Archive

Ethical Issues in International Research, Review of UNAIDS Activities: Ruth Macklin, Ph.D.

DR. MACKLIN: Thank you and Iím pleased to be here again. Iím going to say less than I had planned to say. Alex and I discussed whether he should be presenting the summary of the Washington meeting, and since the summary of the Washington meeting actually included much of what I was going to say, Iím going to avoid redundancy.

Let me begin by saying a couple of the lessons that were learned from the AZT controversy that erupted which, in turn, almost directly led to this series of consultations that Alex described that UNAIDS conducted. One question, and Alex has already pointed to this, that emerged from the controversy is whether existing international guidelines are adequate to address the present and future conduct of international collaborative research.

As it became apparent, specific items in the current version of the Declaration of Helsinki, which is distributed by the World Health Organization to all its collaborating centers in any cosponsored research, and the CIOMS international guidelines, the ones frequently referred to as the Red Book, those guidelines may be open to different interpretations. The guidelines themselves may well be internally inconsistent, and careful examination, as Alex has reported, showed that some of these statements or guidelines may be in need of revision. Let me give as an illustration, in the AZT controversy, guidelines and principles from both of those documents that were cited both in support of and in criticism of the trials following the controversy over the placebo controlled AZT trials.

Let me give a couple of examples rather than speak generally so it will be clearer. Iím sorry, if you had a text, it would be easier. Iím quoting from guidelines which sometimes are in turgid prose. Hereís a statement that appears in the Declaration of Helsinki, and Alex has referred to this. Hereís the whole statement. "In any medical study, every patient, including those of a controlled group, if any, should be assured of the best proven diagnostic and therapeutic method." Now, critics in the AZT controversy charged that in the placebo-controlled trials neither the subjects in the experimental treatment arm nor those in the placebo arm received the best proven therapeutic method thatís available in the world today.

Subsequently, in an article that was published in the journal IRB, a Review of Human Subjects Research, Robert J. Levine argued that the proper interpretation of the phrase "best proven treatment," (this was the interpretation that Levine claimed was intended by the original drafters of the Declaration of Helsinki), should be interpreted to mean best proven treatment in the country or region where the research is being conducted. So right there you have the conflict.

A second statement that was cited from the Declaration of Helsinki is as follows: "Concern for the interests of the subject must always prevail over the interests of science and society." Critics charged that in the placebo-controlled trials the interests of society prevailed over the interests of the subjects enrolled in the study.

However, supporters of the AZT placebo-controlled trials could cite a different Helsinki principle: "Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject." And, indeed, spokespersons from Thailand and Africa, who were from the very countries in which the placebo-controlled trials were carried out, claimed that because the pandemic is so severe in their countries, the importance of the objective was indeed in proportion to the risks that were posed to those subjects.

Now similar difficulties arise in the CIOMS guidelines. Iíll just give one example here. One paragraph states: "In a randomized clinical trial, the therapies or other interventions to be compared must be regarded as equally advantageous to the perspective subjects. There should be no scientific evidence to establish the superiority one over another. Moreover, no other intervention must be known to be superior to those being compared in the clinical trial." And it goes on. Well, itís clear here, as critics charged, that the placebo-controlled trials failed to comply with these conditions.

So these few examples, and we could cite more, serve to illustrate the problem. Which ethical guidelines should be followed? What should be done when ethical guidelines themselves or elements in the guidelines come into conflict? One cannot expect guidelines, being general as they are, to give all the very specific answers. On the other hand, theyíre supposed to be useful. And if critics and supporters of one and the same trial can cite different elements from the guidelines both in criticism and in support of the trials, it indicates that some next steps ought to be taken.

At present, the Declaration of Helsinki is undergoing revision. I donít know how much to say about that. Maybe Iíll just leave it to questions or in the discussion period. There is a process of revision which is probably not going to resolve these problems, but it is a process that is involving a lot of consultation with national and international medical associations since, to remind you, the Declaration of Helsinki is a document that is promulgated by the World Medical Association. So unlike the World Health Association, which is an international United Nations body, the World Medical Association is a consortium of national but not governmental, medical associations.

A second question that arose out of the AZT controversy is whether such disputes might be identified and addressed in advance of initiating the research. And thatís precisely the path that the UNAIDS group has begun to embark on. Alex described the process and I will not repeat that except to say that in addition to a planning meeting that was held in Geneva last September, there were some papers, and I believe, am I right, Eric Meslin, that at least one, maybe exactly one, was distributed to the Commissioners. This was a very thoughtful and useful paper by Dr. Lie.

There were four papers altogether. Let me just tell you what the other topics were. These were focused on vaccines but the UNAIDS group, and, indeed, I think World Health Organization more generally, would like to see this process carried out not only for AIDS research and not only for vaccine research. The other papers were one on protection of study participants, there was one on justice issues by John Harris, a philosopher and bioethicist from the U.K., and a fourth topic on community consultation which was written by a woman from Nigeria, a physician and community activist.

The process of community consultation was actually the model for these regional consultations. In AIDS research, and almost exclusively, although this has begun to spill over into other areas, the idea that one should or perhaps a mechanism should be established for consulting with the community, left vaguely because it is hard to define, in advance of and during the conduct of the research was an idea that came early on in AIDS research and has been suggested in some other contexts as well.

It was that model of community consultation that the UNAIDS group thought would be useful to conduct in a regional sense, and thatís why in the three places that were chosenóThailand, Uganda, and Brazilóare the countries in which the first vaccine efficacy trials will take place. So that was, in a sense, a regional consultation and it included, as Alex mentioned, people from countries in the region other than those particular countries where the trial will take place.

Let me move on and tell you rather quickly a few of the issues that were identified in this process of regional consultation. Again, Iíll try to skip over ones that Alex has already mentioned.

There was a series of procedural issues that pertained mainly to the process by which the sponsors of the trials and the researchers and communities in the host country should make decisions before, during, and after the trial. People in the world of bioethics will recognize this as the classic "who should decide" question, which involves not only the who, but also how the decisionmaking should take place and when. The subject matter of these decisions includes aspects of the trial design, treatment and care of participants who become infected during the course of the trial, who should receive vaccines of some proven efficacy, and similar questions.

Alex mentioned this but I think it needs to be underlined. Participants in all three regional workshops strongly agreed that communities in the host countries should be involved in developing and conducting vaccine trials in a fully collaborative partnership. This, I think, is clear is a distinct departure from the way things have worked in the past. Two out of the three regional groups agreed that the point in research development at which the community should become involved is the earliest possible time. And the shift in concern from what used to be a worry about exploitation, that is, of developed countries and wealthy countries and international organizations barreling in and conducting research on vulnerable populations, this notion was turned on its head in a sense and there was an anti-protectionist, anti-paternalist stance by all of these groups that have now developed in these countries that have themselves capable researchers and mechanisms for review.

That brought us to the discussion of the adequacy for procedures for conducting scientific and ethical review. This is another significant procedural issue. It was agreed at these regional consultations that a necessary condition for carrying out research, collaborative partner research in developing countries, a necessary condition is that there be in place adequate mechanisms both for scientific and ethical review. At least one of the workshopsóI attended two of those three workshops, one was the one in Entebbe, Uganda, and the one in Brazilóit was suggested that another layer of review, perhaps at the international level such as the UNAIDS committee, might be desirable.

Let me turn and very briefly mention a few of the substantive ethical questions that go to the heart of the design of both vaccine trials and, as Alex mentioned, the ancillary care and treatment of participants. Itís assumed, I think, by everyone, not only scientists for the best trial design but others, that a placebo control arm is methodologically necessary and ethically acceptable at the outset of vaccine trials. At the outset is a different situation from what happened with the AZT trials.

However, there will come a point at which a vaccine is possibly effective, marginally effective, or not very effective, and the question then is what should the design of subsequent trials look like. Would it be unethical in subsequent vaccine trials to withhold a partially effective vaccine from people in a control arm when the new vaccine is being tested, and will that compromise the ability to measure what has to be measured?

Alex already mentioned the question that participants in the regional workshops thought was the thorniest question, and that is the type and level of medical treatment to be made available to trial participants who become infected in the course of a vaccine trial in spite of the counseling on risk reduction. Now, this is probably the closest analogy with the placebo-controlled AZT trials, because people who argue that participants in vaccine trials should be given the "best proven treatment," or the treatment that is available in developed countries, argue to withhold what would be analogous to conducting the placebo-controlled trials and withholding a proven known effective treatment to people in the trial. So the problem will not go away - even if we have a different substance and a different type of study.

One of the regional groups came to the fairly strong conclusion that the appropriate type and level of treatment should be decided upon by the host country, the host country being, of course, the country in which the trial is to be conducted, not by the sponsor, not by the manufacturer, but by the host country. And there were discussions, as Alex pointed out, about what kinds of criteria should be used for determining that standard.

One series of questions that Alex did not mention, and Iíll close with this, because this was also important for the international collaborative work, this was a series of questions that were not resolved neither in those three regional workshops nor at the Washington meeting. What should be available to whom after the trial is completed? Or, to put it a different way, what are the obligations of the sponsoring country, the manufacturer of a vaccine, or we could argue other drug, to make available in a region with a high degree of need a product that is proven to be effective, particularly if weíre talking here about something like a vaccine for AIDS? Should trial participants who receive the placebo be entitled to a vaccine? Should individual or groups in the country who are thought to be at high risk for infection receive the vaccine? Should all with a perceived need in the country receive the vaccine? These are questions of justice or distributive justice and they are among the most difficult to answer from a theoretical point as well as from an economic and practical standpoint.

The strong consensus that emerged at all of these regional conferences was that the answers to these and other questions should be derived by a process of advanced negotiations among all the relevant partiesórepresentatives from the sponsoring countries, the host countries, including potential trial participants themselves, opinion leaders in those countries, the vaccine manufacturer, and othersóeven though some people pointed out that this departs from what has been standard practice. No one has generally negotiated in advance of research and development of a product whoís going to get it afterwards.

This is a new model, and itís one thatís being urged. The hope, as expressed at the regional meetings, was that adopting some such procedural mechanism can succeed in preventing the sorts of controversy that arose well into the conduct of the perinatal transmission clinical trials and one that the UNAIDS organization is trying to head off by holding these consultations in advance of initiating the vaccine efficacy trials. Thank you.

DR. SHAPIRO: Thank you very much. Let me see if there are questions from Commissioners before we go on to our next guest.

Yes, Alta?

PROF. CHARO: In some ways this may anticipate what Dr. Nightingale is going to talk about. But Iím struck in this discussion by the degree to which the debate about the ethical standards is being driven by what we perceive to be immovable structural and systemic issues like extremes of wealth, extremes of development, and assumptions about incentives toward exploitation which drive the skepticism about the motivations of the pharmaceutical companies and researchers. It makes me wonder if one could work at that level instead of trying to figure out how one could create a set of ethical rules that govern your behavior against a backdrop of such extreme circumstances.

I donít think that any commission can handle the problems of extreme wealth and development. But it does make me wonder about the pressure point of the incentives to exploitation. If companies are going in to do testing on interventions that will never have an application in the developed world, for example, with the AZT trials, I think that raises very different issues than if theyíre going into countries where they think theyíre going to be testing something that they might be able to bring home to a developed world, to a large market, and they want to test it in a place that they perceive to be easier or cheaper for their testing.

That raises the question about the usefulness of foreign data for local approval of drugs for this particular market. If thatís the scenario that raises the concern about exploitation, the question is whether or not the data from those countries in fact is all that usable, since I presume that the background health status of most of the subjects is likely to be different enough that it raises questions about the generalizability of that data to the American population, as one example. But where it is usable, the question would be, should we discourage its use? And I gather that there has been an active debate within FDA about the acceptability of foreign data generally, not with special reference to data developed in developing countries, with conflicting tendencies; some wanting to use more of it in order to speed the approval process, and others wanting to keep it out in order to have more control.

I wonder if this kind of use of domestic law and domestic policy to change the incentives to exploitation, if you think that this is a productive avenue, or if you think that itís too politically complex domestically, to take away some of the seeming pressure toward exploitation thatís driving some of these finer, more "nuanced," decisions about the ethical standards to be used?

DR. MACKLIN: Iím going to let Dr. Nightingale answer that part, that is the part that particularly has to do with the standards and the FDA standards.

But there are additional complications and let me say quickly what they are. First of all, on the notion of exploitation, the countries in which the vaccine trials will begin are extremely eager for these trials. The community leaders, the people living with AIDS, the ministries of health, and the researchers are all extremely eager for it because itís really the only hope for a vaccine. What theyíre worried about is that the testing will test the prevalent strain of HIV/AIDS that are prevalent in the developed countries, in the Western world and not the particular strains that exist inóthereís a scientific question here, whether they can get cross-immunity across these strains. I wonít even go into that. But thatís one of the worries.

The thing that makes this a problem analogous to the AZT trials, and Alex referred to it and let me just say it again in a clear way, is that the trial of an AIDS efficacy vaccine could not be done in the United States to get the answers that you want to get from a vaccine test because it would mean withholding triple therapy, the AIDS cocktail, which would destroy the scientific results because it would immediately reduce the viral load.

So the worry about exploitation is as follows: Here is a trial that could not be done in the United States because participants in the trial would be made worse off than they would be if they werenít in the trial because the routine treatment is widely available. So you would have to withhold it from participants in the trial and, therefore, arguably, itís the kind of trial that could not be done for ethical reasons because you would make people worse off. However, in the countries where it is absolutely not available because of the health infrastructure and, of course, the economics, there are places where nobody would get triple therapy. So this is a perfect example of conducting a trial in a region where one can do it and could not conduct the same trial in the United States.

The groups in those countries, however, do not view this as exploitation. And it was only in Brazil, which was the country where they are providing triple therapy to people who are HIV infected, that they argued that they should get the antiretroviral treatment just like in the United States.

DR. SHAPIRO: Alex, and then Arturo.

PROF. CAPRON: To add a further layer to that, Alta, you made two contrasting categories between something that would be tested there basically to be exported back to the United States versus something that would be relevant. The difference between Brazil and the other countries I think underlines that Brazil has made a choice about the allocation of its dollars to say that it will make antiretroviral and, one assumes, if the vaccine became available, the vaccine widely available. Another country might say weíre putting our scarce dollars into other forms of medical treatment, or education, or other things that we regard as important. And the question then would be, ought anyone viewing the situation or negotiating in the situation, or criticizing the situationóas the kinds of criticism that came up from various people in the United States about what was going on in Africaóbe viewed as making immoral choices if he or she is going to conduct studies there?

Because it becomes a question not just, "Would you say that the country is making bad choices," but then an American researcher from an American research institution, who has to go before her or his IRB to get approval to participate with a study, in effect, has to then say, "This is the circumstance in the country." It certainly isnít the only way the country could choose to spend its dollars. And the question then is, are they implicated in the results if realistically the country isnít going to be able to afford to buy the drug or vaccine after it has been developed because theyíve made choices about how they are spending their dollars?

And so it becomes a very nuanced situation-dependent question. And itís clear that for American research workers, both at the CDC and private universities, this will be an issue that their IRBs will have to struggle.

DR. SHAPIRO: Arturo?

DR. BRITO: I think Alex mentioned the concerns of American imperialism, and I think you, Professor Macklin, implied this also when you mentioned paternalistic type of concerns at the deliberations over the AIDS vaccine trials. I can appreciate that there would be concerns in this area. But I question, and Iím a bit skeptical about, when these deliberations are ongoing and the community leaders and the scientific leaders from those countries, are they not actually more similar to the scientific leaders of this country and, therefore, not truly representative of the individuals of their host countries? Thatís where I become a little bit skeptical.

Now, the way the CIOMS guidelines are written, theyíre written more to protect the subject, and you quoted one of the guidelines there protecting the subject over the community, and this is more individualistic, which is not just an American ideal, it seems to be in international guidelines. Some of the justifications for the perinatal transmission of HIV and the use of AZT, some of the justifications have been more utilitarian in nature, not individualistic. And these were endorsed by the World Health Organization which, in itself, was partly responsible for the formation of CIOMS guidelines.

I guess Iím a bit skeptical about the leaders of other countries making decisions for their "communities" when they, in fact, are more similar in nature or have more in common with the American leaders. So Iím not real clear why we continue to go back to concerns of paternalistic attitudes when those community leaders are also paternalistic in themselves.

DR. MACKLIN: Yes. I think youíve hit on a major problem, which is the difficulty of identifying the relevant community and the greater difficulty of saying who represents the community. What I should point out about these regional consultations is, first of all, they did not include governmental officials who will of necessity be involved in this in those countries. This was nongovernmental; it did include the researchers who, I think youíre quite right, if theyíre not trained in the U.K. or U.S., may be similar in outlook.

But most of these countries, most developing countries, not all, but most have a very well developed structure of NGOs, nongovernmental organizations, that are much more like grassroots organizations. Those were all represented. There were very many of them in the world of AIDS. And so they donít represent the community in the sense of the rural group from whom some research subjects might be taken, but they do represent people living with AIDS, families of people living with AIDS, and those who are health advocates from the grassroots movement.

Now this doesnít fully answer it, but at least it says that these consultations are not limited to, and the aim is not to limit them to the researchers, the Western trained people, and certainly the governmental leaders.

PROF. CAPRON: If I could just add just one quick point. I mentioned the problem of so-called undue inducement vis-a-vis individual subjects. The same issue arises at the governmental level in exactly the way Arturo is describing. If a condition is placed on the sponsoring company or country coming in to do the research, we want the following things to help in our infrastructure, all of this seems very legitimate. But at some point, it begins to seem as though the interests that are being served are those of the research establishment, when you hear that a major concern is authorship on any resulting papers.

On the one hand, it seems perfectly appropriate to say that people who are going to be participants in the research should be involved in its design and recognized for their contributions; on the other, itís as though there is a group of subjects which we can offer you if the proper inducements are there.

And that comes down to the other question, which Ruth and I have both mentioned, and that is the after-experiment, after-research obligations. Because if a drug or vaccine is developed and if the relevant moral unit is regarded not just as the immediate subjects who were in the first trial and you have some ongoing obligation to them, and not just the immediate community but maybe the nation, then you can even imagine a situation in which neighboring states, each with populations that would be "good research" populations are, in effect, making competing offers to the sponsors of saying "come and do the research with us and this is what we will expect in return," and it would even be, ironically, weíre talking about this, an advantage to be a smaller country because youíd say your after treatment burden will only be providing free treatment for a million people in our country, whereas our neighbor has 5 million people, itís going to be much more expensive for you. And then you get to the question why is the country a relevant moral unit in any case for dealing with international epidemics?

So the questions simply become more and more complex and itís harder to get a firm footing that doesnít sound, as you say, paternalistic from one side or the other or exploitative from one side or the other.

DR. SHAPIRO: Steve?

MR. HOLTZMAN: Just a question to Alex on that last point, and maybe Ruth. To what extent in these discussions were there participants from the pharmaceutical industry, and these hypotheses about the costs and attitudes and their inclinations to do trials that are in this or that place, was that discussed with them, or is this all hypothesis?

PROF. CAPRON: Ruth, do you want to comment about the regional?

DR. MACKLIN: Yes. At the regional workshops and also at the Washington meeting the decision was made not to involve representatives from the pharmaceutical industry at this level because we didnít want the economic issues as seen by the pharmaceutical companies to swamp the ethics. The pharmaceutical companies will be invited, however, to the June meeting, which is the result of all these consultations. There was debate about this, by the way, at what stage representatives of pharmaceutical industries should be brought in.

However, there is a process of negotiation that is going on at the highest WHO/UNAIDS/pharmaceutical company levels with regard to providing AZT. This is a negotiation that is now going on that people from the NIH say should have taken place before the AZT trials and not afterward. But there is actually an agreement being forged, possibly even as we speak, to try to make those drugs available now. And thatís why the urging here was to have this conversation in advance of conducting the trials. So thereís every intention to bring in the pharmaceutical companies.

Just to put this in perspective, and going back to Altaís comment: Uganda has a per capita expenditureóthe government and the people canít afford anythingóso the government has a per capita expenditure on health care annually of $5 to $7. Now when they asked even is the cheaper AZT regime available to all of the pregnant women in Uganda, the answer is going to be no, itís not. So, clearly, if thereís going to be any justice in the aftermath of these trials, itís going to need some assistance beyond the countries themselves, because Uganda will never be able to afford more, unless there are some radical changes within the country.

DR. SHAPIRO: I recognize David, and then I have a question, and then we should go on.

David?

DR. COX: Iíd just like to sort of make a comment about research in general. Itís like playing chess; most of the time youíre not just looking at the first move in playing chess or the move ahead of you - or you lose. In terms of research, itís almost always in the context of a specific hypothesis but toward a specific purpose, at least when it deals with health.

Listening to these conversations, I think that without really looking at the situation and looking at the context, that you can do as you described, Ruth, take one part of the Helsinki Accord or another part of the Helsinki Accord. I would just like to make a plea for a very straightforward reasoned and long-range research goal out of all of this and not each trial by itself. But in each particular case, what are people trying to do? I think that without that situational perspective, this is not going to be something that can be solved. I donít see that itís something that can be solved in a general way.

Itís a little distressing to me that, itís not that people havenít thought of this, but that perspective doesnít seem to be much on the agenda. Could you comment on that?

DR. MACKLIN: Yes. I can make a brief comment. The regional conferences were three-full-day meetings; the Washington meeting was a two-full-day meeting. There wasnít time in our 15 to 20 minutes to go into all of the issues. What I should say is that at both the initial meetings and at the regional conferences there were vaccinologists as well as ethicists. These were people who know what the hypotheses are, how one tests a vaccine, and what the steps in the research process will have to be. So there was a very long prospective look at subsequent steps. I referred very briefly to one of them; namely, once you get a partially effective vaccine, what should the design of the trial look like after that?

So these things were looked at sequentially, I mean not laying out the entire research agenda, but with adequate, I hope, input from vaccine experts who are the ones who would be best able to tell us what the research agenda and hypotheses should be.

DR. COX: Well, I wasnít implying that the researchers should set the agenda because, certainly, itís a social and cultural context, but at least by being involved with the rest of the people they can say what the goals of the long-term consequences are. Without that, I donít know what the research is all about.

DR. SHAPIRO: Ruth, I have a question which may, in a small way, be similar to Davidís. You made a comment regarding the acceptability of placebo trials at some initial stage, but then as the vaccine might be partiallyóyou get some information. The question is at what stage do they become unacceptable? And you just left that as a question or as a proposition that has to be resolved.

I want to ask a question about that, because my own reading of the paper that you mentioned, if I pronounce the name right, Professor Lie ó Professor Lieís paper comes to the conclusion that, indeed, in these matters itís a rather almost sophisticated statistical matter as to whether some things are ethical or not, which people can disagree about. The same thing would be true in the example you gave; that is, when do you have enough information to begin rejecting the placebo trials is a very complex matter of which, at least some of it, is statistical in nature. My question is whether that kind of expertise was available to you and others who were participating in these regional and/or Washington discussions. And if not, do you think thatís important or is this kind of a secondary or tertiary issue?

DR. MACKLIN: The short answer is, yes, that expertise was available and there were extremely high level debates, because, of course, as everyone knows, even experts in a field disagree. And so the experts were available and did give their input. There was disagreement.

And, ultimately, there are value choices, too, even with the expertise. So even when they agree on what are the statistical methods that are required, there is still the overlay of the value questions. Is the highest priority getting an answer quicker and, therefore, making the vaccine available even if it means that some people will be less protected, or is the higher priority to be on protecting or providing some benefit to the individuals in the trial? Youíre going to get a faster answer with the placebo, but youíre going to get more protection for the subjects if some of them receive the vaccine.

And I guess the other wrinkle about this is once you get a vaccine, you canít get a better vaccine for those individuals. So people who get a placebo might themselves be better off getting the placebo because if a more effective vaccine is developed and theyíre still zero-negative, theyíll get the more effective vaccine.

DR. SHAPIRO: Well, I appreciate your response. I didnít mean to imply that there were no value questions that always overlay this. Of course, thatís true. But do I understand, you didnít say this directly, may not have implied it, so youíll excuse me if I pose the wrong question here, that itís true experts will disagree on some of these issues, as will those who are trying to bring different value perspectives to it, and that at some level irreconcilable differences appear? How does one think about dealing with that issue? Is this just a process issue, that is, there has to be a process for discussion and decisions made, or after youíve eliminated all those areas where you can achieve agreement, what do you do next?

DR. MACKLIN: You mean if youíre left with residual disagreement?

DR. SHAPIRO: Thatís right.

DR. MACKLIN: Then it is a procedural or a process issue. But I guess I would say not just a process issue. If there is residual disagreement, whether about the ethics, the statistics, the science, or the trial design, then itís extremely important to have an acceptable procedure for reconciling those differences.

PROF. CAPRON: May I try to underline what I think is the implication for NBAC out of this. If weíre looking at what the role of the U.S. ethics standards are in all of this, weíre not going to be designing the trials and so forth - suppose you have a situation in which the host country within the international process looks at a situation and, in light of the statistics and so forth, says we are going to interpret the ethical obligation as providing for, for example, the control group and for people post-study at the presently prevailing medical standard in the country in question, and we think that is adequate, the researchers say that will allow us to do a good trial, and we think ethically thatís fine, and now a collaborating institution in the United States is reviewing this and trying to apply U.S. ethical standards. If they think, wait a second, we could come in as researchers and bring with us better treatment for the people in the control group, the host country isnít requiring it and the representative, the Health Minister from Trinidad and Tobago say, "We donít want you to do that, we donít want to set up a small group that gets this, this is not in our interest, we cannot do this for everyone, we donít want you to do it," should the U.S. IRB receive guidance from the U.S. guidelines or requirements that would say in this circumstance thatís adequate? Or, in this circumstance, if you have a different sense of what is ethically obligatory, you should say that your researcher should not be participating in this and your institution, whether itís the CDC or Case Western Reserve University, ought not to be a sponsor of this work. Thatís the question as it comes home for people here.

DR. SHAPIRO: Okay. Thank you very much.

Eric, it better be very short.

DR. CASSELL: Well, it is short. I think that is really our issue. Our issue is not whether you should do placebo control or not placebo control. Thatís not our issue. Our issue is simply that point: does the host countryís ethical approach to it prevail or must we prevail with our "superior" approach, and so forth. Thatís the real issue that weíre about. We donít have to resolve a lot of that other [stuff].

DR. SHAPIRO: Okay. Thank you.

I want to introduce our next guest here. I just in advance of that want to welcome our colleague Tom Murray, whom I think of as an unofficial host or perhaps even official host, I donít know. Tom, as a few of the rest of us, was a little late this morning. He had a much better reason than at least I had; namely, he received the Distinguished Alumnus Award from Temple University yesterday. So congratulations, Tom.

DR. MURRAY: On behalf of Dr. Shapiro, I want to argue that his reason for not being here was equally valid.