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

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study participants of research results: an ethical imperative. IRB.
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2. Partridge AH, Winer EP. Informing clinical
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4. Markman M. Providing research participants
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10. Fernandez CV, Santor D, Weijer C, et al. The
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11. Partridge AH, Wong JS, Knudsen K, et al.
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12. Trialists should tell participants results,
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13. Macneil SD, Fernandez CV. Informing research
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14. World Medical Association Declaration of
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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,
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17. Fisher CB, Kornetsky SZ, Prentice ED.
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