Kimberly Nordstrom
Psychiatric Emergency Services, Denver Health Medical Center, Denver, CO, USA
Yes, yes, both statements come from ancient texts and may be considered outdated. But are they? When you became a physician was your goal to have the biggest name in research or to help (not harm) people? Even though these tenets seem obvious there have been several examples in which physicians, in the name of research, chose to ignore them. For instance, there were some Nazis in Germany in World War II and some physician-scientists working with the Tuskegee Institute. They did not do any real harm did they? Well, not only did they have a direct negative effect on the patients, they have profoundly affected people’s trust in clinical research to today.
According to the National Hospital Ambulatory Medical Care Survey, cited by the Centers for Disease Control, there were 129.8 million visits to emergency departments (EDs) in 2010 [1]. With the vast numbers of patients and diverse presentations from emergent to urgent to even ordinary care, the ED allows for the capture of a breadth of information not to be found elsewhere. In the same vein, because the ED is the “front door” and not a specialty clinic, all diagnostic categories and disease types make an appearance. So, why is not more research done in this setting, if there is such a wealth of information? If you have ever stopped long enough and looked around, you will find people hustling from one patient to the next, saving lives. Is there really room for research in such an environment? My guess is that there is, or you would not be reading this. So, what gets in the way and what can we do to get over some of these hurdles?
There are several issues that come up when discussing research in the emergency setting, none bigger than ethical concerns, especially around informed consent. The purpose of this chapter is to delve deeper into research with special (protected) populations found in the acute care environment, and help you navigate the murky waters.
A detailed discussion of ethics in acute care and emergency department research can be found in Chapter 8 of this book, but the issue of ethics becomes especially important when it comes to special populations, so the following is a specific orientation towards these populations. What are the special populations found in acute care? They are the young, or not yet born, pregnant, intoxicated, and incapacitated patients. One may even consider homeless patients as a special population that needs additional consideration.
Firstly, let us review the main ethical principles. Then we will review regulations that pertain to these populations. Lastly, we will look at case examples and apply the fundamentals.
There has been discussion on ethics in medicine since the beginning of time but only after the atrocities mentioned above were the basic elements codified. You may have heard of the Nuremburg Code and the Declaration of Helsinki. Countries have gone further than these early beginnings in codifying ethical principles. In the United States, the National Commission for the Protection of Subjects of Biomedical and Behavioral Research developed the Belmont Report (1979) [2]. Rather than being a strict rule book, this report created an overarching framework to be used to guide researchers in the area of ethics. There are also international guidelines to help direct researchers in this area [3].
Belmont has you consider a few fundamental principles: respect for the individual (this is where you find the idea of informed consent), beneficence and justice. Beneficence usually refers to the costs to the individual and the gain to society; justice is more specific to the idea of not allowing an inequality of those shouldering the burden. An example of justice is not singling out a specific race when testing something that would affect the larger society.
This sounds simple but actually requires a few things (Box 16.1); for example, the patient needs to have “capacity” to be informed, the person must understand what is being requested and what the effect will be on him/her (this could be physical, emotional, or other costs such as time commitment), the person must actually agree (imagine that!) and consent must be achieved without coercion. Ah … new question. What is coercion? Coercion can be in the form of a threat but tends to more likely come in the form of money. Most review boards agree that a small amount of money for the participant’s time and efforts is alright, which is why you may see on research advertisements “$5 for each blood draw.”
In research, beneficence incorporates the idea of giving the participant maximum benefit with the goal of minimizing harm. If you read up on beneficence, you will see that another term tends to show up, “non-malfeasance.” This is the act of not doing harm. Doing no harm does not equal doing good. In fact, sometimes these principles are in conflict. Imagine that you are researching a medicine that helps reduce pain for terminal patients. This medicine, though, hastens death. Your goal is to reduce pain but you are studying a medicine that will shorten the person’s lifespan. In this, you are doing good (reducing pain) and doing harm (hastening death).
The concept of justice is that there should not be inequality in the shouldering of risks versus the benefits. An example of this is use of minority populations for research that benefits society as a whole. The American Medical Association has weighed the concept of justice with that of the fact that some vulnerable populations (chronically ill and socioeconomically disadvantaged) may seek out research for altruistic reasons. The opinion from the Council on Ethical and Judicious Affairs is that research should not burden socioeconomically disadvantaged populations in a disproportionate manner but they should not be categorically excluded or discouraged from research, either. The inclusion or exclusion of particular populations should be decided based on sound scientific principles [4].
Clear as mud? This basically means that you cannot use only one subset of patients when creating your study unless there is a scientific reason for doing so. It may be that all of those suffering from X disease also are economically disadvantaged. You are not purposefully trying to find economically disadvantaged subjects to understand a larger population and, after reading the fine print above, you now understand, you don’t want to exclude them just because they are economically disadvantaged.
There are special provisions within the Code of Federal Regulations for pregnant women or fetuses, prisoners and children; subparts B, C, and D, respectively [5]. In fact, institutional review boards (IRBs) are to ensure that additional safeguards are included in all studies that include vulnerable populations, defined as “children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons” [6]. In the Department of Health and Human Services’ IRB Guidebook [7], they also refer to the terminally ill as a vulnerable population that requires additional safeguards. Why does this matter to the research based out of an ED? Who comes into an ED? All of the above. Rarely do you find the adult, non-minority, non-mentally ill, non-economically nor educationally disadvantaged person in the typical ED. Meaning, most patients have something that might place them into a vulnerable population designation. With this said, it is important to recognize your patient population and make sure that there are safeguards in place to cover all vulnerable populations. If you purposefully focus on one population (either excluding or including) the scientific rationale will need to be stated. Also, if your protocol and IRB approval does not specify the inclusion of specific vulnerable populations, then they are not included.
Let us look at each of these “special” populations to better understand where we stand on our ability to use them in research studies.
Who are the ‘special populations’ in pregnancy? The law has clear rules for the fetus, the pregnant mother, and specific guidelines for the pregnant teenager.
Rules around research that may affect a fetus are relatively strict. If the fetus is in utero, individual regulations regarding pregnant women and fetus apply. The researcher will need to show that the study has been performed on animal models, or, if able, non-pregnant women, and this initial research should be the basis of the risk–benefit analysis going forward. Research is generally allowed if the risk is considered not more than minimal. If greater than minimal, the research must confer an anticipated benefit to the health of the mother or fetus. Also, the consent of the mother and father on behalf of the fetus is necessary. There are a few exceptions regarding the consent of the father: identity or whereabouts unknown, not reasonably available, or if the pregnancy resulted from rape [8]. If these exceptions are not met, there is quite a hurdle to overcome if researching pregnant women in the ED setting.
For the pregnant mother, the research activities have to either meet the health needs of the mother and place the fetus at only the minimal necessary risk or the risk to the fetus is minimal (such as an ultrasound or a maternal diet change). As noted above, consent must be given for the fetus participation [9].
This is a tough one because laws around emancipation are different in each state. It is important to be familiar with the “age of majority” for your state, as this will determine whether one or both parents need to consent or if the teenager is able to do so on her own.
The World Health Organization created guidelines for adolescent research involving reproductive health. The themes include that the research was specific to the population – could not otherwise be done on adults – there is a relevant need for the research, and it is low risk with maximized benefit. Sound familiar – basic ethical tenets. The guidelines also stress the need for confidentiality [10].
Research involving children usually requires assent (instead of consent) of the child/minor and permission by the parents. Similar to the pregnant teenager, there may be state law that is more restrictive/informative on this matter. Research has to comply with both state law and federal regulation.
Even though these three groups are separate clinical populations, they have very similar ethical concerns. With cognitive impairment, there are concerns regarding capacity. This comes down to being able to give informed consent that is free of coercion. There are also concerns that these populations could be targeted by the unscrupulous researcher for studies that are not specific to the population and are otherwise onerous (experimental drugs/surgeries that have high risk and little benefit). Interestingly, the US Department of Health and Human Services and the Food and Drug Administration (FDA) only require that someone who is familiar with working with these subjects is on the IRB. There are no particular requirements regarding the research. That said, there is plenty written on the matter. Generally, a prudent researcher would need to show that there is some relationship between the condition being studied and the target population, especially if the population is considered cognitively impaired.
Subjects with “cognitive impairment” may have capacity. This would need to be determined prior to the outset. In the case of delirium or active mental illness, capacity may change over a period of time. So, if research is being done in this subgroup, measures should be in place to follow capacity. For those who will never have capacity, there are no specific regulations to guide behavior but ethics would suggest that the patient’s guardian/medical decision maker give consent, that the study would benefit the population with minimal risks and that the research actually requires the specific population in order to benefit the population. In the ED setting, you are generally safe if you follow guidelines set for “waiver of informed consent” (see below).
Firstly, it must be shown that this population is being targeted in the research for some reason other than convenience. The major concern of using prisoners in research is whether a prisoner can make an informed decision that is free of coercion. If the benefits of participating in the research (being able to be on a special unit, staying in a hospital for a longer period than just an ED stay, etc.) get in the way of a true risk/benefit analysis, this would be considered coercive. Also, in terms of justice, one would need to consider if the prisoner is having an unfair “burden”; that is, unless the research was for a particular issue surrounding prisoners, to only use inmates would not be considered ethically just. The regulations in place speak exactly to those principals. Researching this population is limited to having a valid reason for involving this specific population (conditions that affect prisoners, causes of criminal behavior, prisons as institutional structures, etc.) [11].
This brings up the waiver of informed consent. In the ED, there may be subjects who cannot give informed consent. This would include those patients who arrive confused, frankly delirious, or even unconscious. Regulators understand that research on this patient population is necessary to forward medical techniques that may save lives in the future. They also understand that experimental techniques can lead to a life saved during a study. The waiver of informed consent was to help aid researchers in EDs in studying these techniques. Even though these concepts are understood, the waiver of informed consent is complicated by stricter state laws. Federal policy allows a waiver of informed consent only in those instances where there is no more than minimal risk to the patient [12]. The FDA expands this somewhat in recognizing that in the emergency department there may be life-threatening situations with no approved therapy available and that the research is more likely to save a person’s life. The statute speaks to an equal or greater likelihood of saving a life with the therapy being studied [13]. There may be more restrictions placed by your state, so make sure to look into any state statutes that might pertain to this prior to IRB submission. Another useful tool is “deferred consent.” Similar to the waiver of informed consent, this needs to be written into the IRB protocol and the procedure needs to be clear. The basics of deferred consent, is that it allows the researcher to initiate the research and get consent as soon as is possible from either the patient (capacity restored) or a proxy. If consent is not obtained, the information needs to be destroyed and not used in the research findings.
So, now you have most of the theory, rules, policies and regulations. How do you apply it? Let us practice with a few case scenarios.
You want to know whether, in patients intoxicated with alcohol, if using intramuscular olanzapine might affect oxygen saturation. You read a retrospective analysis and now want to study it prospectively. In your particular ED, intramuscular olanzapine is used regularly on agitated intoxicated patients; oxygen saturation just has not been followed. So, this is “normal” treatment in the ED with the plan of following a particular measure.
Let us talk about the main ethical principles. Beneficence: maximizing benefit with least amount of harm. In this case, it is treatment as usual. The only difference is measuring pulse oximetry at specific intervals. This would be considered as very little to no harm caused by the research. Justice: Uh oh! You are focusing on a population of intoxicated people. Actually, in this case it is okay, as you are trying to understand something within this population. It would be problematic if you were only doing this research on African American males and extrapolating the findings to all intoxicated persons. Also, you may exclude certain populations (children, etc.) because intramuscular olanzapine is not FDA approved for the population or may cause harm. Last but not least … informed consent. This is a little trickier and may come down to how intoxication is being defined. A person may be “clinically sober” but have a blood alcohol of 0.10. If you define intoxication by a number, you may be able to speak to the fact that some of the participants will have capacity. Otherwise, this would be one of those research protocols that ask for a waiver of informed consent. Remember, federal authorities are generally okay with using the waiver if there is minimal risk to the patient.
You are interested in pharmaceutical research and want to know if a particular new medicine that is supposed to treat arrhythmias works in elderly patients. You want to study all patients ages 65 and up who come through the ED.
Hmmm … can you imagine some issues with this one? It seems that it would be okay to take “all comers” of a certain age because you are not discriminating. Right? Actually, it may be difficult to include “all” seniors – you will be hitting some special classes: the incapacitated, demented patient or inebriated patient, possibly an elderly prisoner. In these cases, you need to talk specifically of why you are including or excluding these subclasses. Is there a reason that the medication would work differently on someone incapacitated or in the penal system? Probably not – so you would need to add these populations to exclusion criteria. In both cases, informed consent would be the main principal – in the first instance, capacity to make the decision and, in the second, possibly coercion.
You want to test a new coagulant reversal agent on patients with massive intracranial bleeds. The agent needs to be given within two hours of the bleed to be effective. You understand that many patients will not have capacity on presentation and there will be times when the patient-subjects arrive without family members.
Of course, the main concern is informed consent. This appears to be a perfect case for the “waiver of informed consent.” You will need to show only a minimal risk (not likely) or that there is not a proven therapy already in place for this life-threatening emergency. What happens if there is already a “proven” therapy? Well, if that therapy is believed to have more risks than the new therapy and if the proven therapy could be given at some point after the newer treatment (after “failure”), the IRB may allow the waiver.
You want to study factors in fetal demise with teenager pregnancy. You will need each teenager to have an ultrasound and several blood tests. The ultrasound would be a standard test performed in such situations but some of the ordered blood tests would be extra and only for research purposes. Factors that you hypothesize to be related to fetal demise in teenagers include drug use, mental illness, and inappropriate prenatal care. Wow! This brings up several issues. Firstly, focus on the obvious issue of the pregnant teenager. Can the teenager consent (without a parent) or assent with parental permission? You need to look to state law on this around emancipation. Since you want to follow all cases that come into the ED (teenagers of all ages), you will have to note the law and how you plan to deal with it. What about the case of the pregnant teenager who wants to participate with a parent that is solidly against the research? Again, there are clear rules on emancipation but there are “subgroups” that may still be considered to not have capacity – very young teenagers and those with chronic cognitive impairment.
The hypotheses of the research lead to subpopulations: the teenager who comes into the ED intoxicated on alcohol or drugs, the mentally ill teenager, and possibly the economically disadvantaged teenager. The intoxicated teenager may not have capacity due to the intoxication. A capacity tool can be used to help determine this. The mentally ill teenager – again, does the subject have capacity, did the subject intentionally harm the child? Is having mentally ill pregnant teenagers necessary to answer the question? To exclude them may negatively affect this special population in the long run by not collecting this important information (think “Justice” here). Lastly, the economically disadvantaged teenager may be coerced to enter into the research if there are monetary inducements. As noted earlier, IRBs do not tend to find minimal payments for procedures to be coercive.
In truth, other than making sure that subjects can consent, this study follows standard care, with the only exception of extra blood draws, which would be considered minimal risk. Also the study does not “target” the subpopulations listed in the hypothesis list. These are all advantages and should ease its approval with the IRB. A word to the wise: your proposal needs to clearly spell out state laws on age of majority/emancipation and exactly how capacity is determined.
The point of this chapter was to help remind you of ethical principles that we sometimes take for granted and to apply these principles to special populations. It is easy to get very excited about a research topic and lose sight of the cost to the individual. Emergency medical and psychiatric research is important and can answer questions that cannot be answered in other treatment settings. Do not be daunted by the ethics; become familiar with them and allow them to help guide your research plan. Remember … it is all about the karma. Good luck.