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AIDS Treatment News
Basic Science and Clinical Trials: Interview with William
John S. James
February 17, 1995
AIDS TREATMENT NEWS Issue #217, February 17, 1995

On February 14 AIDS TREATMENT NEWS interviewed William E. Paul, M.D., Director of the Office of AIDS Research at the U.S. National Institutes of Health (NIH). The new Office of AIDS Research, due to Congressional action in 1993, has budgetary authority over all AIDS research at NIH -- the world's largest AIDS research program by far.

Dr. Paul has long proposed that we need more basic research in AIDS -- leading to public fears of de-emphasis on clinical research intended to find treatments now. We wanted this interview to address these concerns.

We especially wanted to clarify "the role of small, rapid, data-intensive, exploratory human trials of potential treatments for HIV disease," as we wrote in a letter to Dr. Paul in preparation for this interview. We most wanted to learn whether this kind of science-intensive human trial is included within the basic-research emphasis at the Office of AIDS Research.

Basic Research and Human Trials ATN: People in the community have the image that "back to basic science" means retreating into the laboratory and then in five, ten, or 15 years coming out with something useful. What can you say to reassure them? Paul: That is a valid concern; people are right to raise that point. You may remember the article in NATURE on May 12, 1994, by the late Dr. Bernard Fields, that said "back to basics." Our position has always been that we do need to build a knowledge base, but that cannot be done at the expense of efforts to do therapeutic research now. We are searching for a balance. In our opinion the balance shifted too heavily away form "basic" research.

There is great concern throughout the HIV research community, and certainly among patients and their advocates, that the drug pipeline is not very full. People are worried, very rightly, that after the protease inhibitors they do not see a good picture. Our position is that the only way to fill that pipeline is through this kind of scientific research.

People differ in what they mean by basic research. I was struck by one of the proposals in your letter, in which you described what I would call the clinical investigation of people who are on research protocols using one or more agents as therapies, coupled with very intensive laboratory study. We know the very recent and successful example of using this approach to gain important knowledge -- the two papers, one by David Ho and colleagues, and the other by George Shaw's group. This certainly qualifies as the kind of basic research I am talking about.

We do not mean let's abandon everything we have done in HIV and go back to square one. What we mean is that we need to assure a balanced approach aimed at understanding the mechanisms of this disease. Some of that will be done by laboratory-based basic research on model systems, and we need to support that. But [human] work like that in the Shaw and Ho papers, and I think like that which you pointed out in your letter, clearly falls under our mandate. We feel very enthusiastic about that kind of work.

Our position is not an abandonment of therapeutic research that benefits people who are sick now, but rather an effort to build a better knowledge base, that will help us fill up the therapeutic pipeline.

ATN: Will your Office of AIDS Research make sure that this kind of work is done? Paul: At OAR our responsibilities are not to choose the individual trials; that is the responsibility of the individual Institutes [of the U.S. National Institutes of Health], such as the National Institute of Allergy and Infectious Diseases (NIAID), and the National Cancer Institute (NCI). Many people have been concerned about "the extra layer of bureaucracy" that OAR introduced. We regard ourselves as having a very valuable function in setting overall goals, in conducting a clear evaluation and assuring that precious funds for AIDS research are allocated wisely and used effectively; but we do not intend to get into micromanaging specific trials, which lies in the purview of the Institutes. Instead, our job is to make sure that there are programs in place that allow this kind of really terrific work to go forward. We have been asking how we can facilitate the kind of research you described, what mechanisms are available? There are two classes of mechanisms which I believe would be suitable. Particularly with the upcoming recompetition of the ACTG in 1996 [NIAID's AIDS Clinical Trials Group, which has done most of the government's large studies of AIDS treatments], there is going to be a sea change, I think, in the recognition that much more must be done at the level of these smaller, laboratory-intensive, pathogenesis trials. [Note: The recompetition will involve a new selection of ACTG sites, on the basis of competitive review; some sites may be discontinued, and some new sites may be added. In addition, a reorganization of the ACTG management took effect on January 1, 1995.] Dr. Chip Schooley is committed to that; and I believe the Institute (NIAID) is committed to that as well. So the reorganized ACTG is clearly one mechanism through which that kind of trial could be supported.

The second mechanism is conventional grant support for research. Most often [the data-intensive trials] will require a very sophisticated laboratory in order to be carried out. The people with those facilities are in a very strong position to obtain conventional grant support for that kind of work. We argue that both strategies [ACTG support, and conventional grant support] should be applied; these seem like the two most flexible approaches to be certain that this kind of clinical work can be done, well and thoughtfully, and that it has been peer reviewed. One could imagine an infinite number of such studies; obviously there must be a way to choose thoughtfully and well those most likely to provide really useful information. Whoever wants to propose such a program needs to be able to defend why that experiment should be done. There must be a scientific justification that suggests that this is a wise way to use these funds. There will always be more proposals than we have money to support.

The new, recompeted ACTG will have a much greater emphasis on this laboratory-intensive clinical trial. It will have an internal mechanism for more rapid consideration of proposed trials. The advantage of ACTG support over regular grants is that it is somewhat faster. But the disadvantage is that it is largely limited to people already in the ACTG system. We do not want to close out others; we need opportunities for people from outside to do this work.

These are the two approaches which I think are most likely to give people the flexibility to carry out innovative work that will have a message. Everyone was excited by the Shaw and Ho papers that made clear certain things about the dynamics of the infection that we had not understood. These very incisive pieces of work were not exceedingly expensive to do, although obviously the investigators put in a lot of effort. These represent thoughtful experiments, and even more, the recognition of what the result meant. Often that recognition is as important as anything else.

ATN: Although we have heard concern about the amount of enthusiasm for that work, in that it leaves aside the whole immunological area.

Paul: Is their report the end? No, there is much more work to be done; and many of us who are immunologically inclined feel that we still do not understand in detail the T-cell dynamics. The viral dynamics are very well specified in those papers. The T-cell dynamics are more complex, and there is more work that needs to be done.

This kind of work is what we would call a clinical investigation. You carry out an ethically sound experiment on a human. It is ethically sound in that you use something that potentially can do the individual some good. The treatment perturbs them, and the perturbation gives you the opportunity to watch what the immune system or viral system does, in response to a known perturbation. Because we do not have the animal models we need, this work in people is essential. I am a great advocate of that.

ATN: That is exactly the point I wanted this interview to make.

Paul: We agree entirely on that point.

Funding Scientist-Initiated Work ATN: What about the big problem of funding? Fewer and fewer investigator-initiated grants [which fund work proposed by the scientists who will do the work, usually in academic centers, instead of contracts proposed by government scientists] can be funded because of lack of money.

Paul: That is an issue I addressed directly recently in SCIENCE ["Reexamining AIDS Research Priorities," SCIENCE, February 3, 1995, pages 633-636]. One thing the OAR clearly can do is to recognize where a problem exists and take steps to change it.

Let me give you some numbers. You can calculate what proportion of a budget is used to support what I call investigator-initiated research. In discussions with the Division of Research Grants at NIH, we have agreed on the following definition. Traditional grant applications (of which the "R-01" is most well known, but there are also several other similar types) are regarded as investigator- initiated if they are not submitted in response to a "Request for Applications" (RFA). We took the amount of money that was spent in all of fiscal year 1994 supporting that category of grant, and divided it by the total amount of money to support grants and contracts, to obtain the proportion of funding spent on unsolicited investigator-initiated grants.

For non-AIDS grants at NIH, that proportion is about 54 percent. For AIDS, it is less than 25 percent. So right now there is a disconnect. The key now is to make an effort to change that ratio. We can do a lot by changing that ratio.

Obviously to change the ratio you have to alter something. As a first approximation, the kinds of things we would like to see altered are, for example, the heavy use of RFAs and contracts in the Institutes. Some are justified; but they need to be looked at again, because programs go on, and sometimes they outlive their usefulness. Sometimes they are theoretically useful -- but compared to what? There is very little done that does not serve a useful purpose; but when funds are limited, useful purpose has to be graded more toughly. You need to compare it to what else could be done with these resources. We regard this kind of analysis as a very important role for OAR in the system.

Animal Models ATN: A number of people think that SIV (simian immunodeficiency virus) in macaque monkeys is a very good model for studying HIV disease. What do you think? Paul: I agree with that view. There is little doubt that in broad outline, the macaque disease resembles the human disease. The pathogenesis seems to follow very similarly: you have the initial burst of viremia, followed by a rapid immunological control and low virus titers; but eventually the animals get disease. There is the same kind of trapping of virus in the germinal centers on follicular dendritic cells. In broad outline the diseases look very similar. Much can be learned from the monkeys about pathogenesis and immunopathogenesis. I pointed out in my SCIENCE article that we believe this area has real promise. We would like to see much more of such work done.

There is also another model which is not as close but should not be fully excluded. There is a disease in cats, caused by a related lentivirus called the feline immunodeficiency virus (FIV). While it is further removed from HIV, it has advantages because it is easier to work with cats than with monkeys. This is another area where we should not miss the opportunity presented.

Some AIDS research would be very difficult to do in humans -- for example, all of the attenuated virus vaccine work [which involves injecting a live but weakened virus into uninfected animals, as a preventive vaccine]. We would be exceedingly reluctant to begin that work in humans. But there is very little doubt that a robust vaccine response can be induced in the macaques. At the very least we can learn the nature of the immunity that really is protective. Even if we finally reject this strategy for a human vaccine, we may still benefit enormously from such studies in animals.

Specific Issues: Management Analysis; Hydroxyurea ATN: One suggestion and critique of Federal AIDS research says that NIH should use the services of professional management consultants, who analyze large industrial enterprises to find what is working and what is not, and how to improve the system. The suggestion is to bring in these experts and see what they can suggest for making procedures work more smoothly than in the past.

Paul: I don't have any antipathy to systems management, etc. But my own view is that this is a misreading of where we are at, and what our task is. When industry embarks on a research program, it is usually quite definite in what it wants to achieve. A pharmaceutical company, for example, will have identified a series of molecular targets, and then try to build a drug that will react with a particular target. It uses a very clear, precise, and also narrow but deep approach; it wants to get a drug, and the question is what is the best way to go about it.

We are faced with a different problem, because we don't already have the knowledge to accomplish our goals. I do not believe that the systems engineers have grappled with this kind of problem. In general, American industrial research has been very good in the development stage, but it is not known for its discovery. We are dealing with discovery, with research; I do not believe that there is enormous experience in the planning of the acquisition of new knowledge -- in contrast to the planning of the utilization of knowledge to create some product or technology. I know there is a group that presses this view very heavily; but I am not in agreement with their views that this is fundamentally a management problem, that the reason we have not solved AIDS is that we have not had the right managers. We have not solved AIDS because we have not made the right scientific progress, because it is a problem, unfortunately, of real complexity. I do not believe that what we are facing right now is a crisis in management.

ATN: One example of a needed change is illustrated by the problems we have had over the last year and a half in getting any U.S. study done on hydroxyurea. Today there is tremendous interest in doing a trial, but it has been a year and a half since hydroxyurea came out publicly in Dr. Robert Gallo's plenary talk at the Berlin conference. We have not had any trial in the U.S. in that time, not even with a few people to get a sense of where we are; and now people are starting to use the drug without the benefit of those trials. What can be done to prevent this kind of problem in the future? Paul: I am aware that hydroxyurea has been widely used in therapy for several other diseases, including some forms of cancers, and most recently was shown to be effective for sickle cell anemia. Dr. Gallo reported his findings in SCIENCE in November of 1994, suggesting that hydroxyurea appears to be a possible candidate for AIDS therapy. In fact, I understand that the ACTG is currently reviewing the data for the development of a treatment protocol within the ACTG.

The Mission of the Office of AIDS Research ATN: People ask what is the justification for the new Office of AIDS Research. I hear from your answers that OAR should make sure the proper ways of decision making are in place, should increase the proportion of funds going to investigator-initiated research vs. government-requested contracts, should deal with such management without micromanaging by deciding on individual trials.

Paul: I would go beyond that in one respect. The OAR's responsibility is to take into account that research on AIDS is involved in enormously broad and diverse areas. We use a planning process with much outside input -- with many scientists from outside NIH, with scientists from within NIH, and with community representatives.

There is AIDS research support at NIH in all the Institutes. There must be an overall vision for what we are going to do. There must be some process through which we decide, over time, where we put our emphasis. It is not enough to simply let the whole budget go up or go down in exactly the same lockstep without any thought in it. That is the opposite of what we want to achieve.

As long as the planning process occurs only within the Institutes, what individual Institutes will be able to do is simply to look after their own areas. They cannot influence the balance of research across the areas. So one very important role for OAR, in a process as diverse as AIDS research, is to recognize where the opportunities lie, where the greatest hopes are, and to try to put the resources there.