Gay Men's Health Crisis: Treatment Issues - Volume 8 no. 6
David Gold

Treatment Issues (TI): For the benefit of our readers, how much is the NIH investing on therapeutic research for AIDS?

Dr. William Paul: I don't have the exact numbers in front of me. Let me answer it this way. Of the five large areas, therapeutic research is the largest single component, probably in excess of 40 percent of the budget. Vaccine research is probably not more than ten percent. There is also a substantial portfolio in the study of etiology, or pathogenesis, which we would hope would feed into both vaccine and therapeutic research.

TI: From what you've been able to tell so far, are the taxpayers getting their money's worth?

Paul: Let me put it differently. Ours is a very large enterprise, and I would hesitate to say that I yet understand it with the detail that really is required. As soon as our staff is in place we want to begin a process in which we take big chunks of the program, and set in motion an evaluation process - not consisting of me, but bringing in the experts. Getting a serious report. How are we doing? Are we well- organized? Are we spending our money well? The clinical trials program is probably our first target.

TI: When do you expect to have evaluation committees set up?

PAUL: I hesitate to say specifically. We're right now recruiting senior staff. The key to that process is in this case the person who would be our expert in therapeutics. It will take three or four years to do everything, because it's got to be an institutionalized process. I want to put in motion a sensible program for review that is continually on- going.

TI: Why do you think there hasn't been such a process already?

PAUL: That's a very good point and I can't answer that definitively. I would probably respond in the following way. During the period of rapid growth, we were just struggling to find mechanisms to deal with spending the money well - the development of the Division of AIDS for example, from virtually nothing to a very substantial enterprise. One doesn't stop in the beginning, when you're developing a program, to think about the review and quality control. The OAR restructuring gives more of an opportunity to commission reviews that might be somewhat removed from the group that's actually operating the program.

TI: Who is responsible for making sure that the directors of AIDS research programs at NIH are doing their job properly and attracting quality researchers and managers?

PAUL: That responsibility would have to be shared between the leadership of each NIH Institute and OAR.

TI: So you're not going to be responsible for hiring or directing of individual AIDS research programs at the Institutes?

PAUL: No. The role of the OAR is not to replace the institutes. The OAR is always going to be a small organization. The goal is not to create another bureaucracy. All you would do is install on top of everything yet another step, yet another hoop that everyone has to jump through.

TI: So what actual decisions will you be making at OAR?

PAUL: My job is to decide where we're going to put the money. To make the plan and to put it forward. Once we've got a process that works, I don't think I should march in and make all the decisions.

TI: Are you satisfied with the amount of authority you have?

PAUL: I don't think it's good for one person to have all of the authority, [but] ask me in a year when I've had a chance to explore.

TI: How many people work in the OAR?

PAUL: Very few right now. We're in the process of trying to recruit a staff. We hope to make the announcements soon, but we will never be a big office.

TI: Some claim that the NIH is a huge bureaucracy where it is not easy to make changes, replace people not up to speed, or act decisively. How do you respond?

PAUL: The bulk of research done is not at NIH. Only about fourteen percent of funds are for research done on campus - and it's very good research - but this is a national enterprise. And when you're supervising $1.37 billion of AIDS research it's got to be a substantial enterprise.

The ability to act decisively really depends on the amount of money you're getting.

For example, many people had hoped that OAR would do things that are different, more effective or more creative. And we want very much to do that. But that can only be achieved if there are funds available. The way the Office is set up, we have a responsibility or authority only over those funds not in the commitment base [grants and contracts awarded in previous years that have to be honored]. Now, if in any given year, the increase to the NIH is relatively modest, then the amount of money the OAR has authority over, becomes very small.

The available money becomes even smaller since even things not in the commitment base have to be continued at some level. For example, in 1996, the AIDS Clinical Trials Group (ACTG) is up for recompetition [renewal]. Whether you think that's well run or badly run just because it's up for recompetition, doesn't mean we can take that money and do something completely different with it. We have a responsibility to see that there is a functioning, useful, clinical trial mechanism.

Clearly, if new monies are small, the ability of any leader of this Office to reconfigure - if one wanted to do that - AIDS research in a new direction is very limited.

TI: Would there be other ways to organize AIDS research? Do you see a usefulness in putting together all the AIDS researchers so that the person, in say, your position, could hire and set up his or her own program.

PAUL: You mean having the equivalent of an AIDS Institute?

TI: Yes. Right now, outside of OAR, you don't have any direct say in the hiring of the people who are going to be implementing the strategic plan your office is creating.

PAUL: Creating a single AIDS Institute means creating a redundancy for the kinds of talents you need. In the allergy [and infectious diseases] institute, they really have first- rate people in infectious disease and immunology. In mental health, they have mental health experts. We would have to recreate all of those things in OAR. We'd basically be creating a mini NIH, and I am not sure that would be efficient. Even if you thought that this was a reasonable method of organization, I'm not sure whether it would be wise to junk the working organization to start again. It would cost time, money, and would be cumbersome.

My view is that this system can work. Whether we would have created it this way if we were starting from ground zero is an interesting question, but I can't see a lot of justification for not adhering to the current mechanisms.

TI: Do you think there's a problem already in that AIDS experts are too insular and aren't in communication with people in other fields - virology, immunology, or people who study other diseases?

PAUL: That would be a big disadvantage of an AIDS Institute because you would enforce such insularity. The fundamental lessons we have learned about how viruses replicate are often being learned in the study of other viruses, not necessarily in the study of HIV. They should be available to those working on HIV.

TI: The House appropriations subcommittee voted on the NIH budget yesterday and AIDS research received an increase of just $40 million dollars. (See accompanying article by Derek Hodel.) Before, you said if the increase is modest in a given year, you have very little authority to do anything new because all the money is already committed. Is that true for next year?

PAUL: It would be a problem for fiscal year '95 (FY95) which

was prepared six months before I was appointed. [But] I'll have some role in trying to adjust what we get, if we get less than what we asked for. The OAR will distribute those adjustments across the Institutes' boundaries, as efficiently as we can. Most of our energies so far have been in planning the FY96 budget, which we've already submitted to the Assistant Secretary [of Health].

TI: What would you like to do if you had the funds?

PAUL: We've got to more aggressively support investigator- initiated research. With a modest increase this is really going to be hard to do.

There are certain kinds of areas that we need to spend money on. In understanding this disease and developing new molecular targets, we've really been at a serious deficiency because we don't have any models to study. The Macaque monkey model [with simian immunodeficiency virus], is better than it's been given credit for, but it hasn't been used as effectively as it might, and part of that is because the resources aren't available to do it.

Unfortunately, with the FY95 numbers we see, the new grants we fund are going to be substantially less than FY94 and the success rates will go down. I regard that as a very serious problem.

New ideas are going to come more from [independent] investigators than from people here at NIH who say, "Well, how about putting out an RFA [request for applications - a more directed type of research] in a given area?" We'd like to use RFAs as sparingly as we can. There are certain things for which they are important, but in most areas, money should be used in ways that allow the bright investigator to come forward with a new idea.

TI: What are your impressions of the proposals coming out of Project Inform's Future Directions for AIDS Research conferences?

PAUL: I went to the meeting in Madison, and I think the notion of focusing scientific attention is a very valid one. The concept of saying, "Let's identify all the questions and when we have answered all the questions, we'll be that much closer to understanding the disease" has merit. But it implies you know the questions.

Unfortunately, what often happens when you say, "Let's put all the questions on the blackboard" and then say, "Let's design experiments to solve all the questions" is, you usually don't know the right questions to put on the blackboard. So, I'm a little nervous about a very focused effort to develop a research agenda based on such an approach, because it removes the essential element of asking the new question that hasn't been asked before. Phrasing the question is almost invariably the critical step in advancing science.

I'm not enthusiastic about trying to change the basic organizational structure of the research enterprise because such a [focused or directed] structure is not well-suited to gain completely new kinds of knowledge.

TI: Are there any central questions where a more directed effort would have value?

PAUL: Well, there are directed research efforts. For example, the whole RFA mechanism is, in effect, a directed research effort. That is, you identify something and say, "I'm going to ask for ten applications to solve this question." That's what a request for applications is.

Once it's clear that an issue is important, it really doesn't need this kind of approach. At that stage, you've built the scientific momentum, and what works is going to go on. What you need is the wisdom to recognize early that something is likely to be very important and invest in it. That's very important to do, but it's a very risky business because you may guess quite wrongly on many things. You run the risk of wasting large sums of money by over-structuring a process.

TI: What are the practical effects of Bernard Fields' article in Nature and the discussions about basic research versus clinical research and what deserves priority right now?

PAUL: Dr. Fields' article outlines his view that unless we reinvest in the fundamental research, we're not going to solve the problem of AIDS. What he didn't stress - [although] I think he aimed to make this point - is that there needs to be a balance. We've got to invest both in an effort to find new agents now, and also go back to understanding basic mechanisms [of HIV and the immune system's response to the virus].

My responsibility in the OAR is to recognize there's got to be a balance, although there's a lot of merit to what Dr. Fields said. I'm very sensitive to his argument, but I can't move too far in his direction without running the risk of not adequately supporting the drug discovery program and the drug development program.

TI: Can the drug discovery program be made more efficient?

PAUL: More likely, I suspect, it's the drug testing [clinical trials] program where inefficiencies can be found. It could almost certainly be managed in a better way. I'm hopeful that we will achieve equal effectiveness at a lower cost.

TI: What are your thoughts on the quality of AIDS clinical trials programs at NIH?

PAUL: I would still reserve judgment. I want to conduct an in-depth review -.

TI: When will that be completed?

PAUL: I really haven't constructed a time table yet. We might start the process in the fall and a serious review means we're not likely to get a good answer until the spring [1995].

TI: Some suggest that the ACTG, in terms of antiviral research, is inefficient, fails to undertake cutting edge studies, and is run by an insular group who basically approve each other's trials without any sense of accountability. Is this the case and if so, who is responsible?

PAUL: We're going to have a recompetition in 1996 [where we look] at the quality of work at the individual ACTG sites. [In terms of] the overall quality of the whole ACTG enterprise the responsibility for management and quality does lie with the NIH.

TI: Who in particular and where does the buck stop?

PAUL: I'm not certain who specifically oversees the clinical trials program. I would have to examine the set up Dr. Killen [Jack Killen, Director of the Division of AIDS at NIAID], Dr. Fauci [Director of NIAID] and I. We all bear responsibility. None of us should be able to escape responsibility if it's being badly done and we should all get a little credit if it's well done. If we've set up a bad system we all deserve to be held to its consequences.

TI: Many drug companies don't want anything to do with the ACTG system. It's been frustrating to see the NIH not operate effectively in encouraging pharmaceutical companies to conduct specific types of HIV-related research. Do you have any plans in this area?.

PAUL: The place to look for this is in the Drug Discovery Task Force [a joint government-industry-community committee organized by the Assistant Secretary for Health]. One of the key questions they have to grapple with is the notion that drug companies identify agents and decide that they're not really interested in pursuing them even though they may have merit. Or that no one wants to tackle a particular topic even though it looks meritorious. Is this real? And if so, what can we do to respond to it?

TI: There's a couple of concerns that people have about you. Almost everyone agrees that you're a person of impeccable scientific credentials, but some, including Dr. David Baltimore [a leading researcher at Rockefeller University], suggest that while you're a nice "grandfather type," we need a more vocal and visible leader. How do you respond to that?

PAUL: I agree with the view that the leadership of this office has a responsibility to set a tone and to provide statements. I also believe, however, that our chance to have real effectiveness is our ability to guide where the money goes. If we don't have that ability, we can talk all we like. There are a lot of people who want to give leadership, but leadership is linked to our influence on the budget.

If this budget grows at a very modest rate, then what we have to control is very little. And in the end, our ability to be effective is linked directly to the amount of money we can control. We will be passionate, useful leaders when we're in the position to see where the money goes. This enterprise should be judged on what it achieves, rather than on what the appearance is.

TI: Another concern people have is that you don't have specific AIDS experience and that you haven't had experience running a large research program with all its politics.

PAUL: On the first point, I agree entirely. I know a lot of immunology, and I have a pretty good understanding of the etiologic aspects of the disease, although not as sophisticated as those who've worked on it for a long time. I have learned an enormous amount already and hope to learn a great deal more. But it's a fair criticism of my appointment that I wasn't deeply involved in the disease. [But] some regard that as a virtue.

As for the second issue: We are not managing a large research enterprise in the sense that this is a big administrative job. I don't have and will never have, 300 people working for me. Congress decided that's not what they wanted the OAR to do. So I don't think that's a fair criticism. It is reasonable to ask how are my skills in dealing with the political problems because much of the effectiveness of this job will lie in the ability to solve those problems. To the extent that we can get better budgets and help deal with certain things - that's a reasonable way to judge the performance here.

TI: Do you think you're up to that?

PAUL: I hope so. I'm working pretty hard. You'll have to judge whether I am successful or not. But it looks as if the single appropriation [the unified budget for NIH AIDS research - again, see accompanying article by Derek Hodel] has emerged intact. We worked very hard on that. We're not as happy with the magnitude of the appropriation. We want to do better. We know these are difficult times for NIH and for the appropriations subcommittee. They're limited in the funds they have available. But there are a lot of opportunities that we may miss with a very modest budget.

TI: Two years from now, how should we judge whether you've been successful?

PAUL: I'd like to see a budget process in place which puts the money in the areas with the greatest promise. I would like to see some effective drugs on the table, but honestly, if they are on the table in two years, they are probably in the pipeline now. We know how long it takes. We want progress in helping people who are infected and preventing people from becoming infected. In the end that is the only serious bottom line we have.

Now can you judge my performance without that? I don't know. Outcomes are really what counts.

TI: From your background as an immunologist, how far are we from making progress in reconstituting the immune system?

PAUL: We still have a lot of work to do. We haven't applied full contemporary immunology here. We need to recruit people with the greatest skills in contemporary immunology who are outside the field [of AIDS]. We need to move them into the field.

TI: How do we do that?

PAUL: Make it attractive for them. Point out that this is an important and interesting area of study, that there's a possibility of making real contributions and that there's a chance you're going to get funded. We need the money to support this work.

TI: Is it possible, from what you know of the immune system, to think that effective antivirals alone can make HIV into a so called "chronic, manageable condition?"

PAUL: It might depend on the stage of disease and viral burden at the time you begin therapy. But if we had agents that fundamentally could prevent the virus from replicating we could limit the burden enormously. I would be very optimistic about this.

Even in autoimmune diseases, in some of the models of multiple sclerosis, you can interrupt that process in a variety of ways. If we could get terrifically good antivirals and limit HIV replication enormously, I would be very hopeful. Now if someone has no CD4 cells, I don't know what would be the outcome. Even there, if you could limit viral replication, it still may be quite possible to repopulate the immune system from your own bone marrow. There's enormous repopulation potential from stem cells in the bone marrow. So my own view would not be so pessimistic as to that.

TI: What's been your greatest frustration on the job?

PAUL: The number of budgets I have to write. There is an enormous amount of effort expended on coping with the inevitable governmental problems. They're important, but they divert you from what you'd really like to accomplish. I hope that as we get a staff, those things take up less of my time.

TI: Finally, are you committed to continuing at OAR indefinitely?

PAUL: I'm not certain about that. As you pointed out, there is a lot of power in this position. To put a certain person in this job over a long period of time runs a risk. To serve too short a time means you don't know what your doing. Bringing in new people with new ideas is always going to be valuable and I'm not prepared to abandon being a working scientist.

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