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RAY SUAREZ: In a move that shocked officials at Johns Hopkins University yesterday, the U.S. Department of Health and Human Services suspended all federally funded medical research at the university involving human subjects. The decision means that Johns Hopkins’ Medical School, Bayview Medical Center, and other university institutions will temporarily lose $300 million worth of federal funding for clinical trials. The suspension covers 2,400 human experiments involving 15,000 patients and volunteers.
The decision was prompted by the recent death of Ellen Roche, a 24-year-old volunteer enrolled in an asthma study. Roche, a lab technician, died on June 2, one month after inhaling an unapproved drug as part of a study into the causes of asthma.
Earlier this week, Hopkins officials concluded their own investigation, saying the university’s researcher had not adequately checked for problems with the compound, called hexamethonium. Hopkins also found that the researcher had not warned Roche properly about the chemical’s risks.
But in a hand-delivered letter to Hopkins yesterday, the federal Office for Human Research Protections had numerous criticisms. After inspecting Hopkins, the government found that the investigators failed to obtain published literature about the known association between hexamethonium and lung toxicity. Such data was readily available via routine Internet searches. Prior to its approval of the research, the institutional review board did not receive or request from investigators information regarding the drug’s safety, and said the informed consent document failed to adequately describe the research procedures to be followed. Moreover, the report found a pattern of safety lapses in other human trials at Hopkins, which receives more federal funding for human research than any university in the country. Those problems included internal review boards, called IRBs, that did not always examine research at properly convened meetings, multiple cases of discrepancies between the risks outlined in informed consent documents, and the actual trial protocols; and the government found that the basic consent form was often difficult for patients to understand. Last night, Hopkins responded with anger.
DR. EDWARD MILLER: We find it difficult to understand why a relatively new agency would take these draconian measures in an institution that has cared for thousands of people in clinical trials. We have done clinical trials for over a hundred years here at Hopkins. We have had one death in all of these years in a human, healthy volunteer. For OHRP to take this measure and not understand the consequences on patients that are treated here cannot be understood by me at all.
RAY SUAREZ: Hopkins is not the first university to be punished for safety lapses. In recent years, several other universities, including the University of Pennsylvania and Georgetown University, have been sanctioned by the government, and because of broader concerns, the National Bioethics Advisory Commission recently recommended an overhaul of safeguards to protect human research.
RAY SUAREZ: For more, we turn to Dr. Edward Miller, dean and CEO of Johns Hopkins Medicine at Johns Hopkins University, and Ernest Prentice, associate vice chancellor for academic affairs and regulatory compliance at the University of Nebraska Medical Center.
Dr. Miller, now that the H.H.S. investigation is complete and their report has been issued, and you’ve also issued your own findings, what happened?
DR. EDWARD MILLER: Well, OHRP issued their findings on Thursday at noon, and essentially there was no process in place to address the issues. I contacted the Secretary of Health, Education, and Welfare, Tommy Thompson. He responded to me this morning. We now have a process in place where OHRP and Hopkins are working diligently tonight, as a matter of fact, to have a corrective action plan that will allow full accreditation of Hopkins’ research very shortly.
RAY SUAREZ: Well, given what the government body had to say about your institution’s work in this research project, and what your own internal investigations have turned up, what can you tell us about how Ellen Roche died?
DR. EDWARD MILLER: Well, we’re not quite sure of the cause and effect of Ellen’s death, to be quite truthful. Number one, the investigation has not been completed. We still do not have all the studies. While it was causally related, time wise, we don’t truly understand the mechanism of her death. We did everything to save this young woman’s life, and she was part of a human volunteer study. We will have an external review group that will commence its work on Sunday night of this week, and they will finalize their report within the next couple of weeks and get back to us on that.
RAY SUAREZ: Vice Chancellor Prentice, you’ve seen some of the documents involved in this case, and you’ve overseen research projects yourself. Was this an appropriate action on the part of the Department of Health and Human Services?
ERNEST PRENTICE: Well, I also serve as a compliance consultant to OHRP, and I’ve been on ten for-cause compliant site visits, 20 percent of which have resulted in shutdowns. So the action taken by OHRP is consistent with the kinds of actions they have taken in the past at institutions where they felt that there were deficiencies in their program for protection of human subjects.
RAY SUAREZ: But when you find a flaw like this in one particular research project, why not just shut that one down? Why close down the entire range of work that an institution is doing?
ERNEST PRENTICE: Well when OHRP investigates an allegation of noncompliance, they also evaluate the entire program for protection of human subjects. More or less the allegation of noncompliance kind of opens the door for a much wider, systemic evaluation of an institution’s program, and that is what OHRP did at Johns Hopkins, as they have done at other institutions. So Johns Hopkins’ program was shut down not necessarily because of the unfortunate death, but because of the deficiencies identified by OHRP in that program.
RAY SUAREZ: Dr. Miller, let’s look at the particular case of this asthma research. A compound was introduced to several test subjects’ bodies, not to test that compound necessarily, if I understand this right, but to cause a reaction which would help you understand the way the body works better. Was there a problem with using this particular substance?
DR. EDWARD MILLER: Well, this substance had been used in the past, in the 1950s, to treat patients with severe hypertension, given both orally and intravenously. The substance itself had been given to 20 volunteer subjects at four different institutions to look at lung studies, and there’s a vast literature, in Russia, for example, using this drug to control hypertension. So this was not a substance that was totally unknown. It was taken off the market in 1972 by the FDA, and it was taken off the market not because of complications, but because that there were new and better agents that could lower blood pressure.
RAY SUAREZ: But hexamethonium was not approved by the FDA for the use that you were using it for at Johns Hopkins. By calling it a medication in the consent form, did you perhaps create an impression in your volunteers about what was about to happen to them that you may do differently today?
DR. EDWARD MILLER: Well, I’m not quite sure what Ellen thought when the word “medication” was used. Certainly it had been a medication in the past, and because of regulatory issues, it was no longer a medication and was a chemical, but this whole area of medications that become chemicals and what substances do and do not need institution… Or new drug approvals is really a very muddy area and one that we and other institutions have sought to find some clarity about.
RAY SUAREZ: Well, Vice Chancellor Prentice, maybe you can help us out a little bit there. When you’re using something in what’s called a challenge study– that is, introducing a substance to get a reaction– is there a different kind of protocol, a different kind of set of rules from when you are using something that is in itself being explored as a treatment or a therapy?
ERNEST PRENTICE: Well, in terms of the application of the regulations, there really is no difference. We would characterize the protocol that Ellen was enrolled in as a non-therapeutic research protocol, meaning that there is no direct benefit to the individual subject.
RAY SUAREZ: And when someone is involved in a test of that kind, when they are subjecting themselves to something from which they are likely to derive no benefit, is there a different set of rules that play there from, let’s say, sick people who are trying experimental procedures in the hopes of getting well?
ERNEST PRENTICE: Well, the rules are really not different. The IRB must determine that there is an acceptable risk- benefit relationship of the research, and basically it means that the societal benefit, in terms of an advancement of knowledge, must at least outweigh or balance the risk associated with the research. On the other hand, in therapeutic research or clinical research there’s often benefit to the patient that can help balance out the risks.
RAY SUAREZ: And from what you know about this case, do you think the risk-benefit ratio was in proper relationship?
ERNEST PRENTICE: That’s difficult for me to say. I have read a fair amount of material on the case, but I have not read the protocol. Certainly there was an allegation of an inadequate assessment of risk on the part of the investigator and the IRB. That’s obviously a problem.
RAY SUAREZ: When you use volunteers, Dr. Miller, is there really any way that you can fully inform them of every possibility, every downside that might occur in a clinical trial? Can we reduce risk to zero?
DR. EDWARD MILLER: Well, I think everybody’s goal would be to try to reduce it to zero, but human variability will probably not allow us to do that. As an anesthesiologist, for example, I give drugs to people. I’m not quite sure what their reaction is going to be, because everybody is a little bit different. I try to minimize the risk, but I cannot be 100 percent sure that I have minimized it to zero. The important thing in this case, I think, is that ten million people in this country have asthma; it is a condition that is getting worse all the time; and, importantly, hundreds of people in this country die from asthma every year.
RAY SUAREZ: So if you’re looking at perhaps a pause in this work rather than a complete cessation, might it provide the necessary breather to get things in order that you need to get in order at Johns Hopkins? I mean, is there some work that you can do during this suspension that might work to the benefit of future patients?
DR. EDWARD MILLER: Well, as I said, we are probably more concerned about the welfare of patients than anyone. We’re the ones who care for those patients on a daily basis, and patients come to us for it. We will comply fully with the OHRP to try to make sure any of the issues that they have with us are resolved as quickly as possible. I will point out, however, that on October 3, the OHRP sent us a letter addressing some of their concerns. We set up a second IRB group to review protocols, we did a variety of things, and we responded in writing to them on December 28, and we assumed from our December 28 letter that we were fully compliant. It was a little bit surprising that in seven months we have not heard from them that they did not feel that we were doing an adequate job in protection of human subjects.
RAY SUAREZ: Those IRBs, or institutional review boards, are made up of people who work at Hopkins?
DR. EDWARD MILLER: They are made up of some people that work at Hopkins, but also there’s lay public involved.
RAY SUAREZ: Do you think that they are uniformly able, in the various institutions that they’re working in across the country, to do the work that they are charged to do or might the IRB system need a look?
DR. EDWARD MILLER: Well, I think we all would agree that the IRB systems could be looked at across the country at all places that are doing clinical research, and I think probably the best thing that can come out of this would be for academic health care centers, partnering with the FDA and with OHRP, to develop more clear-cut guidelines about how and where we need to go to improve the safety for patients.
RAY SUAREZ: And Vice Chancellor Prentice, on that same subject, is this a Hopkins’ problem or a problem that we see with the system with research oversight?
ERNEST PRENTICE: No, it’s not a Hopkins’ problem; it’s a universal problem. We know from a number of different studies that IRBs have been chronically overloaded and under resourced. So there is a problem out there. I think it’s gradually being corrected, but it’s going to take some time. There are currently plans to have an IRB accreditation system in place. However, we’re talking about thousands of IRBs potentially being accredited, so it’s going to take some time to develop the infrastructure to accomplish that goal.
RAY SUAREZ: And in the meantime, does work, the kind of work that was being done on asthma at Johns Hopkins, does that have to slow down or stop? Can we do this while the car is rolling, sort of repair it on its way?
ERNEST PRENTICE: Well, I think that what Johns Hopkins has to do is they have to negotiate with OHRP in terms of corrective actions on their part. There were a number of deficiencies identified in the IRB or in the OHRP determination letter, and it’s up to Hopkins to come up with a corrective plan that would be acceptable to OHRP, and I would be hopeful that they could get their research program up and running. I mean, clearly they are a world-renowned institution, and it’s very important to them and to all of the patients they serve to be able to get their research program up and running, conducted under the jurisdiction of a state-of-the-art program for protection of human subjects.
RAY SUAREZ: And Dr. Miller, do you think that you can be back in business quickly?
DR. EDWARD MILLER: Oh, I certainly do, and I think we do have an excellent program. We can always make improvements. We will strive to make those improvements, but again, I think it has to be recognized: We have treated literally thousands of patients under protocols here at Hopkins; we have had one death in one human healthy subject in over a hundred years of study– a pretty good track record, not perfect; I wish it were perfect; but we do take it very seriously, the safety and welfare of patients that come to us.
RAY SUAREZ: Gentlemen, thank you both.
DR. EDWARD MILLER: Thank you very much.
ERNEST PRENTICE: Thank you.