Art Caplan on Ethics and Clinical Trials, The Stem Cell Debate, and More

Eli Y. Adashi, MD; Arthur L. Caplan, PhD


May 05, 2011

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Eli Y. Adashi, MD: Hello. I am Eli Adashi, Professor of Medical Science at Brown University and host of Medscape One-on-One. Joining me today is Dr. Arthur Caplan, the Emanuel and Robert Hart Director of the Center for Bioethics and the Sydney D. Caplan Professor of Bioethics at the University of Pennsylvania. An internationally renowned bioethicist, Dr. Caplan has taken on many of the thorny issues of our time. Welcome.

Arthur L. Caplan, PhD: Thank you for having me.

Dr. Adashi: We learned last year that an NIH [National Institutes of Health]-funded study dating back to 1946 or thereabouts subjected vulnerable, apparently unknowing Guatemalans to sexually transmitted infections [STIs]. What is and is not known at this time about this unfortunate episode?

Dr. Caplan: Well, a lot is not known. We're talking about an experiment that was conducted 60 years ago in a very underdeveloped country with poor records and not a lot of means to record what took place because of the nature of the populations -- a prison, a home for the mentally impaired. It's very difficult to get a true handle on what took place. What we do know is that people were deliberately infected with disease and that the attempt was made to see whether penicillin -- the new wonder drug of its time -- could be used in different doses to treat their gonorrhea or other venereal diseases. It's becoming clear that the higher levels of the Guatemalan government collaborated in this study. The study was done with their knowledge.

What I find most interesting is this: it's obviously clear today that the experiment was grossly unethical. You can't exploit a vulnerable population without their permission, and these people couldn't consent. You can't deliberately give somebody a disease just to study the effectiveness of the cure even if you were pretty sure that the drug was curative. But, by the standards of the day, going to a population in prison or going to a population of people in a home for the mentally ill was acceptable. If we brought those researchers back right now for this interview, they would say of course that is where we would conduct such research. The good news is: we've made a lot of moral progress since that time. The bad news is: by the standards of the day, that was probably an experiment where, had we confronted the people then and there, they would have said nothing is wrong with this.

Dr. Adashi: At President Obama's request, the Guatemala affair is now under the study of the Commission for the Study of Bioethical Issues. What has the commission been tasked with?

Dr. Caplan: They basically have 2 very difficult tasks. One is ascertaining as best they can what did happen in Guatemala. Who was involved? Some of my own students are working on this as part of the commission; they have found that one of the investigators who was involved moved on to the notorious Tuskegee Study after working in Guatemala. So there is a continuity of using vulnerable people: in the Tuskegee Study, poor, black men in the south; in Guatemala, poor, prisoners, and mentally ill people. Sadly tracing that legacy and its impact on research is part of their charge. It is a reminder in some ways why we do have the protections we do of informed consent and review by committees known as institutional review boards for research. They have deep historical roots in these kinds of events.

The other charge they have is to take a look worldwide to see whether research protections in poor countries today are adequate. That's a big challenge. A lot of research is being conducted overseas: it's been growing and there's been a lot of offshoring of studies. They'll try to do a bit of survey, but I suspect we'll get snapshots of particular places and particular trials. Taking a look at everything that's going on in every nation is a difficult if not impossible assignment, but that is their charge, to make sure that today we're doing things right.

Dr. Adashi: Based on everything you know, are you concerned at all about how clinical trials might be conducted today and overseen for that matter?

Dr. Caplan: That's a very good question and I am concerned. We know, for example, that sometimes a sponsor in the United States or Europe -- in one of the richer countries -- will take a study into a poorer country partly because it will be quicker to do. Recruiting subjects is less difficult. You show up in a very poor nation, you have a white coat, and you bring them medicine -- people are going to see that as something they want to get involved in. It's very difficult to recruit subjects here for a variety of reasons. Sometimes people are already trying certain treatments. Sometimes the local doctor doesn't want to refer them to a study. But the fact that it's easier doesn't mean that the people in these poor nations really understand what's going on. I have a feeling some of them think it's therapy and not research.

The other difficulty is in many of these poor countries, the situation may be so difficult and so threatening to the population that they're going to sign up for anything no matter what the risk might be from the intervention. It's easy enough for us to make a risk-benefit calculation: do I want to be in a trial for a new drug to treat prostate cancer or a new drug to treat lung cancer? If you're in the middle of a malaria epidemic or an HIV epidemic and somebody says, "We have something that might help you," it's going to be pretty likely that people will sign up. The informed consent protection when it involves very poor, often poorly educated, and sometimes illiterate people is not so strong. It requires tough committee oversight, watching the studies closely. We'll see to what extent that's being done.

One other area that I think is interesting is that in the United States, Europe, or other developed countries, we don't want to be accused of exploiting poor people in studies. What does exploiting mean? Well, at the end of the day, it means we're going to learn something in a poor population in a poor country but the [people themselves are] not going to benefit in the long run. Maybe they can't buy the medicine. Maybe they don't have any way to distribute it and it won't be available at all.

One of the issues that I've been thinking about a lot lately is: what do we owe them? Should we say if we do a study in the Ivory Coast, in Senegal, or in Vietnam, we'll make the medicine available to you after the study if it works? For how long? A year? Two years? And if we're not going to do that because, rightly, a sponsor may say we're not a foreign aid department, we're a company or maybe a university, then should we build them a road or a water treatment facility or give them refrigerators? It's what I call the "left behind problem." What do we leave behind? Forgetting about informed consent and committee review, if we're doing a study there and then coming back here, how can we make sure that we didn't rip them off, so to speak, and that we didn't take advantage of their poverty? What would make them better off and how far do you have to go? I think that's a very interesting question and it's one I hope the commission may venture an opinion on, too.

Dr. Adashi: One cannot help but feel that what began as a very unfortunate story may be catalyzing a very timely review that, by everything you have just said, is more than appropriate at this time given the globalization of clinical research trials and the various traps that one could fall into before doing and perhaps even after a trial is concluded.

Dr. Caplan: It is going to be a good stimulus to take a look. We haven't had a systematic look at research overseas in poor nations. I would say every year in the past decade more and more research is offshored or outsourced to poor countries. It's a growing phenomenon partly due to costs and partly due to populations that are naive relative to treatments. If you want to find people with diabetes who have never had any treatment, you go to China or India, to rural poor people. It's easier to recruit there than to try to study people with diabetes here who may have been through 10 drug trials or 10 treatments and in some ways don't form as good a baseline for doing the research. This phenomenon of looking at how we're doing studies overseas is an important moment in research.

You can see democracy movements taking place in the Middle East, North Africa, and other places. Those people are going to start to pay more attention to autonomy and their rights. We need to get ahead of that a bit and make sure that we are ready to deal with the poor world perhaps turning more into the developing world.

Dr. Adashi: Let's change gears a little bit back to the United States at this time. Stem cells --

Dr. Caplan: Something not controversial.

Dr. Adashi: Here again last year we learned that public funding, at least of human stem cell lines, is under legal challenge as we speak and with an uncertain future until we hear from the courts. That may or may not be the end of the sequence anyhow. What do you think precipitated this crisis?

Dr. Caplan: The immediate crisis was precipitated by something called the Dickey Amendment, which has been in the books since the mid-1990s. It basically said no federal funds can be spent on any research involving embryo destruction. It was before anybody had identified stem cells and preceded the discovery of human embryonic stem cells. This law was never pulled off the books; it has sat there. [The Dickey Amendment] was the basis for the lawsuit that has now been brought to say even though the current administration has said it will permit money from the NIH to go to embryonic stem cell research, it is in violation of this congressionally passed law that has been around for a long time.

I think the Dickey Amendment should be overturned, but the problem is worse than that. If you're a young scientist or young MD/PhD, you've got a track record for the past 10 years of funding is on, funding is off, funding is on, funding is off. It's hard to hitch your star to that particular area with this kind of uncertainty of funding. Some people will say to me, "If it's so interesting, isn't there going to be private funding? Not at this level of basic research. Private investment is going to come later if it looks promising. Without NIH's steady and regular support, it's hard for a post-doc or a younger scholar to pursue work on embryonic stem cells. However the court case turns out, I fear that damage is being done to having a sustained American effort in this area.

Dr. Adashi: In what way, if any, is the stem cell debate affected by the advent of so-called induced pluripotent adult stem cells?

Dr. Caplan: Stem cell research basically tries to figure out how to get cells to regenerate. Some cells in the body do so naturally. We have a certain component of cells that will grow back on our tongue when we rub or scratch it. Our gastrointestinal lining is going to grow back. We know that the body can repair certain things. Then we have the embryo, which hopefully you can manipulate to turn into all forms of cells -- pluripotent as it's described. Different techniques have come about to clone embryos so that you could perhaps transfer cells back to your own body without having to take immunosuppressants if you use cells from a different embryo and finally induce pluripotency, taking an adult cell and tricking it.

All strategies are interesting. It certainly makes sense to pursue induced pluripotent manipulation. However, right now the only way we know how to do induced pluripotency is basically by gene therapy. You're using viral vectors to trick the genetics of the cell to become more embryo-like; however, that has risks. We know that gene therapy can introduce material that you don't want. To understand whether you've made something that's embryo-like, ironically you need to compare it with what is an embryo to know what it can do. So, you can't dispense with all embryonic stem cell research even if you can induce it.

I'm going to put the ethics case this way: if I'm in a wheelchair, if I have juvenile diabetes, if I'm paralyzed due to spinal cord injury, I want to see all bets on all the numbers -- adult, cloned, induced, embryonic. I don't know which strategy is going to deliver in the long run. I don't know which is going to be able to be manipulated in the most facile manner. Not to pursue all strategies for injuries and diseases where we have nothing else seems, to me, to be immoral. I understand the objections about embryo destruction. I've tried to suggest that maybe we could use embryos at infertility clinics that others don't want for that component, but I think you've got to move this area across on all frontiers now. It's too new. It's not well understood. It would not make scientific or ethical sense to just pursue induced pluripotency.

Dr. Adashi: Since you mentioned the frozen embryos, what, if anything, can we learn from policies currently in place that deal with the disposition of frozen IVF [in vitro fertilization]-derived embryos?

Dr. Caplan: As I've looked at that area over the years, it's surprising to me how many embryos have been left behind -- unclaimed, abandoned. Happily, sometimes families have babies and decide they don't want any additional embryos that they may have made. Sadly, sometimes people die or they divorce. Clinics aren't sure what to do with these embryos. The policies about their governance are not uniform. Some clinics are very responsible and will give you a consent form and say keep it and understand that you have to renew this every 1 or 2 years to maintain these embryos in a frozen state. But others don't really get directions about what would happen if someone died, became impaired, or simply just didn't come back.

I think the fate of those embryos is pretty clear. Abandoned embryos are not going to be used. We do hear ideas every once in a while. You can put them up for adoption. People who pursue [IVF] do so because they want to have a biological link to any child. Adopting somebody else's embryo is not going to work. Hundreds of thousands of these embryos exist. It's a lot if 50 embryos were adopted last year. I think all of the embryos ultimately will be destroyed. While we don't have a clear consent to their use in research, given that they're going to be destroyed, it seems, to me, better to use them in research than simply to watch them be destroyed.

I'd like to see the policies updated so that people could say if they don't want [the embryos] or that they could be made available for research if they die or divorce. I think that's prudent, but going backwards I think the fate of those frozen embryos is sealed and that's the place to turn to see what we can do research-wise.

Dr. Adashi: Prenatal diagnosis is changing as we speak. Several things are happening. What used to be mostly a focus on chromosomal abnormalities now could, in time, with the advent of affordable genomic sequencing, become a far more elaborate process and in many ways a more information-rich process. What ethical implications do you see in this potential transition?

Dr. Caplan: I'm really grateful for the advances in genomics combining with the ability to isolate fetal cells or to pull cells off of embryos outside the human body because it's almost the full employment act of bioethics. The area we're now starting to talk about is going to prove to be enormously important in the coming decades; not tomorrow morning, but in the years to come. We have the ability to make children or begin to make them outside of the body. For the most part, that's been a technique that's been used for the infertile, but if enough information started to accumulate on risk factors and propensities both for diseases and maybe for traits, I could see a day coming when people would start to say, I'm not going to make a baby the old fashioned way -- "the birds and the bees" way. I'm going to start them off in dishes and test them, not because I'm infertile but because I'd like to design my children. I can also imagine people saying that given a much better understanding of risk factors and the role that genes might play in contributing to certain traits, both desired and undesired, I'm going to test my fetus at a very early stage: take cells from the mother's bloodstream -- which we can now do -- see what's going on, and maybe end the pregnancy if it's thought that something wasn't the way it was intended.

Medicine is going to face a very difficult question. Are we in the business of treating diseases and disabilities or are we in the business of improving and enhancing, partly for preference and partly for improved function? We do have sports medicine. We do have cosmetic surgery. It's not as if no one has answered that question, but I think lying before us is probably one of the biggest ethical challenges that medicine has ever faced: to what extent are we going to be involved in trying to improve and enhance our offspring as opposed to using genetic screening, as it's traditionally been done, to identify disease and to identify disorder?

Dr. Adashi: Thus far, mostly because of the invasive nature of the technology, there was a modicum of selectivity in the application of prenatal diagnosis. You mentioned the fact that we might be moving to noninvasive prenatal diagnosis by capturing and then interrogating circulating fetal cells in the maternal circulation. What unintended consequences, if any, do you see in this seemingly technological shift? It is, in a way, a new day.

Dr. Caplan: Well, I'll mention one that may seem far out, but I'm going to make a long-shot prediction. Abortion is probably the biggest battleground domestic social issue that the United States has seen and it remains a very hotly contested, deeply divisive moral question. Once you move toward being able to detect genetic problems and risk factors, not just diseases but things that might put you at risk -- and it's not so difficult to obtain the DNA either, in a dish to start the child off or very early from genomic samples from cells in the mother's bloodstream -- I think the debate about abortion could shift to: are we going to start to insist that people who are going to create children with high risk for disease, because of cost, must use these screening techniques, must wind up having to undergo socially sanctioned examination of genetic risk for their children? We have an aging population. Costs are out of control. I could easily imagine a movement starting that it's irresponsible not to test. Moreover, if you do get a result that indicates it's going to be costly, will we shift from do you have the right to end a pregnancy to do you have a right to start a pregnancy?

Dr. Adashi: On a personal note, at this point, you have dedicated your professional life to the study of bioethics. When did you realize that this is what you wanted to do and why?

Dr. Caplan: That's the hardest question you've asked me. I went to medical school at Columbia [University in New York]. I was admitted there from an undergraduate experience at Brandeis University, where I did the pre-med thing, but I also majored in philosophy. When I was at medical school and just getting out into my first clinical experiences, rotating around as a student, I saw all sorts of interesting issues. I asked the administrators at the time, "When do we talk about this?" They said, "Well, we actually don't really talk about that. You should learn about that from your attending." But the attendings didn't seem to be talking about it much either. I had a very supportive dean who is not with us anymore; he was the Dean of Students at Columbia, a guy named Bernard Schoenberg. He said, "Look, you have a philosophy background. Why don't you study more philosophy, get some graduate study, and see if you can then apply it into this area of medicine? I think that you're right, some ethical issues are there."

So that was the trigger. I had a supportive mentor. I did go and study philosophy in the philosophy department, but I have to add that they did not know what I was doing there either. It sort of came together for me. I never finished medical school, but I went on to think that this is the area that ought to be developed. That really was good mentoring: supportive people who said that's an interesting idea, we’re not sure we know exactly what you're talking about, but try it.

Dr. Adashi: Can we consider this a scoop?

Dr. Caplan: It's a bit of a scoop.

Dr. Adashi: On that note, sincere thanks to Dr. Caplan and to you, our viewers, for joining Medscape One-on-One. Until next time, I am Eli Adashi.


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