7.3.3 Physicians' Obligations to Patients in Clinical Research
Conrad V. Fernandez, MD, FRCPC
- To review the availability of guidelines and policies for the conduct of human research, including the role of the research ethics board (REB) in human research.
- To examine the specific responsibilities that physicians have to patients who are participating in research, including issues of informed consent, conflict of interest (COI), confidentiality and disclosure of research results.
Jordan is a 10-year-old, grade 4 student who presents with a 3-month history of back pain. His pain is exacerbated by playing hockey and is associated with progressive difficulty in sleeping at night. He has been well prior to this, but there is a strong family history of breast cancer and sarcoma in young adults. A pelvic MRI demonstrates a probable Ewing's sarcoma arising from the ilium, with invasion of his lumbar plexus.
The Kid's Cancer Group is a multinational, cooperative clinical trials group. A randomized clinical trial for Ewing's sarcoma is available. This trial is examining the use of standard chemotherapy versus standard chemotherapy plus an antiangiogenesis agent (SloVenGrow). The local REB in Halifax has approved the study after institutional review board approval in the USA. There is an understanding that an independent data safety monitoring board (DSMB) has been established. A secondary aim of the study is to collect biology specimens for gene testing to look for potential cancer-susceptibility syndromes.
Jordan is told of his cancer diagnosis. With guidance from his parents, the concept of the research study is presented to him in a way that he can understand. His parents provide consent and he is randomized to the new antiangiogenesis arm. As the trial proceeds, and while Jordan is still receiving therapy, evidence arises from a separate study that SloVenGrow is associated with an increased risk of learning difficulties in children and adolescents. The DSMB recommends continuing this trial pending further information, and this is discussed with the parents. They elect to continue on the research protocol.
The biology specimens are banked with linked but confidential patient identifiers. Two years after the close of the therapeutic study, these samples are analyzed for known cancer susceptibility syndromes (BRC1 and Li-Fraumeni) by a separate clinical laboratory. Following this, a planned search is conducted for novel genes that may be involved in cancer susceptibility. Jordan's specimen is found to contain the Li-Fraumeni mutation of the p53 gene. Jordan and his parents have a careful discussion with the oncologist as to how to notify them of their elevated breast cancer risk as a consequence of the diagnosis of the Li Fraumeni syndrome.
- What Canadian and international guidelines govern the conduct of human research?
- What obligations do physicians have with regard to research ethics review?
- What responsibilities do physicians have to patients with respect to obtaining consent for research? How does this apply to those without the capacity to consent? When should assent be sought?
- What types of COI may arise in research with patients?
- What responsibilities do physicians have with respect to the confidentiality of results that may affect other family members?
Physicians have a moral duty to support human research in order to assist in maintaining evidence-based practice and the advancement of the care of their patients. They may participate in this duty in a number of ways, including serving on REBs, designing and conducting research studies or playing a role in the recruitment of patients or in the routine care of a patient who is participating or has participated in human research. Obligations that arise in these contexts in the conduct of research stem from an over-arching principle of respect for persons and avoiding the treatment of individuals as a means to an end.1
The case presented here illustrates a number of issues, including the importance of complying with national and international research ethics review. It also brings up the matter that assent to research should be considered in children who do not have the capacity to fully consent. The case demonstrates that correlative studies, especially genetic research, may have implications beyond the participant. Issues of confidentiality and privacy need to be discussed prior to the research, and plans made in anticipation of potential significant results that need disclosure.
In summary, physicians have a fiduciary responsibility to the individual patient as their primary duty that supersedes any potential benefit to others from the research being conducted. Physicians may play a number of roles in research. Each of these comes with different responsibilities, but all are linked to the primacy of the principle of respect for persons. The autonomy of the individual must be respected in seeking informed and continuing consent or assent for research participation. Physicians must be aware of potential COIs in the context of their duty of care, and their responsibility to disclose these COIs. Maintenance of the confidentiality of patient data and care in reporting is an essential obligation. Physicians must be aware of the potential limits to this promise of confidentiality, including in situations of risk to the participant and to others. Detailed guidance for these issues is available in a number of policies and regulations that physicians engaged in research must be aware of.
Pragmatic suggestions for residents
- Physicians should be aware of local and national requirements in complying with physician responsibilities in the conduct of human research. In Canada, compliance with the TCPS is mandatory. International research endeavours require compliance with both the Canadian regulations and those of the international site.
- The Declaration of Helsinki and other similar policy statements require that consent from participants must be received before the research is conducted. In the case of potential participants in which the capacity to consent is uncertain (e.g., children, adolescents, the elderly with dementia), the appropriate assessment of the capacity to assent to research is required. Assent should be obtained where possible. If a potential participant is unable to fully consent then a surrogate decision-maker is required.
- In designing research studies, physicians should be aware of their obligation to confirm consent to participation on a regular basis—in particular if relevant, new information arises that may impact upon the continuing consent of the participant. Some studies may require a formal DSMB and a protocol design with pre-set stopping rules based on toxicity and efficacy outcomes.
- It is important that research protocols prospectively establish mechanisms to deal with anticipated and (as far as possible) unanticipated relevant individual results that may have medical clinical relevance to the participant. A plan should be in place as to how to maintain the confidentiality of biological samples, while maintaining the ability to link these to the participant for disclosure.
- Physicians should be aware of their legal obligations to others if important information arises from a patient that is known to potentially compromise others' safety. They should be aware of the debate that is occurring in the genetics community with respect to notifying kin of potentially relevant results.
- Physicians should be aware of their moral responsibility to offer a summary of results to participants.35 (See case Ethical Issues Arising in the Return of Research Results to Research Participants.)
Suggested readings and references cited
- Beach MC, Duggan PS, Cassel CK, Geller G. What does ‘respect’ mean? Exploring the moral obligation of health professionals to respect patients. Journal of General Internal Medicine 2007; 22(5): 692–5.
- Annas GJ, Grodin MA. The Nazi doctors and the Nuremberg code: human rights in human experimentation. Oxford: Oxford University Press; 1992.
- World Medical Association (WMA). Declaration of helsinki. Seoul: WMA; 2008.
- Tri-Council Policy Statement. Ethical conduct for research involving humans. Ottawa: Interagency Secretariat on Research Ethics; 2005. Available from: http: //www.pre.ethics.gc.ca/english/pdf/TCPS%20October%202005_E.pdf.
- Health Canada. Food and drug acts and regulation: Part C, division 5: Drugs for clinical trials involving human subjects. Ottawa: Health Canada; 2008. Available from: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/cta_documents-eng.php
- Council for International Organizations of Medical Sciences (CIOMS) and the World Health Organization. International ethical guidelines for biomedical research involving human subjects. Geneva: CIOMS; 2002.
- International Conference on Harmonization (ICH). Guideline for good clinical practice. Geneva: ICH; 1996.
- Civil code of québec. Québec City: Justice Québec; 1991.
- McMillan JR, Conlon C. The ethics of research related to health care in developing countries. Journal of Medical Ethics 2004; 30(2): 204–6.
- US Department of Health and Human Services (DHHS). Code of federal regulations: Title 45, public welfare; part 46, protection of human subjects. Washington, DC: DHHS; 2005.
- Gill D, Crawley FP, LoGiudice M, Grosek S, Kurz R, et al.; Ethics Working Group of the Confederation of European Specialists in Pediatrics. Guidelines for informed consent in biomedical research involving paediatric populations as research participants. European Journal of Pediatrics 2003; 162(7–8): 455–8.
- Council for International Organizations of Medical Sciences. International ethical guidelines for biomedical research involving human subjects. Bulletin of Medical Ethics 2002; (182): 17–23.
- Pace C, Grady C, Wendler D, Bebchuk JD, Tavel JA, et al. Post-trial access to tested interventions: The views of IRB/REC chair, investigators, and research participants in a multinational HIV/AIDS study. AIDS Research and Human Retroviruses 2006; 22(9): 837–41.
- Zong Z. Should post-trial provision of beneficial experimental interventions be mandatory in developing countries? Journal of Medical Ethics 2008; 34(3): 188–92.
- American Society of Clinical Oncology. American Society of Clinical Oncology policy statement: Oversight of clinical research. Journal of Clinical Oncology 2003; 21(12): 2377–86.
- Protection of human subjects: Belmont Report—ethical principles and guidelines for the protection of human subjects of research. Federal Register 1979; 44(76): 23192–7.
- Barfield RC, Church C. Informed consent in pediatric clinical trials. Current Opinion in Pediatrics 2005; 17(1): 20–4.
- Baylis F, Downie J, Kenny N. Children and decisionmaking in health research. IRB 1999; 21(4): 5–10.
- Caldwell PH, Murphy SB, Butow PN, Craig JC. Clinical trials in children. The Lancet 2004; 364(9436): 803–11.
- Diekema DS. Conducting ethical research in pediatrics: A brief historical overview and review of pediatric regulations. Journal of Pediatrics 2006; 149(1 Suppl.): S3–11.
- Kuther TL, Posada M. Children and adolescents’ capacity to provide informed consent for participation in research. Advances in Psychology Research 2004; 32: 163–73.
- Joffe S, Fernandez CV, Pentz RD, Ungar DR, Mathew NA, et al. Involving children with cancer in decision-making about research participation. Journal of Pediatrics 2006; 149(6): 862–8.
- Hoeyer K, Olofsson BO, Mj�rndal T, Lynoe N. The ethics of research using biobanks: Reason to question the importance attributed to informed consent. Archives of Internal Medicine 2005; 165(1): 97–100.
- Godard B, Schmidtke J, Cassiman JJ, Aymé S. Data storage and DNA banking for biomedical research: Informed consent, confidentiality, quality issues, ownership, return of benefits. A professional perspective. European Journal of Human Genetics 2003; 11(Suppl. 2): S88–122.
- Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: A systematic review. Journal of the American Medical Association 2003; 289(4): 454–65.
- DeAngelis CD, Fontanarosa PB, Flanagin A. Reporting financial conflicts of interest and relationships between investigators and research sponsors. Journal of the American Medical Association 2001; 286(1): 89–91.
- Emanuel EJ, Wood A, Fleischman A, Bowen A, Getz KA, et al. Oversight of human participants research: Identifying problems to evaluate reform proposals. Annals of Internal Medicine 2004; 141(4): 282–91.
- Weinfurt KP, Friedman JY, Dinan MA, Allsbrook JS, Hall MA, et al. Disclosing conflicts of interest in clinical research: Views of institutional review boards, conflict of interest committees, and investigators. Journal of Law, Medicine & Ethics 2006; 34(3): 581–91, 481.
- Johns MM, Barnes M, Florencio PS. Restoring balance to industry–academia relationships in an era of institutional financial conflicts of interest: Promoting research while maintaining trust. Journal of the American Medical Association 2003; 289(6): 741–6.
- American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: Genetic testing for cancer susceptibility. Journal of Clinical Oncology 2003; 21(12): 2397–406.
- Arar NH, Hazuda H, Steinbach R, Arar MY, Abboud HE. Ethical issues associated with conducting genetic family studies of complex disease. Annals of Epidemiology 2005; 15(9): 712–9.
- Burke W, Diekema DS. Ethical issues arising from the participation of children in genetic research. Journal of Pediatrics 2006; 149(1 Suppl.): S34–8.
- Bookman EB, Langehorne AA, Eckfeldt JH, Glass KC, Jarvik GP, et al.; NHLBI Working Group. Reporting genetic results in research studies: Summary and recommendations of an NHLBI working group. American Journal Medical Genetics. Part A 2006; 140(10): 1033–40.
- Offit K, Groeger E, Turner S, Wadsworth EA, Weiser MA. The “duty to warn” a patient’s family members about hereditary disease risks. Journal of the American Medical Association 2004; 292(12): 1469–73.
- Fernandez CV. The return of research results to participants: An ongoing debate modeled in cancer research. Harvard Health Policy Review 2007; 8 (1): 16–28.