PROF. CAPRON: Thank you, Eric. The reason I gather that Eric thought it was appropriate for the Commission to be involved with the UNAIDS activity is that the way in which we were first drawn into the topic of research was through the protests, as it were, the complaints that had been voiced about the AZT trials in Africa and Thailand. And the UNAIDS program decided to establish an ethics committee, which is chaired by Ruth Macklin, and to have a series of regional consultations leading up to a meeting in Geneva next month. The three regional consultations in Uganda, Brazil, and Thailand drew researchers, ethicists, physicians, and the public health officials from those areas of the world in which research is being carried out not only in the antiretroviral treatments, but, more particularly, in vaccine development.

The consultation held in Washington at the Pan American Health Organization last week differed somewhat. First, there were representatives from several of the other regions that had already had their consultations; and secondly, the focus it seemed to me was less on what is happening in North America, but rather on the interaction between the interests of the major sponsors, particularly the governmental as opposed to the drug company sponsors, and the regulations in the United States, the interaction between those and the research design of vaccine trials.

The topic was, therefore, particularly appropriate because the kinds of questions that we’re asking in our own potential international agenda are very much the questions of what are the effects of the American regulatory framework, both within the Food and Drug Administration and in the Common Rule, on the ability to carry out and the suitability of research that is carried out abroad, and whether changes are needed either in that framework or in the Helsinki and Council for International Organizations of Medical Sciences (CIOMS) document. The one aspect that I think is only a partial response to our international agenda is that the focus is solely on AIDS. And when we get to the international agenda I, at least, will argue for the notion that we should use AIDS perhaps as a springboard but ought not to limit our examination to that one disease or to the attempts to find vaccines. I’m very much indebted in what I’m about to very briefly report about that meeting last week to Ruth Macklin, who took very extensive notes, which she has shared with me.

It seemed to me that in ethical terms, the central prerequisite for the vaccine trial is the notion that despite some counseling and encouragement to avoid infection, a certain percentage of the people who are vaccinated will nevertheless become exposed to the virus. If preventive measures other than the vaccine itself were totally effective, then it would not be possible actually to do a vaccine trial.

Now, some of the issues that arise have to do with at what stage in the trial process, whether at a preliminary stage when the dose being given is not necessarily aimed at achieving any immunity but rather looking for reaction and side effects, or later in a trial when a large number of subjects are used with the hope of finding out whether the vaccine in fact will prevent the development of the disease.

I’ll leave it to Ruth to describe more fully the technical questions with which she has become familiar about the vaccine. But one of the particular facets of the vaccine which raises its own set of ethical questions is that it is not a vaccine that will probably prevent infection. Instead, it is intended, if it worked, to hold the viral load at the same low level that antiretrovirals now hold the viral load, which prevent the development of the disease itself.

There were a number of issues; let me just mention two or three of them as examples of the problems that were discussed. One of the questions is something that is pervasive in research generally, and that is the question of when and where one draws the line on inducements to participate. This particular area is complicated by the question of what will be done for people who become infected in the process.

The major inducement that could be offered either to individuals or would, in effect, be offered to the host country and its public health organization or its governmental arrangements is the offer of treatment for people who have the infection, and, again, with the realization that some of the people who are vaccinated will nevertheless get infected and would be, therefore, at risk of developing the disease, and certainly anyone who did not receive the active vaccine would be at risk of getting infected.

The notion of having available a treatment for a person who becomes infected seems to be a moral imperative. But if, particularly among intravenous drug users, the probability of becoming infected for people in certain populations is enormously high at the outset, then you can see that a dilemma arises when the person is offered the prospect, which is not otherwise available to the person and may be just generally not very available in the country at all, to have free antiretroviral treatments for an indefinite period. Because if the person is otherwise thinking, well, everybody I know is coming down with this disease, it’s likely that I will also, but the one thing that would be available to me is only available if I participate in the trial, does that mean that the trial should not be conducted under those circumstances?

In a certain way, that’s the population that researchers would most like to address because of the high risk of exposure. In another way, the question is: can anyone freely consent under those circumstances?

So this question of providing the treatment is central. And it was interesting at the meeting to see that not only have the different regional consultations come to different conclusions about this, but the countries within the regions have reached different conclusions. For example, the regional consultation that was held in Brazil had concluded that the drug should be made available as part of the experimental design. And the Brazilian representative who was at the meeting explained how his government has, indeed, decided to make the drug available to all known cases of infections with HIV. Whereas the representative from Trinidad and Tobago, whose country had been represented at the Brazilian consultation, took the contrary view that it was simply too expensive and burdensome even to the individuals to expect that they would be on a course of antiretroviral treatment for the rest of their lives, and that this should not be part of the research design, and it should not be regarded as, in the language of the CIOMS document and the Helsinki document, "a treatment that is reasonably available and therefore should be part of the research design."

There were many areas of remaining disagreement as to whether or not the level of intervention provided to the subjects—for example, in the AZT trials in Africa involving pregnant women and maternal transmission of HIV— what was meant by the best proven treatment, whether that was a world standard or a host country standard. Barry Bloom, who was a participant in the meeting, was pushing for the notion of the highest attainable standard, which was interpreted by some as too burdensome because of the emphasis on the word "highest," and by others as too low because they took the word "attainable" to mean practically attainable given the resources of the host country. So if there was consensus on any point, it was that it’s not likely that a few words by themselves are going to answer this and that one has to understand the principle or the objective to be gained and the wording comes later.

The final point that I’d like to draw from the meeting was the emphasis that was placed on the desirability of developing a mechanism which would not only facilitate communication between the sponsoring countries and the researchers from those countries, but also the researchers in the host country and the government of the host country on behalf of the potential participants. This emphasis on developing a practical, ongoing means of resolving disputes in the interpretation of these international guidelines struck me as an area where we could make further valuable contributions, even if the particular mechanisms would likely be in themselves international mechanisms.

DR. MESLIN: The Chairman has joined us, but I’ll allow him a chance to get seated.

Were there any questions or comments for Alex?

Jim?

DR. CHILDRESS: I’m very glad that you’re broadening the discussion beyond the AZT trials. I participated in a discussion in the Tropical Disease Division, and we’ve circulated the summary of some of the points that came out in that discussion involving people from around the world. I think some of the issues that come up, for example, in that area are quite different from the ones that arise in the AZT trials. So I’m glad that we’re going to cast a pretty broad net in order to be able to deal with the kinds of issues that may be quite different.

The main example of this in the discussion that came up was, in contrast to having an established drug therapy, you’ve got a reduced course that will work relatively well, perhaps as well. In this particular area of tropical disease research, most often there’s an effort to develop a pilot study that will suggest this thing might be effective and then try to entice a pharmaceutical company into developing it. That’s very different from having something available. So that’s just one example of some of the complexities that might arise in thinking about providing an access to what is developed. The issues would be different in that from the AZT area.

PROF. CAPRON: One of the issues that arose, which I think was probably a question at the tropical meeting and, if not, could be because it’s not at all particular either to vaccines or to AIDS, is the statement in the present CIOMS guidelines which caused a lot of consternation actually on the part of representatives of several of the developing nations that were there, and that is the requirement that any drug or vaccine be tested in phase I and II in the sponsoring country first. There were two objections raised to this. One was that the whole notion of sequentialism here may not make sense and it might be important to test it, in part, because of variance in the biological processes that we’re talking about that can occur: different strains of a virus or different manifestations of a disease in different countries.

But the other objection that was raised is what does this imply about the progress in addressing diseases which are perhaps of much greater concern to other parts of the world even if you could find sporadic cases of them in the United States? There are some things that you’re not going to find in any endemic fashion in the United States that are major problems there. And, clearly, that kind of a barrier, if it was a U.S. or a European drug or vaccine sponsor, would prevent any progress.

My impression, having participated in the CIOMS process, was, as we’ve seen in the pre- and post-AIDS era, the emphasis of the CIOMS document, as recent as it is, is still very protectionistic and it grows out of the experience of drugs being developed for conditions that exist both in the Third World and in the United States, using Third World populations because they were more convenient and cheaper to use, not because one was addressing illnesses that are particular there. And some attention both to that concern and yet not overprotecting to the point where you prevent not just the development of the vaccine or drugs, but the development of the necessary infrastructure in that host country to become an active participant in the process is a real dilemma. And it isn’t adequately addressed by any of the guidelines. We heard a little bit about the process of the Helsinki revisions, and I’m sure Ruth may have more to say about that a little bit later.

DR. SHAPIRO: Thank you. Are there any questions, comments?

Thank you very much. And, Alex, I apologize for coming late. I will catch up with you later on what was heard.

And let me apologize to the Commission members. My only quasi excuse is it took me longer to get from the airport to here than from Newark to the airport. So I apologize for coming somewhat late.

We have three really very important guests here today. I want to turn to them now and apologize to them, first of all, that we are running a little late. I hope we don’t upset your own schedules.

Let me just turn to the first of them and welcome Professor Ruth Macklin here this morning. She’s a distinguished professor of bioethics at Albert Einstein College of Medicine, a member of the Institute of Medicine, and Vice President of the International Association of Bioethics, if I have the association name correctly. Ruth, it’s very nice to have you here again. Thank you very much. We look forward to your comments.