Clinical Ethics in Anesthesiology. A Case-Based Textbook

4. Research and publication

27. Ethics in anesthesiology research using human subjects

A.M. Viens

The Case

A group of anesthesia researchers undertook a research project to determine if injection of a sedative drug into the subarachnoid space would improve effectiveness of pain control post-operatively for labor and delivery. The literature at the time had scant information about toxicity of the drug in question when administered in this way, although some anesthesiologists had been doing so anyway. While a handful of studies had demonstrated no obvious adverse outcomes in animal models, several studies suggested dramatically otherwise, including one study in which rabbits demonstrated serious spinal cord histological changes. No study had examined the use of the drug in the dosage and mode of administration proposed by the investigators. The investigators obtained institutional ethics review board approval and the study was carried out. No human subjects appeared to suffer an adverse effect. A modest improvement in analgesia was seen in some, but not all, patients. The project was written up and submitted to a journal for publication.

All anesthesiologists will encounter ethical issues related to research. It may be through engaging in their own primary or clinical research projects, in their practice treating a patient who is a research participant in a project from another treating speciality, applying for research funding and ethics approval, publishing research results, or even through determining departmental/divisional funding priorities. The focus of this chapter will be solely on the ethics of conducting research involving human subjects – in particular, some of the main ethical issues that arise with the kind of research conducted by anesthesiologists in clinical settings.

The history of anesthesiology research on human subjects, while at times undertaken in varying degrees of ethically permissible ways, has produced many techniques that are the mainstay of modern surgical, peri-operative and intensive care. It should be recognized by anesthesiologists that both clinical research and research ethics share a common reason for undertaking such activities: to improve clinical practice and care. Research constructed, conducted, and disseminated in an ethical fashion will likely lead to quality improvement, improved outcomes, shared knowledge and best practices, amongst other considerations.

Research ethics in general, and the ethical conduct of clinical research in particular, are concerned with ensuring research participants and their interests are protected, and that the clinical research they are involved in serves the interests of science and the community in which it is conducted.

Most anesthesiologists will split their time working in the operating room, intensive care unit, or pain clinic and divide the rest of their time in administrative, teaching, and research roles. Each of these positions and environments will have their own obligations associated with them; and it is often the case that many of the obligations and issues that arise in the clinical setting will have some overlap with research activities.

Anesthesiologists conducting research have obligations to patients, colleagues, and society that should be adhered to. Some of the main research-based obligations include the following.

• Study design and performance should be based on a thorough knowledge of the scientific literature and other relevant sources of information.

• Studies should address a research question of sufficient value to participants to justify risk exposure.

• There should be clear research question(s) that can be answered reliably and efficiently.

• Sufficient number of participants should be enrolled in a reasonable period.

• All research projects should be reviewed by relevant research ethics committee(s) for consideration, comment, guidance, and approval before the study begins (even studies that are noninvasive or involve accepted therapies need approval both for regulatory reasons and to consider issues of confidentiality, cost and voluntariness).

• Informed consent should be obtained for all parts of the project, including any resulting adverse effects that may require modification of protocols or care.

• Undue inducements, duress, or coercion should not be used in recruiting or retaining participants.

• Research should be conducted only by individuals with the appropriate medical qualifications and scientific training.

• Findings should be valid and reproducible.

• Research design should be preceded by careful assessment of predictable risks and burdens to the individuals and communities, and participation should be dependent upon confidence that the risks involved can be satisfactorily managed.

• Research protocols, and information given to participants, should have clear provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the research study.

• Participant privacy and confidentiality in the collection, analysis, storage and/or reuse of identifiable and anonymized data should be ensured.

• Positive and negative research findings should be disseminated.

To some, these may seem like scientific or legal considerations, and not ethical considerations. However, these considerations are ethical in that designing and executing a study that is not scientifically rigorous or exhibits scientific misconduct puts participants at risk of burden, loss, or harm.

Why anesthesiology research is special

The kind of research conducted by anesthesiologists deserves special attention by virtue of the fact that a good deal of the human subject research conducted will be with participants who are potentially themselves vulnerable – children, women in labor, critically ill patients – or in temporary vulnerable states – individuals who are sedated, unconscious, about to undergo surgery, in pain, or being resuscitated. This is not to say that vulnerability is not found in other areas of research, merely that it is an acute and central concern in anesthesiology and peri-operative clinical research. Moreover, the unique environment in which clinical anesthesiology research is conducted and consent is obtained, also presents specific challenges. As a result of this, this chapter will focus on three areas where these issues are especially important for the ethical conduct of clinical anesthesiology research: enrollment and consent, potential conflicts of interest, and the balance of risk and benefit.

Enrollment and consent in clinical research

Free and informed consent to participate in a research project must be obtained from the participant or from an appropriate legally designated representative for participants who do not possess the capacity to consent. Participants incapable of providing consent for research participation require special protection.

The consent process should involve providing the participant with sufficient information – in lay language – that includes the aims of the research and potential outcomes, inclusion and exclusion criteria, what happens if the participant agrees to take part, what methods, techniques, or devices will be used, any risks or benefits to participating, what will happen to specimens or data obtained from research, arrangements for ensuring anonymity or confidentiality, and how results will be disseminated, amongst other relevant considerations.

It should be made clear that the primary purpose for medical research is to understand the nature of disease and/or improve preventive, diagnostic, and therapeutic interventions. As such, the decision to participate in research need not result in any direct personal benefit – even if there are associated indirect benefits. It should also be made clear that a decision not to participate will have absolutely no effect on their clinical care.

Research participants need to be given sufficient time to reflect on the information contained within the project description and consent form, and to consult with friends or family members (should they wish). The unique environment in which most clinical anesthesiology research takes place will make this a challenge that must still be accommodated.

It must be made unambiguous that research participants and their data (assuming it is not anonymised) can be withdrawn from a study at any time without explanation and that this withdrawal will also have absolutely no effect on the quality or level of their clinical care. Research involving general anesthetics or other potent central nervous system depressant medications will constrain a participant’s ability to exercise their right to withdraw from a study and this factor must also be taken into account and accommodated within the design and conduct of a study. Due attention must also be paid to the fact that approaching patients in a clinical setting for research purposes will raise questions about a patient’s privacy and the confidentiality of medical information and research data.

The Canadian Anesthesiologists’ Society1 suggests that pre-operative consent for clinical anesthesiology research may be obtained either before admission or on the day of the scheduled surgery provided that:

(1) Patients are not under the influence of premedication.

(2) Risk to the patient and time commitment to the study are not significantly different from routine clinical care (e.g., during drug trials in which a patient may be randomly assigned to receive one of several anesthetic regimens, using approved medications).

(3) After verbal explanation from the investigator or research assistant, and in the absence of the investigator or research assistant, patients are given time to read the information sheet and consider the risks and benefits. Patients should have an opportunity to raise any further questions or seek clarification on any points concerning the nature of the study, alternatives, risks, benefits, etc.

(4) Patients who feel they are under duress, or require more time to make a decision, should be advised to decline participation in the study.

(5) Investigators document in the healthcare chart the nature of their consent process for patients who agree to participate in a research protocol.

Dual role of anesthesiologist and clinical researcher

When anesthesiologists who treat patients also engage in clinical research, they take on dual roles that have important differences that may give rise to potential conflicts or obligations that come into tension with an anesthesiologist’s duty of care.2

One area of potential concern is financial conflicts of interest.3 While the vast majority of clinical research is undertaken for scientific reasons, it is undeniable that there are a number of positive upshots that can result, including promotion, tenure, funding, prestige, etc. As a result, the existence and even appearance of conflicts of interest must be mitigated or removed. Other financial conflicts of interest may include finder’s fees, institutional funding and sponsorship, owning stock in a company whose product you are researching, or being involved in a spin-off company that may commercialize the results of the study. Research protocols, participant information sheets, the consent process, and publication/presentation of the resulting research findings should include information regarding all potential conflicts of interest, including funding, sponsors, affiliations, and positions.

Another area of concern is that potential research participants may be in a dependent relationship with anesthesiologists – either as the direct treating physician or by being a patient who is treated by a colleague on the same service. Many patients will find an approach to participate in a research project by their treating anesthesiologists or a project being conducted at the institution in which they are receiving treatment more difficult to turn down than they might otherwise have in a different setting. Anesthesiologists need to be careful in their approach of potential participants for enrollment that the attitude, situation, or environment is not in any way coercive or involves an unnecessary pressure. If possible, it may be advisable to have an appropriately qualified individual who is completely independent of the physician or research relationship conduct the participant enrollment and/or consent process.

According to King and Churchill,2 physician-researchers should:

• Discuss the differences between research and medical practice with patients.

• Disclose both physician and researcher roles to patients, and distinguish them (‘‘switch hats’’) as needed.

• Consistently use ‘‘research’’ terminology, not ‘‘treatment’’ language, when referring to investigators, subjects, and experimental interventions.

• Present benefit to society as the sole or primary goal of research.

• Explain that benefit to research participants, while often hoped for, is always uncertain and may be unlikely or impossible, depending on the design and phase of the trial.

• State when clinical benefit from the experimental intervention in a study is not possible or not likely.

• When clinical benefit from the experimental intervention in a study is reasonably possible, describe it clearly, including its nature, magnitude, duration, likelihood, and limits.

• Remember that, even though clinical research is not medical practice, researchers can, do, and should care about and for their research subjects.

The Helsinki Declaration4 maintains that, “The physician may combine medical research with medical care only to the extent that the research is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects.” When holding the dual role of clinician and researcher, in circumstances where the two come into conflict (or the potential exists to give rise to the appearance of conflict), the role of clinician must take priority over the role of researcher.

Risk, benefit, and clinical trials

Many of the risks and benefits associated with participation in clinical anesthesiology research are based on the use of the anesthetic itself and not participation in the research project.1 However, this is not always the case. The case study at the beginning of the chapter, which is based on an actual research study, contains a number of ethical issues of concern that could arise in other clinical anesthesiology research.

The investigators conducted their research project when there was inadequate information at the time the study was performed, regarding the safety of the proposed procedure. The benefits arising from the study were questionable – very effective labor analgesia already existed at the time and, as such, the research outcome did not appear to warrant the risks. The quality of the informed consent obtained could also be called into question, since the investigators very probably did not disclose the results of some animal model experiments, which affects the accuracy of communicating the full risks and benefits of participation. It is difficult to imagine that many patients would have agreed to the experiment if they knew what happened to the rabbits. The fact that these issues were not flagged by the research ethics committee leads one to believe that either there was a failure to adequately screen the study or the investigators did not provide all of the scientific information available on safety and efficacy – or both.

Moreover, even with such issues, the journal in which the research was published could not resist the desire to publish the findings given the lack of negative outcomes and the parallel publication from an unconnected source of a well-designed animal model that, in some aspects, paralleled the experiment involving human subjects. While the journal did include an editorial accompanying publication of the article that outlined the ethical dilemmas in which the editors found themselves in, it does raise the question of whether publishing the results will have the effect of making it easier to justify other cases of publishing unethical research results. The Helsinki Declaration4 requires that medical research must conform to prior “… adequate laboratory and animal experimentation…” and that “[r]eports of research not in accordance with the principles of this Declaration should not be accepted for publication”. (For more on publication ethics, see Chapter 35.)

This example is also illustrative of an issue that frequently occurs in clinical anesthesiology research directed at symptom management (e.g., pain, anxiety, nausea), for which adequate, if not perfect, treatments already exist. That is, that this study exposed its subjects to potential adverse neurologic consequences for minimal gain in an area that already has significant proven treatments. When undertaking this kind of research, investigators should be able to demonstrate that there is no reasonable alternative therapy or methodology that would eliminate or mitigate the risks associated with participating in the research study. (See also Chapter 32.) While we must be vigilant against the increased risk of harm associated with participating in research, it must also be recognized that such risks include being exposed to untested or unevaluated medical interventions.5

While research ethics is a large area with many interesting and complex issues, this chapter has only been able to touch on some of the main ethical concerns associated with clinical anesthesiology research. Researchers are encouraged to apply, and interpret, existing ethical guidance to research design and conduct, as well as to do further research and reading on issues in which they want more in-depth information and analysis. In addition to the ethical issues discussed here, it is very important that professional, institutional and legal requirements concerning research with human subjects within your jurisdiction are adhered to, and respected.

Key points

• Research studies involving human subjects should be based on a thorough knowledge of the scientific literature, and should address questions of sufficient importance to warrant the risks.

• All research should be reviewed by relevant research committees for guidance and approval.

• Informed consent should be obtained from subjects, without undue inducements, duress or coercion.

• Subjects should be given sufficient time to reflect on the information they are given about the research study.

• Decisions not to participate or to withdraw from a study should never affect the quality or level of a patient’s care.

• Conflicts of interest on the part of the researcher should be avoided or mitigated, and where they exist be disclosed to subjects.

• Both positive and negative results of the research should be disseminated.

• Particular care should be given when research is directed at conditions for which adequate, if imperfect, treatments already exist.

References

1* Committee on Bioethics (1999). Guidelines on the Ethics of Clinical Research in Anesthesia. Toronto: Canadian Anesthesiologists’ Society.

2* King, N.M.P. and Churchill, L. (2008). Clinical research and the physician-patient relationship: the dual roles of physician and researcher. In The Cambridge Textbook of BioethicsSinger, P.A. andViens, A.M., eds. Cambridge, UK: Cambridge University Press, pp. 214–21.

3* Lemmens, T. and Luther, L. (2008). Financial conflicts of interest in medical research. In The Cambridge Textbook of BioethicsSinger, P.A. and Viens, A.M., eds. Cambridge, UK: Cambridge University Press, pp. 222–30.

4* World Medical Association. (2008) Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Washington: World Medical Association.

5* Ashcroft, R.A. and Viens, A.M. Clinical Trials. In The Cambridge Textbook of BioethicsSinger, P.A. and Viens, A.M., eds. Cambridge, UK: Cambridge University Press, pp. 201–6.

Further reading

Beauhamp, T.L. and Childress, J.F. (2001). Principles of Biomedical Ethics, 5th edn. New York, NY: Oxford University Press

CIOMS (2002). International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: Council for International Organisations of Medical Sciences.

Faden, R. and Beachamp, T.L. (1986). A History and Theory of Informed Consent. New York, NY: Oxford University Press.

Freedman, B. (1987). Scientific value and validity as ethical requirements for research: a proposed explanation. IRB, Rev Hum Subj Res 17, 7–10.

Maltby, J.R. and Eagle, C. J. (1993). Informed consent for clinical anaesthesia research. Can J Anaesth40, 891–6.

Levine, R.J. (1988). Ethics and Regulation of Clinical Research. New Haven, CT: Yale University Press.

Slowther, A. and Kleinman, I. (2008). Confidentiality. In: Singer P.A. and Viens, A.M., eds. The Cambridge Textbook of Bioethics. Cambridge, UK: Cambridge University Press. pp. 43–8.

Sykes, K. and Bunker, J., eds. (2007). Anaesthesia and the Practice of Medicine: Historical Perspectives. London: Royal Society of Medicine Press.