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Harden: Maybe you’ll walk us through the whole clinical trials process using AZT as an example.
Broder: Yes, sure. It was very clear–and I cannot remember the exact time–that AZT was elevating patients’ T-cell counts and having other positive clinical effects. Other drugs and drug combinations also began showing positive effects. A combination of AZT and ddI and a protease is an excellent regimen. And there is a study in the New England Journal that ddI alone, ddI alone actually had as good a mortality rate as AZT or AZT and ddI in certain categories of patients. I think AZT is important both for what it did clinically–there is no question about it–but also for the principle that it established, AZT laid the groundwork for defining surrogate endpoints in other studies, for illustrating that anti-viral agents could work in patients, and for providing a template for moving quickly from a laboratory observation to a proof-of-concept clinical study, and from there to a randomized prospective clinical trial. AZT proved that we could block viral replication in a human being. AZT could block maternal-to-fetal transmission. That is a simple statement, but it was a radical idea in the mid-1980s. AZT proved that you could reverse dementia, particularly in little children, even with cerebral atrophy. I think that AZT changed the tone, and pessimists were becoming less and less rewarded for their pessimism.
Harden: What about the criticism later? I never know whether it was just shortsightedness or frustration when a later study showed that AZT was not the be-all and end-all, and suddenly people were saying, “We should never have gone with this. We should have worked on something that worked.” Would you comment on these tribulations?
Broder: You will find no statement from me or anyone in my laboratory, or probably anyone in the NIH, that AZT was a cure or was anything other than a first step, albeit an important first step. We always chose our words cautiously and specifically. It was simply a starting point. But without AZT, and all of the issues that I discussed earlier, we would have been very hard pressed to make any progress in the therapy of the AIDS virus.
The scientists at Merck and Abbott and Roche and elsewhere were following the AZT story intently. They’ve said so. They were able to argue successfully with their senior management.
Harden: Would you comment on the suggestion by Peter Duesberg and Robert Root Bernstein that AZT is the cause of, not the cure for, AIDS?
Broder: Well, subsequent events have shown that to be completely wrong
Harden: Why do they continue to press their case?
Broder: I do not know. You’d have to ask them. But nobody in the scientific community believes that. And the advent of protease inhibitors, in combination with drugs like AZT, simply provides a further refutation. There are people now routinely getting better, and they are getting better for long periods.
Some people had hoped that AZT would be a cure. No one at NIH ever said that it would be. And, therefore, when it was not a cure, that reality affected people. And then there was the overreaction the other way. There is, to this day, a group of individuals who argue that HIV is not the cause of AIDS. They argue that the NIH has not been telling the truth. The capacity of antiviral drugs to prevent premature deaths and alleviate suffering in patients with AIDS, to block the transmission of the AIDS virus from mother to unborn child, and a host of other scientific observations, can mean only one thing.
Hannaway: That there is a virus. You characterize Burroughs Wellcome’s development of AZT as a successful commercial venture.
Broder: Yes, no question.
Hannaway: And you said that it encouraged other drug companies to deploy resources in this area.
Broder: There is no question, in my view.
Hannaway: However, some have said that Burroughs Wellcome profited, over-profited, let us say, by the price that they put on AZT. I wonder if you would comment on this general issue.
Broder: Well, that is a controversial issue, and I think people of goodwill have to agree to disagree. When I was the director of the NCI, we had a reasonable price clause put into various Collaborative Research and Development Agreements [CRADAs]. That was considered very controversial and was removed by Dr. [Harold] Varmus when he became NIH Director. I do not object to that, and I think that that is perfectly fine and perhaps, in retrospect, is the correct thing. But it is simply an expression of the fact that you cannot please everybody. We thought that if you had a reasonable price clause put in, it might alleviate the public’s concern about these issues, and then the public would feel that its tax dollars were being used more effectively. But another argument, which I have to say I cannot disagree with, is that that such a policy will discourage innovation and collaboration with NIH. And I think people of goodwill have to just accept that as a reasonable point for disagreements, and I am comfortable with the removal of the clause.
Hannaway: And there was a great debate in 1987 with Senate subcommittees and others–the complaints over the costs of AIDS drugs.
Broder: Yes. That is true. And these issue have to be addressed with respect. I am comfortable with the way the NIH is currently solving the issue. That is fine. But what I am saying is that there are other paradigms for using the NIH’s prestige to make sure that the public does not feel that it is paying more than what is fair for drugs that emerge from the NIH programs, and I think that a reasonable price clause is acceptable and is one way of dealing with this. But it is not the current NIH policy, and I am very comfortable with this fact. These are not easy issues.
Harden: In the wake of AZT’s success as the first anti-HIV retroviral, a lawsuit was brought against Burroughs Wellcome by a company that wanted to produce a generic version of AZT on that basis that you and your NCI co-workers should have been named on the AZT patent. Burroughs Wellcome, however, claimed that NCI had no right to the patent. You were deposed even though neither NIH nor NCI were parties to the suit. We have looked at your deposition and wondered how you kept your cool through some very tough questioning by the attorneys.
Broder: I think that the lawsuit was an interesting example of how bureaucracies deal with things. The government was not prepared to defend its position. It did not want to. The Commercial Litigation Branch of the Justice Department seemed very unhappy with the whole litigation and did not put forward, in my view, a spirited defense, or sufficient energy and resources. Now that I am in the private sector, I understand a little bit more about these things.
The adversarial process in a legal setting is predicated on the assumption that you’ll allow parties who are equals to contest one another. The government, for whatever reason, did not choose to act as an equal in the litigation. The interesting thing is that Burroughs Wellcome did not win. That is a misnomer. The Court of Appeals for the Federal Circuit actually upheld one of the counts, or at least, rather, sent it back for further trial. It was just that people did not want to pursue it. If you read the decision, Burroughs Wellcome had declared my laboratory a "pair of hands,” but the Court of Appeals took the unprecedented step of saying,”They definitely were not a pair of hands,” in their decision.
Harden: The lawsuit represents another example, I think, of how AIDS forced scientists to learn how to do their research “in a glass house,” where people were watching every move and often demanding documents via the Freedom of Information Act process.
Broder: Let me add just one more thing. The Supreme Court actually was asked to take this case, and they wanted to know what the government’s views were. The government asked for the case to be dropped, and I am told that this was against the advice of the NIH. Why they took this position is still not clear.
But in the last analysis the legal aspects are a secondary issue. The drug is out there. AZT is out there. In fact, this whole episode supports my point. If you have people who aren’t doctors and scientists brought into an important public health issue, it doesn’t necessarily advance the interest of solving the problem.
Harden: Is the legal problem of possibly having to defend yourself in courts of law and having to spend time responding to Freedom of Information more of a problem for government scientists than it would be? I mean, do you think that this situation would inhibit drug discovery and development in the public sector as opposed to the private sector?
Broder: I do not think so. But I think it is a factor that, on balance, by and large, the adversarial system depends on equal participation.
Hannaway: Some other scientists we’ve interviewed have said that getting embroiled in these things distracted them completely from science.
Broder: Well, I think that is true.
Harden: Would you like to make any further comments about any of the drugs that you’ve worked on?
Broder: All I can say is that, with comparably small resources, my laboratory produced three drugs that went through the Food and Drug Administration (FDA) approval process within a short period of time, and we helped support a lot of others. I think that dollar for dollar, the taxpayers got their money’s worth out of that intramural commitment. And I think that that would not have happened in any other setting. But, more important, by far, is the fact that the public got its money’s worth from the entire intramural AIDS program. That especially includes the NIAID group: Tony Fauci’s group, Cliff Lane’s group, and the whole range of people who worked on AIDS both from a clinical and basic science point of view. And I think that a lot of the people in a lot of different functions had a very critical role. The nursing staff played a critical role, a lot of people are unsung heroes, so to speak.
Harden: Would you like to comment on how AIDS changed your career, changed your life?
Broder: In some ways, the development of drugs and responding to a public health problem like AIDS was a very satisfying experience, a once-in-a-lifetime opportunity. I told people in my lab at the time that this was a once-in-a-lifetime thing, that they had to look at it that way. Most scientists can work their whole lives and not see any practical application of their work.
Hannaway: One more general question, and you are uniquely qualified just to comment on this. We are interested in seeing how the NIH interacted with other government agencies, and specifically in this instance, the FDA. I mean, you are one of the people who had the most interaction with the FDA because you were interested in drug treatment, and you were very knowledgeable. Would you provide an overview of the NIH-FDA interaction in developing AIDS drugs?
Broder: By and large, the individuals at the FDA had among the most unfair and painful jobs in government, in my view. And I do not always agree with the FDA and I have clashed with them before I left government and since I left government. But by and large, I think the FDA is made up of very fine people who want to do the right thing and do not always have the resources to do it, and certainly do not get any public recognition for what they do but will be blamed when things go wrong.
I think there was an enormous outpouring of anger and resentment against the FDA by the many members of the affected communities, and the FDA became a scapegoat for a lot of anger and anxiety. The FDA building was trashed and occupied, and throughout it all, the agency staff responded with dignity and professionalism.
Harden: Thank you, Dr. Broder, for talking with us.
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