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PSNet: Patient Safety Network

 Cases & Commentaries

Abnormal Volunteer Results

Commentary By Conrad V. Fernandez, MD

The Case

A healthy 52-year-old woman volunteered to participate in a radiology study in which she underwent magnetic resonance imaging (MRI) of her abdomen and pelvis. Several weeks later, she received a phone call from the study coordinator reporting that a "major abnormality" was discovered on her MRI. She was told to see her doctor as soon as possible. After seeking further evaluation, she was diagnosed with uterine cancer and started on chemotherapy. While her diagnosis was likely hastened through her participation in the research study (as she expressed no symptoms), the patient wondered whether the delay in reporting the MRI findings to her led to growth in the cancer prior to starting treatment.

The Commentary

Returning Research Results to Research Participants

Increasingly, medical researchers are recognizing a moral and professional obligation to offer participants an opportunity to see their research study results in an understandable and timely manner.(1,2) The main moral argument for this reporting is that it avoids treating participants as a means to an end. Some have argued that this offer should apply for all research studies, while others believe that the obligation extends only when there is direct anticipated benefit to the participant.(3,4)

An ongoing debate also exists around researchers' obligation to offer individual clinical results.(5-7) One can imagine potential scenarios when individual research findings may be immediately relevant. Examples include identification of severe depression, unexpected positive human immunodeficiency virus (HIV) status, and—as described in this scenario—finding a life-threatening malignancy. Providing this information to individuals offers other benefits, such as opportunities to make informed reproductive choices, initiate prophylactic interventions, or, when results demonstrate the absence of a disease, ease worry.(1) One must also remember that many researchers serve dual roles as clinicians and researchers—a dichotomy that the patient is apt to blur, and one that underlines an obligation of appropriate medical care to the patient.

Much of this debate centers around the degree to which individual results have adequate reliability and validity and are relevant to the participant, and how stringently these criteria need to be met.(3) The National Heart, Lung, and Blood Institute (NHLBI) suggests that an obligation exists if there is a high degree of reliability/validity, the individual result defines a disease, and there is an intervention available to address the finding.(8) Others would call for less rigorous criteria, in essence erring on the side of placing more weight on informed patient decision-making. Notwithstanding these theoretical and ethical arguments, studies have demonstrated that researchers fail to routinely offer results to participants, despite the participants' expressed interest.(9-12) Moreover, few institutional review boards maintain specific guidelines about providing research results to participants.(13)

Institutional Review Board (IRB) and Researcher Responsibilities

The Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects is an international statement that provides guidance for the ethical conduct of all human research.(14) It requires that a committee, operating at arm's length from the researcher, review the ethical integrity of research proposals and ensure that they comply with local laws and standards. In the United States, ethical conduct of research is regulated by the U.S. Department of Health and Human Services (DHHS) and the Code of Federal Regulations (CFR) Part 46 Protection of Human Subjects.(15) These regulations, called the Common Rule, require that all research on human subjects supported by DHHS be reviewed and approved by a local institutional review board (IRB). The regulations also require institutions to provide written assurance of compliance with stated policies. At a minimum, compliance with the CFR Part 46 entails: an institutional statement of support for ethical research principles, the designation and appropriate support of an IRB, the publication of detailed IRB membership information, a written set of IRB procedures, and a specific written set of procedures for prompt reporting of unanticipated problems (or risk to study participants) or of non-compliance with IRB requirements to the Office of Human Research Protections (OHRP). The regulations also stipulate that IRBs operate with a minimum of five members who can address the scientific merit and ethical issues raised by the research, with at least one member at arm's length from the institution.

Although an institution may approve or disapprove research approved by its IRB, the institution may not approve research disapproved by the IRB. IRBs have the authority to review and suspend human research that fails to comply with their recommendations. Furthermore, institutional, federal-wide assurances that allow research may be suspended by OHRP, if they are shown to fail to comply with CFR Part 46. Thus, research participants included under the protections of the Common Rule are afforded a uniform system of checks and balances at both the IRB and the institutional level. However, interpretation of the regulations by IRBs varies in part because the regulations are sometimes ambiguous, and in part because detailed descriptions of standard operating procedures for such issues as how to provide safety results are not present. Evidence exists that continuing effort is required to improve consistency and application of these regulations by IRBs.(16,17)

Investigators conducting human research must first obtain approval from their institutional IRB. IRBs are specifically charged to review research proposals and ensure that (i) risks are minimized and reasonable in relationship to anticipated benefits; (ii) informed consent is sought and documented; (iii) privacy and confidentiality are maintained; and (iv) when appropriate, "the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects."(15) Some interpret the last point narrowly as safety related to the research intervention. I believe that it should be construed more broadly—as safety relating to any information that is learned and relevant to the participant. With this interpretation, a mechanism exists for the researcher to consider (and for the IRB to ensure) a plan to monitor findings that have direct impact on the safety of study participants. For example, if a research project planned to use a validated psychometric measure that identifies suicide risk, a specific real-time plan for managing certain findings (such as a patient found to be at high risk) would need to be in place. In this scenario, a plan of action might include prompt timing for analysis of the data and communication of key results to the participant or guardian.

Returning to this case of an asymptomatic tumor discovered on MRI, one could argue that such a finding may have been predictable across a large study (albeit unanticipated for individual patients). The IRB should have anticipated this issue in their review and requested that the researcher describe a plan of action. In turn, the researchers should have made the participant aware of the possibility of these serendipitous findings and established a process for reporting such to the participant as part of the original protocol.

Building Processes to Report Individual Findings from Research Studies

Once researchers identify the need to incorporate specific reporting mechanisms into their study protocols, several issues must be addressed. First, informed consent documents should capture a mechanism to communicate unexpected but potentially relevant information to participants. Next, researchers should provide real-time data analysis when the findings are likely to warrant immediate attention. A less stringent timeline may be acceptable if the findings do not have immediate or severe consequences. The determination of what is meant by "timely" should be a negotiation between the researcher and the reviewing IRB in the context of the specific study details and will vary with the nature of the potential finding and the immediacy of the threat to the participant. The researcher has the responsibility to then carry through the methods exactly as prescribed in the IRB approval. A system already exists in the Federal regulations (§46.109) that mandates continuing IRB review of human research at intervals appropriate to the degree of risk. From a patient education standpoint, the consent process should also include any potential negative consequences of receiving research results—such as the impact on insurability, psychological state, or other related factors. Finally, all research protocols should identify how, by whom, and to whom unexpected findings will be communicated. The specifics will vary from study to study but may include information being provided to the participants themselves, to parents or other surrogate caregivers, or to primary care providers. Many factors (reliability of the test, nature of the results, impact upon participant, and availability of a therapy that can mitigate the finding) will need to be considered in establishing a final plan of communication. Researchers must be prepared to direct participants to appropriate resources if they are not able to interpret or follow up on the findings because such findings may have both physical and emotional ramifications, as they did in the presented case.

Take-Home Points

  • Researchers have an ethical responsibility to anticipate discovering unexpected but relevant individual findings—and the need to communicate these to study participants.
  • Researchers must balance a responsibility to analyze data in a timely manner with the estimated likelihood (and magnitude) of potential harms that may be identified.
  • IRBs exist to ensure the ethical conduct of research, including ensuring that a plan exists to provide relevant results to participants.

Conrad V. Fernandez, MD Pediatric Hematologist/Oncologist Departments of Pediatrics and Bioethics IWK Health Centre and Dalhousie University Halifax, Nova Scotia, Canada

References

1. Fernandez CV, Kodish E, Weijer C. Informing study participants of research results: an ethical imperative. IRB. May-Jun 2003;25:12-19. [go to PubMed]

2. Partridge AH, Winer EP. Informing clinical trial participants about study results. JAMA. 2002;288:363-365. [go to PubMed]

3. Ravitsky V, Wilfond BS. Disclosing individual genetic results to research participants. Am J Bioeth. Nov-Dec 2006;6:8-17. [go to PubMed]

4. Markman M. Providing research participants with findings from completed cancer-related clinical trials: not quite as simple as it sounds. Cancer. 2006;106:1421-1424. [go to PubMed]

5. Knoppers BM, Joly Y, Simard J, Durocher F. The emergence of an ethical duty to disclose genetic research results: international perspectives. Eur J Hum Genet. 2006;14:1170-1178. [go to PubMed]

6. Shalowitz DI, Miller FG. Disclosing individual results of clinical research: implications of respect for participants. JAMA. 2005;294(6):737-740. [go to PubMed]

7. Meltzer LA. Undesirable implications of disclosing individual genetic results to research participants. Am J Bioeth. Nov-Dec 2006;6:28-30; author reply W10-22. [go to PubMed]

8. Bookman EB, Langehorne AA, Eckfeldt JH, et al. Reporting genetic results in research studies: summary and recommendations of an NHLBI working group. Am J Med Genet A. 2006;140:1033-1040. [go to PubMed]

9. 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. 2004;96:629-632. [go to PubMed]

10. Fernandez CV, Santor D, Weijer C, et al. The return of research results to participants: pilot questionnaire of adolescents and parents of children with cancer. Pediatr Blood Cancer. 2007;48:441-446. [go to PubMed]

11. Partridge AH, Wong JS, Knudsen K, et al. Offering participants results of a clinical trial: sharing results of a negative study. Lancet. 2005;365:963-964. [go to PubMed]

12. Trialists should tell participants results, but how? Lancet. 2006;367:1030. [go to PubMed]

13. Macneil SD, Fernandez CV. Informing research participants of research results: analysis of Canadian university based research ethics board policies. J Med Ethics. 2006;32:49-54. [go to PubMed]

14. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2000;284:3043-3045. [go to PubMed]

15. Department of Health and Human Services, National Institutes of Health, Office for Protection from Research Risks. Code of Federal Regulations. Title 45, Part 46: Protection of Human Subjects; 2001.

16. Shah S, Whittle A, Wilfond B, Gensler G, Wendler D. How do institutional review boards apply the federal risk and benefit standards for pediatric research? JAMA. 2004;291:476-482. [go to PubMed]

17. Fisher CB, Kornetsky SZ, Prentice ED. Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations. Am J Bioeth. Mar 2007;7:5-10. [go to PubMed]