Research Ethics in Critical Care Medicine
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Research Ethics in Critical Care Medicine P. D. LUMB Research in critical care medicine is founded on the trust of our patients and their families. In order to understand the integrity of this mutually responsi- ble relationship, it is important to review the foundations upon which it is built. Two core questions define our understanding of the importance between the patient’s expectations and our inherent clinical responsibilities. It is equally important to recognise that much of what has become today’s accepted critical care practice derives from uncontrolled clinical experimen- tation that each of us perform in the context of providing optimal patient care. Therefore it is important to understand the founding principles of the ethical considerations of patient care and research in the intensive care unit (ICU): Where do the principles come from and what do we learn from their application? Stated simply, there are four concepts: beneficence, non-maleficence, respect for persons, and justice. It is more important, however, to understand what they mean and how they apply to patient care in the current environ- ment in which accountability, transparency, and increasingly informed con- sumers are creating an environment that is much different from the paternal- istic climate in which medicine was practiced for centuries. Indeed, the pres- ent state provides for increased opportunity as outcomes-based therapeutic interventions become standard practice. Primum non nocere, first do no harm; a simple sounding phrase, but it is the core of an interesting argument between research and routine in practice. Ethical principles are important because they are the foundation of all legitimate research with, and the care of, human beings. Equally, they inspire and support society’s confidence in research concepts and support biomedical research autonomy while provid- ing useful tools that aid in the design, approval, and adjudication of research protocols. Finally, they serve as a set of specific rules and procedures that enforce humanity and humility. 106 P. D. Lu mb Three interesting viewpoints are shown in the writings of individuals whose reputations stand for ethical, humane treatment. Moses Maimonides (1135-1204) believed that patients were ends in themselves and should not be used as a ‘means of learning new truths’, while Roger Bacon (1214-1294) stat- ed that ‘the body demands that no error be made in operating upon it and so experience is so difficult in medicine’. It is interesting to note the significant difference in the experience of Walter Reed, whose ‘Yellow Fever contract’ indicated that his ‘volunteers’ preferred to intentionally risk contracting yel- low fever because it was implied that by so doing they would receive the ‘greatest care and most skillful medical service’. As an added incentive to vol- unteer, those soldiers who agreed to be exposed to yellow fever were prom- ised payment in gold, a significant inducement at the time. It appears that Reed felt the disease to be so endemic in the region, and that its isolation and treatment were so important, that this type of experimentation was warrant- ed. Today’s institutional review boards (IRB) and practicing physicians may feel differently. The first signs of research controls relevant today appear in a 1900 series of Prussian prohibitions that included the following concepts: the competen- cy of the experimental subject must be confirmed; full disclosure of experi- mental risk must be provided to the subject and/or surrogate; and informed consent must be obtained. At Nuremberg, additional safeguards were intro- duced that included: the concept of ‘voluntary’ consent; that the results of the experiment were anticipated to be fruitful and for the good of society; and that the subject should be at liberty to discontinue the experiment at any time. It is interesting to note that after World War II and the introduction of the Nuremberg Code, in which Principles 1 and 9 restate the importance of voluntary consent and the ability to discontinue the experiment respectively, and despite the recognised abuses to individuals during internment, many physicians viewed the problem as primarily belonging to a particular place and time, i.e. Nazi Germany, and was not seen as relevant to their practice. This belief was shattered by publications in the United States that revealed the extent to which experimental subjects required protection and that a defini- tion of subject protection that included incarcerated individuals had to be established. Also, the influence of experimental design and appropriate appli- cation of statistical methods leading to justifiable conclusions became a trou- blesome topic. Specifically, two studies – the 1966 New England Journal of Medicine Beecher Study indicating that analysis and therefore conclusions in large numbers of publications were flawed and the 1972 exposure of the results of the Tuskegee syphilis study in which US federal inmates were denied treatment in order to allow the disease to progress naturally – indi- cated that even under the ‘best’ circumstances, experimentation had to be controlled. Research Ethics in Critical Care Medicine 107 The breach of medical and ethical trust leading to the requirement for and consequences of the Nuremberg declarations occurred because the intent of experimentation was not to investigate outcomes of the scientific application of clinical protocols designed to promote the healing process. Rather, the investigation concluded that blatant experiments on humans that was in no way motivated by a therapeutic premise had been performed. It is recognised that the consequences of participation in a controlled clinical trial may be, and in some cases tragically, unexpected. Nonetheless, there must be the underlying expectation and principle that therapeutic benefit underpins the therapeutic regimen and that outcome will be closely watched and appropri- ate interventions to terminate unnecessary studies made if interim data analysis warrants such action. The above statements underscore the importance of respect for persons that is one of the cardinal beliefs in the management of medical research endeavours. Respect for persons incorporates the following two convictions: those individuals should be treated as autonomous agents and that persons with decreased autonomy are entitled to protection. Despite the fact that these principles have been mentioned above, it is the following actions that must be implemented. There is an inherent requirement for all medical inves- tigators to recognise an individual patient’s autonomy and that, especially in critical care practice, individuals with diminished autonomy must be provid- ed protection. It is largely in this area that current critical care research is both hampered and aided. The concept of beneficence is an easy one to understand and simply stat- ed indicates that physicians should do no harm to their patients, and should always attempt to maximise possible benefits while minimising possible harms of therapeutic intervention. The obligations of beneficence affect indi- vidual investigators, the institutions in which they work, research sponsoring organisations, and society at large because they underpin the framework of human investigation. Development of IRB’s and pharmaceutical watchdog panels have developed in the past few years, yet today’s headlines and National Public Radio broadcasts still retain the ability to shock. Recent alle- gations that Merck attempted to hide early reports of Vioxx’s cardiac danger are now being defended; yet, superficial arguments have already lost the pub- lic’s trust in the company and make ongoing enrollment in current clinical investigations increasingly difficult. In the case of particular projects, investi- gators and their institutions are obliged to give forethought to the maximisa- tion of benefits and the reduction of risk that might occur from the research investigation. Despite numerous false steps, principles alluded to in the preceding dis- cussion have become more formally adopted in a number of well established rules. Namely, respect for a person is easily recognised as the well-established 108 P. D. Lu mb requirement to obtain informed consent from any study participant, and the concept of beneficence requires that odds ratios and risk minimisation are taken into account when designing experimental protocols. Statistical avenues must be available that will indicate if and when studies need to be terminated, either because the results are unexpectedly good and it would be unfair to withhold therapy from non-participants, or the converse. Justice is easily identified as the common practice to include multiple ethnic and cul- tural populations in any trial; certainly, no racial selection bias is acceptable, especially if there is a presupposition of increased benefit to be derived from study participation. There is an increased public awareness that in order to advance medical therapeutics and interventions human experimentation is required. Therefore, a new tension is apparent in the ethical undertaking of new clini- cal interventions and therapeutic trials. Redefinition of the situation in which the ethics codified at Nuremberg and in prior thought and practice (Maimonides, Bacon) equaled subject protection to the current requirement of medical innovation in which ethical principles must provide access to human subjects for medical therapeutic trials is necessary. This is a difficult paradox because all investigators