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Mr. SHAYS. Thank you very much. And I guess we are going next to Dr. Wilfond.

Dr. WILFOND. I thank you, Mr. Chairman.

Mr. SHAYS. I didn't say your name well, so when you heard me say it, you wondered who the heck is he talking about. Is it Wilfond?

Dr. WILFOND. Wilfond.

Mr. SHAYS. Thank you, Dr. Wilfond.

Dr. WILFOND. I'd like to thank you for inviting me to participate in this meeting. Currently, I'm an assistant professor of pediatrics in the sections of pediatric pulmonology and medical and molecular genetics at the University of Arizona in Tucson. As a pulmonologist I care for children with cystic fibrosis and asthma as well as other lung disorders. I also teach bioethics, and I'm a member of the American Academy of Pediatrics Bioethics Committee. I've been a member of IRBS for the last 9 years, and I have a particular interest in research issues related to children.

Informed consent has been a central tenet of research ethics since the Nuremberg trials 50 years ago. In fact, as a legacy of the trials, in the 1970's there was great debate whether children ever should be able to participate in research, since they are unable to give their consent. This debate was considered in the Belmont Report and expressed in the Federal regulations by acknowledging that parents give permission and not consent for their children to participate in research.

This distinction is important, although it's subtle. But it provides a conceptual justification for IRBS having a greater role in terms of the review of projects on children. For those studies that involve greater minimal risk, the IRB is to make a normative judgment about whether or not the risks are balanced by the benefits before the parents are able to give the decision to allow their child to participate. I think this is a very good thing, although there still remains a lot of conceptual vagueness in exactly how this is carried out. There is room for a more conceptual work trying to understand even what counts as minimal or a minor increase over minimal risk as a regulation state or considering this review.

Although the regulations tend to be more careful in how research. is done on children, often the regulations are misinterpreted and are used as a justification for why research in children is not done on a more routine basis. In fact, as a pediatrician, often because of a lack of research, there are many circumstances in which clinical judgments must be made without the availability of sound clinical data. Additionally, many drugs that are used on children are off label.

In fact, taking care of patients with asthma, there are very few drugs that have been approved by the FDA for the use in children. I don't think, though, this problem is really because of the regulatory mechanisms for research. I actually think that it's more related to the lack of incentives for conducting research on children. Once a new drug is approved, pharmaceutical companies have few incentives to conduct studies in children. And so that there need to be requirements to conduct studies in children concomitantly with those of adults. Because it's better to expose children to the risks of research than to the risks of unscientific practices.

What I'd like to do is talk about what I see as some of the problems with IRBs. What I'd like to do is mention five problems I see, but only will talk in detail about one of them. As was alluded to earlier, there needs to be a better mechanism for the oversight and monitoring of multicenter trials. This is a real challenge for IRBs when they review a study that's being done at 10 different places. And if one IRB has problems there's no opportunity for us to correct those problems at all centers. All we can do is choose whether or not we want to accept or reject the proposal.

As was mentioned before, some research that's done in the private sector does not fall under FDA or NIH purview. And so there can be some research that could be done without the involvement of either oversight institution or organization. But I think more importantly and related to that, there needs to be a single mechanism for oversight of IRBS that includes not only the FDA and NIH but for all research. But what I'd like to do is to talk with you about one particular problem.

Mr. SHAYS. I just missed your point. And it's a very important point.

or

Dr. WILFOND. OK.

Mr. SHAYS. You said there may not be review by either FDA

Dr. WILFOND. If-OK. Certainly any study that involves the use of drugs or investigational devices will come under FDA. Any study that is done with NIH funding will come under the review of NIH. Any study that is done at an institution that has a multiple project assurance from either of those organizations will come under their review. But if

Mr. SHAYS. Come under their review?

Dr. WILFOND. Come under the review of a local IRB.

Mr. SHAYS. Of a local IRB?

Dr. WILFOND. Right.

Mr. SHAYS. But you're basically telling me that the FDA-the question I had put to FDA was: Who oversees the private sector? And you're suggesting that there's some private sector that they don't oversee.

Dr. WILFOND. If there's research that's being conducted that does not involve an investigational drug or investigational device or even one that's been approved for other purposes, then-for example, nutritional modifications or behavioral issues, that it's being done by somebody

Mr. SHAYS. Let me just clarify something. I'm making a leap here. My mind is thinking this way.

Dr. WILFOND. Sure.

Mr. SHAYS. If something is not going to the marketplace, are you suggesting that the FDA wouldn't be involved?

Dr. WILFOND. That is correct.

Mr. SHAYS. There are a lot of circumstances where something isn't coming to the marketplace. That isn't being funded. Well, who the heck

Mr. KUCINICH. Nobody.

Ms. FLYNN. No one.

Mr. CAPLAN. No one.

Dr. WILFOND. But actually, even when it does come under FDAactually what I'd like to do is talk to you about a particular problem in more detail.

Mr. SHAYS. Do you all have any other little secrets you want to tell me about?

Dr. WILFOND. Well, actually, the next one is the one I want to tell you about in more detail

Mr. SHAYS. OK.

Dr. WILFOND [continuing]. Which has to do with researchers who are in private practice where they have greater incentives for recruiting patients-and this is a case where the IRB mechanism is very different, and essentially are for-profit IRBs. Let me try to explain what I mean by that. Recently at the University of Arizona, we reviewed a study for a new anti-inflammatory treatment for childhood asthma.

Mr. SHAYS. Don't feel you have to read so quickly. You can slow down a bit.

Dr. WILFOND. OK.

Mr. SHAYS. OK.

Dr. WILFOND. We reviewed the study for a new treatment for asthma. The study involved putting patients either on this new anti-inflammatory treatment or a placebo. The problem is that there already are currently available good treatments-anti-inflammatory treatments for asthma. When our IRB looked at this proposal we said this is unethical to do because it denies half of the patients a known effective therapy.

Even with the permission or consent of the parents we felt that this was unfair and unsafe to expose children to this risk. So this was a multicenter trial. All we could do is say, you can't do it here. Two miles down the road there is a physician in private practice who also was doing the same study. What he did was, he had it reviewed by an IRB in another State, and he paid the IRB to review the study and they approved it.

And so I think there are two problems here. One is the obvious problem of the investigator specifically paying an IRB to review their protocol. But more importantly, this review occurred in another State. And I think it completely subverts the whole notion of an institutional review board. In other words, this person was not from the community. And I think that becomes really a challenging thing. I'm not sure I would agree with this. The way IRBs really work is not only looking at the consent forms but trying to be careful that we understand that the investigators, when they present the information, hopefully will do it in a non-coercive way.

Because we don't really have a good way of monitoring exactly how well they do that. The best we can do is to know about the integrity of the investigators. And I want to give you an example of how this happened with this particular study. When it was submitted to the University of Arizona the patients were going to be paid $250 to participate in the study. Our policy is that if payment is going to be made for children two things must happen. First, it cannot be advertised in newspapers in terms of a dollar amount. Our concern is that parents will see a dollar amount. That may be an incentive for them if they're a little short of cash that month

to have their children enroll in studies. So we exclude dollar amounts.

Second, although money may be paid, it's usually paid in the form of a savings bond that is made out in the name of the child. The physicians in private practice usually will have advertisements with dollar amounts. But often the dollar amounts are much higher than we would have otherwise approved. So for example this one study that we looked at, the dollar amount at the university setting was $250, but at the private sector it was $750 that the parents would be paid. And this is being advertised in local newspapers. I see this as being a very big problem.

You know, in the community setting there is greater financial benefit to the investigator to recruit patients. They have increased promotional activities. The studies themselves may be more risky and they're getting less review. And I think this is really one of the biggest issues I think that needs to be addressed. Because I think more and more research will be happening outside of academic institutions. My recommendation would be that whenever feasible all research be reviewed within the same community and that the same IRB have a jurisdiction over all the particular investigator's protocols. One of the problems that the investigator can mail his protocol to different IRBS. So if he gets turned down at one place he can go somewhere else. And I think there needs to be some way of having some control over that.

Mr. SHAYS. Elaborate a little bit on that.

Dr. WILFOND. OK. For example, if a person is in private practice, and he sends it to IRB A and IRB A turns it down, he could send it to IRB B and have them approve it. There's not one designated IRB-whereas in the university setting, at the University of Arizona, if we don't approve a protocol, that investigator essentially can't do that study.

Mr. SHAYS. If you're not part of the university and you're in the same town as the university, tell me where you would go?

Dr. WILFOND. Wherever you want. Whoever gives you the lowest price. There are IRBs around the country that are essentially commercial IRBs that are set up, where they will receive protocols from investigators who mail in a check and mail in the protocol and they will review it.

Mr. SHAYS. I wish this panel had gone first.

Mr. CAPLAN. It's called IRB shopping, by the way.

Ms. FLYNN. Yes. IRB shopping.

Mr. SHAYS. OK. Keep going.

Dr. WILFOND. That's really the main thing I wanted to say. I think this is the biggest issue. I agree with Art about the issue of monitoring in the future. But I think this is really a problem that needs careful evaluation. I think at this point I'll stop and let the other people go.

[The prepared statement of Dr. Wilfond follows:]

Pediatric Pulmonary Section Respiratory Sciences Center ege of Medicine

THE UNIVERSITY OF

ARIZONA.

HEALTH SCIENCES CENTER

1501 N. Campbell Ave.

PO Box 245073

Tucson, Arizona 85724-5073

(520) 626-7780 / 6754

FAX (520) 626-6970

Benjamin Wilfond MD
University of Arizona
May 8, 1997

I would like to thank the subcommittee for inviting me to participate in these hearings about the adequacy of informed consent for biomedical research. I have been asked to make comments about research on children. I am an Assistant Professor of Pediatrics in the sections of Pediatric Pulmonary and Medical and Molecular Genetics at the University of Arizona in Tucson. I am a member of the Committee of Bioethics of the American Academy of Pediatrics. I teach bioethics, including research issues, to medical students and graduate students. As a pediatric pulmonologist, I care for children with lung disorders, including asthma, cystic fibrosis, and chronic lung disease of prematurity. My main research interests are the ethical and policy implications of new genetic technologies. I have a particular interest in the issues of research in children. I have been a member of Institutional Review Boards (IRB) for nine years.

Informed consent has been a central tenant of research ethics from the time of the Nuremberg trials fifty years ago. However, consent is neither necessary nor sufficient to make research ethical. Had the Nazis obtained consent, it would not have altered our judgment about their medical experiments. As a legacy of Nuremberg, there was great debate in the early seventies as to whether it was morally justified ever to conduct research on children since they cannot give consent. This debate was considered in the Belmont Report and expressed in the federal regulations by acknowledging that parents give permission, not consent, for children's participation in research. This distinction, while subtle, is important, because it provides the conceptual justification for a greater role of the IRB in assessing the balance of benefits and risks to which children can be exposed. While the intent of the regulations is to place greater restrictions on research on children, the regulations are often misinterpreted to suggest that research that otherwise might be valuable cannot be done. In fact, as a pediatrician, there are many circumstances where clinical judgments must be made without the benefit of sound empirical data. Additionally, many drugs that are used in children are off-label. This problem is not necessarily the result of regulatory restrictions but often, as a result of decisions to not expend the resources to conduct studies in children. Once a new drug is approved, pharmaceutical companies have few incentives to conduct other studies in children. There

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