Ethics in the Ambulance

The participants must be unable to consent as a result of their medical condition and the intervention involved in the research must be administered before consent from the participants’ legally authorized representative is feasible. These regulations require a number of special protections be provided whenever such a waiver is obtained, including “community consultation” and “public disclosure” before the study is performed. The regulations leave the specific form and extent of these activities to the discretion of the Institutional Review Board granting the waiver of informed consent and the investigator conducting the study.

The regulations define specific circumstances under which a waiver of informed consent for emergency research can be obtained: "The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular interventions." Several additional criteria must be met: the medical condition being studied must render the subject unable to give consent, the intervention involved in the research must be administered before consent from the subjects' legally authorized representatives is feasible and there is no reasonable way to prospectively identify individuals likely to become eligible to participate. Furthermore, the research must offer the prospect of direct benefit to participants and there must be no practical way to carry out the research without the waiver.

The regulations specify a number of special obligations for the investigator and for the IRB reviewing the waiver application to provide additional safeguards. These include a requirement for consultation with the community in which the research will be conducted and from which the subjects will be drawn; public disclosure to the community(ies) prior to the initiation of research of the risks and expected benefits; public disclosure after completion of the study of the results and the demographics of the participants; and an independent data monitoring committee. The regulations leave the specific form and extent of these activities to the discretion of the Institutional Review Board granting the waiver of informed consent and the investigator conducting the study.

The Ethics of Research without Consent In the case of emergency treatment, patients are presumed to want life-saving treatment and health care providers routinely act under the doctrine of presumed consent. While it is true that not all patients in all situations consent to life-saving treatment, the exceptions are so few and so narrowly circumscribed that the practice of treating patients in emergency situations without consent is universally accepted as an ethical practice.

There is no consensus about the presumed preference of an individual who is unable to consent to research. Many believe in that the inclusion individuals as research subjects without their consent or the consent of those who speak for them is inherently wrong. This position appears to presuppose that participation in research is not in the individual’s best interest. Yet, it is often patients who are critically ill or injured and are at high risk of morbidity or death, who are in greatest need of innovative treatments. Furthermore, participation as a research subject may sometimes be an altruistic act. In a setting where certain death is the expected clinical outcome, an opportunity to benefit future patients might be an individual's preference even when no benefit to oneself is expected. Thus it would seem that summarily prohibiting research without consent might be as much a violation of patient autonomy as requiring such participation.

The regulations attempt to limit the waiver of informed consent to situations where both the research participants and future patients are likely to benefit. By limiting the waiver to lethal conditions for which no good treatment exists, and to interventions that have scientific data supporting their potential effectiveness, and to protocols that hold out the prospect of direct benefit to the participants, the rule defines a narrow window within which research participation might be presumed to be the choice of most individuals. Under these conditions, the principle of respect for persons would therefore support research participation without consent, on the same basis that it supports emergency treatment without consent. However, because of the greater potential for the goals of research to diverge from the interests of the individual, these vulnerable individuals are afforded several other protections. The provisions requiring attempts to notify surrogate decision makers, the requirement for an independent data monitoring committee and the special provisions regarding community consultation and public disclosure all serve this purpose of protecting the interests of the participants.

My experience in talking to the communities about the PAD trial and the Community VOICES study, most people actually in the setting of a life-threatening emergency where the experimental treatment may be the patient's only chance of survival don't understand why we wouldn't just give it to everyone. So I think we need to help them understand the difference between formal research and a physician just trying to do what's in the best interest of their patient.

They don't become fearful and say "No don't do anything." They seem more amenable to allowing even high-risk interventions when the stakes are very high, when we're dealing with life-or-death diseases and injuries.

I think the requirements for community consultation and the requirements for public disclosure of the results after the trial including the demographics of the participants were really designed to try to guard against this problem.

On the other hand, let me say all of these criticisms presuppose that participation in these clinical trials is not in the patient's best interest, and that may or may not be the case. I don't think we can presuppose that without knowing more about the specific trials, the specific interventions, and what current treatments are available.

Often participating in a clinical trial is in fact in the individual's best interest. I talk a little more about that in the opening statement that I just posted to the web site.

I believe in crafting the current rules, much of the ethical debate about the underlying ethical principals of conducting research, were studied, and the evolution of informed consent being an absolute requirement to the consideration fo including vulnerable subjects who could not consent by themselves is often cited in the argument supporting research without consent, that the requirement of respecting persons is different when you have someone who cannot exercise their own autonomy by making decisions for themselves. Many of these same issues are raised in ethical arguments supporting research wtihout consent, that we must look at what is in the person's best interest.

I think an important point is that it's the medical condition from which the person is suffering that has deprived them of their autonomy. It's not these regulations. Given that the condition has rendered them incapable of making decisions for themselves, we now have described the conditions under which research can be ethically done among such subjects. It's not that we're taking the autonomy away. The disease, the injury is taking the autonomy away.

There are lots of similarities to this and discussions about pediatric research -- how you set up safeguards, how you do it appropriately.

I think the federal regulations are purposefully vague because the community consultation has to be tailored to the specific research study and the specific communities in which it's being conducted.

That said, I think that investigators are struggling with the question you raise: What sort of consultation is sufficient and necessary?

A national consensus conference on this topic last year identified the need to define effective strategies for community consultation as a very high priority on their research agenda.

I think anyone who has tried to do this realizes how complex a question this is. What may seem a simple issue of even defining "community" is much more complex when you try to operationalize it in a way that you can have effective communication about a specific study.

I personally believe that community consultation serves important ethical purposes, and that the requirement to perform it is an important part of these regulations. I just think that we as investigators need to do some work about the method and the evaluation of community consultation. I think once we develop some standards for how to evaluate whether or not consultation has been sufficient, then I think we'll be where we need to be.

So I think the real questions are not whether or not such research should be allowed, but how we can conduct such research ethically and safely. And I think the issue of being able to evaluate the effectiveness of community consulation and community notification is key to that.

Let me just point out the difference between community consultation and community notification, because these aspects of the regulation have created a great deal of confusion.

Community consultation is a dialogue. It's a two-way exchange of information between investigators and IRBs on the one hand and community members on the other. This is supposed to happen before the study has started and may allow the community to give important information to investigators about risks they had not considered or special circumstances that should be taken into account in a given community in a particular study. Community notification is the one-way flow of information out to the general public about the study.

I think the process of community consulation is really key because it actually has the potential to improve the research that's being performed. It can actually protect research subjects in a very real sense. So figuring out how to do that and how to do it well I think is very important.

Now some variability is a good thing, because different communities are different. But we've now had experience with several large, multi-centered trials where the same research protocol is submitted to multiple IRBs and wildly different requirements are placed on the investigators regarding community consultation activities and community notification activities.

This is why I think establishing standards to evaluate whether community consulation is effective is so important, because right now I can't say which of the 50 different activities required by the 50 different IRBs is the best approach -- we don't really have metrics to evaluate that, and I think those are very important to understand.

However, to answer your question as asked, I do think the regulations define a very very narrow window within which research can be done without consent. My personal feeling is that that window probably could and should be broadened, and that opinion frankly has been informed by my conversations with community members about this topic, and the data I've collected in a structured interview of community members about these issues.

I think some of the requirements certainly when they are very conservatively interpreted by IRBs are too strict. For example, the regulations required that the condition being studied be life threatening. Something like cardiac arrest, that carries an 80 or 90 percent mortality rate, is obviously life-threatening. What about a condition that carries a 50% mortality rate? What about 10%? Does that qualify as life threatening? What about conditions that may not be life threatening, but carry a risk of serious disability?

So I think some aspects of the regulation I would like to see revisited, because I'm not sure that they really distinguish between ethically different situations in terms of what is allowed and what is not allowed under the current regulations.

When we had the luxury of a 90-minute focus group, we were able to get people to understand and think about the issues involved in research without consent. I'm not certain that all investigators are prepared to undertake a 90-minute group process with large numbers of people in terms of their community consultation. So trying to distill how to do that effectively and efficiently is something we're working on.

I think the words you use, the way you present the information, can really affect people's response, and so you have to be careful not to use trigger words that create an emotional response. Then you really don't get people to think objectively about what you're asking. For example, we have an interview in which we described the same circumstances using different words and got different opinions from the same individuals depending on the wording.

I think we've learned a lot from the community VOICES study about how to communicate with community members that we'd like to encapsulate in individual modules that could be used by other investigators when they're trying to consult with community members.

I don't think it's a simple head count. I don't think you can just add up the number of people who show up at a meeting or the number of phone calls made in a random digit dialing approach. I think the evaluation has to include some look at the quality, the content, of the communication. It's not just how many people in the community did you talk to, but did you have a real conversation with people who represent the community in some relevant way, about what would be involved with conducting this study in this community.

And so I hope that as we go forward to establish standards that they are not merely numeric targets of numbers of people that have to be spoken to, but that we really focus on the quality of the communication. And we actually are starting to do some pilot work on how to go about doing that.

I don't think there is any apriori reason why the in-hospital use of a blood substitute couldn't meet the requirements of the exception from informed consent regulations. I think the question is a scientific one rather than an ethical one, and I've read quite a number of articles and commentary from individuals who don't seem to me to understand the scientific aspect of evaluating whether or not a trial qualifies for the exception.

So I don't really want to weigh in specifically on PolyHeme, but I do think the question of whether or not there is "clinical equipoise" is a scientific one, not an ethical one. I think the question also points to another difficult aspect of the regulation in terms of what is "unproven or unsatisfactory." I think if one looks at the clinical scientific evidence supporting the use of blood, they would be surprised at how little proof there is. But again, this is a scientific question, not an ethical one.

There's one other point I want to add, which is very important to me as an investigator. It is often the case that everyone who participates in a research study benefits from that participation regardless of the treatment group to which they are assigned. And for me, this is essential before I, as an investigor, will undertake a study.

For example, in the PAD trial, I believed that it was an open scientific question as to whether or not defibrillation by lay people who improve survival for out-of-hopsital cardiac arrest. However, I know that every building that I enrolled in that study benefited from participating in the trial, because whether or not the defibrillation was effective, all of the buildings got an emergency response plan and responders trained in CPR, so anyone suffering a cardiac arrest in any of those buildings was better off than they would have been if that building had not participated in the trial.

And so that's how I apply the issue of potential benefit to participants. I think it's usually possible to design a trial in such a way that there is benefit to participants regardless of whether or not the treatment you're studying is effective because of other things built into the trial, and I think it is my obligation as an investigator to design my study in that way.