Basic Protections for Human Subjects in International Research: Marjorie A. Speers, Ph.D., Centers for Disease Control and Prevention (CDC)

DR. SHAPIRO: [Dr. Speers Introduction - inaudible]

Dr. SPEERS: [Inaudible]...and access to health care is limited. Public health infrastructure is weak in many of these countries; that is to say, that in many countries these -- they do not have systems for collecting national data on diseases, as we have in this country. They do not have clinics necessarily available. They do not have the medical supplies, and so on, that are often needed for treating even the most basic conditions. Iíd also like to distinguish that the difference often lies in economics, and not in scientific, or in the ethics arena. And what I mean by that is of these 50 countries that we work with, only between three and five of them do not have an ethics committee in place. In the other countries, they all have an ethics committee that we have worked with. And those ethics committees in those countries arenít lacking necessarily in their understanding of ethics and their practice of ethics, nor are they lacking necessarily in their ability to provide scientific and peer review to protocols. Another distinguishing feature of many of these countries that we work in, is that we are working with people of color, which makes it somewhat different from the situation often in the United States, and often opens up discussions about exploitation for the research thatís conducted in these countries. May I have the next overhead please? In this next overhead, what I have listed for you are the various diseases, and conditions, exposures that we are studying in these countries. And I have put this up there for a couple of reasons. One is to give you just a very quick sense of the breadth of research that CDC is involved in internationally; also to point out to you that we are dealing with, in many cases, global problems that when we look at issues around HIV, tuberculosis, other sexually transmitted diseasesóthese are global problems. They are not problems that we just have in the United States. In addition, you can see that many of the conditions that we work on are infectious diseases, infectious in nature. They are diseases or conditions that do not exist in this country. In fact, many of you may have never heard of some of the conditions that are listed here, which allows me to make the point to you that the research that we conduct is research that is relevant to the host country. And I will come back to this point and make this point again later; but that when CDC collaborates on international research, it is because it ultimately benefit the host country for that research to have taken place. Next one. I want to talk a little bit about the characteristics of our collaborations. Generally, when CDC conducts research in a foreign country, it is as the result of a relationship that CDC has developed with the Ministry of Health in the foreign country; that is to say, that it is a government-to-government collaboration, one in which CDC has been invited in. And, generally, what this means is that decisions that are made about research are not unilateral decisions; that it is both the government of the host country, as well the CDC that is making decision about research design, methods, data analysis interpretation, and so forth. In cases where we do not work with the Ministry of Health, we then generally are working with an NGO, a nongovernmental organization. Very rarely does CDC work with a university in a foreign country. It is generally, as I say, with an NGO. That will usually be in a country where we may not have diplomatic relations; for example, in Cuba, or in Nigeria, where the U.S. Government is not able to work directly with the government of that country, we will be working with an NGO in that type of country otherwise, we are working with the Ministry of Health. Secondly, another characteristic of our collaboration is that we have usually not given a grant, a cooperative agreement, or contract to the foreign country. The funds that are used to support the research either come from another U.S. organization such as USAID, who funds a lot of the research that we conduct in foreign countries, or may come from the World Health Organization, or from the foreign country. Some funds may come from CDC to support salary of our staff, which I will talk about in a minute. But it is generally not the model where we have provided a grant to a foreign country to conduct the research, which leads me into the last point, which is that in virtually every study that we have ongoing, we have on-site investigators involved in the study. They generally fall into one of three categories. One may be that we actually have a field operation going on longstanding in the country, such as in Thailand or in Cote díIvoire. We have had a field station there for over a decade, where our researchers work side-by-side with the in-country researchers. If it is not that situation, then it is a situation where we will have a field assignee assigned to the Ministry of Health in the country, who essentially works as an employee of that Ministry of Health involved in research, the third situation is where we will send investigators in for a short period of time, for six weeks, for two to three months to conduct a study, and then they will leave and come back. It is very rare for CDC not to be directly involved in conducting the research by having investigators in the country at the time. This means that for many of the countries where we were, we have had a long-term relationship with the country, and we expect to continue to have a long-term relationship, and to help that country develop its public health programs, its program health research agenda, and its capability to conduct public health research, and to implement public health programs. Move to the next overhead. Iíd like to talk a little bit about characteristics of the research in which we engage. The first, as I said earlier, is that the research that we undertake is relevant to the host country. It has relevance to that country, and it is undertaken to meet some type of local need. The agenda for research is set by both the host country and by CDC. The research is generally part of a larger public health program collaboration; and that is to say that often when we negotiate a working relationship with a Ministry of Health. What we are negotiating is a working relationship to help them develop their public health infrastructure, and to implement public health programs nationally within that country. Research will be a piece of that, and is undertaken generally for one of two reasons, which I have highlighted here as well, which is, it may be undertaken to help us better understand a particular condition; that is, maybe the problems of the condition, or risk factors associated with it, so that the results may be directly fed back into the program; or the research maybe undertaken in order to set policy in the country; and that is to say, that before the Ministry of Health is willing to implement the public health program, it wants to have information that will help it then set the policy to move forward. The next overhead. When we engage in research with foreign countries we follow, as I mentioned earlier, the Federal regulations for the United States, which is 45 C.F.R. 46, that means for all of these host countries, we have negotiated for these countries with the Office for Protection from Research Risks approved assurances for these host countries, that is, for the Ministry of Health, and those Ministries of Health have ethics committees. Those ethics committees meet the requirements of the U.S. regulation, and they review protocols according to our regulations, as well as according to the ethical guidelines that are followed within the host country. The CDC IRB approves the protocol as well as the host country ethics committee approves the protocol. CDC has four Institutional Review Boards in Atlanta that reviewed these international protocols. On each of those IRBs, we have members who have had international experience. That means that they either themselves have conducted international research, or they have served for some period of time living in at least one foreign country. The other thing that we often do before we conduct international research, is we do what I have listed here as some preparatory studies. Studies may be a bit more formal than what I mean here. But in many cases before we have gone --we go in and we conduct a study, there will be meetings that will occur with the community. We consult the community, and the community is actually the population from which we --with which we expect to conduct the study. Sometimes, we will be involved, for example, in conducting focus groups that will help us design the consent form, raise the issues that are going to be raised for recruiting individuals to participate in the study, try to address the issues that we know are going to come up and be issues that will be involved in recruitment and enrollment of individuals into studies. So, a lot of preparatory work often goes into developing the protocol before that protocol comes to the IRB at CDC, or the ethics committee in the host country. Okay, the next overhead. What Iíd like to do very quickly is bring to the Commissioners several issues that we have encountered in the process. And Iíve actually divided the issues into three categories: The first is assurances; the second is consent; and the third is what Iím going to call standard of care. We have touched on many of the issues today, first, in Alexís presentation, and then in Ruthís, and then in Stuartís. And I am not going to go back over those same points and details, but just touch on some of them very quickly. As I say, one of the first issues that I want to talk about is the issue of assurances. Because CDC is a Federal agency and is governed by the Federal regulations, we are required to negotiate in the countries where we work assurances, assurances that are in compliance with our Federal regulations. You have to remember that we are working with sovereign nations -- at least, they perceive themselves as sovereign, and we need to be respectful of that. In requiring that they sign the assurance document, I believe those documents have been shared with the Commissioners from OPRR, we have often been accused of imperialism; and, in some countries, asking them to follow standards that they consider even lower than their own standards. Secondly, in these countries all of them follow and list as their ethical principles, either the Declaration of Helsinki, or the CIOMS guidelines for conducting international research, which is acceptable to OPRR and to CDC; that is to say, they do not have to list the Belmont Report or Federal regulations as their guidelines for ethical principles. However, what we do require is that they then follow the particulars of our regulations, which specify very clearly what an IRB, or an ethics committee needs to look like, and how protocols are to be reviewed, which can be different from what is required in the Declaration of Helsinki or in CIOMS. The second point that I would like to make, with regard to the Declaration of Helsinki and CIOMS, is that --and Ruth mentioned this --and that is, there is inconsistency between those two documents and within those documents. If you then put our documents, that is, the Belmont Report and the Federal regulations up as well, there are inconsistencies across then those three or four documents. Some of our regulations are silent on some of these issues, whereas, the other documents are not, and some harmonization across documents would be very useful for us who need to implement these documents if the Commission were to consider them. I just wanted to talk about ethics committees. As I mentioned, these countries do have ethics committees, and they do comply with our Federal regulation, in part, because we have required that they do that. We have had some countries that have refused to work with us, and some of these countries have been the Arab countries, where they refuse to put a woman on the ethics committee. So, sometimes issues around the make-up of the committee, particularly, around having a woman represented on the ethics committee has been an issue for us, which has actually led to a breakdown in the negotiations with the country. The other is in defining a nonscientist, and how that -- how a nonscientist is defined. It is not as clear as one would, perhaps, think that it should be. The other issue around assurances, the two situations that we encounter, where this has been an issue, is in countries where there are -- where there is a civil war, where we have not necessarily been able to negotiate an assurance in a country where there is a civil war. And there has not been any other organization necessarily that we are working with, or that could take over where the government was working with. So, we have had in the last year five instances where we have had to stop research because of civil war, where an assurance could not be put in place. The other issue is in working with refugees. Who represents refugees? What organizations? And, again, how do we deal with this issue of assurances, where there does not seem to be an entity for which there --for whom that person is in the role as a collaborator, and, therefore, where we would obtain an assurance if we needed to do so? Next overhead. Issues around consent. We have touched on some of those today. I was actually going to mention the one that Ruth mentioned earlier; and that is, that a signature on a consent form has a very different meaning in some of these countries from what it has in this country. It is a big deal for some individuals to put their signature on a consent form. And it is important I think for some deliberation about that requirement, and that that requirement is not the same as an ethical principle --the ethical principle of informing, and then having a procedure in place for documenting that that has taken place. In many of these countries, we are dealing with illiteracy, illiterate populations. And so, again, around this issue of consent, there is the notion of a written consent, having the consent signed, many issues around having a consent process that is understandable to the people that is not different in many cases from issues that we have in this country. It is only highlighted more in some of these countries, where an illiteracy rate can be quite high. In some of these countries, the notion of getting individual consent is a notion that the U.S. is imposing upon the citizens of that country. In some countries, it is perfectly acceptable to get community consent, or consent from tribal leaders, or it can be consent from husbands, instead of wives. And we have had to deal with that issue. The issue of minorsó that is, when is an individual of legal age to give consent comes up repeatedly in foreign country, where age limits are quite different from what they are in this country. Generally, we think of the age of the majority in the United States as being 18, but in some of these foreign countries it is much younger. What we have come across in the countries that were part of the former Soviet Union is that there is no concept of consent --of them giving consent. And so, when we have gone in to work in these countries and made a requirement straightaway that they must get informed consent, it literally freaks out the people who participate in this study, because it raises concerns that there must be something wrong with this, if you are asking for my permission to do it; and that is to say, that we --that is, I donít want to imply that we donít want to move to that ethical standard, but what we need to build into this process is time for countries to change, particularly, those countries where for 50 years they lived under a particular type of regime that has changed now, and now we are working with them. They are now developing research agendas and studies and trying very hard to live by a set of ethical principles --of the ethical principles of either the Declaration of Helsinki or CIOMS and they want to rise to that standard, but it takes time to do that. The last one that I want to mention is the --in 45 C.F.R. 46, there are the eight required elements of informed consent. For the most part those can be implemented in foreign countries, but not all of the time. For example, we require that to be very up-front that weíre conducting a research study and state that. In some African languages, there are no words for research study. And so, when we write consent forms, we translate them; we ask for that translations. We often get something back that looks different from what we had, not because itís a bad translation, but because we had differences. There are differences in language; there are differences in culture that are transformed into language. And so, a foreign consent form does not necessarily -- is not necessarily deficient just because it is different. We need to be very sensitive to that issue. Some of the requirements that we do now. For example, we require in consent forms that we list the name of a research contact, and a human rights contact with a telephone number --canít do telephone numbers in a lot of these countries. And so, we have to look at ways that we can clearly implement the spirit of the regulations, if not the actual letter of the law. The last one --the last overhead Iíd like to go to is to talk just very briefly about this issue of standard of care. This has certainly come to your attention as a result of the perinatal AZT trials. Do remember that CDC did conduct two of those trials, but that is two trials, or two studies out of the 120 that we have ongoing, and this issue of standard of care is an issue in most of those studies. Because in many of the studies that we conduct, what we are looking at is trying to implement interventions, whether itís drugs, educational programs, HIV testing and counseling, whatever the intervention is, it is often an intervention that is below what is the standard in this country, but we are trying to implement something that is feasible in the developing country, feasible in terms of costs, and feasible in terms of their public health structure, infrastructure to implement it. The issue of standard of care has clearly come up regarding placebos, and I am not going to discuss that. I want to mention two other situations that we deal with. One is with screening and treatment; and that is to say often in studies we are not even able to offer the best screening techniques for diagnosing conditions, and we often cannot offer the best treatment. Many of the studies that we have going on now, that are looking at ways to prevent and control malaria, tuberculosis, we are not using the best treatment available in the U.S. to test in these countries. We are using treatments that will work, we believe are feasible in those countries. Secondly, often in studies that we undertake what is considered an acceptable outcome, in terms of health, often will differ from in this country. An example of what Iím thinking of is, we have a number of studies involving looking at anti-malarial treatments, and this is looking at this treatment in children. In these countries it is acceptable for children to have very low levels of parasitemia; that is, to actually have the parasite living in them. And it is only when it reaches a certain level that it would then invoke treatment. That is not --would not be acceptable in the United States. We would not allow any child or adult to live with parasitemia; and, yet, that is acceptable. So, how we define healthy, if you will, differs as well. Which brings me to the last issue of how one defines normal healthy subjects, which is what we often use for controls in this country. Again, we adjust that definition because in these foreign countries people will live with conditions that are considered in that country to be normal and healthy. So, this issue of what is the normal healthy subject or control also differs. Iíd like to end by asking the Commission to consider four issues, if you would --or at least raise them for you to consider. One of the issues that we would like the Commission to consider is in international collaboration, where the United States organization, in this case, CDC, but it could be certainly more broadly any -- the U.S. organization follows 45 C.F.R. 46, and the host country is following one of the other accepted guidelines, Declaration of Helsinki, or the CIOMS guidelines. Whether it is appropriate for the U.S. organization to defer to the code of ethics used in the host country; that is to say, particularly, when there is a difference between the guidelines, which ones do we use, which one should we use? And we would like to have some thought or discussion about that issue. Another is that when a foreign country follows a set of ethical principles and has an ethics committee, and has a comparable review process, should we require the assurance as is required in our Federal regulations? As I said, we have negotiated now almost 50 of these assurances. The concern that we have is that that has cost us, in terms of credibility and in trust, often with this countries. Because it is --as I had mentioned, it is often viewed as imperialistic of the U.S. to require this assurance. The third issue is, how do we incorporate the host countryís cultural norms into our IRB process? Our Federal regulations clearly state that a countryís cultural standards and norms should be taken into account, but doesnít go much beyond that, in actually telling us, or giving us guidance how we do that. And the fourth issue is actually a broader issue, that doesnít relate just to international research, but applies domestically as well; and, that is, the broader issue of how public health research is covered or is not covered by U.S. Federal regulations. Thank you.

DR. SHAPIRO: Thank you very much. We have only five or, at most, ten minutes this morning. We can come back to this after our session, but we do have public comments shortly. I donít want to keep those people waiting too long, but we have time for a few questions. Bette?

MS. KRAMER: It really was excellent. It really flushed out the problems quite well. But, apparently, though, your protocols --if I understood you correct -- if I understood the --what was inclusive; for instance, when you come up against problems like consent issues, where you have got the husbandís consent, or the wife, or the tribal consents for the entire tribe, which are contrary to our regulations, do you go forward under these instances? In other words, where there is a discrepancy between the local guidelines and U.S. guidelines; and if, in fact, your protocols do go forward despite these discrepancies, and a product emerges, such as a drug or a vaccine, what happens then when you come back and seek FDA approval, which I presume you have to get?

DR. SPEERS: That is actually two issues there. The first one is: What we tried to do is, we tried to strike a balance between what is the norm in the country, and what is required by our Federal regulations. So, that is to say, we try very hard, for example, when it would be okay, for example, to --in a country to obtain community consent, but we require individual consent to try to move the country to get individual consent, so that we will often do a combination or get community consent and individual consent, as well. In some countries, if they have refused to do that, then we have not done the research. I canít tell you how many instances as that occurs. I only know about it at the point where a protocol is going through our IRB, and then negotiations break down, and I know about that failure. What I can tell you are the number of cases that donít ever make it to the protocol stage, where there is a breakdown in those negotiations. Another example --and I donít want to focus too much on the AZT trials. But because I know you are aware of them, I will use them as an example. In those trials, because we were intervening with pregnant women, there is a requirement in our regulation that fatherís consent is obtained. And if you donít --and there are criteria in the regulations, where if itís not feasible to get the fatherís consent, then thatís not necessary. That was a particularly problematic issue in Cote díIvoire, where about 60 percent of the women in that study are not married. So, it is often difficult to know who the father is, or to locate the father. The fathers do not come to clinics. Because this is a study about HIVóto go out into that population and try to find the father would then expose to that community the womanís HIV status, just the fact that she had been in that clinic. So, the way that we compromise, if you will, in that situation, is we have a consent form and process that allows for fatherís consent if the father is there and it is easy to obtain it. But if it canít be obtained, we do not go out and try to find those fathers to do it.

MS. KRAMER: And you go forward with the womanís consent alone?

DR. SPEERS: We go forward with the womanís consent in that case. Then your question regarding FDA, what do we do in those cases? In many cases, when we are conducting studies that involve a drug or a vaccine, we are not doing --we are not working with experimental drugs for the most part. These are drugs that are generally licensed for commercial use. And we may be using them off-label, perhaps; or we may be using them slightly differently. But our intention in doing that is not to change the FDAís regulation of those drugs, or the labeling of those drugs. We are using them because we are trying to change policy in that country. So, often we are not reporting information back to the FDA, particularly, in the international setting, where that issue would come up.

MS. KRAMER: Thank you.

DR. SHAPIRO: Okay. Alta and Eric, then weíre going to take a break. Alta.

PROF. CHARO: Iíd like to take you up on your invitation to discuss the assurance process for a moment. And, first, I want to make sure Iíve got my facts right. Iím under the impression that the CDC seeks assurances in large numbers. It is my impression that the CDC process of actively seeking assurances is relatively new. I mean the two AZT trials that have been the subject of such discussion took place without any assurances in place. And you mentioned 50 assurances that you have gotten, but there were more than 50 countries out there. So, Iím curious about your experience in what happened last year seeking assurances, and your description that it occasionally has engendered criticism as being somewhat imperialistic. My understanding was that the assurance can be that the host countryís institution is going to be following either U.S. rules or rules that are based on the Helsinki or CIOMs guidelines. In other words, there is a lot of flexibility in the set of particular rules that are used in this country, so long as they adhere to the basic principles that are shared by all of these various organizations and regulation statements. So, where exactly is it that you have run into this complaint about imperialism? Is it so serious that you find that you would actually like to get out from under the requirement that you comply with the regulations that have asked for years for you to have assurance?

DR. SPEERS: CDC has obtained assurances for --I just want to be clear on this. CDC has obtained assurances, and always has for the past several decades, for the domestic research. We did not obtain assurances for our international research until last year. It has actually been about one year that we have been obtaining assurances. Part of the reason that we did not obtain assurances is because there were basically two mechanisms that were available. And I think youíve heard about multiple project assurances, and single project assurances. When you look at the language of those assurances, there are several things that you will notice: One is that they are very difficult to understand. The legalese of the language is difficult to understand. Secondly, in these countries where we work, those countries see themselves as equals -- equals to us, or we see ourselves as equal to them. And so, we have them sign a form that says you will do this, you will set up an Ethics Committee thatís got five people; and you will have annual reviews -- because not all of them would do annual reviews on their research; that you will keep minutes, and you will keep records. It is the nitty gritty detail that goes into the assurance that these countries have found offensive in the past. We had been working with OPRR for two years prior to last year, to develop an assurance document that was more readable, and that was more respectful of the sovereignty of these countries. And we actually did develop that document, and thatís what we are now using. It comes under whatís called a cooperative project assurance, which is kind of in-between a single and a multiple project assurance. And itís been specifically adopted so that it meets the kind of research that we do, and it binds CDC to do the same things that we are asking these countries to do, which has been a very strong negotiating point with these countries. Part of the difficulty for us was that when we began to implement assurances last year, we had almost 100 studies at that time in place that were not covered by assurance, and we went into these countries where we had been conducting research for ten years or more, and said, "We have to do this, and we have to do it now." They could not understand the C change, because this had not been part of negotiations. In many of our cases, our negotiations start initially with the State Department negotiating a memorandum of understanding between the country and the U.S. Government, and then coming down to us.

PROF. CHARO: Iím sorry. But why is this subject to the regulatory requirement of assurances prior to one year ago? But why are you subject to the requirements to seek assurances from one year ago, when --

DR. SPEERS: We were subject to that requirement. There had been discussions over the year with OPRR about how we should handle this and what the issues were. The advice that we had gotten previously from OPRR was conduct the research according to whatís required in the regulations. Theyíll have Ethics Committees have reviews, and so on. Follow the spirit of the regulation, even though you donít have these assurances in place.

Dr. SHAPIRO: Thank you. Eric.

DR. CASSELL: Itís really follow up and reflects the same thing. So what happens when you are in a host country, which is the only place that you can study the disease, and, yet, you are not satisfied with their protection of human subjects?

DR. SPEERS: Iím hesitating on that question, because I am trying to think of a country that has not had an Ethics Committee, or a --or a review process that either hasnít been up to our standard, if you will, if you consider our standard the high standard. I am very sensitive to that, because some countries think the U.S. standards are low --or has not been willing to change over some time, that are willing to change. And I have trouble thinking of a country that falls into that category, other than the former Soviet --countries that were part of the former Soviet Union. In that situation where it occurs, we donít do the study. I mean we either --we have either --we either have not done the study at all, or we delay implementing the study until we can get everything in place. We have several studies that have not started, and they may have been a year. They may have been postponed as long as a year, because everything is not in place yet for them to start. Let me give you maybe an example of what youíre talking about as Cuba, for example. We are involved in conducting research through Paho in Cuba. We do not have diplomatic relationships with Cuba; and, yet, studies that weíre doing there is the only place in the world where these studies can occur because of the unique situation that exists; and, yet, the information we get from this information can be used worldwide. What we have negotiated is through the State Department, and with the Cuban government. We have negotiated a way that we will eventually be able to sign an assurance with Cuba. And so, we have, through now eight months of negotiation, gotten to where we can actually sign the assurance. So, we often take the steps within government that we need to make things happen. The problem is it takes time. And for many of this conditions -- for example, malaria, you have to go in and study malaria during the rainy season. So, there may only be a window of opportunity in certain countries over a three or four month period. If you missed it for that period, then you wait till the next year; or if you have the case of Ebola, for example, if Ebola breaks out again, we will, as we did the last time, we will go in and we will do patient care, and we will do research studies. If we miss the opportunity to do those research studies, then we have to wait until there is another outbreak in order to undertake those studies.

DR. CASSELL: That is precisely the point, which is here is an opportunity that it will disappear, and you wonít get another chance unless there is another outbreak. What Iím trying to find out is how much are you willing to give up ethical standards for research in order to take advantage of that outbreak? After all, if you find something that helps the people with Ebola, whatís the price --and the price is some deterioration in ethical standards, what difference does it make?

DR. SPEERS: Well, that is a very difficult question for us, and one that we would like the Commission to consider as well. Because in --if you look at the emergency situation, if the emergency situation does involve research, then I think you have to look at the ethical standards in two ways: The ethical principles that must be upheld; and the procedural issues, or the procedural standards. And which ones can --which ones are negotiable, and which ones arenít?

DR. CASSELL: Well, thatís what Iím really trying to find out from you, which ones have been negotiable, and which ones have not been negotiable. Because youíre in the particular positions -- itís not like a drug study. Youíre in a position where the disease, or the condition pushes the schedule, rather than your interest pushing the schedule.

DR. SPEERS: Right.

DR. CASSELL: So, Iím truly trying to find out whatís actually happened. What I hear you saying is that most of the time, and, point of fact, and our host countries are equal or better, etc., but sometimes they are not. So, I hear you and I hope I am being fair to say, and sometimes when we are not we have to proceed anyway because the urgency of this situation demands it. Is that a fair statement?

DR. SPEERS: Thatís a fair statement, although what I --I guess in the past year since we have been implementing assurances, which is one of the major --is potentially one of the major barriers for going forward with this study because of the length of time it takes often to negotiate the assurance. In the time that we have been doing that, the assurance has not been --there has not been a barrier to us proceeding with research. Even in the case where there was the outbreak of Grafalli fever in Kenya in February, we were able to get two protocols through an assurance approved by OPRR in a matter of days. So we have actually been able, in the one situation weíve had, been able to move very quickly. Now, Kenya is a country where we have some history of working. In some of these other countries where our history is not as long, or there is a greater difference in where we are on ethical issues, we might either not be able to do the study. I can see where we would absolutely not do the study, rather than proceed.

DR. SHAPIRO: I have a suggestion, because weíre going to have to end the questioning, to move to public comments. And we do want to have some time for lunch. It would be helpful, if possible, or plausible under the circumstances to understand rather more directly when you have a moment, or when your colleagues have a moment, illustrations of what kinds of standards are relaxed, in what kinds of situation - a very straightforward question I think. I understand the situations. Things are complex and require judgment. And Iím not trying to imply any moral values here, I understand these points. But it would really help me, in any case, to understand in what kinds of situations you make what kinds of sacrifices, from either our own regulations, or someone elseís regulations. We donít have time to discuss it today, but that would be helpful. If I could make one editorial comment before we go to public comment. On this issue, there are two words, which are used over and over again here, both by us and others, which I think obfuscate the issue. One is "imperialism.". Thatís an insult of the well-known pedigree, and it just obfuscates the issue when we talk about it that way. The other is "equals." Of course, we are all in favor of equality, and we are more equals of each other, and so on. It has, as far as I can see, no implication for how you act. Because you either have some principles, or you donít have. The more you have some mixtures. It has nothing to do with whether one is morally -- declaring oneself morally superior to someone. I can disagree with someone, even though I donít think I am superior. I just disagree, and have a different set of moral values. It strikes me that we, ourselves, on the Commission, as well as others who talk to us, use these terms all of the time, as if that settles an argument, rather than enlightens the arguments. So, maybe in our own discussions, at least as we have discussed, leaving everyone else to their own devices, we will not use those words because I donít think they help us move the discussion forward. But I want to express my great thanks to all three presenters this morning. It was very, very helpful. Obviously, you had spent some time thinking about this, organizing your presentations in ways which I found extremely helpful. I am very grateful to you for the effort, to say nothing of your ongoing work in these areas. You, of course, are welcome to stay. Any part of this meeting, if youíd like to participate. And we will have a chance later on to come back to other questions as time allows, because I know Iím cutting the discussion period short right now. But I do want to go to public comments. And I wanted to --I want to apologize to Tom. I had thought I was going to give him an opportunity to welcome us all formally. I went right into the session. I am going to give him that opportunity to say something about what options are for lunch in a few moments. But that kind of priceless information will wait following public comments. I think we have two people here this morning who have signed up. First on my list is Ms. Vicki Casagrande. --I hope I have pronounced that correctly -- from West Bloomfield, Michigan, who wants to talk to the Commission regarding the human telebiostimulation and control. Just let me remind you that the rules here are five minutes each person for public comments. And Iíd ask you to keep it that, if possible, please. Thank you.