The following address by Christine Toevs will briefly review the history of medical research and the regulations surrounding emergency consent research, and discuss the ethics of research in a population that may not truly be informed of the risks and benefits, or even of the research itself.
This address was originally given at CBHD's 2015 Annual Conference, Science, Research, and the Limits of Bioethics.
So for those who haven’t heard me speak before my name is Christine Toevs. I am a trauma surgeon and with all that comes with being a trauma surgeon including the ability to speak loudly. I also have a particular interest in end-of-life issues and went and got a master’s in bioethics and I also have board certification in hospice and palliative medicine. As my husband says I’m a little overqualified and I’ve started talking about maybe getting an MBA if for no other reason than to poke him. He’s like, “Really, another degree?” and I’m like, “Well, you know, you kinda get board after a while. I need a little something to do.”
I want to talk today a little bit about ethics of emergency consent research. And to do that, we need to talk a little bit about the history of research. We’re talking research on human subjects, obviously, and emergency consent. Since the beginning of time we have been doing things to human beings without their consent, and there’s been a large number of documented studies. Everything from within institutions, outside of institutions, people signing up for things that they thought they were signing up for and getting something entirely different. And so we started this. And well documented at least in terms of current history in terms of the 1800s.
As you guys know the Nazis were sort of the big ones that brought most of this to the forefront in terms of what was being done. And if any of you remember during the [19]80s and ’90s the massive amount of discussion that occurred in the ethics literature about whether or not to actually use any of the research that they had done, which fortunately they determined—or unfortunately, depending on how you look at—it wasn’t done correctly and added nothing to the scientific knowledge anyway, so that all went away. But, you know, we immersed prisoners in cold water, we used high altitude chambers, we used typhus, and then ultimately we had the medical trials in ’46 and ’47 which went after 20 physicians, 23 defendants and convicted 15 of them. I’m unclear why all of them were not convicted based upon the research that they had done.
As a consequence, the Nuremberg Code came out which came out with ten rules. And we all know [when] we write rules people follow them, that’s right? That’s why there’s 50,000 pages a year in the Federal Register of all the things we’re supposed to follow and we all keep up with everything we’re supposed to follow. So we’re going to write another set of rules after World War II and that’s going to make things all better and people are going to behave ethically and they’re going to do what they’re supposed to do. And so they determine that in order to do this you needed voluntary consent, good science, potential benefits, minimize the harms, the degree of risk had to be less than the potential benefit, and subjects could end their participation and they could terminate the study. Of course, none of which happened in the world of the Nazis or for any of the unethical research that had occurred up to that point.
And so then they also said that this could apply only in certain situations and they began to look at when is research actually criminal and when are we not doing this correctly and when do we need more guidelines? So after World War II, now that we have the Nuremberg Code, everybody’s going to behave, right? So then we did the radiation experiments for many many many years and I would encourage you if you have any interest to this to look at the source of all knowledge, which is not the Bible that sitting here, according to Wikipedia, but I would encourage you to look at Wikipedia, which actually has a pretty phenomenal summary of all the radiation experiments that were done on people. And they’re pretty terrifying actually. And we went even further even despite all of these codes and regulations. We went and infected disabled children with hepatitis, we went through the institutions again, and we started doing more of this. The expectation was that since we’re Americans we were doing it, it was okay as opposed to the rest of the world. Really tragic actually.
So we come out with more regulations. In 1964 we come out with the Declaration of Helsinki with 7 revisions about how we’re going to respect the individual and how we’re going to do this because now that we’ve written it on paper everybody’s going to behave again. And we’re going to look at informed decisions and the investigator’s duty to the patient and the subject’s welfare should come first and that you have to be very careful with vulnerable populations.
So Henry Beecher in the New England Journal of Medicine in 1966 looked at research up to [that] date and whether or not with all the new regulations we had actually been following them. And guess what? We’re not. So out of all the research that had been published, they had 22 recent unethical medical experiments at major medical centers with prominent researchers, most of them funded and most of them published in prestigious journals. So despite all of these regulations, multiple codes that had come out, people still weren’t following them and they were getting funding and published for this unethical research, and ethical problems remain mainstream.
And you guys all remember this, right? It’s interesting. This is really a fascinating study. If you look at the details of how this happened. So 600 African-American men in Tuskegee, Alabama. The researchers flat-out lied and coerced. And they promised them free health care and they promised them that they were getting better, and the ones that actually sought medical treatment outside of Tuskegee and were told to get penicillin went back to the researchers and the researchers said, “No, you don’t need that.”
So it really was catastrophically bad and as a consequence they had a tiny drop-out rate because they went for very poor people who truly couldn’t afford money to go anywhere else and to get opinions from anywhere else. And part of it is they paid for the funeral, they offered free medical care, and then we published this, and we published it every five years up through 1972. And even in the [19]60s when objections were raised about this being pretty substantially unethical it still continued. And it continued with federal funding. And remember, the feds of the ones that keep coming up with all these regulations about what we’re supposed to do. And this was all federally funded.
So the solution of course is more regulations. So we’re going to write a whole bunch more regulations. And so there’s a whole list of them and I just list them here for you, just so that you get an idea of the solution to everything clearly is not more regulations. I would argue the solution to everything is this but they don’t use this in the court system apparently so that doesn’t quite work either. So nonetheless they came up with a whole series of more regulations. And even more regulations. And these continue to be updated and changed and updated and re-emphasis and emphasis on research and people have IRBs and they’re told to go before the IRBs and you’re told to do this to the point that those of us who try to do what I consider to be ethical research...
I’ll give you an example. [If] I’m going to look through my trauma registry (which is mandated through the state) and I’m going to look at the number of stubbed toe injuries, the amount of paperwork that I have to gather to just look at the number of stubbed toes—which the data I’m already gathering because I’m mandated by federal and state law to gather—to actually look at that data, to look at the number of stubbed toes that we’ve had—the paperwork is hundreds of pages and I have to go before committee. So those of us who do the right thing are very much punished in order to try to prevent those who are doing unethical things from continuing to do unethical things.
And then there’s the therapeutic misconception which says “If I sign up for a research study it is going to benefit me.” There was an article this week in the New York Times: a patient wrote in about how tragic it is that nobody shows up for clinical trials—that only 3% sign up for clinical trials, that cancer trials are having a great deal of difficulty enrolling people—and then he sits there and he concludes “Well, of course I would sign up for this trial because I’m going to get a benefit.”
Well, okay, wait. I mean, you suffer from therapeutic misconception, which is you think you’re going to get a benefit. It may not actually benefit you; it may only benefit the people who come after you, and so there’s this misconception that says “If I do sign up for research that I will get a benefit from it,” and you may actually not.
So, because of all these new regulations and because of the IRB and because this is all on the front page of the newspapers every day people behave, right? Not so clearly. So in 2012 two neurosurgeons—both the chairman of the department of neurosurgery as well as another neurosurgeon who worked in the state of California who is not actually licensed but had a special permit—took patients with brain tumors and injected poop. And the thought was that by injecting the bacteria that are found in poop, you could create a local immunological response and you could cure the tumor. Anybody want to guess if they had IRB approval to do so? The answer to that would be “no,” and they didn’t go down that route because they used the argument that this wasn’t research, this was treatment. Two of the patients died, [there was a] huge investigation, and this was actually all over the news too, this was pretty fascinating. Apparently we can inject poop in patients’ brains and that will make them all better.
You guys all remember this right? [referring to a cartoon slide] If you’re signed up on Facebook, I can guarantee Facebook is manipulating your Facebook page to control your emotions and what you post on Facebook, and it’s been proven. So Facebook took 700,000 people’s websites and they took everything that you saw on your Facebook website and they either made it positive or negative and they watched what you posted in response to what was on your website. So they were manipulating your emotions to see if they could control what you posted on the website. You think they got IRB approval for it? Of course not. And, actually, not only was this published, it was done by several researchers at several universities who helped control Facebook do this so they knew better, and yet they still manipulated 700,000 people. And Facebook’s response was, “You signed up for Facebook; we can do whatever we want.” And that really was their response. Thus the cartoon.
In the whole argument of “We’ve done it before therefore it should be ethical and we can do whatever we want,” and of course that’s ethical because we’ve been doing it forever because Facebook (believe it or not) has been manipulating what you see on your Facebook page. Needless to say, I’m not on Facebook, but nonetheless that’s all out there. And then there’s retraction. So it started with the vaccination study, but now there’s been a whole boatload of them: the “whether or not you can change someone’s opinion about their perceptions of gays,” that’s the big one that’s come out in the last couple of weeks where they figured out the graduate student manipulated the data.
So there’s been a piece again in the New York Times about the number of scientific studies that have been redacted. Another piece came out that said about 30% of all cancer scientific studies use the same graphs and the same photos in each of their papers. So clearly we’re not doing something well, despite all of these regulations.
So I’m going to talk a little bit about emergency consent research because clearly what I do—I mean you come in you come in in extremis, you’re on a ventilator, the EMS has brought to you in, you’re dying, and we’re going to do what we can to save your life. Now at some point in time, we have to begin to say, “What do we do in order to save your life?” And how do we look at that? And how do we do research on that? And how do we investigate that? And how do we do that safely and ethically?
I’m not sure that there’s any good answers and if you want the answer for how to do it I’m not sure I have that for you today. But I want to talk about some of the things that were done. Bob Orr was involved in this in terms of getting this shut down. This was pretty amazing. So PollyHeme came out; it was a blood substitute. We all know blood is good if you’re bleeding to death. Blood is not necessarily so good if you’re in an [unclear] or a bunch of other situations, but if you’re bleeding to death, you need blood to stay alive. But blood is hard to keep; it’s hard to preserve; it’s hard to use; it outdates quickly. So they came up with a blood substitute called PollyHeme. And the goal was to use it in pre-hospital transport, and then once you got to the hospital, you would go back to regular blood and you would use the standard of care which is packed red blood cells that somebody donated at the Red Cross or another facility.
The problem was that wasn’t how the trial was designed. The trial was designed that once you hit the emergency department, you still continued to receive the PollyHeme, or the blood substitute, for another 12 hours, and that’s where Bob Orr got involved. They looked at doing it in Vermont and he said flat-out, “No, this is unethical. It’s okay to do it in a pre-hospital setting but once you get to the hospital, the standard of care is a unit of blood and you’re not doing that.”
So the people wrote in defense of this—the people who did this research said, “This is completely defensible and this is why it is completely defensible:” First off, they did a fairly extensive communication and I want you to pay attention to this communication because it makes a difference for one of my later slides. But what you did was you could opt-out. So it’s an automatic opt-in. You’re bleeding to death, you’re going to be enrolled in the PollyHeme trial. So it’s an automatic opt-in type phenomenon, but they did a huge public awareness campaign: 9 newspapers, 41 non-daily newspapers, radio stations, internet, community group hearings, radio call-in shows, I mean, so they really did a pretty good public awareness. Even those of us that were in institutions that were not enrolled in the PollyHeme trial knew about it. I mean, they really did a pretty good job in terms of that. But their response was, “We want people to live, so, how can you argue against this research? We know it’s good. We’re just going to prove it’s good. So, of course you’re going to sign on for it. So how can caring and informed individuals disagree? And really, I mean, let’s face it, is packed red blood cells proven to be effective?” (The answer to that would be yes, and of course it is and that’s been the standard of care for a very long time).
We all understand, but their argument was, “Well, we haven’t proven that red cells are beneficial, so what difference does it make if we use a blood substitute? And by definition PollyHeme is good, therefore the research used to prove it would be good.” And in fact, they even argued in their article that PollyHeme was superior to blood. Probably not. So they published a study in the Journal of the American College of Surgeons in 2009 that said the mortality was the same. Whether you got PollyHeme or you got blood the mortality was the same. You bleed to death it’s probably a bad thing. And as a consequence the company that designed this lost about 220 million dollars. And this really brought emergency consent ethics to the forefront.
So there’s a fair amount of emergency consent ethics that goes on, especially when you talk about stroke, and you talk about thrombolytic-type treatment, and a variety of other conditions. Obviously the ones that I care about are related to trauma, but this really came on my radar a couple of years ago when the hospital across the river from me in Pittsburgh, UPMC, signed on with the Department of Defense to do a suspended animation trial.
So if you’re shot and you come in in near arrest, they are literally going to suspended animate you. They’re going to drain all of your blood, they’re effectively going to put you on ECMO, which is cardiopulmonary bypass like they used when you’re on a heart-lung machine—heart-lung machine type procedure when you go to have heart surgery. So they’re going to put you on ECMO and they’re going to flush your entire body with saline to allow them time to fix all the holes and then they’ll put the blood back in (or put new blood back in), but basically it’s a suspended animation trial. Okay. So, who is this experiment going to be on? It’s going to be on gunshot victims. Okay. So who gets shot in Pittsburgh? About 83% of them are African-American males. So that creates a problem right then and there.
So what they did for community notification was they did an internet page. Well, I just went back out to check the internet page, it’s not on the UPMC website. It’s actually called acutecareresearch.org and it doesn’t even mention UPMC. So if you type in “UPMC suspended animation” you can’t pull up the website to opt-out. If you go to UPMC, you can’t pull up the website to opt-out. So I’m not sure exactly how you’re supposed to know where you go to get to the webpage to opt-out. They did a phone survey. They did two open meetings on campus.
Now, the University of Pittsburgh is an incredibly expensive college. There are many there in Pittsburgh who do not have the money and the resources in order to go to this college. So do we think a campus community meeting is going to be one that’s going to reach this patient population that’s going to undergo this procedure? They advertised on buses and they did newspaper. Now, be honest. When was the last time you read a newspaper as we think about a newspaper? When was the last time you read local news online and actually looked at everything? Yeah, not too much. So how would you even be reached? I knew about it because I live in the city, but if you don’t live in this city, how would you know about this?
So I knew the guy who was running the trial so I had coffee with him, and I said, “I absolutely don’t want to be in this trial, but I don’t know how to get to the web page. I don’t know how to do anything.” So, you know what happens? It requires that I write a letter to them and then it requires that I wear this handy-dandy bracelet 24/7 in order to not be in this trial so I don’t undergo suspended animation. So I will pass this around if everybody wants to look at it. So I get to wear a handy-dandy bracelet that says, “I don’t want to be in this trial and I don’t want you to suspended animate me.”
Now, let’s face it. Realistically, am I likely to get shot in Pittsburgh? The answer is “no, probably not.” Except, this is my house, and I have been shot. Not me, but the house was shot, and that’s halfway across my living room. I chose to live in this city, and so it could happen. It’s not very likely. I’m not quite the patient population that they’re looking for. But remember this entire trial is funded by the DOD, and its main purpose is to effect and to save the lives of those on the military field, but we do this type of research not actually within the military, they pair with universities to do so.
So it turns out UPMC is doing three of these. And so if you go to acute care research[.com] they’re doing a TXA during transport, we use TXA all the time in the trauma bay, [it’s] standard treatment to try to help with blood clots and those types of things and they want to actually... it’s tranexamic acid. It prevents the breakdown of clot, and we really need people who are bleeding to death to make clot and keep making clot.
So we use this in the operating room. It’s used routinely in heart surgery. It’s a well-known drug; side effects aren’t very much, but they’re doing a pre-hospital trial. I can opt-out of that one also, and I will get another bracelet for it. And then, they’re doing another trial of plasma during transport. Now we use plasma all the time. You hit the emergency department door, you’ve been shot, you’re critically injured, your spleen... I mean, I hang plasma immediately. It pretty much is the standard of care. We just don’t know the benefit of carrying it around on helicopters, and if we start it at the scene, do patients do even better? So they’re doing one of those trials and if you want to opt-out of that too they’ll be happy to send you another bracelet. So you in Pittsburgh can walk around with your three bracelets. Now what if you don’t live in Pittsburgh? Well you’re kind of sort of screwed and you don’t really know that these research projects are going on. You come in through the emergency department, you get injured during a car wreck on one of the major interstates going through Pittsburgh, guess what? Too bad.
And let’s face it. What group of people are we talking about? We’re talking about a group of people I think we would all acknowledge over the last six months has become pretty profoundly disenfranchised and disengaged from American society. And we’re asking them to read the paper, go out to the internet, and opt-out, and if they opt-out we are asking them to wear three bracelets to do so.
Do any of us really think that this is a patient population that is really been given informed consent and a choice? And are we ethically doing research? Now granted, I get it. I get it, guys are dying on the battlefield every single day, if we can figure out a way to try to stop their bleeding to death from gunshot wounds, I get it. And we can’t really set up a suspended animation lab in the middle of the battlefield in Afghanistan and Iraq. I mean I get it. I totally understand the intent.
The question becomes the logistics and the implementation. And are we really doing this correctly? And with a patient population that is so disenfranchised and so separated from what we are doing in the world and what we’re doing in universities is really an internet page and two campus meetings appropriately notifying people? And is an opt-out method completely appropriate for a group like this? And if you are going to do this kind of research, how do you do it? And how do you do it ethically? Because clearly we have bad science going on every single day.
And I’ll stop there for questions.
