regulatorsFRONTLINE presents Organ Farm

how do we regulate the larger public risks?

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animal welfare
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the regulators

Transplanting pig organs, tissues and cells into humans presents a risk that infectious agents from the pig might jump the species barrier to man, infecting not only the human recipient but spreading to the general population Here, xenotransplantation researchers and a medical ethicist discuss what mechanisms will be needed to safeguard the public if pig-to-human xenotransplantation moves forward.

Daniel Salomon, Md
Virologist, Scripps Research Institute:

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. . . Because of the possibility of moving an infectious agent from the animal organ to the human--and because of the possibility that it might move from the patient to the family--at a regulatory level, we have broached some really new ground.

We're talking in terms of asking not only the patient, but also the patient's family, to basically consent to a long-term follow-up. We're talking about years during which we would take blood samples, we would monitor their clinical course, we would look for any unusual sorts of diseases or complaints that might give us the first clue of a possible infectious agent that we didn't predict. We would actually get blood samples from the nearest relatives, the wife or husband and the children of these patients. We would not allow them to give blood or semen or other tissues for donation, as many public-spirited individuals are wont to do.

And there are really very few legal precedents for what we're expecting a patient to do. Inherent in a consent, right in bold black at the bottom of the consent, it has to say that, at any time, you can withdraw from the trial. If we do a xenotransplant and six months later the patient can withdraw from the trial, and we have no call to legally enforce sampling of that patient for any infectious blood -- in fact, that patient never has to report to us again; he can disappear, she can disappear -- it raises some very interesting questions.

On one hand, we've gone to all these extents to reassure the public that we have all these safeguards. We're going to do the testing and we're going to follow the patient long-term and we're going to keep track of them and we're really going to stay on top of it. And yet the truth is that because of the legalities of the consent process in the United States today, it really will require a tremendous amount of voluntary participation by the patients and the patient's family for this to work. . .

. . . The actual truth is that you're never going to get public consent for this. And in fact, the idea that you're going to get public consent is something that's been manipulated by some people. What scientists and physicians are obligated to do in xenotransplantation or in gene therapy or any new cutting-edge technology is, frankly, to outline for the public the spectrum of risks, the spectrum of benefits, to help the public comprehend what we call a risk-benefit ratio. And in the context of an intelligent discussion of risk and benefit, allow the public to see what the ethical world is around those problems, contribute, discuss, ask questions, understand. That, to me, is the purpose of public discussion. . .

Moreover, when we think about a consent form and these issues, we're really talking about all of new biotechnology; we're not talking about the pig virus risk. So even if tomorrow I would feel comfortable sitting here and quantifying for you the risk of a pig virus, these questions about the public's risk in a consent form that an individual signs go way beyond anything to do with a pig virus. It goes way beyond xenotransplantation. It extends to all new biotechnologies.

So I don't know if specialists in some of these new technologies, like myself, can really know where the public wants to go, where the federal government wants to go, in constructing a consent that works for everyone -- a consent that guarantees reasonable consent for a new biotechnology for a public that's worried about its impact.

With that said, admitting that this is a difficult area, it's critical that we don't regulate a promising technology out of existence. If we take a position like that, if we say, "There's a risk, therefore we can't do it, we can't allow it, we can't develop it," then the history of medicine ends right there, on that day. There's no future, because nothing that's ever occurred in medicine had no risk.

And exactly what are we asking them, concerning long-term follow-up?

At the moment, the kinds of things being proposed for clinical trials of xenotransplantation for long-term follow-up include at least yearly sampling of blood, possibly saliva, possibly semen from patients, and also from intimate contacts -- spouses and children. We are specifying that if the patient develops any sort of disease during this period of time, that that information be disclosed to the regulatory agencies -- not to the public, of course -- so that symptoms of new diseases might be linked possibly back to the xenotransplant.

We would very much like to be able to get permission for an autopsy if the patient should pass away during the period of follow-up, and permission to do experimental research on the tissues and the organs from that autopsy in order to look for possible pig viruses. We'd want to look for anything that could potentially have caused the death of that patient from the xenotransplant. These are things that are way beyond the current definition of the universe for a consent form today. . .

Jonathan Allan
Department of Virology and Immunology, Southwest Foundation For Biomedical Research

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The risk really isn't to the individual; it's to the population in general. So an individual can sign a consent form and say, "Hey, I'm going to die. I'll accept the risk. I don't care if I get a virus and it causes AIDS or something else horrible or I get cancer. I'll take the risk, because without it, I'm dead."

The problem is that that person accepts the risk, but if that person survives and transmits that virus to someone else, and it gets into the population, that person has essentially signed a consent form for the whole population.

Fritz Bach
Professor of Surgery, Harvard Medical School:

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... The Hippocratic Oath I think should at least imply or explicitly cover the responsibility that we carry to consider both the patient and others who might be affected. The dictum of medicine is, "Primum Non Nocere." ["First do no harm."] That's not only for the patient; that's for anyone else you affect by what you're doing. And it's a very difficult problem, but it has to be attended to. You can't just say, "I have a patient dying; I have to save the patient's life." . . .

How are we asking something different of someone in a xenotransplantation situation than we have asked in the past? What's new about this issue of informed consent for a patient?

If we speak about informed consent with regard to the patient, it's exactly the same. There's one huge difference. . . If that patient, having heard all the disadvantages and advantages, still wants a xenotransplantation, then we need that patient, and probably the close contacts of that patient, to sign on the dotted line and say, "I am willing to be monitored for life." I'm not sure there's a legal structure that permits that. I think that the dignity of the human being, the rights of a human being, allow that patient, as is true under informed consent, to withdraw from the trial.

Let's take it that one step further -- the close contacts of concern. It's possible that the disease could get past a close contact, and that patient would first show the symptoms even before the organ recipient showed symptoms. What if the person changes their close contacts? How are we going to handle that? I just want a discussion of this. I'm not sure there are solutions. But the facts have to be out there, and the people that are being put at potential risk have to have a serious say in this after being well informed. . . .

What are we asking of people? How realistic is it?

. . . If you see a patient whose choice is a xenotransplantation or death, I think that most patients would say, "I'm willing to be put under a lot of restrictions. I like my life." But for the sake of society, we have to have the right legal structure in place and the right ethical concepts that would allow one to say," You will have to be monitored for life," if that is the decision of the experts, and after the public input has come in.

Hugh Auchincloss
Chair, FDA Subcommittee On Xenotransplantation

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It's an extremely complicated question to know exactly how to incorporate the public's view on an issue that is clearly of importance to the public. It is so complicated that, frankly, the experts don't really understand entirely what the risks are. How do you turn to Mr. Man-in-the-Street and say, "How do you feel about this?" when no one knows what the risks really are?

I think that the right way to handle this is to continue to involve the public to the extent that the public finds this interesting. The public is best served by turning to its official agencies -- in the United States, the FDA -- which can gather the expertise on behalf of the public to address these issues, with the public's welfare in mind. I don't know of any other reasonable way to go about this. This is not something you can take a vote on; you wouldn't get an intelligent answer. . . .

Norman Daniels
Professor of Medical Ethics, Tufts University

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Let's suppose for a moment that there's a public health risk. We don't know how to quantify it. This is a decision that the public has to undertake. And my view is that this has to be through a fairly elaborate process that involves a broad range of stakeholders in the decision. Not only the experts, who obviously have to be involved, and the clinicians that are anxious to save their patients, but representatives of a broader group of the public have to participate in this. And the mechanism has got to be a broad one that engages in education of the public over time.

Otherwise, we risk a harm that we haven't talked about yet -- the harm that, if it turns out these are dangerous procedures, people who have been undergone them may become stigmatized, may be viewed as Typhoid Mary, and will be the object of enormous concern by the public. The people who did the procedures will build public fears of new technologies. It seems very important to have a process in place that undertakes a careful evaluation of the risk and gives the public some broader way to consent to that risk, rather than simply leave it in the hands of a narrow group of experts.

Hugh Auchincloss
Chair, FDA Subcommittee on Xenotransplantation

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In a sense, do you, as one of the regulators, feel the pressure or the responsibility of not lifting the lid on Pandora's Box?

I do, but I think it would be an equally wrong thing to prevent potential benefit to as many people as can benefit. I see no way of going at this except to proceed very cautiously, very responsibly, and to do the monitoring. I don't think you flip open the box and let everything out. I think you peek and you peek a little bit more and you peek a little bit more. I don't see that you can stand still, and I don't see that you should just assume that it will be okay.

... As you know, xenotransplantation is regulated by the FDA. You cannot do xenotransplantation in this country without formal approval from the FDA. And I believe the FDA has taken on its responsibilities in a superb manner -- involving the public, conducting the debate, involving the experts, gathering the information, and proceeding ahead with trials in a responsible, cautious manner. So I think the regulation is happening. And I think it's happening in exactly the way that you would want it to happen, namely, by the responsible agencies of your government setting out to protect both your welfare and your future welfare in the best possible manner.

Professor of Surgery, Harvard Medical School

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Has there been a real public discussion about xenotransplantation? Where are we now?

As I see it, we're not very far in the United States. In the United States, the Food and Drug Administration has had open hearings, which means that a person would have to know the hearing is taking place, pay their way to Bethesda, Maryland, and then try to get time to speak. I went down there. I think I'm a rather prominent individual in xenotransplantation, and I was told that I couldn't speak from the podium, that I should speak from the floor, and keep it very brief. That's very difficult; it's not a way to get public participation. There's been a lot of coverage in the news, but it hasn't been in a way to catch the public's attention. If you ask the vast majority of people, they still say, "What are you talking about?" ...

What kind of discussion do we need to have?

We need much more effort to inform the public in the United States. The public needs to be aware of the potential risks in a balanced way, along with the potential good, which . . . is potentially enormous. But then we need a discussion with select informed groups, probably across the country, who will be able to cross-examine the experts, who will really try to grapple with this and define the issues that the public is concerned about. They'll help us define the conditions under which those issues would be acceptable. And that should go in with the opinions of the experts or the other stakeholders, and then a decision should be make. Doing it without that, no matter what the great potential of xenotransplantation -- which I applaud and participate in -- is unethical.

David Cooper
Immunologist, Massachusetts General Hospital

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When we go into a war, we don't usually ask the public. I'm not sure it's possible to actually ask the public. But it is important to inform the public of the possibilities, and then it's up to the public to try to make themselves heard. . . . I think we're going to actually have to depend on committees appointed by the Public Health Service or the FDA or somebody to represent the public. And those committees -- which will include not only physicians and scientists, but also laypeople -- will be responsible to determine if this is safe enough to move ahead.

Daniel Salomon, Md
Virologist, Scripps Research Institut

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From a regulatory point of view, there has to be a balance. There has to be a group empowered to review the data as it comes out, and objectively decide when it's time to go forward with specific xenotransplantation procedures. You're breaking brand new ground. There's going to have to be an inspired balance, if you will, between allowing a field to move forward into absolutely brand-new territory and yet, at every point along the way, ensuring that safety is utmost in the minds of the scientists and physicians doing these studies. I think that that kind of balance is perfectly possible. We've moved forward with gene therapy under those guises; we've moved forward with new drugs, new vaccine trials.

So, from a regulatory point of view, there is already a very well defined regulatory context established by the Food and Drug Administration in partnership with the National Institutes of Health and the Centers for Disease Control in Atlanta. And it's all being overseen by the secretary of health and human services at the presidential cabinet level. So I think that we're in a pretty good situation right now, having a strong regulatory oversight to help guide xenotransplantation safely through the first clinical trials. ...

In the last four or five years, the public, in partnership with governmental regulatory agencies like the FDA, the NIH, and the CDC, and scientists and physicians in xenotransplantation have done a very good job of defining the issues. They've showed the spectrums, from the impassioned physician who needs to save the patients who are dying to the others that are concerned about a catastrophic health consequence -- public health epidemics -- from this.

So we've defined the issues. And now what should the public do? Nothing. The public should wait while we do the science that we owe the public to fill in the gaps; to provide knowledge and results upon which to come back to the public; and to reenter the debate, but with more knowledge.

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