much more acute in the individual setting as discussed below. In general, recommendations have suggested that there is an obligation to plan for the possibility of individual results being uncovered in research, both as a direct target of the research question and incidental to it18,21-28 (the latter example being a cancer predisposition gene being discovered in the context of a cardiac study). This obligation is now espoused in the TriCouncil Policy of Canada (chapter 13 article 13.2).
Prospective consent for the disclosure of individual research results (should they occur), should be sought from participants with appropriate counselling of the risks and benefits.23,25,29 These risks are magnified compared to aggregate results with a greater potential impact on self-identity, potential work and insurance repercussions, and familial consequences. On the other hand, the potential benefits are also magnified with uncovering of genetic defects in which direct actions of surveillance or treatment may be life-saving. Most consensus statements now recommend that individual results be offered if there is a: adequate analytic validity, b: serious clinical impact, c: an existing strategy that can mitigate harm and d: consent from the individual.23,30 The issue of return of individual genetic results is complicated in a number of special research settings. Many existing bio-banked samples were collected before the power of genomic interrogation possible today was contemplated and thus consent for the return of genetic results not considered.31-33 How to handle individual results, especially of serious actionable clinical impact, remains under debate.22,23,34 A similar active debate revolves around the testing of children engaged in genetic research.15,35,36 What information of the child should be disclosed and to whom, whether or not it should be limited to childhood onset conditions, and the obligation of researchers to retain contact for the purpose of sharing results years or their responsibility to reanalyze data over time, all become challenging questions in this population.37,38 Thirdly, an emerging topic of consideration is what to do with clinically actionably genetic results from patients who are now deceased but because of shared heritage, might be relevant to surviving family members.39-41
It is important that the participant be informed of the limitations of the interpretation of individual research results, including the increased rigour of testing and quality assurance in a clinical laboratory versus a research laboratory.42 They should be cautioned about undue enthusiasm for acting on results without confirmation in an approved lab. There are also strong recommendations that results be shared with the expertise of a trained genetic counsellor or similar health care professional who can aide in the interpretation of sometimes very complex and incompletely defined genetic conditions.43
In summary, there is a moral imperative to offer to provide aggregate results to participants even if those results are not clinically relevant. Similarly, individual results that have significant clinical impact, especially if there are mitigating strategies to reduce harm, should also be offered. Note that no participant is obligated to receive results that they do not wish, except perhaps in the case of parents who have an obligation to protect their child.
The researcher is obliged morally to support this process with appropriate safeguards and supports that have practical implications with respect to appropriate grant budgeting of the costs and timelines to return results.18,44,45 Detailed guidance should be available from regulatory agencies, including the research ethics boards that review human research.
Pragmatic Suggestions for Residents
- It is already routine practice to incorporate evidence-based medicine into daily clinical care. Highlighting for patients and families that the information and recommendations being provided arise from health care research to which they may have contributed will raise their awareness of its utility.
- In situations where participants are being recruited or are known participants in clinical trials, determine whether there is a plan to offer individual or aggregate research results. If so, assist in informing participants of their right to this information and the expected risks and benefits of receiving results. If there is no plan, advocate and raise awareness of the moral obligation to offer aggregate, and when relevant, individual results with researchers.
- In situations where participants are returning for clinical follow-up after research participation, plan to spend part of the clinical consultation discussing the implications of the results with participants who wish to receive them.
- Consistent with many recommendations, individual results should be offered if adequate analytic validity, clinical utility, action-ability and consent apply.
- When designing one's own research, plan to budget time and effort to the offer of aggregate and/or individual results to participants in the operating budget. This should include a means to notify the participants of the availability of the results and the actual dissemination of results. The mode of distribution will be contingent on expected consequences of receiving results.
- Empiric research is needed to examine a number of issues related to the return of individual results including impact of providing individual results on the participant, especially if the finding is incidental to the research aims; exploration of how to enhance the consent process; impact upon relatives given the shared genetic make-up that exists between family members and a deeper understanding of the drivers for saying yes or not to receiving individual results.
- Fernandez CV, Kodish E, Weijer C: Informing study participants of research results: an ethical imperative. Irb 25:12-9, 2003
- Partridge AH, Winer EP: Informing clinical trial participants about study results. Jama 288:363-5, 2002
- Fernandez CV, Kodish E, Shurin S, et al: Offering to return results to research participants: attitudes and needs of principal investigators in the Children's Oncology Group. J Pediatr Hematol Oncol 25:704-8, 2003
- Rigby H, Fernandez CV: Providing research results to study participants: support versus practice of researchers presenting at the American Society of Hematology annual meeting. Blood 106:1199-202, 2005
- Markman M: Providing research participants with findings from completed cancer-related clinical trials: not quite as simple as it sounds. Cancer 106:1421-4, 2006
- Schulz CJ, Riddle MP, Valdimirsdottir HB, et al: Impact on survivors of retinoblastoma when informed of study results on risk of second cancers. Med Pediatr Oncol 41:36-43, 2003
- Markman M: What must research subjects be told regarding the results of completed randomized trials? Irb 26:8-10, 2004
- Ravitsky V, Wilfond BS: Disclosing individual genetic results to research participants. Am J Bioeth 6:8-17, 2006
- Partridge AH, Wong JS, Knudsen K, et al: Offering participants results of a clinical trial: sharing results of a negative study. Lancet 365:963-4, 2005
- Halverson CM, Ross LF: Attitudes of African-American parents about biobank participation and return of results for themselves and their children. J Med Ethics 38:561-6, 2012
- Partridge AH, Hackett N, Blood E, et al: Oncology physician and nurse practices and attitudes regarding offering clinical trial results to study participants. J Natl Cancer Inst 96:629-32, 2004
- Fernandez CV, Skedgel C, Weijer C: Considerations and costs of disclosing study findings to research participants. Cmaj 170:1417-9, 2004
- Fernandez CV, Gao J, Strahlendorf C, et al: Providing research results to participants: attitudes and needs of adolescents and parents of children with cancer. J Clin Oncol 27:878-83, 2009
- Macneil SD, Fernandez CV: Informing research participants of research results: analysis of Canadian university based research ethics board policies. J Med Ethics 32:49-54, 2006
- Fernandez CV, Bouffet E, Malkin D, et al: Attitudes of parents toward the return of targeted and incidental genomic research findings in children. Genet Med 16:633-40, 2014
- Wolf SM, Annas GJ, Elias S: Patient Autonomy and Incidental Findings in Clinical Genomics. Science, 2013
- Green RC, Berg JS, Grody WW, et al: ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15:565-74, 2013
- Bookman EB, Din-Lovinescu C, Worrall BB, et al: Incidental genetic findings in randomized clinical trials: recommendations from the Genomics and Randomized Trials Network (GARNET). Genome Med 5:7, 2013
- Biesecker LG: Secondary variants and human subjects research. Genet Med 15:157, 2013
- Klitzman R, Appelbaum PS, Fyer A, et al: Researchers' views on return of incidental genomic research results: qualitative and quantitative findings. Genet Med 15:888-95, 2013
- Johnson G, Lawrenz F, Thao M: An empirical examination of the management of return of individual research results and incidental findings in genomic biobanks. Genet Med 14:444-450, 2102
- Hull SC, Berkman BE: Grappling with genomic incidental findings in the clinical realm. Chest 145:226-30, 2014
- Weiner C: Anticipate and communicate: Ethical management of incidental and secondary findings in the clinical, research, and direct-to-consumer contexts (December 2013 report of the Presidential Commission for the Study of Bioethical Issues). Am J Epidemiol 180:562-4, 2014
- Thorogood A, Joly Y, Knoppers BM, et al: An implementation framework for the feedback of individual research results and incidental findings in research. BMC Med Ethics 15:88, 2014
- Appelbaum PS, Parens E, Waldman CR, et al: Models of consent to return of incidental findings in genomic research. Hastings Cent Rep 44:22-32, 2014
- Kleiderman E, Knoppers BM, Fernandez CV, et al: Returning incidental findings from genetic research to children: views of parents of children affected by rare diseases. J Med Ethics 40:691-6, 2014
- Driessnack M, Daack-Hirsch S, Downing N, et al: The disclosure of incidental genomic findings: an "ethically important moment" in pediatric research and practice. J Community Genet, 2013
- Bombard Y, Robson M, Offit K: Revealing the incidentalome when targeting the tumor genome. JAMA 310:795-6, 2013
- Lipworth W, Ankeny R, Kerridge I: Consent in crisis: the need to reconceptualize consent to tissue banking research. Intern Med J 36:124-8, 2006
- Fabsitz RR, McGuire A, Sharp RR, et al: Ethical and practical guidelines for reporting genetic research results to study participants: updated guidelines from a National Heart, Lung, and Blood Institute working group. Circ Cardiovasc Genet 3:574-80, 2010
- Hens K, Van El CE, Borry P, et al: Developing a policy for paediatric biobanks: principles for good practice. Eur J Hum Genet 21:2-7, 2013
- Zawati MH, Knoppers BM: International normative perspectives on the return of individual research results and incidental findings in genomic biobanks. Genet Med 14:484-9, 2012
- Wolf SM, Crock BN, Van Ness B, et al: Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genet Med 14:361-84, 2012
- Middleton A, Morley KI, Bragin E, et al: No expectation to share incidental findings in genomic research. Lancet 385:1289-90, 2015
- Evans JP: Return of results to the families of children in genomic sequencing: tallying risks and benefits. Genet Med 15:435-6, 2013
- Dove ES, Avard D, Black L, et al: Emerging issues in paediatric health research consent forms in Canada: working towards best practices. BMC Med Ethics 14:5, 2013
- Green RC, Berg, J.S., Grody W.W., Kalia S.S., Korf B.R., Martin C.L., McGuire, A, Nussbaum, R.L., O'Daniel, J.M., Ormond, K.E., Rehm, H.L., Watson, M.S., Williams, M.S., Biesecker, L.G. : ACMG Recommendations of the reporting of incidental findings in clinical exome and genome sequencing. , 2013
- McGuire AL, Joffe S, Koenig BA, et al: Ethics and Genomic Incidental Findings. Science, 2013
- Wolf SM, Branum R, Koenig BA, et al: Returning a Research Participant's Genomic Results to Relatives: Analysis and Recommendations. J Law Med Ethics 43:440-63, 2015
- Wilfond BS, Fernandez CV, Green RC: Disclosing Secondary Findings from Pediatric Sequencing to Families: Considering the "Benefit to Families". J Law Med Ethics 43:552-8, 2015
- Taylor HA, Wilfond BS: The ethics of contacting family members of a subject in a genetic research study to return results for an autosomal dominant syndrome. Am J Bioeth 13:61, 2013
- Fernandez CV, O'Connell C, Ferguson M, et al: Stability of Attitudes to the Ethical Issues Raised by the Return of Incidental Genomic Research Findings in Children: A Follow-Up Study. Public Health Genomics 18:299-308, 2015
- Wiens ME, Wilson BJ, Honeywell C, et al: A family genetic risk communication framework: guiding tool development in genetics health services. J Community Genet 4:233-42, 2013
- McEwen JE, Boyer JT, Sun KY: Evolving approaches to the ethical management of genomic data. Trends Genet, 2013
- Ayuso C, Millan JM, Mancheno M, et al: Informed consent for whole-genome sequencing studies in the clinical setting. Proposed recommendations on essential content and process. Eur J Hum Genet, 2013