HTLV III Targets for Antiviral Agents.......Robert Gallo, NCI 9:15 9:45 10:10 10:40 Strategies for the Development of Antiretroviral Agents Daniel Bolognesi, Duke ..Anthony Fauci, NIAID Mr. WAXMAN. Thank you very much, Mr. Mason. We wanted to know what is being done for research into treatment; 6,000 Americans have died, 20,000 will die by the end of next year. We are also concerned about the budget. In April 1984, your budget was prepared for fiscal year 1986. You testified before us in February, and at that time it became clear that the administration's budget was inadequate. And that budget was prepared in April 1984. Why has it taken so long, until last Friday—and I am honored and flattered to think that maybe this hearing had something to do with the fact that the budget was improved-but why has it taken so long for the administration to decide that the budget recommendation to the Congress needed to be changed? Dr. MASON. Mr. Chairman, I think part of the problem is that this is such a rapidly developing, complex area that it took agencies within the Public Health Service some time to clearly estimate what their needs for fiscal year 1986 would be. After the budget amendment was compiled at the Public Health Service level, it was referred to the Secretary and to OMB where there was fairly rapid response to the request that I submitted to them. Mr. WAXMAN. Well, if it took that long to come up with what you think the budget should be, can't we assume that you are at least 6 months to a year behind what it ought to be as of this date, since you started on this project last year? Dr. MASON. This budget includes increases for fiscal year 1985, as well as increases for fiscal year 1986. I believe we are basically staying current. Mr. WAXMAN. The request is for almost 50 percent more money for AIDS research. I know not all of that money is going to be for treatment research. Could you outline your new projections in the treatment area? Dr. MASON. Some of that money will be going to the Food and Drug Administration to expand its surveillance and monitoring efforts for activities such as an evaluation of blood donors who are found positive to the virus screening test. Within CDC, there will be work on analysis of the natural history of aids to enhance what was being done, increased surveillance, expanded epidemiology, and there will be community risk reduction, health education programs. Much of the money for the risk reduction/health education activities will be going to the local level where cases are occurring. There is also money for the National Institute of Health additional money for diagnostic and therapeutic agents, for vaccine development and for other academic research activities, coordination and network establishment. Mr. WAXMAN. The kind of crisis we are facing with AIDS is a very frightening one. The Secretary called it public health emergency No. 1. Are we approaching this whole issue of AIDS with the kind of urgency that such an epidemic ought to be dealt with? Dr. MASON. We totally agree with you, that this is an emergency. As you say, the Secretary has declared it number priority, and speaking for the scientists within the agencies of the Public Health Service, they are indeed approaching this as a crisis, as an epidemic, and everything that can be done is being done. No stones are being left unturned. And where there have been shortages of resources, we have taken from one place and given to another to make sure that we more rapidly in those areas that we felt were high priority. Mr. WAXMAN. Well, we are going to hear from others this afternoon, and I would like their evaluation of your conclusion that no stone is being left unturned, that we are doing everything that we possibly can do. I commend you and the administration for increasing the budget, and I am pleased that we have that increased money. I wish we had had it earlier. And I worry about the kind of projects that were left unfunded because it has taken so long to give some sense of urgency to the treatment area and research that can lead to some treatment. We have thousands of people who have AIDS. Are we going to condemn them to die without trying to figure out what kind of research could be used to treat those patients and give them some chance? It is my impression the vast majority of work on AIDS treatment is being done either intramurally or as a result of individual research applications on specific drugs. Why is the NIH not issued a general request to the research community setting out a sufficient sum of money for screening all known drugs and asking researchers to apply. This sort of contract procedure might be allowed under the new budget. What can we expect? Of course, here, why has it again taken so long for these kinds of research projects to be initiated? Dr. MASON. I will address that question to Dr. Galasso. Dr. GALASSO. As was stated in the opening remarks, before we can evaluate drugs, we need to do the phase I studies. To the best of our collective knowledge, and we have with us today two of the clinicians working with AIDS patients, no antiviral agent or immune enhancer is out there that we have not been looking at, provided the FDA has approved it for phase I studies. Why aren't we doing more to have centers out in the community? We currently have circulating a request for applications [RFA] with applications due September 15, for cooperative agreements for studies stressing innovative approaches to the problem of AIDS from the epidemiology to basic research to clinical studies. This is an RFA issued by the National Institute of Allergy and Infections Diseases. There has been $1 million set aside for this undertaking. Mr. WAXMAN. In order for researchers to know whether a drug or therapy is working against the AIDS virus, they need to be able to isolate the virus from a patient before and after the treatment. Right now there are very few labs that can isolate the AIDS virus. Are there plans for the Federal Government to test for the AIDS virus, and will you establish isolation labs elsewhere? Dr. GALASSO. I would like to give you an example of what is involved here. Dr. Lane is doing some studies intramurally to evaluate drugs, these phase I studies; in order to evaluate 20 patients per week, we have had to award a contract for $300,000 a year just to do the virology on 20 patients per week; so it is a very expensive undertaking. It is also an undertaking that is rather difficult, and requires technical expertise. It is not the sort of thing that you can turn over to a routine laboratory to do because special facilities are required in which to do the work, so it is a very costly as well as labor intensive project. We have some facilities available, and as we have agents that go into phase II studies, we will have to provide what is necessary to do the studies. Mr. WAXMAN. I have in front of me a document from the National Institute of Allergy and Infectious Diseases, explanation of fiscal year budget requirements for AIDS, fiscal year 1986. Is this ongoing? If so, what is the base in fiscal year 1985? What additional work will be done? Another statement: Contracts for this purpose are not ongoing. We are evaluating available antivirals such as suramin and ribavirin. We have a new master agreement for clinical evaluation of antivirals that became available. We do not have contracts that are designed to screen for and develop new antiviral agents HTLV-III/LAV, and that is specifically what these contracts are proposed to do. How do you explain that statement in this document with the testimony you just gave us? Dr. GALASSO. We feel that the current way of isolating, quantitating the virus is difficult and costly to perform. We are spending a considerable amount of research effort in finding an alternative way of doing it, a way that they will be simpler and more easily accessible to individuals. Rather than set up regional centers to do this willy-nilly, we are trying to find a better way of doing it. Now, the agents that are being evaluated are in phase I studies. Once we scale up to phase II studies, we will have to go with whatever is the best way of monitoring the patients for efficacy. [The following information was submitted for the record:] (The response given by Dr. Galasso was in the vein of clarification of information provided to questions previously asked by Mr. Waxman. Specifically, the response was intended to address a question concerning PHS plans to establish facilities around the country where viral isolation and quantitation studies would be conducted. As Dr. Galasso stated, the current means of isolating and quantitating the virus is difficult and costly to perform. For this reasons, NIH is expending a considerable amount of research effort toward finding an alternative method so that these studies can be performed on a larger scale in the near future. In response to the questions raised by Mr. Waxman on the NIAID document in his possession, the information therein was intended to provide an explanation for the additional AIDS requirements identified in the proposed FY 1986 budget amendment. This document addressed the need for contracts to screen for and/or develop new antivirals for potential activity against HTLV-III/LAV. Previous responses were primarily focused on ongoing intramural studies evaluating existing antiviral drugs.) Mr. WAXMAN. How long will it be before we know? Dr. GALASSO. How long before we proceed from phase I to phase II studies? I perhaps should let Dr. Lane, or Dr. Broder answer as to where we are in terms of evaluating these drugs. Mr. WAXMAN. Or developing new ones. Dr. BRODER. New drug development? Mr. WAXMAN. Can you respond to the question of how long this is going to take? Dr. BRODER. I can do so by giving you an example by mentioning that well over 100 drugs have been screened in the intramural program, of which several active agents are now being explored. To give you an example of the time scales which can be done, the agent was found to be active, was submitted to the intramural program from the private sector, and was found to be active within the intramural program in February, and humans with AIDS are now being treated with that agent, so that is probably from initial recognition of the efficacy to implementation of a trial in patients, is approximately 5 months. We received approval from the FDA for an IND application within 1 week of submittal. That is probably as fast as one can implement such trails. As soon as appropriate, initially, this agent had never been used in humans beings as soon as appropriate phase I safety monitoring is completed, we will, as with suramin, make all of our information available to the extramural community and encourage extramural scientists to undertake studies. Mr. WAXMAN. As you come across an antiviral medication, you think it looks promising, we can look at a possibility of 5 months before being used on patients? Dr. BRODER. We have done that. That is not theoretic. That has been done. That is dependent on a number of factors. For example, if one encounters unexpected toxicology in the preclinical screening of an agent, that could delay its implementation, or eliminate it. Assuming all goes well, it is possible to take an agent from the time of its initial discovery to have activity, to phase I studies, 5 to 6 months is not an unreasonable expectation. As in the case of suramin, there was no need to do preclinical toxicology, it is possible to virtually instaneouslly initiate a trial. Phase I study, yes. Mr. WAXMAN. Suramin, is there enough available for extramural researchers now for this drug? Dr. BRODER. I am aware of seven centers, extramural centers, in this country that have approved protocol for its use and one center in France. I believe that all of the supplies that are necessary for those protocols are in hand and a shortage for those centers will not take place. Mr. WAXMAN. As I understand, it, well, suramin sounds promising, it may or many not be the cure we all hope for, as of May 15, there were only nine patients that were being tested with that drug. A suggestion is that maybe hundreds more could have been used for that purpose. Will the new budget allow funding for larger trials? Dr. Mason. Dr. MASON. A good deal of the additional money for the National Institutes of Health is in this area. Suramin is specifically mentioned a number of times as are viral titration studies. About $8 million will be assigned to these specific areas of activity. Dr. BRODER. Nine patients or 10 or 11, whichever the exact figure would be, it would refer exclusively to an intramural pilot trial. I |