CHAIRMAN KASS: In this session the Council returns to the general topic of oversight and regulation of development and uses of biotechnologies, a subject of interest to us in general and also, I remind you, in relation to our work on cloning and stem cells, in which many of the people on both sides of the aisle on the cloning debate were interested in exploring the prospects for and the principles of regulation.

In previous meetings we have been looking both at what other countries are doing and also learning about the current regulatory activities in the United States. So far, we've had an overview of what is happening around the world with Lori Knowles and a report on the Canadian practices in reproductive technologies with Patricia Baird. We've had three sessions domestically on the patenting of living organisms.

Tomorrow morning we will hear from Professor Simitis on Germany's practices and policies, and today we will be looking at the Institutional Review Boards, those local bodies that are now charged with oversight and approval of all federally-funded research involving human subjects.

We are very fortunate to have as our presenter this morning Dr. Ezekiel Emanuel, physician, oncologist, Doctor of Political Philosophy, Chair of the Department of Clinical Bioethics at the NIH. His paper he wrote with co-workers, Ann Wood and Christine Grady, entitled, "The Crisis in Human Participants Research: Identifying the Problems and Proposing Solutions," was distributed to Council members in advance.

I remind everyone present that the opinions expressed in this paper and in this presentation are those of the authors. They do not reflect any official position or policy of NIH, the Public Health Service, or the Department of Health and Human Services.

It's a special privilege for me to welcome Zeke Emanuel here who I first met when -- I shudder to think when -- he was still a student, a senior at Amherst, and I was a much younger fellow.

Zeke, welcome and thanks for being with us.

DR. EMANUEL: My speech coach always tells me to stand and never sit. So I hope the Council will indulge me in that.

It's very wonderful to be invited here, and many of the Council members have been my mentors, many are my current colleagues, and many are people whose writings and work and research I have admired over the years.

I think it's fair to say that everyone seems dissatisfied with the current system of protecting human research participants. Many of our researchers find the system onerous and more of a hurdle to get over than something that is value-added.

IRB members who serve on the oversight bodies -- IRB stands for Institutional Review Boards -- find the regulations quite opaque, feel in a bind between federal oversight and what they're supposed to do for their institution. The pharmaceutical and biotechnology industry finds the process very time-consuming, very inefficient, and very resistant to innovative and novel approaches in research.

Regulators feel frustrated. They get criticized by the federal government and the public for not doing enough. They get criticized by institutions for being too intrusive.

And the public is afraid, uncertain. They believe greatly in biomedical research, but recent polls have certainly shown them to be much more concerned than they ever were. I think the cover of Time magazine over the summer that showed a human subject in a guinea pig cage attests to this concern.

I don't think it is misplaced. Since 1999, the federal government oversight body, OHRP -- that is the Office for Human Research Protection -- has stopped or suspended research at 13 major research institutions. This includes two of the top ten medical centers in this country, and a third of the top ten medical centers in this country had a major scandal involving the death of a patient, but was not actually closed.

Now that dissatisfaction has led to tremendous activity to respond to the problems. You can see all those acronyms up there. You know you're in Washington; it's alphabet soup time.

Recently, there was the creation of this Office for Human Research Protections during the end days of the Clinton Administration that reports directly to the Secretary of the Department of Health and Human Services.

At the FDA there was the creation of the Office for Good Clinical Practice to oversee all their ethical issues. The NIH, my employer, has issued requirements on training and education of investigators and one-time grants to improve the function of IRBs. There are new initiatives for accrediting IRBs, which I'll talk about in a moment. And there's introduction at least of two bills by Senator Kennedy and Representatives DeGette and Greenwood in Congress for reforming the system. This attests to a huge amount of activity.

I think there's a problem, though, and a lot of this activity really tends to address specific problems without stepping back and assessing the whole system. In the next few minutes I really want to sort of systematically delineate what I take to be the problems of the system, evaluate how the various proposed reforms address or don't address those problems, and then I want to float for you a more comprehensive solution.

It is at this point which I want to just reiterate Dr. Kass' disclaimer for me, which being a federal government employee I always do at every talk, which is that these are my opinions and the opinions of my colleagues, Ann Wood and Christine Grady, and our Department, and these are not the official opinions of anyone else.

I can tell you, having circulated the manuscript you saw inside the NIH, many people certainly disagree with, but they also thought it was important that these issues be aired and discussed. I greatly appreciate their commitment to free inquiry.

For those of you who aren't sort of up, as it were, on human subjects research and the regulations, I thought a brief historical digression would be helpful. From basically the mid-sixties to 1972, there were a series of research scandals in this country that really began in 1966, where Henry Beecher, a Professor of Anesthesia Research at Harvard Medical School and the Mass. General Hospital, published a very important paper in The New England Journal of Medicine that delineated 22 violations of research ethics at major research institutions.

He said he culled these 22 from a further 50 cases which he couldn't produce because of reasons of space, and that was from a further 100 cases. He made very clear that these events were occurring at the premier research institutions in the United States: Memorial Sloan-Kettering, NYU, Harvard, the NIH.

For the next six years a series of scandals happened in the country, culminating in the Tuskegee syphilis study, which was stopped in 1972 by the then-Department of Health, Education and Welfare after it was revealed in the press, although it is important to emphasize Tuskegee was not hidden; it was not done surreptitiously. Papers were coming out annually from that. As recently as 1969, just three years before it was stopped, it had been reauthorized by the Public Health Service.

Tuskegee led directly to the appointment of a National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1974. That was chaired by Dr. Ken Ryan, an obstetrician and gynecologist at the Boston Lying-In Hospital.

Over five years, the National Commission issued some very major reports, including reports on research with prisoners that has already been mentioned and many other topics. Its probably most enduring report is so-called The Belmont Report, which established the sort of framework, ethical framework, for research ethics.

Soon thereafter, the federal regulations on research -- that should say, "on research" -- 45 CFR 46, were enacted in 1981. In 1991, they became what's called the Common Rule, when 17 federal departments and agencies adopted them, although it is important to mention that there are some federal departments that still don't adhere to these rules, notably the Department of Labor.

What's cut off (referring to the viewgraph) should say that the FDA maintains similar but slightly different rules regarding research that is being applied for approval as a drug or a device.

All right, the Common Rule focuses predominantly on local institution-based IRB review of research protocols and continuing review, at least annual review, of those protocols. It is also relies on informed consent of individual research participants, and there are special rules that have been in place for research with children, prisoners, and pregnant women.

With that brief historical background, I want to try to systematically and coherently look at the problems of the system, because I think a large part of the debate, certainly inside the Beltway, focused on one or another of the problems, but not on a sort of overall structure to the problems.

I think the problems can be divided into sort of three domains: structural, the whole system is laid out in the regulations; the IRB review process itself, and assessing the performance of both clinical research and that process.

Before I proceed, I would need to insert two caveats. The first is that there's a serious paucity of data documenting these problems. We just don't have a lot of studies of the whole system and of clinical research and how it is performed. So my claims here that there are problems is born of my experience as a clinical researcher and as an IRB member, discussion with lots of clinical researchers and IRB members, collection of the limited available data that's been published, and we'll look at the actions by the federal oversight institutions.

I also personally think -- and I'll get back to this at the end -- that the absence of performance data on the system is also an indication of serious defects. If Ford didn't know how many defects there were in its cars, you would think there was something wrong with their production system.

Second, while the review of the problems here is systematic, I don't by any means suggest it is comprehensive. There are lots of other problems I'm not going to talk about, such as the application of the regulations which were originally created for biomedical research to things like social and behavioral research and whether they fit or don't fit very well.

So with all of those caveats and hesitations, I want to talk about some structural problems. The first structural problem is that it may strike you and the public as ironic, but not all research, biomedical research, in this country is actually covered by the federal regulations. Research that's not funded by the NIH, research that's not seeking FDA approval doesn't have to get, isn't covered by oversight. This covers some very important research.

A lot of reproductive research falls into this category, and, in addition, research such as on dietary supplements isn't covered by federal regulation. Research on surgical procedures that aren't looking for approval as drugs or using devices is not covered.

Second, currently in the system there's no mechanism in a systematic way for addressing major ethical issues in research or for assessing the social value of research. There was a national commission; there was a President's commission; there was NBAC; there is this Council; there is another group called NHRPAC, which has just been disbanded -- for occasionally looking at major ethical issues in research, but these are stop-and-start events. They're not systematically organized.

Importantly, assessing the social value of research -- Is it really going to contribute that much? What are the down sides of research? Is it designed so that it will affect the most citizens? -- is not systematically evaluated in the system, and to some degree is discouraged from being evaluated.

The third problem: We rely on local institutional-based IRBs. When this was developed 25 years ago, that might have been reasonable when a lot of the research happened at our major academic settings like Johns Hopkins, the NIH, Harvard, UCSF, but in fact a lot of research, or maybe even today a majority of research, has now filtered out into private practices, clinics, and a lot of other organizations. There is a mismatch, many people feel, between the fact that we have institution-based IRBs, but a lot of the research isn't even occurring anymore at institutions.

Fourth, even within institutions there's no dedicated funds for IRBs. When the NIH gives out grants for research, there is no extra money for the IRB function. It comes out of what's called indirect money, and there's not even a line item in there.

Many IRBs, certainly before these recent scandals, were resource-starved, I think is an accurate way to put it. Now the scandals have gotten the attention of many institutions, especially if you can close down Johns Hopkins, and Johns Hopkins has announced or indicated that they have doubled the amount of money they devote to their IRB. But I think in general there's still a lot of lack of resources there, and, importantly, IRBs have to compete with all the other demands for medical institutions that are under increasing price pressure.

Fifth, there's a lack of attention to institutional conflicts of interest. One of the problems of having your IRB be institution-bound is that the IRB is actually regulating the research within the institution that is paying the IRB. That is an inherent conflict of interest. I, myself, have twice experienced some of the pressures that can be brought to bear by reviewing research done at the institution and people, powerful people, in the institution having some interest in getting that research going.

Sixth, there's a very poorly defined mechanism for investigator conflict-of-interest rules and the IRB's role in enforcing those rules. An investigator in this country can be subject to as many as five different conflict-of-interest rules: one from the institution where they work; one from the NIH; one from the FDA; one maybe from their professional society, and if they work at a state institution, there's frequently state conflict-of-interest rules.

They all differ. It is very unclear how to follow them, and it is very unclear how that is matched with submitting a protocol. The IRBs also don't know what they are supposed to do.

Seven, there has been inadequate education of clinical investigators and IRB members. The NIH has recently mandated that for its grantees there be education and training, although there's no curricula requirement; no one knows what the content is supposed to do, and, importantly, therefore, no one knows what the sort of core material they're supposed to understand and any way of assessing whether it works or not. This, by the way, is in marked contrast to animal research.

Eight, the system is replete with repetitive reviews. So, for example, if I do a research study, which I once did at Harvard, involving five other cities and hospitals in all those other cities, and ultimately there were 40 different hospitals, I actually had to get that protocol reviewed at 42 different places to do the research, all of them looking at the exact same thing over and over again. Sometimes this process can take a year and involve a lot of people's attention and energy. I know that another project I am currently involved on, we have one person who is full-time, worked for a year, just in getting all the paperwork together.

Those are structural problems. Now I want to shift to the IRB process problems. I think it is fair to say that a lot of the attention that we have today is really focused on these IRB process problems. A lot of the legislation, the accreditation process, really take these as key. I, myself, think they're important, but I don't think they're the whole story, and that is one of the reasons -- and the previous eight problems are a large part of that reason.

Getting your research approved is a time-consuming process. It has become longer and longer. I will say that most investigators are increasingly frustrated. Six months from submission to approval is not unusual. You often have to go through scientific review, which can take several months. Then the IRB frequently meets only monthly, and if you don't get on the schedule, the IRB frequently has corrections or modifications they want made. You then have to go back in front of the IRB. It is a very lengthy process.

Ten, there's poor quality control of the IRB reviews. One of the things we learned from the Johns Hopkins episode is that the investigator submitted information about the drug being used, but it wasn't complete or comprehensive information. The IRB relied on that information, did not proactively investigate further. This happens frequently.

Sometimes the IRB will get a protocol in an area. There's no one on the IRB who's an expert. Well, IRBs always could get ad hoc members, could actively investigate. That requires time, resources, and it is frequently not done.

Eleven, there's is excessive focus on the informed consent process at IRBs and excessive focus within that just on the document and what is, I think, derisively but not inaccurately called "wordsmithing" of the document. Now some of that wordsmithing is important to make sure that the language and the level of comprehensibility is correct, although we don't always get it right, but a large part of it is just altering words for preferences without any real focus on its importance.

There is good reason why this is true. Frequently, IRBs have been criticized by federal regulators for leaving out something when a scandal happens. This happened at Johns Hopkins. But a large part of the deliberations are about the document and really ignore many, many other important aspects of the research.

Twelve, there's substantial deficiency on how IRBs monitor research and conduct these continuing or annual reviews. It's frequently said, and very accurately said, it seems to me, that IRBs see the research protocol at the start, and then the ball rolls down the hill. They have no idea whether the research is actually being implemented as stated, and continuing review, the annual review, is a very perfunctory thing, done frequently in just a handful of minutes for very complicated studies. This is a very, very serious problem.

I think one of the most serious problems personally is we have a very inefficient and ineffective adverse event reporting system. Adverse events are those problems that arise in the course of a trial, people having reactions to drugs or complications that need to be reported.

It is now required that every IRB get informed. The FDA has a very strict timeline, a strict rating criteria. The NIH is a much more loose, very undefined system.

More importantly, if you have a large trial with lots of centers, you have to send the same information to all the IRBs and they have to make a decision, each individually, what to do, frequently without knowing how many people have been enrolled, are these three cases a large number of cases, a small number of cases, how serious. It is a very time-consuming process, but doesn't do a lot to protect the people on research studies.

The last two problems I want to talk about -- cut off at the top, unfortunately (talking about viewgraph) -- are what I call performance assessment problems. I think these are extremely important and not very well-appreciated.

We have almost no data about IRB function and how well they do their function, and whether, in fact, they actually protect patients. We don't know a lot about what goes on, where they spend their time. Is there a relationship between bad continuing review and harm to patients?

Fifteen, probably more serious is no one in this country, not the Director of the NIH, no one at Pharma or at Bio, and not the commissioner of the FDA, can tell you how many research trials are going on today in the United States, how many people are enrolled in research trials, how many people experience serious toxicities, and, indeed, how many people die on research trials. We don't record that information anywhere.

Again, it seems to me it is hard to know whether the system is better, worse, going in the right direction, going in the wrong direction, if you don't systematically, regularly, routinely even know how many people are on research trials. We don't even know how much we spend on it. I might say we don't even know exactly how many IRBs there are. I am sure General Motors knows exactly to the number how many dealerships it has. We know that there's somewhere between 4,000 and 6,000 IRBs in this country.

Let's talk about the reform proposals now. There are a number of reform proposals: accreditation of IRBs, which I'll talk about in-depth; credentialing of IRB professionals, which I won't talk about because I think it addresses a very small number of these problems; some of these legislative proposals, which I'll talk about. OHRP, again, that federal oversight body has some quality improvement initiatives and conflict-of-interest initiatives. There's been an effort at the National Cancer Institute to create a central IRB, which is in a pilot phase, and I won't say more about that. In a few months we think the Institute of Medicine is to report on its view of how to change the oversight system.

So I want to say a few words about accreditation of IRBs. There are two accreditation processes, again the alphabet soup here. NCQA, the National Committee for Quality Assurance, was hired by the Veterans' Administration to reform and look into and to accredit veterans' IRB programs, and AAHRPP -- and I can never even remember what all the initials stand for -- is an independent group that is doing voluntary accreditation of institutions and research hospitals.

There's some overlap in what they are evaluating. They are looking at the educational programs of these institutions. They are looking at the specification of IRB membership qualifications, how they're trained, how they're kept current. They are looking at policies on conflict of interest in other areas that the IRB has to deal with, and they are developing guidelines and assessing how many resources are provided to IRBs.

At the request of the Department of Health and Human Services, the Institute of Medicine, as the first part of its oversight, examination of the oversight system, reviewed these projects on accreditation. Basically, they said that the standards being developed do not apply to all types of research in all types of settings, that they really focus on biomedical research in the academic setting.

They argue that neither set of standards is tested or ready, as it were, for prime time. They said that accreditation is really best viewed as a pilot project, to be evaluated over a substantial period of time.

I would say -- and this is my summary; they didn't put it in this language -- at best, the IOM gave what I would call tepid support for the accreditation initiatives. It was certainly not wholehearted.

Importantly, which we can confess to you we just learned yesterday, as of April 17th, the Veterans' Administration suspended the NCQA accreditation process because of concerns about the standards and the process itself. It is anticipated they will resume in January, from what we have heard.

Part of what is happening is that the number of standards is being decreased from 130 to 100, and the revised process is supposed to be more VA-friendly. It was felt that the accreditors were not, in fact, very sympathetic to the institutions and that any deficiency on any one of those standards flunked people.

Now accreditation might affect a number of the concerns and problems I raise, such as resources for IRBs, some of the conflict-of-interest issues by forcing policies, some education issues, quality control, but they, by and large, concentrate on the reforms about the IRB process. They cannot affect the structural issues and do absolutely nothing regarding collecting performance data.

I want to talk a little bit about legislative proposals, and those of you who know about these things are much wiser than I about these. But these are proposals. They're clearly going to get reformed as they work their way through Congress. They may never get passed. We know how these things happen.

But both Senator Kennedy and Representatives DeGette and Greenwood have introduced bills into Congress, and they overlap in many ways. They have some individual characteristics. All the proposals want to apply the federal regulations to all of human research regardless of the funding or the location of the research. All mandate investigator education. Both of the bills mandate disclosure of investigator conflicts of interest. They permit central IRB review for these multi-center trials, so that you don't have the repetitive review process, and they mandate collection of some basic performance data.

Senator Kennedy's bill would require accreditation of IRB six years after passage, and the DeGette-Greenwood bill talks a little bit about requiring institutions to provide some money for the IRBs and funding, although it doesn't actually say where the money is supposed to come from.

Now, again, these legislative proposals I'm sure are going to change as they evolve, but they do some important things, but they obviously have some deficiencies, again, when we look at all of the problems we have in the system. While they will cover all research regulations and they will shift slightly away from reliance on local IRB review, they do at least nod towards providing some resources for IRBs, address issues of conflict of interest and repetitive review process. There are still many issues they don't address, such as the larger ethical problems that IRBs are going to confront and need to confront.

Finally, OHRP, the federal oversight body, has undertaken several initiatives, including a quality improvement program and to get conflict-of-interest rules. As I understand that, the conflict-of-interest rules are awaiting the Department of Health and Human Services' final approval.

The quality improvement programs are an important self-assessment program for institutions where they provide a survey that institutions can do for themselves and see where they are deficient. This at the moment is sitting at the Office of Management and Budget and, as I understand it, hopefully, by the end of the month, will be approved.

They also offer some site visits to particular institutions to address particular problems, and they are beginning a program on continuous quality improvement, which I think is quite innovative. But this is really their form of accreditation.

The conflict-of-interest rules, at least as gone up to the Department, apply to institutions, investigators, and IRB members. Again, at best, many of these initiatives will concentrate on the process problems, not really on the structural, and certainly not on the performance assessment.

So those of you who know me as always being bold, a little reckless, I thought I might offer a more comprehensive reform proposal for this Council to consider and to enliven the debate. I, again, hasten to add that many of my colleagues at the NIH don't agree with me, but they think it is important to elevate the debate and to begin to consider all possibilities.

So I want to suggest an alternative reform of the current system that would have these qualities: It would extend federal oversight regulation to all research. It would abandon local IRB review. It would create Regional Ethics Board to conduct all independent review of research studies, monitor research, train investigators, and formulate ethical policies and assess the value of research studies. It would entrust to a federal agency coordination of these Regional Ethics Boards.

We imagine that the Regional Ethics Boards would be geography-based in this country, that there would be 10 to 20 to cover the whole country. They would have something like this structure:

Each Regional Ethics Board would have a number of Regional Review Committees. It would have a liaison between the Board and particular institutions. It would have ombudspersons to interact with research subjects, and it would have an Ethics Policies Committee that would develop comprehensive policies.

There would be a federal oversight body, as I said, that would coordinate and monitor the function of these Regional Ethics Boards. The federal oversight body would collect data, publish performance data, and I give you some suggestions as to what I think that data should include, so that sometime someone in this country can actually say something authoritative about the clinical research landscape.

Importantly, it would also coordinate the Regional Ethics Boards to share best practices, to share operating procedures and, I think importantly, share ethical policy reports, which we really don't have today.

At the heart of these Regional Ethics Boards I think would be Regional Review Committees. There would be multiple Regional Review Committees per Ethics Board, I think possibly specialized and focused, so you would have one on cancer, one on heart disease, one on eye diseases, one on infectious diseases.

At least a quarter of their membership should be lay people. They should meet very frequently, weekly, not monthly, and they should conduct all prospective reviews of research studies in the geographic region.

Importantly, I think each research study should be submitted to one, and only one, Research Ethics Board. The Research Ethics Board in the geographic region of the Chief Investigator should review the study, and approval by that should be sufficient for doing research anywhere in this country.

Importantly, I think one of the things we don't have, and I didn't mention this as a problem but I think it is an important problem, is we need an appeals process for any adverse rulings by a Regional Review Committee. If you are going to concentrate power, you need an examination of that decision.

So I would suggest that if a Regional Research Committee rejects a study, the investigators should have the option of appealing, and that the federal oversight body should assign that research study to another group.

Importantly, I think the Regional Ethics Boards would collect data from investigators and report the number of people approached to enroll in research studies stratified by key variables like race, sex, age, diseases, number of people who actually enroll, number of participants removed from research and the reasons why they were removed, number of people who stopped participating in research, number of people who experienced what we in the industry call grade IV and V toxicities -- that's serious, serious toxicities, usually accounting for removal, but not always -- number of participants who died in research.

I also think that these Boards would be responsible for developing educational material and educating all the investigators in their Region.

I think all of the Regional Ethics Boards should have to establish a Regional Ethics Policy Committee that would create a forum to examine major ethical issues arising in research. Again, right now we do that haphazardly. We do it on a national level, very distant from people.

The kind of problems or issues I have in mind are: Should we pay children to be on research studies? A lot of studies do, probably unbeknownst to you. What are the ethics of it?

What about xenotransplantation, transplanting tissues from animals to people? What about having children to provide therapies for a sibling, conceiving and having a child? These are big issues that we really don't have a sort of systematic forum for addressing.

These Regional Ethics Policy Committees should engage the public in thoughtful discussion of the issues and develop coherent, consistent policies. Again, part of the issue is to educate the public and elicit their views. They could convene public deliberations, develop a draft report that could be the focus of public discussion, revise the report, establish a policy, and begin sharing the policies. This is a way of bringing the public into these discussions, educating the public, but also developing policies in areas where we have no policies today.

We also think that institution liaison is important. If you remove this review process from institutions, you need to connect with them. So we think each Regional Ethics Board would appoint individuals to serve as liaisons with major research institutions and probably liaison with smaller research institutions and physicians who individually in their practices conduct research.

Their responsibilities would include coordinating submission of protocols, clarification of policies, feedback, alerting the Regional Ethics Boards about problems and deficiencies.

Finally, I think an ombudsperson is very important. Right now if you get a research trial, if you have a problem, the number on the research form given to you to contact is the principal investigator. That's the person who you contact. We think there should be an ombudsperson who provides an independent view, so people who participate in research can contact them about any concerns they have about a research study.

Now any reform is going to have a lot of problems. I, by no means, catalog all of them. But I think it is very important to keep some in mind.

Again, I have mentioned the distance from and resentment by investigators is possible. At least if it is in the institution, the people you resent are your colleagues. If it is 100 or 200 miles away, it is some bureaucrat. I think that can cause a lot of resentment.

The concentration of power, I don't have to tell this Committee, can lead easily to the abuse of power. That is definitely a potential problem.

Uniformity of policies among 20 Regional Ethics Boards can certainly lead to rigidity, and that I think is also a problem.

Finally, no doubt, some people are going to worry about the high cost of having multiple Regional Ethics Boards. Cost is always a problem. Clinical research in this country is estimated to be a $40-billion-a-year industry. That is the research part of it. It seems to me a few hundred million dollars is not too much to pay for protection, and that is probably what we're paying now, although it is very hidden.

I thank you for your time and attention and welcome discussion.

(Applause.)

CHAIRMAN KASS: Thank you very much.

The floor is open for discussion. Michael Sandel.

PROF. SANDEL: I would first like to ask one or two naive factual questions, and I may be the only one who doesn't know the answer to these questions, except maybe my friend Gil. I hope maybe he doesn't either.

(Laughter.)

The IRBs, as they currently exist, that's only for federally-funded research?

DR. EMANUEL: It is a little more complicated than that. It is for federally-funded research and research that is seeking to get FDA approval for device or drug.

Now the federal oversight body has used its authority to mandate, to create agreements, for example, with Harvard that any research done at Harvard, even if it is not NIH-funded or if it is not seeking FDA approval, will still abide by the rules. But those are voluntary agreements. There's no law that requires them.

Furthermore, there is a lot of research, research that's not seeking FDA approval, like on dietary supplements; research that is not NIH-funded, such as many reproductive research studies, that don't have to abide by those regulations.

PROF. SANDEL: If there's a private company that doesn't take federal money, they don't have --

DR. EMANUEL: And not seeking FDA approval.

PROF. SANDEL: They don't have any IRB?

DR. EMANUEL: They might.

PROF. SANDEL: They might?

DR. EMANUEL: They might, but, again, the issue is whether they are legally required to.

PROF. SANDEL: And the people, let's say there's some biotech company someplace that has an IRB. Can they just appoint employees or do they have to appoint certain people to it?

DR. EMANUEL: Usually companies don't appoint or have their own IRBs. What they do is they contract out with proprietary or for-profit IRBs, some of which are probably the best IRBs in this country actually. So there is a private IRB market out there, as it were.

PROF. SANDEL: And it only applies to research on human subjects? IRBs don't deal with ethical questions of research apart from research on human subjects?

DR. EMANUEL: Right, and human subjects are defined in the regulations. They, for example, don't include dead people, are not human subjects.

PROF. SANDEL: And just one last question: This is no longer now in the category of the naive factual questions, but about your proposal. The thing you're proposing, that would apply, that would look at ethical questions beyond necessarily human subject research?

DR. EMANUEL: That would depend on what's crafted, but it seems to me one of the -- it would certainly be more than enough ethical questions regarding human subjects research. Importantly, how human subject research interfaces with many other aspects of clinical care and society are important issues that we haven't looked at.

The inclusion, in our view, of the importance of examining what we call social value of research, that's widely considered to be part of the ethical requirements of research. It would be wrong to do research that has no social value. It's now currently not systematically looked at at all.

PROF. SANDEL: And for your setup, are you only interested in the ethics of research, human subject or otherwise, or are you interested in the ethics of biomedical practice, and is there a clear distinction between the two? The reason I ask is that you gave the example of people conceiving a child for a blood match or a bone marrow match, or conceivably, as we'll discuss later, sex selection.

Suppose an IVF clinic wants to engage in various practices like those, not research practices but clinical practices. Would your proposal cover those, too?

DR. EMANUEL: You're getting to the issue of what distinguishes research from practice --

PROF. SANDEL: Right.

DR. EMANUEL: -- and there's not a -- I mean there's some stipulative definitions, but it's an open question as to exactly what the criteria are.

Certainly the early cases of conceiving a child for therapy were done on research studies. My current conception is that this is related, ought to be related to research, but, obviously, the considerations and the rules that you set down and the research setting would have some moral force, it seems to me, to extend beyond.

One isn't going to engage necessarily in some of these things in the clinical setting before you do it in the research setting. So it's very frequently, it seems to me, that you will address or at least confront the issue in the research setting before you get to the clinical practice setting. Certainly you ought to.

CHAIRMAN KASS: Let me follow on this, too, Zeke. I mean, I'm mindful of the fact that the talk is about the reform of existing institutions that are problem-ridden, and much of what you say in the proposal and the summary makes sense to me. But what's missing in the discussion, and what is somehow tacitly assumed, is some notion of what the goal of the IRBs or of your Regional Ethics Boards would be. If they remain defined as the protection of individual human subjects of research, then it seems to me you have -- I don't mean inappropriately, but you've limited only one piece, you've limited off only one piece of the larger ethical issues that, for example, concern this body. Point one.

There is for many people a sense that the crucial ethical issues in biomedical technologies are, in fact, the research ethical questions, and one will try to force almost all of the other questions into that model, and we had our hand at that actually earlier this year.

But if you then go on to say, as the statute does, that what you mean, what you're looking at, the protection of individual human subjects, that you will consider risk-benefit analysis, that you will consider questions of subject selection, and that you will see to it that there is informed consent, that is a further narrowing even perhaps of what it is you want to consider when you're taking account of individual research subjects.

So the large question is, the largest way to put the question is, assuming you wanted to design a system that would in fact protect the individual subjects of research in as rich a way as you can, would such an institution devoted to those goals be reasonably expected to address some of the larger social and ethical questions or do we need something different to do that?

DR. EMANUEL: I don't think I said anywhere that these groups should limit themselves in the way that current -- that we simply should take the way current IRBs limit themselves to individual research subjects and simply protecting them as necessarily the paradigm. I don't think I meant that, and I certainly don't take that to be the case. I'm very much on record in getting at, among other things, concerns about how research affects communities. It's very important and underplayed.

Second of all, it seems to me that many of the questions that ought to be taken up do go beyond a narrow conception of either risk or subject selection. Let me just point out the way I conceive it, and maybe we're talking here a little orthogonally.

If you take the question of, should we pay kids to participate in research, now you can conceive it very narrowly, but you can also conceive it much more broadly. How does it express how we value children in our society? How do we understand the relationship between kids and their parents, if you pay the child independent of the adults? What kind of payments communicate different things? What's their both material and symbolic value?

It seems to me you can't answer those questions in any narrow way, and part of my alluding to the kinds of things that I think are on, or would have to be on the agenda, this is a burning question for lots of IRBs, I take it, I know, in this country.

I would tell you that there are probably only two things written on paying kids in research. We've written one of them, and the American Academy of Pediatrics has written another. Actually, the European Union has a third. But that's it. I think discussing the underlying values of what you are trying to achieve in policies is absolutely critical. That's part of the reason for having an ongoing body.

Similarly, other topics that would have to be taken up that are burning issues today have broad social meaning. For example, what are the obligations of researchers from this country who are going overseas to developing countries to provide medical care beyond the end of their research for the people who have been involved in their research studies? And maybe not just on the disease that they've looked at, but on other diseases. How long does that occur? Who is supposed to shoulder the financial obligations? You cannot answer that kind of question in a very narrow frame of just protecting subjects.

Third, it seems to me that when you include the notion of assessing the value of research, the social value of research, you go to the heart of the question: Why are we doing this? One of the things we have certainly learned over the last decade or 15 years, and I think was alluded to by Professor Dresser, was a lot of the research we had structured was very narrow, you know, assessed only white males between the age of 50 and 59, and had no greater social implication, or couldn't be extrapolated without significant danger.

How we understand the research we're doing, make sure that it is maximally valuable to society, I think is very important. Again, it is widely recognized as an ethical requirement for research and simultaneously widely ignored in any review of research. It seems to me that's exceedingly important for us to examine.

So I think it is hard to see how, if you take one of these issues seriously, if these Ethics Policy Committees took it seriously, how they would stick to the narrow question of just protecting individuals. Almost all these questions open up larger questions of social values.

CHAIRMAN KASS: Just a very brief followup: It does, then, seem to me that you've got enough trouble, I suppose, peddling this proposal as it stands, but I think it would be enriched if it began really with an articulation of the kinds of things you're now saying, where you somehow talk about your perception of what it actually means to call something a Research Ethics Board as opposed to saying Institutional Review Board, and to make some of these tacit goals explicit and call attention to what might be different in the overall ethical and social intent of this, I mean if you mean it.

DR. EMANUEL: Yes.

CHAIRMAN KASS: So that it becomes -- people will see really what's at issue. They may not like it. The individualistic focus is very prominent in the society; communitarian perspectives have an uphill battle. But, nevertheless, it does seem to me that the proposal itself could be enriched upfront with some kind of discussion that doesn't begin just that there are dissatisfactions with the way the system works, but to talk in a more positive way about what one is trying to accomplish.

PROF. SANDEL: Okay.

CHAIRMAN KASS: I'm sorry. Charles and then Michael.

DR. KRAUTHAMMER: Michael Sandel said he was asking a naive practical question. My job is to ask the naive philosophical questions.

Why regional and not national? I know that obscenity is defined locally and regionally in this country. Is ethics also defined that way?

DR. EMANUEL: Well, I think moving to a national body would be, for practical reasons, unwieldy, just sheer volume and considerations of that. I think many of the standards are universal and aren't particular to a region. So part of the regional focus is a practical focus.

It is also an attempt to try to avoid the rigidity problem. While I think having 4,000 to 6,000 IRBs is probably more akin to chaos, having 10 or 20 think through some of these problems and some of the implications is probably a good way to keep the pot stirring and keep innovative ideas.

I think in this country I don't have to tell you, a better historian of American culture than I, national things obtain a lot more resistance than even local things.

One of my colleagues did ask a similar question, which is, well, then, let's look at the Ethics Policy Committees, why are they regional and why that could be national. I would consent to that.

DR. KRAUTHAMMER: Am I overinterpreting you to say that this is more of a political, practical, what-is-feasible consideration rather than philosophical? If you were creating a system from scratch and had no political constraints, would you have any -- is there any reason in principle, other than the idea of the laboratory of democracy, different regions learning things and teaching each other, other than that, which I think is a consideration?

It would seem to me more logical, if you were going to have a set of ethical regulations and people applying them, that it would make sense to have one system or at most one or two or three regionally. But I don't quite understand, other than what you're saying, that it is politically impossible to go the other way. In principle, would it not be desirable to have as few as possible?

DR. EMANUEL: I guess I am somewhat of a student of political history. Concentration in one place I think does tend to ossify. I think that is not a trivial concern here, especially as research progresses in some areas. I am not a big believer that it raises, you know, the argument that it raises new questions, but it certainly puts them in different lights and makes different kinds of challenges.

I think in that light, having everyone having to troop to Washington or Chicago or something, it is probably a much better idea to have different places looking at things.

DR. KRAUTHAMMER: Could I just have one quick followup? So, in practice, if you have an investigator who's headquartered, say, in Boston, under your proposal he goes to the regional one there, but he might involve a hospital in San Francisco that is operating under a different set of rules. Yet, that protocol, as practiced in San Francisco, would have to adhere to the Boston rules rather than the local rules. Wouldn't that lead to all kinds of jurisdictional problems?

DR. EMANUEL: It might lead to jurisdictional problems, but I think I don't see the different rules per se; there might be different interpretations of some rules. But, again, I think that's possible, but it is a problem that is better lived with than either the current system or one system.

PROF. SANDEL: I hadn't thought about this before Zeke's presentation, but one argument in favor of having Regional Ethics Boards might be to allow not just a laboratory of democracy, diversity for that reason, but different arguments to be developed and positions taken on ethical questions, analogous to the way it works with federal district courts and courts of appeals.

Now there is a Supreme Court. And one question you might have put to Zeke was, why not have a Supreme Ethics Review Board to handle the appeals rather than some other regional one, which is what I thought you were going to ask?

But there is currently the law now, as a result of regionally-based federal courts of appeals, that you are allowed to count race in admissions to law schools in Michigan but not in Texas, because the courts of appeals have come out with different positions on affirmative action. The Supreme Court could take those cases up to resolve it, but so far they haven't.

There is something to be said -- I don't know if it is enough to be said -- for having debatable questions like these medical ethics questions and like affirmative action be reasoned and debated differently by different regional courts.

DR. KRAUTHAMMER: But, Michael, that structure really only makes sense because you ultimately do have a Supreme Court which will in the end adjudicate on the critical issues. If you didn't have that, you, I think would agree, that having a system, a legal system in America of circuit courts and no Supreme Court would be incoherent and ultimately hard to defend.

PROF. SANDEL: Well, incoherent I'm not sure. There are those who defended the federalist system who would say there's something to be said for that degree of decentralization.

But you could add to Zeke's thing a Supreme Ethics Review Board.

DR. KRAUTHAMMER: But you would have to find a better name.

(Laughter.)

CHAIRMAN KASS: Mike Gazzaniga.

DR. GAZZANIGA: There are efforts going on, or about to go on, to address some of these things. I know that Dartmouth just received a large grant to start a database of all the IRBs that are funneled through the NIH. So some of these coordination efforts are started.

But I have three questions for you. One, are you knowledgeable about any cross-cultural models that might help us think about this?

Two, have you really thought about the time to study? I'm the clinical investigator who uses the current system, and I'm about to inherent your system. Have you thought it through to what's involved there?

Three, a little more thought, apparently, you're in total agreement on this, but the monolithic problem of an agency with an ethic. If I have learned anything in the last six months, there's no one ethic; there's all kinds.

The ossification you talk about I think is a huge problem. Science, for example, if it only had one vendor, one source for all money, the beauty of the process would come to a screeching halt.

Lastly, I don't think that local control is all bad. I see in our IRB process that people learn quickly who is responsible, who are good. Whereas, if we mailed this off to somebody in Manchester, New Hampshire, or to Boston, or whatever, it sounds like a nightmare.

So, as a friendly skeptic, maybe you could comment on some of those.

DR. EMANUEL: First, in the cross-cultural models, all through Europe there's different models. Some countries have a national system, like Denmark. Some countries have a regional system like this. I think it is fair to say that there is a European directive now; they want to facilitate review, and review is in a few years going to be required to be 60 days, no longer than 60 days.

Places like The Netherlands are fulfilling that review by basically getting rid of all IRBs at the bottom end, that don't deal with a lot of protocols, don't have a lot of experience, don't have a lot of standard operating procedures. They've acknowledged that essentially it is going to be a regional system.

Second, I think we actually have home-grown examples of how this might work. The proprietary IRBs are, in fact, a model of a regional IRB system. At least in this country, as I alluded to, they are quite good.

Now those people who are at academic centers I know are quite skeptical of this, but, in fact, we have some good data about that, because every time the federal government closes down a major research institution like Hopkins, they don't send their protocols from Hopkins to Harvard; they send them to Western IRB out in Olympia, which is a for-profit, proprietary IRB, which they think is good not just to review them, but also to give Hopkins and other institutions ideas about how to reform their system and remodel it.

Now if you look at the Western IRB, unlike most institutions, they actually keep track of how long between submission of a full protocol and actual action occurs. Their time on average is 10 days.

I worked at the Dana-Farber Cancer Institute in Boston. We couldn't get the 10 days to even get in front of the IRB, and I'm sure at your institution it's no different.

So if you want to know, could it be more efficient, could a regional system actually work, and would it be better than what I live with, the answer is we actually have models that suggest it is true. Now one of the virtues of these big regional models is the Western IRB has 210 employees doing all the background, you know, the back-room work, as it were. I don't know what yours at Dartmouth has, but most IRBs have two-three people even that are considering a thousand protocols a year. So that can be a substantial big difference. I think, yes, they are going to be distant from you, but, on the other, they are also going to be -- they might be more efficient.

As far as the single ethic versus multiple ethics, I think it partially does draw into the discussion back and forth between Charles and Michael. The fact of the matter is I am sympathetic to your view. I don't think there is going to be disagreement on some of these very, very tough issues.

I think one of the things we don't have in the current system is an established, systematic way for addressing these issues and discussing them. So you raise the issue of paying kids for participating in research. You get a lot of gut reactions, and I can tell you what the gut reactions are. Absolutely no, it's wrong.

But you don't have a lot of reasoned thought about it and reasoned argument. Is it wrong because you're exploiting the kid? Is it wrong because it symbolically suggests that kids are to be used? Is it perverting their incentive structures, et cetera, et cetera?

It seems to me that part of what we do need in the system are much deeper ways of thinking and developing those arguments and considerations, laying them out, and seeing how we think about it.

One of my other hopes, which I actually didn't emphasize, is, you know, some of this actually is not just theoretical arguments. It actually might depend upon data; you know, what does the practice lead to? Are people more callous?

I mean, I heard earlier when someone asked the question, well, you know, in the current research, if people don't identify, do we get a lot more poor and ignorant on research? Well, it might be good to know the answer to that question.

We don't even know the answer to the question that the Council was debating in the morning: Do people identify with the research studies they're on or not? We assume somehow that they don't. Well, there's at least some evidence that they do, but it's not great evidence.

Anyway, I think a large part of -- I mean, there are multiple considerations. In a pluralistic society we are going to have debates, but on some things I think we might actually come to some good consensus, and on other things at least we could come to some greater clarity about what is at stake. Again, I guess Charles' fear is different places might do different things. To some extent, that might be good, and we might see the consequences of that.

DR. GAZZANIGA: You wouldn't be opposed to this being run by the private sector then, from your lionizing of the Western --

DR. EMANUEL: Well, let me step back. I do think Western is a great model actually, and I ought to say here that I started out being a skeptic, went out there, and its president now is a colleague and a friend of mine. I think she has a great thing going, and partially because she has been quite dedicated single-mindedly to it.

I'm not sure turning it over to the private sector is necessarily the way to go. I do think the private sector ought to contribute, since pharmaceutical and biotech companies do a lot of research, but so does the federal government. Like everything else, it is likely to be a public-private partnership because it's got virtues on both sides.

CHAIRMAN KASS: Janet, please.

DR. ROWLEY: I just wanted to say that at the University of Chicago we've gone from having a single IRB with 15 members to three IRBs. They do meet monthly, but now we have 45 of our faculty plus lay members involved in this. I just wanted to add that because you mentioned that one or two or three, or some such, as a number of IRB individuals involved at some institutions. Rebecca was saying, I guess, at WashU they've got four IRBs going simultaneously to meet the increased demands.

DR. EMANUEL: Let me just clarify what I was commenting on. It wasn't just two or three people on the IRB. Yes, most IRB panels are good size. Especially at major research institutions, 15 is not an unusual number. It's the back room that I'm talking about, the people who are actually monitoring, say, the regulations and trying to understand how they apply or monitoring the literature to try to understand how new thinking might apply to research, or actually getting the protocol together and overseeing and collecting data like adverse events. Those tend to be starved areas, areas that don't get a lot of resources and I think actually are quite important for protection, for actually thinking through the system.

Because, let's face it, most IRB members have lots of other jobs; this isn't their primary function. They're not bioethicists. When an issue of, you know, this protocol says they're going to pay children $1400, you know, they're going to make a gut reaction without having thought it through for very good reasons. No one at the IRB or in the institution, might I say, and dare I might say even in most of the country, has really thought it through.

DR. ROWLEY: And I just follow up on that in terms of the back room, which I have no way of knowing right now how many we have. But these are costs that are actually borne either by the medical school or the hospital, which you alluded to, and you're saying, well, you get a certain amount of indirect costs and so some portion of your indirect cost is allocated to trying to compensate for this. But as these costs increase dramatically, it does make it extremely difficult to do this with the funds available.

DR. EMANUEL: Right. I agree with you 100 percent. The current system isn't made to support it.

DR. KASS: I have Rebecca Dresser, then Gil, Bill May, and Paul.

PROF. DRESSER: I think on this issue of how much diversity among regions or localities we would want, it would get stickier the higher up we go with sort of broad policy issues and value judgments, such as if one region says, "Well, xenografts the risk is worth the percent of benefit," but another one doesn't. I think that could be problematic. Or say, getting to this afternoon, one region says, "Well, any more new drugs on sort of cosmetic psychopharmacology, those aren't justified," you know, that could create some difficulties. But that was just a sidebar.

One thing I would add, which you talk about publishing policies, and so forth, I think we also need kind of a common law system. We need IRBs who wrestle with difficult cases to then publish them, and I think that would be excellent. Because there really are a lot of these conflicts that can't simply be resolved at the legislative level. I think IRBs need to see how different ones handle these things.

I guess the final comment I would have is, I really agree that the way the human subjects' protection system has been applied has left out a lot of the more crucial values conflicts, which I think underlie a lot of things. Belmont actually gets to a fair number of them, but then they sort of were left aside.

For example, I think so many judgments, say on the value of studies, the regulations say the risks have to be reasonable in relation to the benefit in terms of the knowledge that will be advanced and any direct benefit, if there is one. That is such a value judgment.

When we talk about reasonableness, in law we are talking about the jury system, you know. They also refer in there about, when you're talking about how well-informed should people be in making a decision to be in a study, well, we could talk about the standard of the reasonable subject. These reasonableness judgments are throughout.

You talk about 25 percent lay people on your Regional Boards. I don't think that fully gets to this problem of, how do we inject the democratic element and input from people who are not part of the scientific enterprise or the academic enterprise?

Robert Veatch wrote a really good article back in the seventies alluding to some of these things. He said, basically, everyone in universities is convinced that advancing knowledge is valuable. As somebody who works at a university, I certainly buy into that.

However, not everyone in this country takes that point of view. If we are talking about a democratic process, we ought to have that point of view.

So I think it is not just a matter of what percent of public representatives, lay people, you have on; it is also a matter of: How do those people get educated? How do we get people on there who are not intimidated and who don't learn everything from the people who are part of the establishment, which I think is often the case now, and really can represent an independent point of view?

I actually think there are good patient advocates out there who are knowledgeable enough, who are skeptical in ways that I think are healthy, who might be able to help out here. But I think that is something that is not so much addressed in your proposal.

DR. EMANUEL: Let me first go to the point about case law, which I think is absolutely a great point: that if you are making lots of ethical choices, and there are hundreds to be made in this process, you need some way of sort of recording them, being consistent, having some institutional memory. That is impossible, it seems to me, with 4,000 to 6,000 IRBs running around the country, all basically on a starvation financial diet.

It becomes much more reasonable when you have 20 or something and you have a coordination system. Coordinating 20 is a lot different than coordinating 4,000 or 6,000. Part of that coordination is sharing things like policies and practices and decisions.

Second, I'm not sure -- and I would love to have your ideas on it, and everyone else on the Council -- I agree with you it's very important to have people who have some independent thinking and can think who aren't necessarily wedded to the research enterprise or don't get their daily bread from it, but are thoughtful about it. Other than specifying numbers, it is hard for me to figure out what you do to engender that democratic process.

Now we have tried, one, to increase the numbers so they are not isolated and they are not intimidated necessarily. Another element that we have tried to include is to try to think through how an Ethics Policy Committee might actually involve the public and create focus for discussion.

I think my at least peripheral or cursory look at the way Britain handled much about the cloning and stem cell issue is, you know, there over the course of about 15 years they had a report. They had a lot of public discussion about the report. They had a second commission looking at things.

First of all, it was an expanded period of time, but also there was a focus for discussion. I mean, if we just talk about some of these ideas without a focus and without someone presenting a paper, I mean, it seems to me one of the -- I don't want to speak for Dr. Kass, but one of the reason to have a paper at the start of a discussion is to provide a focus for thoughts on the matter at hand, but we don't have that system currently.

We have commissions coming and going, reports sort of collecting dust because they haven't really -- there's no ongoing continuity. There's no actual implementation to test out the ideas, see what the problems are, revision process.

So while I am sympathetic to your concern about having a more open process and having people who thoughtfully engage, it seems to me very hard to figure out, other than the sort of structural and procedural elements, how you actually guarantee that.

CHAIRMAN KASS: Gil?

PROF. MEILAENDER: Just a question for a little more information about -- and I suddenly find myself blanking on the name. Did you call them proprietary IRBs?

DR. EMANUEL: Yes.

PROF. MEILAENDER: You said we have several illustrated examples of these that are really very good, although you only mentioned one. But what makes them good? The only thing I've gotten so far is it sounds like a resources issue; namely, that they hire a bunch of people who do the kind of legwork that is required. But is there something more than that? That is one thing I want to know.

Then kind of where do their ethical principles come from? Do they just tell you how to apply the Common Rule? I mean, are they doing independent ethical thinking? So tell me a little bit more about what makes you think they are so good, and especially ways that extend simply beyond resources, although maybe that is the answer; I don't know.

DR. EMANUEL: Like almost everything else, I think there's a lot of reasons that make Western and a few of the others very good. One is certainly leadership and dedication to doing the right thing, and believing that by doing the right thing, you'll be successful, and in their case profitable.

I do happen to know the, I guess, presidents -- I don't know exactly what their titles are -- of several of them. They really are dedicated to doing the right thing, and they actually created their proprietary ones because many of them started out in institutions and found that there were limits.

Now some of it is resources. If I did have a criticism of these places, I think one of the criticisms is that they don't do enough sort of independent ethics thinking.

At Western, which is by far the big gorilla in this area -- I mean they are the dominant player -- they have, I think, four to six people dedicated to their regulatory office, which isn't just looking at regulations, but does scan the literature, read articles, try to understand the impact of articles for the protocols they are reviewing.

For one thing, that I think is admirable. It is certainly more than the several IRBs I have been on do. But I think it is inadequate. I have sort of chided the president there about they have a wealth of information and knowledge and experience, and maybe they ought to be developing their own ethical guidance. I mean, they do have many standard operating procedures which embody some ethical values on these complicated issues.

But I think that the final thing I would say is they actually may have an advantage in being institution-independent. This might sound a little heretical. They don't have to kowtow to any one place. As long as most of their money doesn't come from one pharmaceutical company or one organization or something, they can think independently of how things go.

Actually, an institution-based, you know, part of what they think about is, how is this going to affect the institution? You know, if I keep turning down those studies from Merck, they're not coming back to us. If we keep turning down the research of one of our investigators, it is hard for him to get NIH grants or her to get career advancement. There are those considerations. It seems to me you don't have any of that in an independent IRB.

So there may be some structural things. There are certainly some leadership things. There are certainly resource things. But are they perfect? No. Do they provide a model for some of what I have suggested? I think so.

But I do agree with you; I think if you are going to investigate big ethical questions that have large social ramifications, many of these places are hesitant under the current system because they don't think they have the imprimatur to do it. Certainly our regulations don't encourage it. If anything, they discourage it.

I quote in the paper some of the language that says, you know, limit very carefully what you're allowed to consider, which I don't think is quite proper and certainly it limits how you can really ethically evaluate the protocols.

CHAIRMAN KASS: Bill and then Paul, and we're coming up to a break.

DR. MAY: It sounds like a budgetary question. You have mentioned $200 million to mount this Regional Board system. But I am interested in what kind of people you would be calling on here. You said they would meet every week, and if it is regional, it doesn't mean you slide into another office in the hospital; you may have to go out of town, come back into town.

DR. EMANUEL: Uh-hum.

DR. MAY: Institutional Review Boards I have been a part of were largely pro bono. Now you are talking about an amount of time invested. Are you really thinking about a shift from pro bono work over to paid staff and some kind of mix of ethicists and people out of institutions? The regional problem is it is more convenient to get people still in the city, where your regional office is located.

But I think the basic problem here is not whether we go with, one were to go with, for-profit institutions, but the whole shift over from volunteer to paid staff seems to me to be a fundamental issue. There are two ways of conceiving it.

One is a staff that has preset standards and then efficiently applies these standards. We know about that even in academic institutions, which have committees, which are largely janitorial and custodial.

(Laughter.)

I mean they apply what is already preset, and even curriculum committees in universities like this, they process that material.

The other way of looking at a Regional Ethics Board is to think of a deliberative body. That is a very different kind of activity. I am wondering how you build that in, especially since it seems to me you are moving in the direction of a paid staff of specialists as you move toward a regional solution to his problem.

DR. EMANUEL: Let me take the first part.

DR. MAY: May I add just one point? The local problem is conflict of interest. What you may end up with is flagging of interest. That is another kind of problem that leads to inadvertent inattention to issues until you get a public crisis that comes along, and then people get very excited about it. That flagging of interest seems to me to be another dimension or problem that one has to think about.

DR. EMANUEL: You are describing Washington, I take it.

(Laughter.)

DR. MAY: Well, I am thinking of some corporations as well, their boards of directors.

DR. EMANUEL: Let's take the first problem. It certainly seems to me that we are going to have to have more professional staff, but I would not want the Review Committees to be professionalized and bureaucratized. I think that would be a disaster.

DR. MAY: So they would be a staff serving the Board?

DR. EMANUEL: Yes. I think, again, in most academic institutions I have been a part of, they undervalue that, minimize its importance in proper and efficient functioning.

Nonetheless, I think if these Boards do meet weekly, the question is, could you maintain a voluntary or at least nominally-paid group? Again, institutions now are having to go to pay their faculty to serve on these things because they are a big-time commitment. So it is not even voluntary there.

Second of all, if you do look at the Western model, which I have suggested here might be very instructive, they actually get people for $150 a day. They meet four hours for the day, separate from reading the protocols, which is at least another four to eight hours. They re-evaluate these people each year. They are not making money, these people, by participating in this.

They have a number of physicians who want to do this to stay intellectually active. They have a number of scientists who want to do this. They have a number of just interested people in the community.

We haven't experimented or seen how big an interest there might be in doing this, and we assume that the options are voluntary or a full-paid staff. I think that this is a very rich country, and volunteerism, even for nominal pay, is something that people do, and for adults who want to stay intellectually active this may be very interesting.

I think, again, I don't like the model -- we are trying to create a hybrid model. There's clearly some things these groups are going to have to do efficiently.

I have estimated that there's something like 40,000 research protocols per year in this country. It seems you can't grind the system to a halt; we're going to think deeply about every single thing. Some of it has to just be applying rules.

On the other hand, we do need a system where we do confront serious issues or we confront issues repeatedly that raise deep ethical questions. We need a system for figuring out how to reason about those. That is why we suggested sort of differentiating those kind of functions into different kinds of committees but having them under one rubric, so that there is a lot of cross-talk. That is our view of how it would go.

I am under no illusion that any single Regional Ethics Board with a regional sort of Ethics Policy Committee could address all the issues that come up. I mean, there are just an unbelievable number of serious issues and new issues or issues again coming to the fore or we are being alerted to all the time.

But it does seem to me it needs to be systematic and ongoing rather than sort of what we have had for the last 25 years: start-stop; cancel that commission; put its findings on hold; get another one. They are going to take up a different set of issues. No continuity, no way of implementing in policy/practice any of the decisions.

CHAIRMAN KASS: Paul McHugh?

DR. MCHUGH: I was very interested in what you said and the series of problems that you think your proposal will address. But what I haven't heard is how you think some form of institutional review is going to coordinate with the responsibilities of NIH study sections, which are, after all, peer-reviewed and protocol-focused.

You, quite rightly, criticized the Johns Hopkins issue of having overlooked a piece of important results and research prior to the submission to the IRB, but I also want to point out, as you should, that the peer review study section also had passed that and the like.

If the issue that these organizations need is a better back room where they can study the literature and back it up, well, isn't that what the NIH study sections are supposed to do with their peer review, protocol focus groups?

DR. EMANUEL: Well, I can safely say that I have never received an NIH grant, and that entire process is a complete labyrinth, of which I don't understand anything.

(Laughter.)

DR. MCHUGH: It is a terrific group. Having been a chairman of one of the study sections, I am very proud of it. I think it is a great achievement for the United States.

(Laughter.)

DR. EMANUEL: I wasn't criticizing it. It is just I don't understand it. It is a little different. And I don't understand --

DR. MCHUGH: Well, you should. You should understand it.

(Laughter.)

DR. EMANUEL: -- how exactly it should interface with this. I think that is probably another whole area where the current system is just as opaque as our suggestion and probably needs a little more thinking. But there is re-review of science there, and that is obviously a very important element of good research, but it is far from the only element.

DR. FOSTER: Just one quick question: We have talked about the changing culture. I also chaired a study section, sat on the Council, and so forth, but that culture has drastically changed. So that now study sections do not look just at the science. They look at the priorities. It is a very different system. I don't know of a better system, but it is drastically different from your glory days than what it is now.

So even the time for the number of protocols is greatly enlarged. You are worrying about budgets. You are doing all those things. So that would take back-room people there, too.

CHAIRMAN KASS: Well, I want to thank you, Zeke, for a very stimulating talk. I would hope that we might down the road call on your help as we continue to talk about this regulatory question, and in particular the kinds of questions, not just the mechanical things which were the subject of very interesting discussion, but also the large issue, for example, that Michael Sandel and I tried to raise with you at the beginning: To what extent this can be, for this Council, a source of practical hope for the kinds of questions that we have been addressing?

Perhaps as this paper evolves, if you might see fit to try to address that, or maybe we can have you down to the office for further conversation, it would be very welcome.

But thank you very much.

We are adjourned until -- what is it? -- until 1:45, when we will meet to have some discussion of happiness and sadness and pharmacology -- if that's not the wrong way to characterize that.

(Whereupon, the foregoing matter went off the record for lunch at 12:20 p.m. and went back on the record at 1:50 p.m.)