Questions Raised over New Treatments and Consent The Food and Drug Administration debates the testing of experimental blood in trauma patients who can't always give their consent. Also, a new report by the Institute of Medicine says research conducted using prisoners needs more oversight.
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Questions Raised over New Treatments and Consent

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Questions Raised over New Treatments and Consent

Questions Raised over New Treatments and Consent

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JOE PALCA, host:

This is TALK OF THE NATION: SCIENCE FRIDAY from NPR News. I'm Joe Palca, in for Ira Flatow.

Up this hour, protecting human research subjects. It's probably safe to say that most of the human subject research that's done in this country, is done adequately, with adequate protections for subjects, but there have been some stunning lapses.

In 1972, a reporter for the Associated Press revealed that for 40 years, the U.S. government studied nearly 400 black men who had syphilis. The men were studied not so they could be treated and cured, but so that researchers could see would syphilis does to the body as the disease progresses.

When the details of that study, the Tuskegee Syphilis Study, were made public, it became clear that the laws governing the use of people and research needed to change. Congress held hearings, and the government issued new guidelines, meant to protect people from unknowingly being used as research subjects.

Those guidelines remain in force today, and one of the most basic rules, says all research participants should give their informed consent. In other words, they should be able to decide for themselves whether to participate in an experiment.

But there are occasions when informed consent is waived, and the FDA is set to decide on one of them soon. The United States Navy wants to start trials of a blood substitute. It would be given to people who are in a trauma, but who may be unconscious and couldn't give their consent to use the blood substitute. Should that trial be allowed to go forward? That's one of the issues we'll be talking about this hour.

We'll also look at a new Institute of Medicine report about prisoners and research. The report says there needs to be more oversight on research done in prisons, and we'll talk about it.

If you want to join our conversation, give us a call. Our number is 1-800-989-8255. That's 1-800-989-TALK, and if you want more information about what we'll be talking about this hour, go to our Web site at where you'll find links to our topic.

And now let me introduce my guests. Mary Faith Marshall is associate dean for social medicine and medical humanities. She's also a professor of family medicine and community health, and a professor at the Center for Bioethics at the University of Minnesota Medical School, in Minneapolis. She joins us by phone. Thanks for talking with us today.

Professor MARY FAITH MARSHALL (Associate Dean, Social Medicine and Medical Humanities, University of Minnesota): Thanks for having me. Delighted to be here.

PALCA: And Larry - Lawrence, I'm sorry, but Lawrence O. Gostin is professor of public health at Johns Hopkins University. He's also a professor of law and the director of the Center on Law and the Public Health, at Georgetown University Law Center. He joins us also, by telephone.

Professor LAWRENCE O. GOSTIN (Director, Center on Law and the Public Health, Georgetown University Law Center): Hello, how are you?

PALCA: I'm fine. And Mary Faith Marshall, let's start with you. Can you give us a broad picture of the kinds of protections that went into place, subsequent to this 1972 revelations about the Tuskegee Experiment?

Prof. MARSHALL: Well, I can. I think probably, you know, as you already said, Joe, the most important one is that there's informed consent to participation in research. And there were some basic principles that informed how the government went about making regulations for research, that it either did itself or that it funded.

And they had to do with making sure that we were respecting people by getting their consent; making sure that we were balancing benefits and risks appropriately; and making sure, that in terms of how we spread those risks about, that there was justice - that we weren't disproportionately affecting a group of people who were less vulnerable, or were more vulnerable than others. Or, for example - we'll talk about prisoners later - that we weren't using people because they were simply more convenient or, you know, all aggregated in one place, for studies.

PALCA: Right.

Prof. MARSHALL: So those were the primary principles. I think, unfortunately, and this'll come out in our conversation, the limitation of those regulations is that they don't apply to all research subjects in this country, where research is being done. It depends on who's doing the funding and who's doing the research.

PALCA: Really? Who's not covered, then? Who is vulnerable from, and not subject to, these rules?

Prof. MARSHALL: Well, there are three parts to the regulations, and the first part, Part A, we call the Common Rule - and they're about 19 federal agencies that have signed on to that. So it's the broadest part.

But basically, if - you could be doing research that's either, not funded by the government and doing research in a way that - so that you're not associated with a university or an institution that has an assurance or an agreement with the government to follow its regulations - or you're not part of a government agency yourself. So I could be a private individual doing research in my garage and - research with humans - and I wouldn't need to follow the federal regulations.

PALCA: Although you'd have to convince somebody that they'd come into your garage, I suppose.

Prof. MARSHALL: Sure, absolutely, absolutely.

PALCA: But...

Prof. MARSHALL: So there are big holes in the system. And then if I'm developing a new drug or a new device, and I'm doing that on my own, I do fall under the purview of the FDA, but a lot of that is done retrospectively, not prospectively. So there are some major holes in the system, that have been identified over and over and over again.

PALCA: But for the - I would imagine there are holes - but I would imagine, also, that the bulk of the research is covered by these rules. And I guess I'm wondering, who's responsible for enforcing them?

Prof. MARSHALL: Well, that's a good question. I want to speak to the first thing you said, though. And because we don't have a registry in this country, of all the research that's being done with humans, then what you just said is accurate. You would have to assume that all of the research is being done well. But unless we have a registry, and we know all of the research that's being done to begin with, we would have a hard time proving that or even - or knowing that.

And for - in terms of enforcing the regulations, there is a government agency -the Office for Human Research Protections - that is the government's oversight agency. So it's the agency that a research university would make an agreement or an assurance with, that says, if the government's going to give me money to do research with humans, then I promise, or we promise, and our investigators promise, to follow those federal regulations.

PALCA: I see. Dr. Gostin, perhaps I can turn to you now, and ask the question, before we get to the report that you chaired for the Institute of Medicine -the Department of Health and Human Services has this office that Mary Faith Marshall just mentioned, but there's also local control of research at research institutions. Isn't that right?

Prof. GOSTIN: Yes, there is local control in research institutions, if they've got an assurance with the federal government. But I think what Marianne really put her finger on, on the two big problems. One of those problems is just simply the fact that there have to be specific federal funding for this to be covered most of the time.

And one of the things we found out in the Institute of Medicine Committee, say, for prisons, was that we really had no idea what was and what wasn't covered because we don't know what research is taking place, and there was a lot of private research taking place, and so that becomes a real issue.

PALCA: Can you elaborate a little bit, on why the use of prisoners represents a different kind of a problem, than just people, normal and out of prison would represent, in terms of doing research?

Prof. GOSTIN: Well, the reason is, is that prisoners are in very constrained, controlled environment. And we had a prisoner liaison committee for the Institute of Medicine, and we had hearings where we went to prisons and we heard from prisoners - and they would tell us repeatedly, that it was very constrained. When your very liberty depends on the favors of those who hold you in liberty - that hold the keys to your cell - it makes it extremely difficult for you to be a healthy volunteer.

The other big problem is that they're captive audiences. It's just much cheaper and easier to do research on an enclosed, captured population. And as a result, before the rules went into effect, there was just horrific experimentations done on prisoners involving burning their skin and things that were just unconscionable. So we never want to go back to those dark days.

PALCA: We're joined now by Roger Lewis. He's a professor of medicine at the David Geffen's School of Medicine at UCLA. He's also an emergency room doctor at Harbor UCLA Medical Center, in Los Angeles, and a researcher at the Los Angeles Biomedical Research Institute. He joins us from the studios of KUSC, in Los Angeles.

Thanks for joining us today, Dr. Lewis.

Dr. ROGER LEWIS (Professor of Medicine, David Geffen's School of Medicine, UCLA): Thank you for inviting me.

PALCA: So at the start of this hour, we mentioned that there is a study that is being contemplated, that would compare a blood substitute to - I guess what they use now is saline - to keep at least the volume of fluid inside somebody steady. And the question is, how if your patient is unconscious, do you get their approval, their conscious consent, to try this in it. Because it's obviously an experimental substance?

Dr. LEWIS: Well, I think the answer to that question is that you can't get their approval. And there are some kinds of research that are intended to develop new therapies for diseases that strikes suddenly, and unexpectedly, and are life threatening, for which it will never be feasible to get consent. And I think the important question, is whether that's a kind of research that should be done, and if it should be done, what are the appropriate safeguards to make sure that the rights of individuals, and the societal values, are incorporated into those decisions?

PALCA: But you can imagine a situation where it should be done, can you not?

Dr. LEWIS: Absolutely. Everyday when I work in the emergency department, I see people who have been suddenly struck by life threatening injuries or illness. And I know that the treatments that we use that are considered state of the art often are ineffective at returning unto a reasonable quality of life, or saving their life. And so everyday I am reminded that we have a tremendous need to develop therapies for these devastating and predictable things; like multiple trauma, or strokes, or cardiac arrest.

PALCA: So this is the conundrum, I guess, that you have to test them before you can know if they work. And it's a questionable thing, whether to test them, if you can't get permission.

Dr. LEWIS: Well, I think that's exactly the issue. When I'm asked about this, I frequently make the point that the decision is whether to go ahead and sometimes enroll subjects, who are unable to participate in consent, in such studies of unproven therapies, or to essentially accept the current state of treatments for these diseases, and ensure that our children won't be receiving therapies that are any more effective than those that would be used on us today.

PALCA: Well, Dr. Lewis, we have to take a short break, and then we'll be back for more discussion on the subject of protecting research subjects. Stay with us.

(Soundbite of music)


We're talking this Friday about using humans as research subjects. My guests are Mary Faith Marshall, she's the associate dean for social medicine and medical humanities, at the University of Minnesota Medical School. Roger Lewis is an emergency room doctor at Harbor UCLA Medical Center, in Los Angeles. And Lawrence O. Gostin is professor of public health at Johns Hopkins University.

And let's take a call now and we'll go first to Cody in St. Charles, Missouri. Cody, welcome to SCIENCE FRIDAY.

CODY (Caller): Hi. I was just wondering, what's the defining line for a trial procedure or medication becoming standard protocol in the field?

PALCA: Dr. Lewis, how much testing is enough, I guess, is what Cody is asking?

Dr. LEWIS: Well, I think there are really two questions there. In fact, many of the treatments that are used in the field were never adequately evaluated, and just came into common practice because it was people's assumptions, or prior beliefs, that they were effective. And a great example of this is the MAST suit, or anti-shock garment that was used for many years to try to keep the blood pressure up of trauma patients who had lost large amounts of blood. And about 10 years ago, a study was done in which, for the first time people actually evaluated that therapy, and found out that for people who are victims of stabbings or gunshot wounds, the garment actually caused more deaths than saved lives.

So the first point is that, many of the therapies that are used in the field have never been tested - partially because of the difficulty in testing therapies for sudden diseases that are life threatening. In the best of all possible worlds, and especially for new therapies, I think we believe there's an obligation to be sure that they are safe and effective, prior to widely disseminating them in the field or in the hospital.

PALCA: Okay. Just quickly, on this question of the blood substitute that we talked about at the top of the hour. I mean that - there is some experience with that, and there is reason to think that it is, that it does cause an increased risk of a bad outcome.

Dr. LEWIS: There actually are three separate trials, although I know that the Biopure trial that the Navy is helping to sponsor is the one that's sort of getting the most press right now. But back in the late ‘90s, Baxter Healthcare tested a form of human hemoglobin that had been cross-linked. And this was also a study done under a waiver of informed consent for seriously injured adult trauma patients. And that study was stopped early, because they had an excess mortality in the subjects that received the cross-linked hemoglobin, compared to those that received saline in the field.

And that was maybe due to lots of things. Some people think it was bad luck, and some people think it might have to do with the tendency of these things to cause the blood pressure to go up, which can actually be damaging to someone with certain kinds of trauma. But as much as been learned about these kinds of substitutes, the goal has been to develop ones that have less of the side effects and are more effective at carrying oxygen.

Northfield Laboratories is currently finishing a clinical trial. It has received lots and lots of public notice that also involves multiple trauma patients. The agent's is called polyheme. It's also a human hemoglobin substitute. And they've enrolled over 700 patients out of a planned 720. An independent board has looked at their data after 500 subjects and recommended the continuation of the trial.

I read into that, that there is not suggestion of harm, although it's unclear whether there is benefit from the agent until we see it replaced. And then the third trial, is the Biopure study that you mentioned, in which the Navy is proposing using this blood substitute among trauma victims in the field. The important difference between that study and the Northfield study, is that in the Northfield study, the blood substitute is continued in the emergency department, even after a traditional blood transfusion would be available.

So much of the outcry, has been, that that study requires withholding of human blood even when it's available. The planned Biopure study, would only use the blood substitute where a traditional transfusion is not an available option.

PALCA: Let's take another call now from Bruce in Atlanta, Georgia. Bruce, welcome to the program.

BRUCE (Caller): Hi. I was thinking that it's dangerous to decide that any drug is too important to not require informed consent for it to be tested. On the other hand, it seems like that shouldn't be a problem if in the same way that you can send an advance via organ donor card. Couldn't there be a special category of drugs, treatment, marked as aggressive, possibly experimental treatment. And for those who opt for that in advance, they get that treatment and you've got plenty of people who would go for that option.

PALCA: Bruce, let me put that question to Mary Faith Marshall. What do you think about that, advanced consent?

Ms. MARSHALL: I think that it's an interesting idea and it's the first one that comes to mind. The problems with that are really pragmatic. For example, you would assume that let's say we were going to have that clinical trial here at several hospitals in Washington, D.C. You're going to have to get in touch with everybody in Washington, D.C. so that they can think about it ahead of time and make his or her own decision, about whether or not to enter the trial and then maybe wear a bracelet or something.

So, he general idea has been, you try and get the word out, and if somebody doesn't want to be in the trial and they opt out of it, then they would wear a bracelet. But, the other problem with that, is that then you would have to wait, sort of, for every multiple trauma person who comes into that clinical trial to have thought about it and has said yes, I'm going to consent prospectively to be in it, and it will take a really long time to get those data.

So, the model that's been thought of and worked out is, we're going to go to the community as a whole. So we will go around Washington, D.C., and we will have focus groups with members of the community. And in a sense, we're going to get prospective consent to do this research, from the community itself.

And we're going to let special individual, sort of groups, know, so that people who might object to blood products on religious grounds, we're going to make sure that they know that this is going on so that they can opt out.

So it's pragmatic, in terms of being able to bring enough people into the clinical trial, to make it meaningful and not last 10 years, as opposed to three years. And also,, to balance that, with allowing people to opt out. So that's been the model, the model of community notification and prospective community consent.

PALCA: Lawrence Gostin, I wonder if I can ask you. Does that seem like a reasonable approach to you, or is there problems there as well?

Mr. GOSTIN: Well, first of all, I think that consultation with the community about research is interesting. I wouldn't call it consent. I don't think there is such a thing as community consent. But I think that some knowledge in the community of these kinds of trials are important. But I am a lawyer, and I was once a board of directors of the ACLU, and the head of the British Civil Liberties Union. So, I understand the importance of consent.

But I think we make too much of it. What we know from research is that even those who are fully adult, fully capable, have real problems with consent. So we have to think of other kinds of safeguards. So consent is only one. We have to think of really careful reviews of these studies, making sure that the risk benefit ratio is very positive, that we do have consultation with the community. And I know in the IOM prisoners study, we spent a lot of time thinking about other models to provide safeguards against abuse. So I think we've been just overly focused on consent in the United States.

It's important, but we need other ways of thinking about problems, hard problems like this one.

PALCA: Interesting. Okay. Let's take another call now and go to Debra in Kent, Ohio. Debra, welcome to the program.

DEBRA (Caller): Hello. I'm a bioethicist at Kent State University. My research team examined the perceptions of white Americans and African Americans of emergent protocols - in which informed consent is waived. And every briefly, in my study population, African Americans didn't find waivers of informed consent ethically acceptable, even with community consultations.

I was wondering about the panel's views that the ethical framework of the Common Rule and the Belmont ethical principles are just simply not persuasive to some communities, especially those who've been taken advantage of in the past.


PALCA: Well, Deborah, we're going to have - now we have to explain what the Belmont principles are. But Mary Faith, that's okay. I think Mary Faith Marshall can do that briefly and talk about the perceptions and the different perceptions.

I mean, that's why it's so hard to define a community, it seems to me.

Dr. MARSHALL: Absolutely. And I'd be delighted to do that. So the Belmont Report is the report that I was talking about at the very top of the hour that sort of provides the philosophical underpinnings for the federal regulations that govern research. And so they have to do with respecting persons, and they have to do with balancing risk and benefit, the right to informed consent.

I'm not surprised at all at your findings. It sounds like a wonderful, interesting study, because we've known for a long time, just in the area of informed consent, of what we might think of as proven medical treatment, that there's a lot of distrust among the African-American community of the medical establishment, and for very good reason.

And certainly the observational study of syphilis in Macon County, Alabama, what's referred to as the Tuskegee study, is the paradigm example of that. And, you know, I've lived and worked at the Medical University of South Carolina for many years and a third of the citizens of South Carolina are African-American. And I can tell you that Tuskegee legacy is alive and well.

And as Professor Gostin will tell you, the research and the work that his committee did on research with prisoners in looking at the fundamental principles and whether the regs needed to change focused, I think, probably certainly a great deal on who is in prison today.

And we know that the people in prison today are disproportionately African-American or persons of color or persons who may be socially vulnerable in one way or another.

And so there's a great deal of distrust. And I'm not surprised that the African-American community, according to your findings, have not bought into the notion of community consent.

One thing that has been pointed out about the PolyHeme Study, or studies in urban areas of substitute blood products, is that they may actually disproportionately affect the African-American community or vulnerable communities, because that's who lives in the urban - inner-city urban or high-trauma, high-crime areas.

So I think those are very legitimate concerns. And interesting study. Good work.

PALCA: Okay. Let's take one more call now, or another call, and let's go to Dave in Alameda, California.

DAVE (Caller): Hi. I'm a paramedic in Alameda County here, the public agency. And I had a question about kind of two parts here. One is actually conducting a field study like this where it would be sort of the paramedic's call to give this blood agent.

And then also, how, in a study like this, is personal liability limited? For example, somebody gets this blood product. There's a bad outcome. The family says they weren't really on board with it and then starts suing everybody from the paramedic up to the ER staff.

PALCA: Yes. Interesting question, Dave.

DAVE: And I'll take it off the air.

PALCA: Okay. Thanks. Maybe Dr. Lewis, you're in a position to address that.

Dr. LEWIS: All right. I will do my best. The first part of the question regarding how is this done, studies of this type should have some very clear criteria for whether or not the patient actually qualifies for the study, usually based on their mechanism of injury and their initial vital signs.

And so hopefully there's little judgment on the part of the individual paramedic in the sense that the criteria are pretty objective.

Studies of this sort that are sponsored by large agencies, whether they're commercial or governmental, usually involve some form of indemnification for people involved in the study.

And historically, the rate of litigation over clinical research has been really very, very low, largely, I think, related to the general public belief that medical research is important and perhaps because of the indemnification provisos.

That said, of course, it's incredibly important that the protocol be well reviewed, be medically and ethically appropriate, and that everybody involved in the study do their best to follow the procedures as they're written.

PALCA: We're talking about the protection of human research subjects. And we'd like to take your calls. Our number is 800-989-8255. That's 1-800-989-TALK. I'm Joe Palca, and this is TALK OF THE NATION from NPR News.

Dr. Gostin - I mean, sorry, not Dr. Gostin, Mr. Gostin, I'd like to turn back to you now and talk a little bit about this - the predicament of people in prison. It seems to me that this is one of those difficult situations where it might be of a benefit to a prisoner to participate in a study, A, because they might get better healthcare, or B, because they might, they might get some privilege that they wouldn't otherwise.

I realize there's a coercive aspect to that, but isn't there a benefit as well?

Prof. GOSTIN: There is. And I think, you know, this committee was probably the hardest one I've ever chaired, precisely because of that reason.

I mean, if somebody - suppose that a prisoner - and we heard this a lot. Suppose a prisoner says, I would really like to participate in this study. And he or she may have a lot of reasons. One of the reasons might be that they might get better healthcare or that they might just simply be relieved of their boredom, or it might be that, and many told us this, that they just simply want to contribute to scientific knowledge and feel that they're giving something to society.

And so, you know, should we say, no, you can't do that? Or should we second-guess their reasons for doing it? So it was really hard because on the other hand, we know that when they get these benefits, it is coercive. And if we want to respect people and we don't want to go back to the kinds of abuses we used to see - and what still may happen in prisons at present, then you have to be overly protective.

And so it became a really hard problem. And we tried to find a good balance.

PALCA: Yeah. Yeah. Well, it's obviously - I mean, as we've been having this conversation, I've been sitting here trying to think, okay, so what's the answer? What's the simple way to put this all together?

And it seems impossible with so many conflicting values. But I'm afraid that's where we're going to have to leave the discussion because we're not going to resolve it today.

So I'd like to thank my guests for this segment. Mary Faith Marshall, associate dean for social medicine and medical humanities at the University of Minnesota Medical School, thanks for joining us.

Dr. MARSHALL: Thanks for having me.

PALCA: And Roger Lewis is an emergency room doctor at Harbor-UCLA Medical Center in Los Angeles. Thanks very much for talking about this blood study and the problems that the emergency medicine field face.

Dr. LEWIS: Thank you.

PALCA: And Lawrence O. Gostin. He is a professor of public health at Johns Hopkins University. And he chaired a panel that just wrote a report about how to protect research subjects who might be in prison.

Prof. GOSTIN: Thank you.

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