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DISCUSSION OF INTERNATIONAL RESEARCH ISSUES - Dr. Harold T. Shapiro and Commissioners

DR. SHAPIRO: Thank you very much. A number of Commissioners would like to ask some questions. Larry?

DR. MIIKE: I was interested in your brief discussion about the difference in clinical and public health research. Is the issue with the public health research where you can override the privacy rights of the individual the characterization of the potential harm that occurs in clinical versus public health research?

PROFESSOR DICKENS: Yes. But this turns on the distinction that is sometimes drawn between privacy and confidentiality. Privacy is taken to be the power to control what others know, and we all give that up. On every occasion when we appear in public, people can look at us and draw implications about our health, even our lifestyle. The issue, of course, in medicine is that one gives more to physicians and those who offer health services than one might be willing to give even to close members of oneís family. And sometimes health professionals can infer from what is presented more than the patient realizes that he or she is disclosing.

DR. MIIKE: I guess the issue for me is as an individual, and maybe Iím mis-characterizing it, thereís a collective judgment that I can make a decision to participate in something that might be physically dangerous but nobody gives a damn if I get totally offended by their using information on me without my permission.

PROFESSOR DICKENS: Yes. And this has to be put into the wider context of the public interest. This Latin text ó

DR. MIIKE: Yes, but one can make the argument that clinical research is for the public good, so I can interchange clinical research with public health, and I would come out topsy-turvy. You can think that clinical research trials for therapeutic reasons are as much a public health benefit for the population as your classical epidemiological-type studies. It begins to become a matter of semantics to me.

PROFESSOR DICKENS: Yes.

DR. MIIKE: The reason I raise this is that I think where weíre heading in our biological materials side is that if there is harm or an invasion of privacy on the individual then we need consent, and you canít just impose studies on them. So Iím not sure weíre making a distinction between clinical research and public health research in our human biological studies.

PROFESSOR DICKENS: The distinction often drawn is that there is no justification in public health terms for undertaking physical invasions. Though, of course, we have seen compulsive vaccination programs and that, obviously, is physically invasive. That is justified in terms of the public interest.

Normally, one supposes that public health studies would essentially be data-driven epidemiological studies, and information would be taken, even identifiable information, from individuals whose individual veto may not be accommodated. That is, the decision to conduct the study is a public/political decision.

DR. MIIKE: But thatís exactly the point I was trying to make. That in public health initiatives, in the old days you could have been in prison, a TB patient, so there times when there are physical harms to people in public health initiatives for the public good, but itís a physical harm against the individual. So Iím having even greater trouble in those instances distinguishing that from the clinical research situation.

PROFESSOR DICKENS: Yes. The difference, of course, is obscured in the emphasis we give to the phrase "public health." We emphasize the health component. But, in fact, I believe the U.S. constitutional law and in the laws of other countries, the public health power is derived from the policing power of government. It includes the power to detain people who have not committed any offense, thatís quarantine, it includes the power to treat people over their preferences, it includes the power to force them to give information for contact-raising. The Public Health Service is a uniformed service represented by the leaders in the field. The Surgeon General appearing in uniform in public is making the point that this is a public service. And perhaps if one emphasizes the "public" rather than the "health," you get some sense of this.

DR. SHAPIRO: Alta?

PROFESSOR CHARO: First, Bernard, you can be gallant for me anytime. I kind of miss those days.

I feel like in the discussion in the CIOMS document that there are two themes that are in conflict with one another, and I just want to understand which way theyíre being resolved. On the one hand, the question of inclusion has been addressed as part of the new paradigm of research and implicit in here is the notion that inclusion is not something limited simply to women or to racial and ethnic minorities within a particular country, but that really research on a global scale with globally representative populations is necessary if youíre doing basic health studies and you want to understand how things operate against a backdrop of nutritional patterns, other kinds of lifestyle patterns, etc. Which would argue for the fullest possible inclusion of people from all economic walks of life and from all levels of development in their home countries.

At the same time, there is in many of the guidelines that come down the pike, starting from I think around seven, a lot of attention to the specific problems that take place when youíre doing transnational research in developing countries where there is not as well developed a research ethic, where there might be stratifications in society that are quite extreme on a broad scale and that invite exploitation as a pattern, or diminish the capacity for genuine independence and consent, which would seem to argue for avoiding those settings until one has an identifiable need to operate in those settings. Isolating your research as much as possible in the more educated, developed country settings, even within the developed countries in the more educated populations in order to maximize your chance of genuine independence, particularly when it comes to altruistically opening yourself up to taking on risks for the benefit of general knowledge.

The two tendencies seem to be conflicting. I couldnít quite sense in this document, even in the most general way, which way youíre trying to see international research jump on this question.

PROFESSOR DICKENS: I think in part you addressed this in an earlier question when you mentioned the need for ethical review both in the sponsoring country and in the host country. The supposition is that the host country reviewers would have a sense of local needs, local priorities, what values can be sacrificed in promotion of which others. The functional problem, of course, is that frequently those who claim to speak on behalf of their countries have no democratic credentials and have no democratic answerability. And in that sense, one has to guarded about what sort of initiatives one takes.

It is hard, and one canít really answer it in any adequate way in the abstract except in the rather cynical comment sometimes made about the ethic of inadequate resourcesóthat if something is really worth doing, itís worth doing badly. That is, if the alternative to doing it badly is not to do it at all, then do it as best you can. A number of studies Iím afraid are undertaken on that basis. One hopes for better. But if the ideal is the enemy of the adequate, then you have to do the adequate.

DR. MURRAY: Professor Dickens, as youíre well aware, one of the issues around international research which has gripped the American public at least in the past year or so has been the issue of the use of placebo groups in less developed nations when there are standard treatments available in nations which can afford them. I wondered if any of the documents that you spoke about today offer a specific guidance as to how to respond to those kinds of concerns?

PROFESSOR DICKENS: Not very specific. The Helsinki Declaration as amended does address the need for individuals who are involved in studiesósick individuals in need of careóto be measured against the best standard available; that is, not against a placebo. But this raises the questions that youíre well aware ofóof how effective the standard treatment is. The issue remains contentious, though the general momentum I think, is against having the placebo controlled studies when there are therapies that are availableónot just in a clinical senseóbut in a functional economic sense.

DR. MURRAY: Iím sure youíre aware that in some of the cases that have been brought to public attention, we donít make judgments about particular cases on this Commission but we use them to raise general issues

The claims at least from some of the local defenders of these studies had a couple of components. One of which was, this is a treatment that simply because of the lack of infrastructure, that is a standard accepted treatment in developed countries, it simply is we canít do it here. Even if we had the money, we canít do it here because we lack either the health infrastructure, refrigeration, follow-up, etc. We canít do it, number one.

And two, even if we could do it, we couldnít afford to do it. And there is a plausible case to be made that a less expensive, less onerous form of treatment or prevention might actually be as, or almost as effective, and we would like to test that.

Thatís the kind of defense that has been offered. I just wondered, again, if you have any comment about that?

PROFESSOR DICKENS: None of the international documents that Iím aware of deals with the issue at that level of sophistication or specificity. Sometimes the guidelines are inverted, in that although they say that there should be access to the best possible standard care, the inversion comes in the interpretation that this means individuals should not be deprived of what they would otherwise enjoy. If, of course, they wouldnít enjoy anything, then thereís nothing really to deprive them of and you may, therefore, say that provides a justification for a placebo-controlled study.

DR. SHAPIRO: Thank you. Alex, then Eric, then Bernie.

PROFESSOR CAPRON: I guess Iíd like to follow up on that. You may not have been here when Duane Alexander quoted Pavl Riis of Denmark, one of the drafters of the original Declaration of Helsinki, who gave us a drafterís gloss on the phrase which he thought was self-evident, the one to which Tom Murray just alluded and which you cited, which is Section II.2 in the Helsinki document. Iím tempted to put you in the role not of James Madison but of John Marshall, to use an extension of our Constitution, since you are so widely regarded as an authoritative interpreter of these documents.

The gloss that was cited was the notion that it was understood that the best current method available in local practice was part of the unspoken phrase. Do you know of other situations where international bodies or other commentators have addressed this issue prior to the current concern over the AIDS research where we might get some sense if we try to reach conclusions about the most sensible way to interpret guidance of this sort?

PROFESSOR DICKENS: The short answer to a sophisticated question is, no. Iím not aware of any more profound addressing of this issue than Dr.Riis has given.

PROFESSOR CAPRON: I wanted to ask you to clarify two points very quickly that came up in passing. One was this mention of the notion of incomplete disclosure of the objectives of research to subjects under the heading of the epidemiological studies. It is true in that circumstance, however, that the IRB has to be fully informed and has to be agreeable. Is that theó

PROFESSOR DICKENS: Yes, yes, absolutely.

PROFESSOR CAPRON: And that where the emphasis is on study of a community it is the expectation that there will be representatives of the community on that IRB, really representatives of the community in a way in which just being a member of the community isnít as representative, as I understand it. The sense is somebody who can really speak for the community; is tható

PROFESSOR DICKENS: Yes. The CIOMS guidelines do require that membership of the committee include those from the community to be studied. But the question of how representative that person is - is really a political question.

PROFESSOR CAPRON: Another point you mentioned was situations in which the community could assent to research which is then not carried out with individual consent. And I think you and Dr. Miike had an exchange then about what public authorization lies behind such a public health study. There is also reference to community agreement where the interests of the community might be harmed by the findings of research. Thatís suggested in, the other was one was I think Section 5 and Section 39 thereís some suggestion there. Is it your reading of that if a researcher had willing subjects but the representatives of the community were unhappy with the research going forward, and you mentioned, for example, Ashkenazi Jewish women in the cancer studies, that under a correct reading of the CIOMS guidelines that research ought not to go forward?

PROFESSOR DICKENS: No. The guidelines I think address the process of decisionmaking rather than what the decision itself should be. The research is not prohibited under the guidelines. But any committee willing to approve research over the known opposition of those claiming to speak for the community would have to give an account of why they felt that was ethically appropriate.

PROFESSOR CAPRON: And then if I could ask a question to you and also get a response from our HHS representatives. You mentioned two things which it seems to me are very important for our understanding. The first is the effect for a researcher of following research regulations where the activity is said on other grounds to have violated the positive law of the jurisdiction. I understood you to suggest that in most of the world following the research guidelines wouldnít do you any good but your understanding was that in the United States it would. Iím not aware of that as a reading of the U.S. regulations. That is to say, I took the regulations to say this is what you must do to get Federal funds but if, in the process, youíve actually departed from some law of the jurisdiction and committed harm to someone, you are still liable and this is no defense. Your reading was somewhat different, unless I misunderstood you.

PROFESSOR DICKENS: No. It wasnít a reading, it was an attempt to summarize what Iíve heard. Clearly, I defer to your interpretation of the status of the Federal regulations in U.S. law at both Federal and State levels. It was my understanding that because of the legislative foundation of the Federal regulations conformity with them meant that research that was in compliance was lawful research.

PROFESSOR CAPRON: Maybe we could get then an answer from the U.S. side from Dr. Puglisi?

DR. PUGLISI: The HHS regulations and the Federal policy include the specific statement that the regulations do not preclude any State or local law that provides more stringent protections for human subjects. So conformity to the HHS regulations or the Federal policy does not make something okay if itís not permitted under state law.

The only qualification I can make would be that in some States, specifically California where there are specific statutes that relate to human subject protections, thereís a provision that research that is conducted in accordance with an HHS assurance may follow the Federal regulations rather than the State regulations.

PROFESSOR CAPRON: But I gather that is just a reference to whether in areas where there wouldnít be Federal jurisdiction the State expects the researcher to follow the U.S. rules anyway. But that none of this is a waiver of tort law standards if there was a finding that despite whatever regulatory things youíve gone through there really wasnít adequate consent, etc.?

DR. PUGLISI: Thatís correct.

PROFESSOR CAPRON: And the final question, also for both of you, is, it seems to me that the Helsinki Declarationís division of the beneficial-nonbeneficial or therapeutic-nontherapeutic or clinical-nonclinical, which is the actual language it uses, is not reflected in U.S. rules. I want to know, do you agree that there is that difference? And then from the U.S. side, I wonder, if that is the case, then how is it that we can accept an institution abroad saying that it will comply with the Declaration of Helsinki as an equivalent of following our rules since the Declaration of Helsinki seems to me to give a broader sweep to the so-called clinical research and is, indeed, I think historically as a document, understood as a reaction to the Nuremberg Code for the very reasons that Bernard Dickens said. The Code was drafted by American judges passing judgment on people who had used subjects who were clearly non-volunteers in a prison situation for research that was not for their clinical benefit. And, yet, the research community, the World Medical Association, realized there was going to be a lot of research which couldnít be carried on if you sort of took Nuremberg to be the full statement, and they created a document which had this other, and indeed, predominant role for clinical research with much wider judgment, and itís been toned down in subsequent years, but in the original declaration much wider scope for the judgment of the researcher.

I wonder whether, (a) you agree that there is that difference between the U.S. rules and the Declaration of Helsinki; and (b) from the U.S. side, I wonder how is it then that we can allow the Declaration to stand instead of the U.S. rules when there is this at least tension in the way that they regard so-called clinical research, which Belmont and the National Commissionís work seem to say we shouldnít make that divide; therapeutic-nontherapeutic wasnít a good divide to make.

PROFESSOR DICKENS: Clearly, I canít comment on the U.S. position. But I think it is increasingly recognized, not just in the American Medical Association, that the contrast drawn between clinical research-nonclinical research in the most recent variant of the Helsinki Declaration is inadequate. The 1993 CIOMS guidelines say that the Helsinki distinction does not provide for controlled clinical trials and, equally, Phase III vaccine trials would not be accommodated. So I think itís clear that this is a fragile distinction.

Again, I would go back to the introductory language of Helsinki. It is a recommendation, it is a guide and justifiable departures from it I think would be perfectly proper.

DR. PUGLISI: An assurance contains two parts. The first part is a general statement of principles that applies to all research regardless of funding. The second part applies specifically to HHS-supported research. So the reference to an ethical code such as the Declaration of Helsinki, or anything other than the Belmont report, is in reference to research that is non-HHS-supported.

For the research that is HHS-supported, we have the second part of the assurance which outlines the specific protections that are to be enforced, and then secondly, in the case of a single project assurance, we have the particular project being reviewed and the consent document being reviewed by OPRR. In the case of the cooperative project assurances, we have the project and the consent document being reviewed by the funding agency. For a multiple project assurance, I donít think we could accept an assurance that didnít reference U.S. regulations.

DR. SHAPIRO: We have three more people and then weíre going to have to take a break because weíre running a little late in our schedule.

Eric, then Bernie, then Alta.

DR. CASSELL: My comment may be muddled because my headís muddled about this. Assurances and codes abound, as Professor Dickens points out, but when you get to particular cases, as Tom Murray brings up, theyíre not much help. Iím trying to go back to the issues that followed the Second World War when the United States was bringing medical care into other cultures, and people were outraged if anybody locally died when there was so much food here and so forth. So we exported dried milk to places where a lactase deficiency was so common that we exported diarrhea. We made mistake after mistake because of lack of knowledge of what could happen in another culture. And that kind of thing at the time was called "cultural imperialism." And we finally learned and all of that sort of stuff.

And then I have this quality of an "ethical imperialism" now. We know exactly whatís the right thing to do. On the other hand, in our own country we have seen in the war on poverty the creation of medical services which were then withdrawn the minute the money ran out, causing great harm. And once again, if we did what people wanted us to do and thereís no placebo group, we would do the same thingóthe study would leave and when the study left so would the medications leave, and we would leave a culture no more able to deal with the disease that they actually have. And I donít have trouble with that.

I have trouble with how we make it clear, not just to investigators but to the public that watches. After all, the outcry didnít come from a bunch of investigators, the outcry came from editors of medical journals, and that certainly must be a pristine place to live, and the citizenry. So I think one of the things we have to come out with is not another code, there are really a lot of codes, but some way to think our way through it and to make that thinking clear to other people.

DR. SHAPIRO: Thank you.

Bernie?

DR. LO: I wanted to ask Professor Dickens to offer his suggestions as to what role NBAC might fill in this debate on international research. And I want to sort of break that into two parts. You very nicely took us through the major codes. I guess one question is, is there a pressing need to try and revise some of these codes in the sense that they really are thwarting important research? And then the second part of the question is, putting aside the codes for a minute, are there issues other than the ones youíve raised in your discussion that are extremely important for international research that need more attention and more clarification?

PROFESSOR DICKENS: First on the question of codes, the Nuremberg Code of 1947 is relatively unsophisticated in contrast to the German Medical Code of the early 1930s. This perhaps makes us a little guarded about how valuable it is to have codes. If one sees the spirit with which codes are observed, perhaps one gets closer to their relevance.

With regard to other issues, perhaps I could just mention one. Weíve seen the United Nations Human Rights Commission and the monitoring agency under the Convention on the Elimination of all forms of Discrimination Against Women (CEDAW), in concluding observations on nationally submitted reports, being very critical of countries that have an unduly high rate of maternal mortality and morbidity associated with the nature of their abortion laws and the operation of their abortion laws, that some have purely repressive laws, other have laws that are more accommodating but donít support those laws with any services.

Perhaps instead of answering the question, I could ask if this is something that you think it appropriate for you to address.

DR. LO: Thank you.

PROFESSOR DICKENS: Perhaps I could add that both the U.N.-Cairo Conference of 1995 and the U.N. Conference on the Status of Women, the Cairo Conference was on population development, the conference of 1996 in Beijing on womenís interests, both targeted the problem of unsafe abortion as a public health problem in many countries of the world and not simply a clinical issue.

DR. SHAPIRO: Thank you very much. Alta?

PROFESSOR CHARO: Iíd be interested in some clarification on one of the answers that you gave to a question from Alex. He was asking about the community consultation that can take place so that research that might reflect upon a community, he mentioned Ashkenazi Jews as an example, would be open to discussion by community representatives. And you had suggested that if an IRB were to approve such a protocol over the objection of community representatives, they would do it subject to being accountable for having overridden those objections.

What I wasnít clear about is accountable to whom? Since IRB deliberations are confidential, and, at least in the United States, in most cases what youíve approved never gets funded anyway so thereís never an actual study that goes on that can be the trigger for public discussion, what is the accountability mechanism that you had in mind?

PROFESSOR DICKENS: Itís really in a political setting. If research was approved that representatives of the affected community objected to, or if components that they required were not included, then the investigators and the sponsors of the study would have to give some political account perhaps in public health terms of why they thought it proper to undertake research and risk imposing it.

PROFESSOR CHARO: But thatís assuming though that youíre bringing in outside people. If you have those community representatives on your IRB, they are not allowed to speak outside about what went on in the IRB, at least in the U.S.

PROFESSOR DICKENS: No, but they would be free to engage in public comment, not necessarily saying that their objections were discounted, but saying as members of their community that they find this objectionable because of what it includes or because of what it excludes.

PROFESSOR CHARO: Okay.

DR. SHAPIRO: Thank you very much.

I really want to thank todayís speakers for taking their time to come down and share their expertise with us. Itís been very valuable to us.

This word to the Commission. I would like each member of the Commission to think some over this afternoon and this evening about our own agenda in this area. I would like to take a few minutes tomorrow perhaps at the very beginning of the morning session, maybe 20-25 minutes, to really get suggestions from Commission members as to how we should focus the scope of our own work in this area.

Iíve asked Alex to help mobilize those of us really interested in this area to focus the Commissionís efforts as we have done in other cases. Those of you who are especially interested in working in this area, please let me know because Iím sure Alex would welcome your assistance. So you might just think about whether thatís one of our projects which you are especially interested in. I think there are a lot of fascinating issues here.

But also, more importantly perhaps, to begin a more focused discussion on just what our agenda might be, just which aspects of this fascinating yet multifaceted problem you think is useful for us to take up. I would like to at least begin that discussion first thing tomorrow morning.

Once again, we thank our guests for coming.