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INTERNATIONAL RESEARCH: A RESEARCHERíS PERSPECTIVE - Dr. Duane F. Alexander, Director, National Institute of Child Health and Human Development (NICHD)

DR. ALEXANDER: Thank you very much. Itís a pleasure and a privilege to appear before this group. Iím going to discuss in a relatively brief fashion, why international research is a topic of concern, give you some idea of the scope of NIHís international research activities, talk briefly about some current issues in the international research scene, and make some mention of the role of international guidelines and the role of the United States in that process.

If we look first at why international research is a topic of concern, we can really look at it from three different perspectives. First is the scientific imperative, if you will. Scientific solutions to such problems as communicable disease, unsustainable population growth, environmental health, and famine require a coordinated global response. Public policy decisions of national and international dimensions require thoughtful assessment of the scientific data thatís collected through international efforts. I think the scientific imperative is pretty clear, and as thatís not the major focus of your interest I wonít say much more about that.

The second, if you will, might be a self-interest imperative. From the self-interest standpoint, the direct and secondary consequences of the health status of developing nations on the American public are significant. Consequences include the spread of new pathogens, deforestation, worsening pollution, mass migrations, and diversions of our national revenue for humanitarian and emergency aid. Thus, it could be argued that self-interest should reinforce our efforts to mobilize the worldís scientific talent to address the special health needs of three-quarters of the worldís population who live in developing countries.

Third, thereís also an ethical imperative. This ethical imperative is built not on self-interest, but rather on concerns for beneficence and justice. Here the arguments remain compelling. The health problems of developing nations constitute only 5 percent of the worldís expenditure on health research, but these countries suffer 93 percent of the burden of premature morbidity and mortality. Acute respiratory infections result in 7.4 million deaths a year in developing countries predominantly. Diarrheal diseases alsoó5 million deaths, predominantly in developing countries. Complications of pregnancies present significant maternal and perinatal risk and are estimated to be responsible for half a million maternal deaths a year. That is in contrast to about 300 in the United States. The burden of parasitic infection also constrains economic development through the loss of significant productivity.

These public health problems are exacerbated by population pressures. It increases disease burdens and exceeds health care capabilities. Thus, if weíre truly concerned for our fellow men and women, weíre obliged to direct resources to improving their health and their well-being. So how do we do this mechanistically and ethically? For whichever of these three reasons, we have found a way to do so through our international programs, and Iíll talk primarily about the NIHís approach in these international activities.

International programs are conducted as a direct extension of the domestic health mission of the NIH. Support for these activities is broadly provided for across the NIH through research grants and contracts, through fellowships, scientist exchange programs, and international agreements. The Fogarty International Center, one of the major NIH divisions, serves as an organizational focus for international activities and supports international programs through its legislated mandate.

The NIH awards grants and contracts to foreign investigators under provisions of the Public Health Service Act of 1944. Before a foreign grant is made, all applications for such a grant have to be individually reviewed and approved by the national advisory councils of the awarding institution, and they also must take into consideration whether identical studies could be conducted in the United States. If they could, they may not recommend awarding that particular grant to a foreign country. Also, the proposal must fall in the top 50 percent of priority scores for approved applications. This isnít usually a problem since essentially everything we fund falls into that category .

I should also note that the average funding level for foreign grants is less than half that of domestic grants, in large part because labor is cheaper in foreign countries, but even more so because foreign institutions are ineligible for indirect costs. So thereís no indirect cost applied to foreign grants, which consumes about a third of the total cost of a grant awarded in the United States. We should also note that except for the Human Frontier Science Program of the "Group of Seven" and the Commission of the European Union, and grants that are made from funds supplied by countries to those programs, the United States is the only country that makes grants to scientists in other countries.

I want to use a little different type of visual aid. Instead of slides, I invite you to turn to the NIH Annual Report of International Activities that is at your desk. If you would open to page 3 and look at the table thatís there, or Figure I.1, this gives a graphic display of the distribution of NIHís international funding in Fiscal Year 1996. The total was about $195 million, representing 1.8 percent of the NIHís budget.

In recent years the dollars have risen, but the percentage has been unchanged over the last fifteen years; about 1.8 percent overall, with about half of that amount provided in grants and contracts, and most of the rest provided in fellowships for foreign scientists to receive training and conduct research at the National Institutes of Health intramural program. About a third of the NIHís intramural scientific staff is in this international exchange program. They receive superb training, then take these skills back home. The other half is for research awards.

If you will now turn to pages 3 and 4 and look at Table I.2, this provides more detail on the expenditures in this program. It might be easiest to focus on the Total Column at the right. Again, youíll see that the grant dollars are evenly divided into two categories, the first two lines. First is the grants that are made directly to investigators in foreign countries, constituting about $32.9 million.

PROFESSOR CAPRON: Excuse me. Could I just ask a question?

DR. ALEXANDER: Yes.

PROFESSOR CAPRON: Would you like us to hold our questions, or would you like us to, if we feel it necessary, interrupt as you go through?

DR. ALEXANDER: If you feel itís urgent, please interrupt as I go.

PROFESSOR CAPRON: So "urgent" is the criterion?

[Laughter.]

DR. ALEXANDER: Otherwise, it is probably smoother to go ahead with it. But if you have a burning question and itís about something thatís on that page, letís do it now.

PROFESSOR CAPRON: Thank you. No, questions.

DR. ALEXANDER: Okay. So about $32 million, then for research directly provided in grants to investigators in other countries. And then the other foreign component is about $36.9 million, which is awarded as a foreign component to a domestic grant. This is an applicant from a United States institution that has a foreign component as part of what they will do. This has been the largest and fastest-growing component of this grant activity; it has tripled since 1989, and Iíll get to the reasons about that in a minute.

If youíll turn to pages 6, 7, 8, and 9, and probably look primarily at page 9, Table 1.3, this provides the distribution of these dollars by country. You can see, if youíre interested in that amount of detail, which countries get what kind of support. In summary though, it shows that 184 research grants worth $32.8 million have been awarded to investigators in foreign countries. If you look at the subparts of that table, youíll also note that half of the grants, 99, go to investigators in our neighbor to the north, Canada; 18 to the United Kingdom (UK); about 16 to Israel; and then other countries tail off after that. So most of it is to Canada and the UK.

In the next vertical column you will notice that foreign components of U.S. grants, again, account for 572 different grants for nearly $40 million. This is an especially dominant mechanism for a developing country that has difficulty competing on its own with the U.S.-based investigators. So this has been a rapidly growing program. There has, in fact, been a modest decrease in the total numbers of grants awarded directly to scientists in other countries because of the competition, and this more effective strategy has been a collaborative proposal with the U.S. investigators. If the proposal is awarded, NIH provides funds to the U.S. institution, which is responsible for carrying out both the domestic and the foreign components of the proposal.

This has been a particularly effective way to collaborate with developing countries. The NIAIDófor example, biology and infectious diseaseócurrently supports special international programs in such areas as tropical medicine, tuberculosis, and HIV/AIDS. Over 70 percent of NIAIDís specialized research and training programs go to either developing countries or democracies of the former Soviet Union.

So that gives you kind of an overall picture. If youíre interested in more detail, the rest of this report provides brief summaries of almost every project thatís underway. You may want to give some attention to that at your leisure.

PROFESSOR CAPRON: Dr. Alexander?

DR. ALEXANDER: Yes?

PROFESSOR CAPRON: For the record, the research going on in Africa and Thailand on AZT for pregnant women, was that NIAID?

DR. ALEXANDER: Some of that was CDC. The two recent studies reported were both CDC studies. But there are studies supported by NIAID and NICHD in developing countries on related topics.

PROFESSOR CAPRON: And the CDC funding is not included in this report?

DR. ALEXANDER: Thatís correct. This is just NIH.

When you do have a chance to review this fuller report, you will see that the scope of international research is enormous and basically contains pretty much the same kind of scope of activities that are done domestically, plus research on diseases that donít occur in the United States. It is important to remember that weíre not just talking about developing country research in international activities, but research done in fully industrialized countries of Europe, Asia, Canada, Australia, Israel, and elsewhere.

Not only do we have the same kinds of research, but, as you will hear in a little bit from Tom Puglisi, we also have NIH and Public Health Service guidelines for doing research with human subjects that follow the dollars if they are from the Federal government. We also have FDA rules that apply to nongovernment funds if the data will be submitted to the FDA in support of a licensing application.

Thus, if weíre doing genetic studies in a large cohort in South America, the same privacy issues pertain. If weíre doing a vaccine study in Europe or Africa, the same issues of an appropriately treated control group apply. If weíre doing a contraceptive study in Asia, the issues of dealing with controls and with contraceptive failure have to be dealt with. And when the NIH implements its new policy requiring the inclusion of children in research, unless thereís a good scientific reason for excluding them, this will challenge existing policies in Europe as much as elsewhere. Even in the most recent document from Europe, the Council of Europeís Convention on Bioethics, the approach to children and others who cannot give full informed consent themselves is to exclude them from research unless countries make specific provisions in their national law to include them. This really contrasts with the U.S. approach of inclusion along with everyone else, but providing special additional protection for these individuals.

DR. SHAPIRO: I have a question here.

PROFESSOR CHARO: A similar issue arose several years ago about the inclusion of women of reproductive age, and NIH then adopted a policy favoring inclusion against the backdrop of exclusion. My understanding from France, in particular, and a couple of other European countries, is that the standard there was still an exclusionary standard. What experience did NIH have in implementing its new policy of inclusion of fertile women when they then tried to export that to transnational research collaborations?

DR. ALEXANDER: I wish I had data on that, but I donít. Iím sorry. We can try to look at that and get that information back to you specifically, but I donít know. Itís new enough a policy that we may not have a whole lot of experience with it yet. But I will check and see what I can find and get that back to you.

PROFESSOR CHARO: Iíd much appreciate it. Thank you.

DR. ALEXANDER: What really does differ is the general standard of care from country to country which, as weíve seen from the HIV/AIDS maternal-infant transmission studies, can be a source of conflict. This brings into focus the discussion that Professor Dickens will be presenting on existing international documents and the protections that they provide. One problem with these documents is that they sometimes can be reinterpreted by people to suit their own ends, as happened in one case with the Declaration of Helsinki, which was reinterpreted by some to require the standard of care in developed countries to be used for studies in developing countries.

This misconstrual of the intent of that document was pointed out in a letter from Professor Pavl Riis of Denmark to Dr. Harold Varmus at the height of the controversy. Professor Riis wrote, "public citizen points to the 1974 Declaration of Helsinki," and quotes the sentence, "every patient, including those of the control group, if any, should be assured the best proven diagnostic and therapeutic method." Professor Riis then says, "as one of the three Nordic authors of the Declaration of Helsinki and consequently of the sentence, I must emphasize that to any knowledgeable reader it is implicit in a global perspective that this means `in accordance with national accessibility.í Thus, the analogy to the Tuskegee study is without meaning."

Unfortunately, we donít always have the original authors of documents around to consult regarding their intended meaning, nor would, for example, James Madison necessarily agree with what todayís Supreme Court says about what the Constitution that he wrote means. Thus, it is important that we have international documents periodically reviewed and updated by international groups.

That brings me to my final point. I donít know what the Commission projects as its role in this arena, but to me it would seem that rules and guidelines for international research are best developed by international bodies with participation as broad as possible. The U.S., through NBAC or any other organization, is one player, although a highly influential one, on the world bioethics stage. We can be a valuable resource or conduit of information and even play a lead role, for we have much to offer. But in no way are we a solo or dominant act. A concern at present is that there are a number of international groups vying, if you will, for a primary role in this process. Sorting out these competing roles is a major challenge that perhaps NBAC can help to resolve without entering into the field as yet one more competitor.

In conclusion, I hope this information and perspective are helpful to you as you address this important issue. Iíll be glad to answer any questions.

DR. SHAPIRO: Thank you very much. Let me turn to the Commissioners first. Mr. Capron, then Dr. Lo.

PROFESSOR CAPRON: Duane, two questions. The first is, the Fogarty volume you mentioned indicates there is roughly $200 million of U.S.-sponsored research throughout the National Institutes of Health.

DR. ALEXANDER: Right.

PROFESSOR CAPRON: And about half of that is spent abroad and the other half spent for training foreign doctors and so forth in the United States. So weíre talking roughly $100 million. Could you help me to understand how that compares with other spending, specifically U.S. government spending through other branches of HHS, or through DOE, DOD, etc. if you have knowledge there, and if you have any sense of how it compares to pharmaceutical or other private research funds for studies by U.S.-based companies or multinational companies in other countries?

DR. ALEXANDER: I donít have figures on expenditures of other agencies, either in HHS or Defense, for research in other countries. Perhaps someone here from the FDA might provide an indication of drug company investment in research in other countries. I think the FDA has a policy of requiring at least one domestic study but they will accept data from other countries.

Can anybody from FDA comment on whether they have information on expenditures of pharmaceutical companies overseas too? Nothing? No data? Iím afraid we donít have that.

PROFESSOR CAPRON: I would hope that in light of any report weíre going to do on this that we wouldóit doesnít have to be through testimony, but through speaking to PHARMA, whatever the other groups that would know that, just orders of magnitude, not dollars and cents, as to who would be affected by any recommendations potentially if there were any modifications that come out of our recommendation.

The second question takes up on your comment of the relative status of the United States in this area as an international player, but not a superpower as we may be in other spheres. You have been the U.S. contact with the Council of Europe, their ethics activities. I understand we were provided with the convention in draft form but it has been promulgated last April. As I understand itóI went to the web site the other day and I can turn this into staffóthere are 22 signatory nations. It is open to signature by non-member states of the Council of Europe who have participated in the drafting process, and that includes the United States, as I understand it.

DR. ALEXANDER: Thatís correct.

PROFESSOR CAPRON: Has there been any official review of this document as something to which the United States might become a signatory?

DR. ALEXANDER: Not in an official way. I have had communications with people at NIH and with the State Department regarding this document and the possibility of the United States becoming a signatory to it. Though there are now, I think, 26 countries that have actually signed, only one, so far, has actually ratified it through its national parliament or assembly.

There are significant differences in this document from the United Statesí policies and procedures, from the protection of human subjects guidelines. I mentioned just one example: the differences in participation of children or other persons who canít give consent in research. There are a number of things that, if we were to sign this document, we would have to make a commitment to significantly change our policies and procedures.

I can provide, if it would be the Commissionís wish, a list of those differences in our policies that are certainly inconsistent with what is required in the convention.

DR. SHAPIRO: That, in fact, would be very helpful to us. Weíre trying to understand just how our tentative views on some of these subjects relate to whatís going on elsewhere. So if you could do that, it would be very much appreciated.

PROFESSOR CAPRON: Right. Do you have sort of like a crosswalk that puts together ó

DR. ALEXANDER: Yes. I published an article with Bill Dommel in the Kennedy Institute of Ethics Journal last year, a summary and a side-by-side comparison, really, of U.S. provisions from NIH and FDA, and comparing this with the provisions of the convention. If the Commission does not have that, I can make reprints of that available to you as well.

PROFESSOR CAPRON: Perhaps it would be useful, once weíve had a chance to go over that, to ask Dr. Alexander to come back with us, because the specific mention you made of the childrenís provision was not one of those that I thought was that different, and so Iím obviously missing something. And rather than taking our time now, Iíd be happy to hear more about that.

DR. SHAPIRO: Dr. Lo?

DR. LO: Duane, I wanted to ask you to comment on what you think NBACíS role might be as we begin to tackle this very important but also very large topic. You gave us a few suggestions, such as warning us about acting unilaterally in international issues. But are there issues you think that NBAC could play a special role in on this large issue of international research?

DR. ALEXANDER: Well, I think youíll probably be able to have a better feel for this after Bernard Dickensí presentation when he talks about some of the international documents and perhaps gives an update on the status of some of the activities that are going on with regard to revisions in existing ones or developing new ones on the part of the U.N., of CIOMS, of other organizations. Clearly, I would think that there is a role for the U.S., probably through NBAC, in these activities as a partner with other countries in helping to make sure that the views of the U.S. are represented in these documents and that they are written as clearly with respect to intent as is possible to do for an international document.

Again, I think that the role for the U.S. and for NBAC is as a partner with other countries in these international activities. There also is probably a role in assuring that the U.S., as it gets involved in activities in other countries, does adhere to the basic principles that underlie research here and should underlie that research abroad as well, taking into account differences in setting that do occur but making sure that work that is done is acceptable and something that we can be proud of.

DR. SHAPIRO: Thank you. Alta?

PROFESSOR CHARO: Just a couple of procedural questions. When it comes to deciding whether to be a signatory to something like this Council of Europe statement, is there the possibility of reservations so that one can become a signatory to all but a few identified provisions?

DR. ALEXANDER: The ratification document part of the Council of Europeís convention allows for reservation to specific parts only, primarily reservations with regard to embryo research, and only for countries that already have differing national laws at the time the convention was passed.

PROFESSOR CHARO: Okay. The second question is, within the U.S. government, obviously, there is going to be consultation about whether to become a signatory, but in which agency or which department does the real decision get made about whether to become a signatory?

DR. ALEXANDER: I believe that is in the State Department.

PROFESSOR CHARO: Thanks.

DR. SHAPIRO: Thank you.

PROFESSOR CAPRON: Itís a treaty, which the U.S. as a policy does not go out of its way to seek signing.

PROFESSOR CAPRON: I will pass up to the ChairóI printed it yesterday when I was preparing for the meetingóthe Council of Europeís chart of signatures and ratifications which shows, as Dr. Alexander mentioned, that only Slovakia has actually ratified the document, although there are 20-some signatories recorded here, all going back to last April when the document was first put forward. They are mostly the smaller countries of Europe.

DR. SHAPIRO: Thank you very much. Any other questions for Dr. Alexander?

First of all, thank you very much. I hate to impose on you. If you can stay, it would be more than welcome and you might be able to help us with some of the underlying discussion.

DR. ALEXANDER: Iíd like to stay for the rest this discussion. Thank you.

DR. SHAPIRO: Itís very much appreciated. Thank you.

Let me turn now to Tom Puglisi, Director of Division of Human Subjects Protection, the Office for Protection from Research Risks, better known as OPRR. He will talk to us about issues relating to the protection of human subjects in international research funded by the U.S. government; in particular, mechanisms to contract with foreign institutions.

Thank you for coming. Itís a great pleasure to have you here.

BASIC PROTECTIONS FOR HUMAN SUBJECTS IN INTERNATIONAL RESEARCH - Dr. J. Thomas Puglisi, Office for Protection from Research Risks (OPRR)

DR. PUGLISI: Thank you very much and thank you for inviting me. As you all know, Iím from the Office for Protection from Research Risks (OPRR). And Iíd like to point out to you before I start that there is a handout that you were given both in your briefing books and today that looks like this. It is a front page with bullets. The handout itself consists of the first page and then there is an example of an assurance document to which Iíll refer as I speak.

I believe that Iíve been invited here today because the Commission recognizes that the Department of Health and Human Services and, particularly, the National Institutes of Health, is a principal player in the funding of international research by agencies of the United States government. But I would like to point out, as Professor Charo has pointed out, that HHS and NIH are not the only players in this arena. So I will limit my remarks today to the enforcement of the Health and Human Services regulations for the protection of human subjects, the HHS regulations, and I canít speak for either the implementation of the Federal policy or common rule by other Executive departments and agencies, nor can I speak to research that may be conducted by other agencies of the government that are not signatories to the Federal policy, and I cannot address the issues related to international research that would be related to the approval of drugs, devices, and biologics. Those would be FDAís purview. I would recommend that as you get more deeply involved in this area you also think about the issues that FDA would raise related to international research.

So what weíre going to talk about then is the HHS regulations, the enforcement of the HHS regulations, specifically 45 CFR 46. The bottom line here, and I could deliver a very short talk , as you see on the slide behind me, all sites, both domestic and nondomestic, must comply with 45 CFR 46. They must comply with the HHS human subjects regulations if the research is conducted or supported by the department. There is, however, one exception. The regulations provide that the department may publish a determination in the Federal Register that international research will be conducted under a national procedure or a local procedure that provides at least equivalent protections to the HHS regulations. The regulatory phrase is "at least equivalent protections."

To date, OPRR has published no determinations of equivalent protections. We have not found any national code to offer the same level of protection that the HHS regulations provide, particularly in terms of the enforcement mechanisms in provisions of HHS regulations. Most of the national codes that we have been asked to review have offered protections that are voluntary or advisory but do not have the kind of enforcement mechanism that the HHS regulations have. As a result, we have not made any determinations of equivalent protections.

To review for just a moment: You will recall that the regulations provide three core protections for human subjects, the first being review by an Institutional Review Board. IRB review consists of review by a board of at least five members made up of both men and women. The five-member board must include at least one scientist and at least one non-scientist, who must be present at the convened meeting at which the research is discussed, and must also include one member who is otherwise not affiliated with the institution conducting the research.

This same standard is expected whether the research is conducted in the United States or in another country. And in reviewing assurances provided by institutions conducting HHS-supported research outside the United States, we enforce this same standard of protection. We look for an Institutional Review Board that has five members, scientists and non-scientist, and unaffiliated member.

The second of the core protections provided by the regulations is the requirement for informed consent, the legally effective informed consent of the subject or the subjectís legally authorized representative. You will probably recall from the very first meeting of the Commission, Gary Ellis (the Director of OPRR) outlined for you the eight required elements of informed consent that are listed in the regulations. These eight required elements must be present whether weíre talking about domestic research or international research.

Notice, however, that thereís one additionally complicating factor relevant to international research. The definitions of legally effective and legally authorized will depend in part on relevant law in the jurisdiction in which the research is conducted. So that just as these terms may vary from State to State within the United States, they will also vary from country to country in international research. In order to have legally effective informed consent in HHS-supported international research, the informed consent must include the eight required elements and be in compliance with local or national law.

The third of the core protections under the HHS regulations is the requirement for an assurance of compliance. An assurance is a written agreement approved by OPRR provided by the institution to conduct the research, pledging that it will comply with the HHS regulation 45 CFR 46. OPRR accepts and uses several different kinds of assurances, which Iíll describe in a moment, but every assurance has to include several basic elements.

First, there must be a statement of ethical principles. Those ethical principles must guide the conduct of research at the institution providing the assurance, and the ethical principles must apply regardless of whether the research is funded by HHS or funded privately or by the institution. Most domestic assurances cite the Belmont Report, with which Iím sure youíre all familiar, as the statement of ethical principles to which the institution subscribes. Many international assurances cite some other statement of ethical principles, most commonly the Declaration of Helsinki. Occasionally, an international assurance will cite a national policy or a national statement of ethical principles. That is certainly acceptable as well.

The assurance must also include the designation of an Institutional Review Board with a membership roster. The Institutional Review Board in international research is often called something other than IRB. In Europe, for instance, it is commonly called an ethics committee. In other places it may be called something else. What the board is called is immaterial, as far as the assurance goes, and as far as protections for human subjects go. What is important is that there is a body that is configured in compliance with the regulations that will review and have oversight authority over the research to be conducted.

And, finally, the assurance must describe, at least to a minimal degree, the procedures that the IRB will follow and the reporting procedures that will be used for reporting to OPRR on anticipated problems involving risks to subjects or others, or the suspension or termination of research, or noncompliance with the assurance, or the IRBís determinations, or the regulations. These documents may be modified to some degree to fit the particular needs of the institution involved, but most assurances follow our sample documents fairly closely.

There is, however, one exception thatís important for international research. International assurances often incorporate specific protections for human subjects in lieu of repeated citations of 45 CFR 46, in lieu of repeated citations of the U.S. regulations. If any of you are familiar with the assurance documents that your home institutions have provided, you will know that 45 CFR-something is mentioned probably five, ten, to fifteen times per page in that assurance document. This is something that we do not require of international institutions when they are providing assurances. Although some institutions are certainly willing to use the same sample that we would expect from a domestic institution, international institutions have the option to use an assurance that simply states and describes the protections that they will enforce rather than repeatedly referencing HHS regulations.

We have essentially three kinds of assurance documents that we use in assuring HHS-supported research. The first is called a multiple project assurance, or simply MPA. An MPA covers all federally-supported research that is conducted at the institution over a period of time, usually five years. We currently have roughly 450 institutions that have been awarded MPAs by OPRR. Only one of those 450 institutions is a non-U.S. institution. We have one Canadian institution that has successfully negotiated a multiple project assurance with us. That assurance, by the way, looks pretty much like the other 449 assurances that we have received from domestic institutions.

The second kind of assurance that we use is called a cooperative project assurance, or CPA. A cooperative project assurance covers participation in certain HHS-supported multicenter, usually multi-trial, research. It covers what we call participation in a cooperative protocol research program. What is a cooperative protocol research program? Itís a program in which there is significant oversight of protocol development and sample informed consent language by the HHS funding agency. Examples include the National Cancer Instituteís clinical trials program and the Centers for Disease Control and Preventionís international initiatives.

A CPA is like a multiple project assurance except that it covers participation only in the designated HHS-supported multiprotocol research programs that OPRR has recognized. A copy of an international CPA is attached to your handout. If you look at the language in that CPA, you will see an example of what I meant a moment ago when I said that we can accept an assurance from an international organization or group that simply describes the procedures that are in place rather than citing the regulations over and over and over again. We currently have about 1,500 cooperative project assurances, about 125 of which are with institutions outside the United States.

International CPAs often include multiple sites. For example, the Cancer Research Campaign (CRC) in the United Kingdom is a single assurance that actually covers 19 individual sites that participate in the CRC. The EORTC, the European Organization for Research and Treatment of Cancer, has an assurance that covers 110 sites. One single assurance covers the 110 sites spread out all over Europe that participate in the EORTC. So we have a significant amount of international research of primarily a clinical trial nature, or a CDC initiative that is taking place at multiple sites throughout Europe and the rest of the world.

Finally, we have a document called a single project assurance. As the name implies, a single project assurance, or an SPA, applies to a single HHS-supported research project. For research covered by a single project assurance, OPRR actually reviews the informed consent document and a summary of the research prior to granting the assurance. This is obviously not the case for an MPA or a CPA where the assurance covers many, many protocols.

OPRR currently has about 3,000 active single project assurances, including more than 700 active assurances in an international setting; 700 single project assurances from non-U.S. institutions. Historically, OPRR has negotiated assurances in over 110 countries, on every inhabited continent. Some of those assurances use a sample document, a boilerplate that is virtually identical to that used by domestic institutions; other single project assurances use a document that simply describes protections for human subjects somewhat like the international CPA that Iíve given you. In either case, we believe the assurance provides a commitment by the institution to provide protections for human subjects that are in compliance with the HHS regulations.

This has been a quick overview of how OPRR enforces the HHS regulations in international context. I would be happy to try to answer any questions you may have about how we do what we do.

DR. SHAPIRO: Thank you very much. Laurie?

MS. FLYNN: Is it fair to make the assumption that given the scope of this research and the many other responsibilities that you at OPRR have that youíre not able to do much in the way of site visits to follow up on any of this? Has there been any history of following up that might be helpful to us?

DR. PUGLISI: As far as I know, we have never conducted a site visit at a non-U.S. institution. Weíve had one or two compliance oversight investigations that involved non-U.S. institutions. In at least one, we contemplated doing site visits but thereís an obvious problem in that the site visit would have had to have been organized through the State Department and could only have been done with the permission of the host country. It is my feeling that there are probably not very many host countries that would let in an OPRR investigative site visit team to examine research at their institution. In that particular case, we were successful in being able to interview investigators over the telephone and in person in the United States, and we were able to take some action in terms of corrective actions relative to the research.

But you are quite correct in that we certainly donít have the same oversight authority that we would have to conduct an inspection, for example, in another country.

DR. SHAPIRO: Alex?

PROFESSOR CAPRON: Can you tell us how many requests you have had, if any, for your waiver because of the equivalent provision?

DR. PUGLISI: For equivalent protections? I donít think we have ever had a formal request. Certainly we have never had a request from another country for a determination of equivalent protections. We have occasionally had researchers who have said to us, "These are the protections that are in force in our country, we would like you to accept them, can you accept them?"

Typically what happens is that we very delicately negotiate an assurance that spells out those protections without actually citing the U.S. regulations. In other words, what we have done is negotiate an assurance on a case-by-case basis that incorporated those national protections without a formal declaration of equivalence.

PROFESSOR CAPRON: Iím a little puzzled as to how you would go about negotiating an assurance in situations where you have no first-hand basis for knowing whether whatís being represented to you is accurate or, if accurate, is fully revelatory of whatís relevant, or where there are local laws or customs that may affect the way the research is conducted. There may be ethnic groups who were the researchers and other ethnic groups who were the subjects. How do you assure yourselves that youíre entering into a document that is truly protective of the interests as the regulations require?

DR. PUGLISI: I think the concern that you raise is a valid one. I think itís one that the GAO pointed out even in the domestic context when it evaluated human subject protections; Iím sure you are all familiar with that report. All I can say to you are two things. We have a system of human subject protection in the United States that is essentially based on trust relationships. We trust institutions and researchers to follow the rules and the commitments that they have made to us until we find out that they are not doing so.

Secondly, in terms of international research, in negotiating a single project assurance, we have typically a good deal of contact with the principal investigator. And what our assurance coordinator tries to do through talking with the investigator is to make sure that the investigator understands what his or her obligations for human subject protection are. Now, admittedly, that is partly a subjective process and certainly not a perfect process.

PROFESSOR CAPRON: You made mention of the legally effective or legally authorized requirements under the informed consent that you draw from national law. How do you determine that? Do you have consultation with independent persons knowledgeable about the national law of the countries involved?

DR. PUGLISI: We donít engage in those kinds of discussions. What we do is remind the responsible institution or review board, whether it is one in the United States where there are, for instance, perhaps field researchers going to another country to do research, or whether itís a local IRB in a foreign country, that they are bound by their own legal requirements and they have an obligation to make themselves aware of the legal requirements in their jurisdiction, just as we would do with the domestic institutions where IRBsí determinations vary somewhat according to State law.

PROFESSOR CAPRON: I would gather that if in the United States one of the States were to adopt a statute saying that children could be used for risky, non-beneficial research with the consent of court-appointed guardians, letís say children in foster care could be used in this way, that law would attract a good deal of attention in the United States.

DR. PUGLISI: Certainly.

PROFESSOR CAPRON: And you would be aware of it if California, to pick a random example, had adopted such a statute. How are you aware ifóI donít even want to mention another country for fear of offending.

DR. PUGLISI: Youíre absolutely correct, weíre not aware of it.

PROFESSOR CAPRON: And, in effect, such regulations or national laws on who is legally authorized to give consent and what is legally effective consent, are the substance at the heart of what you regard as one of the three primary protections provided by our Federal rule. And if we are dealing with a nation, and Iím not saying we are, Iím just saying we apparently donít know if we are, that varies in that respect, might we then be in a situation where the compliance with our national expectations would be on paper only and, in fact, research could be conducted which would never be allowed domestically even though sponsored by Federal dollars?

DR. PUGLISI: I think there are two considerations. First of all, the regulations do set a minimum standard for what constitutes legally effective informed consent. So there would have to be, for instance, the eight required elements that are specified in the regulations. On the other hand, youíre quite correct in pointing out that we have no way of knowing who would be a legally authorized representative for either a child or someone who had diminished capacity to consent.

PROFESSOR CAPRON: Finally, you mentioned this problem that you would face in investigating a complaint. I am slightly puzzled by that and I wonder whether the Department has resisted the notion, or just hasnít yet had the authority, or thinks it doesnít have the statutory basis for the authority, to link with the assurance a requirement that states, in the case of a problem in need of investigation, that by accepting these funds and filling out this assurance, you agree that you will allow inspectors to come and make an onsite inspection or otherwise produce documents for them to answer legitimate concerns about the research?

DR. PUGLISI: Clearly, a commitment has been made through the assurance that the institution would allow appropriate review of documents by OPRR and by the funding agency if there were a problem. Theyíve made that commitment on paper. The reality, however, is that things become infinitely complicated when the constraints of diplomacy become involved. I can only speak from the one circumstance where Iíve had personal experience. In that particular case, the situation was complicated by the fact that there was no actual HHS support in terms of money provided, but rather an intellectual contribution by HHS employees and HHS materials provided to the researcher.

PROFESSOR CAPRON: Iím not sure that I understand. Are you saying that in a situation in which you actually had funds, part of this $100 million-plus that flows just from NIH, and I gather thereís more money from CDC, and so forth, even within HHS, that flows to an international researcher, that if you had the kinds of complaints that we have heard about some domestic research, you would feel that the assurance form would allow you to investigateóand then you would be subject, I understand, to the greater difficulties that you would have to have support perhaps from the State Department or otherwiseóbut that you would feel you had the agreement that they would allow it? Or is the agreement limited to their providing whatever documents they choose to provide, but not allowing you to do the kind of onsite inspection that youíve done domestically when there have been problems?

DR. PUGLISI: We would operate under the assumption that we had the authority to conduct whatever inspection or investigation we needed to. The first thing we would do would be to try to determine on the basis of the evidence that we had at hand, even if it is limited evidence, whether or not human subjects were at risk. If human subjects were at risk, we would suspend the assurance, which would have the effect of stopping the flow of HHS funds to the institution. That, ultimately, is our greatest weapon, being able to stop those HHS monies.

If we thought human subjects were at risk, we would stop the flow of HHS funds and then we would begin the process of trying to do an investigation. That would include both getting whatever documents we could get from the institution and initiating the process of trying to conduct an onsite review, for which we would have to go through the State Department.

PROFESSOR CAPRON: I gather that in the United States the threat is much greater than it would be, stopping the funds, if the threat could apply to the institutionís eligibility. If you have 450 multiple project assurances, only one of which is international, those are the assurances, along with the cooperative ones I suppose, where the threat that funds will be stopped is the greatest. If you have a single project assurance and the funds have been sent, the institution then faces the difficulty of getting another single project assurance.

DR. PUGLISI: Thatís exactly the case.

PROFESSOR CAPRON: Your leverage is a good deal less. I want to make it clear that Iím asking these questions because one concern of our looking at the international area would be are there adequate means of assuring that when Federal dollars are spent, they are spent in a way which is appropriate? And if the answer is that you donít now have the authority, itís not a matter of criticizing OPRR for what it has done, it may be a matter of saying additional legal authority is needed. My own understanding of your answer is, no, you feel you have the authority to both threaten that funds will be stopped and to stop them if necessary, and to gather whatever information you need by whatever means. There may be logistical difficulties, but you have that authority. You donít feel you need additional statutory or regulatory authority.

DR. PUGLISI: Thatís correct.

DR. SHAPIRO: Thank you. Arturo?

DR. BRITO: A general question and clarification for the regulations. There are some exceptions to IRB approval within the common rule. How does this apply to international research? In other words, the surveys, et cetera, of general populations and all, how does that apply?

DR. PUGLISI: The exemptions that would apply domestically also apply for international research. Also, an international IRB has exactly the same prerogatives as a domestic IRB would have; for example, to waive the requirement for informed consent under certain circumstances. It works exactly the same way.

DR. SHAPIRO: Alta?

PROFESSOR CHARO: I want to pull it back a little bit to kind of a big picture scale so I understand the range of concerns that are raised here, some of which seem to be uniquely procedural and some seem to be more substantive.

The three areas so far that I have heard that are troublesome are, first, the quality of the independence of the human subjects and their ability to genuinely consent, with subsidiary issues about the evidence of that consent.

The second are the kind of distributive justice questions that were raised by the AZT trials, some of which are not answered by compliance with the regulation because they are about the substantive judgments of the IRBs; that is, risk-benefit analyses, levels of care for the controls, equitable selection of subjects, some of which are addressed by the subparts. But, in general, for those agencies subscribing to the common rule in the U.S. that donít subscribe to the subparts, those are topics that are beyond the purview of our current regs.

And the third being enforcement, which Alex has talked about.

Would you say that there are any other kind of large categories of concern in the conduct of transnational research that donít fall under this?

DR. PUGLISI: I think the biggest concern I have, given that we, as I said before, essentially have a system that is built on trust, is making sure that the investigators really understand their responsibilities for protecting human subjects. We need to make sure that we do a very, very good job of educating people who collaborate with U.S. researchers in research or receive HHS funds for research.

In the example that I referenced earlier, we had an investigator who had signed a single project assurance and we questioned him directly about his failure to comply with that assurance. He told us very straightforward and candidly, yes, I signed it, I didnít know what it meant, and I didnít really read it very carefully.

So, getting a signature on a piece of paper is all very nice from a legal standpoint. The more important protection I think is making sure that researchers, both international and domestic researchers, really understand what their responsibilities are for protecting human subjects. Thatís really the big challenge that we face.

PROFESSOR CHARO: May I follow up with just one other question? When youíve got an example of collaborative research between a U.S. investigator and a foreign counterpart, such as under the multiple project assurance at my own institutionóand I wonder if this is typicalóIRB review is going to be required at both our institution, the U.S. institution, and at the foreign institution, as well as where the research is going on or where the collaborating investigator is located.

Just as in multiple IRB reviews within the United States, we have found distinct differences in tolerance for certain kinds of risks as between these different IRBs. And in these cases, it is often strongly influenced by local culture, as well by regard for certain kinds of people. Weíve seen it particularly with women where there are additional complications on consent. The resolution weíve had so far is to simply tell our investigators that they just canít do it unless we agree, period, end of story. And theyíre not happy with that.

DR. PUGLISI: Thatís what youíve pledged to do, by the way, under your MPA.

PROFESSOR CHARO: I know thatís what weíve pledged to do and weíve been doing it. But I would be interested in knowing about the way other institutions have handled this, or if there is any other way that theyíve handled it, because this seems to be the classic recurring situation.

DR. PUGLISI: I donít have any data. I can give you impressions. I think there are a fair number of institutions that handle it just the way you have described. I think there are some institutions that are willing to defer to the IRB onsite, or at least to listen very carefully to the point of view of that other IRB. There are probably other institutions where they simply do not require a local review unless there is HHS funding involved.

The ideal situation would be for the two IRBs to communicate with each other and reach an understanding. Thatís pretty hard to do even domestically. Itís much harder to do internationally.

PROFESSOR CHARO: Thank you.

DR. SHAPIRO: Any questions from the members of the Commission? Once again, thank you very much and I hope, Tom, youíll be able to stay a few moments longer till we complete this part of our program.

DR. PUGLISI: Certainly.

DR. SHAPIRO: Next, weíre very fortunate to have with us this afternoon Professor Bernard Dickens from the University of Toronto. He will talk to us about international instruments for human subjects protection, with particular emphasis on the characteristics of ethical concerns in research conducted in underdeveloped countries.

Professor Dickens, itís a great pleasure to have you with us today. Thank you very much for coming.

INTERNATIONAL INSTRUMENTS FOR THE PROTECTION OF HUMAN SUBJECTS - Professor Bernard Dickens, University of Toronto

PROFESSOR DICKENS: Thank you, Mr. Chairman, itís a great pleasure and privilege to be here. Iím afraid I do have to begin with multiple apologies. The first, of course, for being late and causing you to change the sequence in presentations. The second apology is because although most of the documents that Iím going to cite you have already distributed, I do have one or two others that, because of travel, I didnít have the chance to make available in advance. The third apology is that, to an extent, I am going to be a little repetitious in that I will be touching on some of the issues already raised.

The initial point to make about international documentation is that it reflects international sensitivities and these evolve over time. We tend to suppose that we have the appropriate language in which to discuss research, and itís quite common to speak about research involving human subjects. But it could be that although this is a convenient description, that those who take part in research, it may be objectionable. There was a meeting in the Summer of 1996 of a circumpolar research group involving people from Greenland, Siberia, and Canada of the native aboriginal populations and they took very strong exception to being described as "subjects of research." They pointed out that subjects are persons under the control or authority of others and, while in the past they recognized that they had, indeed, been subjected to procedures, they felt that their autonomy and dignity required that they not be described in this subjective state. The contrast was drawn between autonomous sovereigns and those who were subject to sovereigns. And they demanded that the word "subject" not be used and, in fact, the description of "participant" was more agreeable to them, though this raises ambiguities, of course, because investigators are also participants in studies.

The instruments that Iím going to refer to are essentially the ones that you have, in particular from the Council of International Organizations of Medical Sciences (CIOMS). Professor Capron has been very much involved in the activities of CIOMS, on steering committees of one of the conferences and consultant to the other. And, in a sense, Iím certainly not telling him anything that he doesnít already know.

The relevance of CIOMS, which is set up jointly by the World Health Organization and UNESCO, though it functions essentially from the World Health Organization based in Geneva, is that it attempts to mediate between investigators from developed economies and those from industrially developing countries. In addition, we have heard that the Council of Europe are dealing essentially with industrially developed countries. There has been activity in the field of regulation of a number of biomedical activities in which research is prominent. And this range does give us a need to pay attention to the way the United States is perceived. Somewhere in between we have the British Commonwealth Medical Association, which deals with both developed and developing environments, though in the context of research, in order not to reinvent already well-rolling wheels, the Commonwealth Medical Association hasnít taken special initiativesóit simply requires that existing guidelines be observed.

An important difference though is that a number of industrially developing countries look to the United States for technological and economic advance and leadership. But in many developed countries, there is a sense that the United States social justice, in equity and access to health services, is less advanced, and this creates a somewhat different environment, a different background against which health preserving and promoting interventions can be assessed.

The Nuremberg Code is perhaps the benchmark that we ought to take. The code itself, you realize, was essentially based on U.S. practice. The Nuremberg War Crimes Tribunal conducted proceedings against the major war criminals, but the trial of the so-called Nazi doctors was conducted under United States auspices; the judges, the council, the expert witnesses came from the United States. Nevertheless, the Nuremberg Code, interestingly called a code, bringing in together what already exists and making it obligatory, has been widely accepted internationally as setting a benchmark.

Thereís a certain analogy, I think, to the Hippocratic Oath; that is, the phrases used with reverence and deference. But the code is more frequently cited than actually read. And when one reads it, one finds surprises in the Hippocratic Oath because of what it includes, and in the Nuremberg Code because of what it excludes. It serves a useful function, though. It gives us some measurement of how far we have evolved and, in that sense, it gives a focal point on what has changed. The Hippocratic spirit dominates the practice of clinical medicine. The spirit of the Nuremberg Code, evolving from the cynical exploitation of vulnerability where individuals were literally tested to destruction, gives us a benchmark to measure from.

But if you actually look at the Nuremberg Code, and reference has already been made to this, because of its rigid insistence that those who are participants in studies give their free and adequately informed consent to it, it follows that those incapable of informed consent cannot be participants in research. This, of course, would exclude the whole field of pediatric research. It would exclude the field of research in many affected with mental health conditions and those suffering traumatic head injuries.

In addition, of course, thereís no reference to confidentiality in the sense that those who were subject to the experimentation that Nuremberg focused on might have regarded confidentiality as the least of the interests they had to lose. But this is something that today we regard as very significant.

The Nuremberg Code also focuses on biomedical experimentation. And, of course, today we recognize that there are other disciplines that can contribute to our understanding of health care. The social sciences, the natural sciences, psychology, for example, are now regarded as very important in developing research into clinical medicine and obviously into health system research.

The origins of the Nuremberg Code, again very specific to time and place and circumstance, couldnít contemplate ethical duties of equitable inclusion in research of those who could benefit from the outcome. The inclusion of women is something of importance, the inclusion of minorities, the inclusion of low-income people, and of elderly people, these are all matters that today you would regard as critical to social justice and the access that is guaranteed by international instruments to the benefits of scientific progress. So today we recognize that there are ethical duties not only not to undertake violations of the physical integrity of nonconsensual, vulnerable people, there are also duties to include research on those who want it because of the benefits they believe it to promise. And clearly, because of the origins in the Nuremberg Code, there was no reference to including people in studies.

In addition, and this is perhaps one of the major points I want to make, the focus of Nuremberg was essentially what today we might call micro-ethical. It was concerned with the protection of individuals. But public health studies and epidemiological studies, are currently recognized to be very important to health care. Of course, one is frequently confronted with the recognition that many of the contributing factors to the health stages we enjoy have not come through pioneering work in drugs or surgery, but through public health innovationsóthe control of polluted water supplies, the quality of the air that we breath, environmental ecological factors. And, of course, none of this is reflected in the Nuremberg Code.

The Declaration of Helsinki, promulgated by the World Medical Association, is frequently taken as one of the more significant modern variants of the Nuremberg Code. This has been successively revised in 1975, 1983, 1989, most recently in 1996, and Iíll be commenting shortly that the American Medical Association took initiatives to have a further revision at a meeting in November of last year. Because of the relatively short notice at which I came to this meeting, I havenít been able to see what came out of the November 1997 meeting of the World Medical Association.

An interesting feature of the World Medical Associationís declaration is its modesty. It begins as recommendations guiding physiciansórecommendations that guide, not govern. It goes on to observe thatóIím quoting now from the final paragraph of the introductionó" because it is essential that the results of laboratory experiments be applied to human beings to further scientific knowledge and to help suffering humanity, the World Medical Association has prepared the following recommendations as a guide to every physician in biomedical research involving human subjects. They should be kept under review in the future. It must be stressed that this plan as drafted are only a guide to physicians all over the world." Its final sentence is, "physicians are not relieved from criminal, civil, and ethical responsibilities under the laws of their own countries."

This is a matter that warrants some degree of attention because I gather that in the United States conformity with Federal regulations will make legal what otherwise might be illegal. In other countries, including my own, conformity to ethical guidelines does not give any absolution from ordinary liability under common law or statute. We have a major problem, and I think it is shared in other countries, with regard to pediatric research on newborns, children, and infants, in that itís not clear that parents have general legal authority to dedicate their children to medical interventions other than for the benefit of those very children; not for the benefit of the community at large. And itís not clear that conforming even to the fastidious standards of the U.S. federal regulations would give any protection to a parent or a research institution before a Canadian court and this is something that we struggle with.

Another basic principle of the Declaration of Helsinki has come under some degree of challenge, and, indeed, one of the proposals of the American Medical Association for reform focused on this particular provision. It comes in the fifth of the basic principles, and perhaps I could read that to you. "Every biomedical research project involving human subjects should be proceeded by careful assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society."

Now this is a noble principle and, of course, we can see its origins in the Nuremberg Code. But it presents problems that perhaps we can conceptualize by thinking of the testing of a new drugóletís call it Thalidomide Mark II. Now if there is a risk to the unborn from the use of the product, one could understand the exclusion of women of reproductive age. One might want to go further and try to estimate the actual risks of the woman being pregnant, but this can involve very indelicate questioning of lifestyle and it could be, in a number of circumstances one might think of, that it is better not undertaken on grounds of ethics and, perhaps more historically, even gallantry.

The difficulty, of course, is that if the product indeed is like Thalidomide Mark I but it is not tested on women of reproductive age, then its devastating effects on the unborn wonít become apparent until perhaps after a decade of "therapeutic" use undertaken in good faith by both prescribing physicians and consumers, and epidemiologists may eventually be able to measure the nature and extent of the devastation caused by the drug.

Now, the American Medical Association has recommended that there be an addition to this provision. It has recommended that the same phrase be used, the interest of the subject prevailing over the interests of science and society, but it then has proposed this addition: "Subjects may, however, elect to participate in research that they are aware will have no direct benefit to themselves if the protocol has been approved by an independent research ethics committee and the anticipated benefits of the knowledge to be gained are proportionate to the known and anticipated risks." In this circumstance, fully informed prospective research subjects may voluntarily and altruistically consent to accept discomfort or inconvenience in order to advance societal and/or scientific interests knowing that there will be no personal health benefit.

Now this, of course, may open the way to the inclusion of women of reproductive age and circumstance in studies that could be harmful to the unborn child. But, of course, even this language only permits the participants themselves to waive their own protective interests. This leaves the ethical question of the extent to which women can jeopardize the interests of unborn children and the extent to which investigators can ask them to do that.

The Helsinki Declaration also draws a distinction, that is on the verge of being abandoned, between clinical research, described as medical research combined with professional care, and nonclinical biomedical research, that is nontherapeutic biomedical research. A leading U.S. authority, Dr. Robert Levine from Yale, has been very critical of this distinction, saying that it is a false distinction and sort of confusion and danger. And the American Medical Association proposal is that this distinction be abandoned and that the different elements in the study be addressed as such.

Let me come to the CIOMS guidelines, that is the 1991 guidelines on epidemiological studies, and the 1993 redrawing of guidelines initially promulgated in 1982. The first, the international guidelines for ethical review of epidemiological studies, and the second, international ethical guidelines of biomedical research involving human subjects. The latter of these, the more recent, in the sense is more traditional. Clearly, it is the epidemiological guidelines that I think warrant particular attention because they do address the need for public health research.

The 1991 guidelines were really driven by the WHO component of CIOMS and, in particular, the global program on AIDS. This was confronting problems in HIV/AIDS research, particularly in developing countries, not limited to East Africa though East Africa was a focal point of major concern, and many of the examples in the 1991 guidelines are drawn quite deliberately from the HIV/AIDS area of research. Today, perhaps we could project this on to the issue of research in developing an HIV/AIDS vaccine. The principles, of course, are applicable to other medical technologiesónew reproductive technologies, organ and tissue transplantationóand they really draw attention to some of the cultural shifts between industrially developed countries and those that may have a very profound culture but which are not industrially developed.

One of the issues that has been addressed and it has many ramifications is the appropriate role for commerce and the extent to which individuals can seek to profit in material ways from their own availability and the availability of their body tissues for purposes of research. In the context of organ transplantation, for example, some cultures based on social reciprocity would see a so-called rewarded gifting as simply being culturally proper, whereas in industrially economically developed countries, we tend to regard the exchange of body tissues for money as being of essentially commercial character. So there can be cultural difficulties.

In view of the time, I wonít elaborate on this. But I will draw attention to the fact that in the United Kingdom, which today, of course, is culturally pluralistic and has gone far beyond its historical Anglo-Saxon origins, the Human Fertilization and Embryology Authority last month in February issued a consultation paper on the implementation of withdrawal of payments to donors of gametes, and this could be applied to pre-embryos as well. This gives some intimation of how immediate this issue is of seeing the proper accommodation and the proper prohibition perhaps of commerce in making materials available, in this context, of course, for the birth of children, but it has an application to research as well.

Let me come to the field of public health studies. These are different from clinical studies in a number of material ways. The first is that individual consent may not be relevant; indeed, it may not be obtainable if one is dealing with a population group. If one is dealing with access to even individually identifiable medical records, it may not be economically or practically feasible to trace the individuals and ask for their informed and free consent. That is, consent may have to be given at a collective, at a political, at a social level. And in some countries, including my own, in my own province of Ontario we have legislation setting up a mandatory cancer registry in which those diagnosed with cancer will have quite intimate details recorded and the recorded data will be available without their knowledge and consent to cancer investigators. This is because of the political assessment that the public interest in gathering information and having superior interventions in the context of cancer justifies this invasion of ordinary principles that at the clinical level we think ought to predominate.

The 1991 CIOMS guidelines deal with community agreement, sometimes called authorization, and this is something that could transcend individual consent. This leaves the ethical challenge of how one accommodates individual dissent; that is, if individuals want to be excluded from the study, there are practical and ethical questions about how one responds to that. Of course, one crude response is to say it canít be accommodated because it would damage the epidemiological interpretation of data. And if resources are going to be allocated with some precision, then one needs accurate figures and one canít let individuals exclude themselves if they want to. Of course, there are lesser harsh responses that may also be proper within limits.

The guidelines also address different sorts of collectivities, that is those that exist independently of any intent to study them, that have perhaps their own social, political leadership where individuals in democratic authority within those institutions can claim in some legitimate way to speak on behalf of all of their members, not to compel individuals to submit to what those individuals may find objectionable, but to say that they can be approached and their individual judgment can properly be taken. In contrast, of course, we have groups that are simply the construct of investigators. That is, if one proposes to do studies on the individuals within a given age range, 18 to 38, who are 25 percent above average weight, one can create that group as a statistical construct. But, clearly, you canít speak to any member of that group as a representative of any others. So just what is a group, what is a collectivity becomes a matter of importance.

We get some sense of this by considering studies that have been proposed quite recently into detection of the gene associated with breast cancer. Weíve had objections, in particular, by Ashkenazi Jewish women that even if individual participants give their free and informed consent, this research could be harmful to the group as such because those identified with that group could be prejudiced in obtaining health insurance, disability insurance, and life insurance. And so although each individual may find this agreeable, it could be that the collectivity is harmed by this sort of research. And how this weighs in the ethical balance is a matter of concern.

The 1991 guidelines also deal with research in the discipline of the social and psychological sciences, including incomplete disclosure and sometimes incorrect disclosure, deception, which could be necessary in certain methodologies. The so-called Hawthorne effect is that individuals, as a courtesy and a social lubricant, are inclined to do what they think others expect of them. And if they believe that investigators are looking for something, they may be disposed to make it available to them in terms of their responses or behaviors. That, of course, confounds the whole nature of the study. So it could be that one canít state what the purpose of the study is. One may have to misstate what the purpose of the study is.

There are rules governing this of debriefing individuals, perhaps even letting them withdraw data that have been obtained this way. One also has the rule that nothing can be withheld that might induce people not to take part in the study. In that sense, there can be no deception about the nature of the risk; there can be deception about the object of the study. And the 1991 CIOMS guidelines attempt to deal with this.

Other issues affect the acceptance. There canít be coercion, there canít be duress, but there can be problems of undue inducement. That is, if one is dealing with people who are in underdeveloped communities, deprived communities, then they may easily be induced to take part in studies. And, of course, an international aspect of this is that if, for example, a drug company from a developed country proposes research in a developing country, then it could that a benefit to the participants in the country itself is that there will be access to superior health services to those ordinarily available. Is that an undue inducement? One accepts that there can be obligations to train local people so that something of value is left in the country, and objection has been taken to the so-called bleed-and-fly research projects in which investigators from developed countries move into a developing country, take their body samples, get their data, fly out and leave nothing of any advantage. But what is proper inducement, what is undue inducement is a matter of some difficulty.

The final point Iíll make is the one already addressed, that is the need to make relevant assessments of what is culturally appropriate. Not every community even within North America gives the recognition to autonomy that has become very fashionable in modern practice and rhetoric. Again, what is to be protected under rules of confidentiality could be a matter on which views differ. Some individuals could be hypersensitive to an ordinary way of looking at things, or they may well have no inhibition about their disease state or the genetic characteristics of their family being publicized. Family structures and family functioning could well differ, and weíve heard that assessments of risk could differ.

So the different guidelines that we have do try to sensitize investigators and provide some modus operandi under which research can be conducted of a transnational character in which there are cultural incompatibilities that have to be overcome between investigators, sponsors of studies, including international agencies, and the inhabitants of countries and regions within which research is conducted. Perhaps a true final word is that if we take attention to underdeveloped communities, we can find those even in the centers of our own vast cities.