Date: Fri, 17 Feb 1995 22:19:01 -0800 (PST) From: "John S. James" AIDS TREATMENT NEWS Issue #217, February 17, 1995 phone 800/TREAT-1-2, or 415/255-0588 CONTENTS: Basic Science and Clinical Trials: Interview with William Paul, Director of the Office of AIDS Research AIDS Clinical Trials -- Why They Have Recruiting Problems Valacyclovir Study Stopped -- Worse Survival AZT: Pediatric Study Changed After Worse Monotherapy Survival Kaposi's Sarcoma: DOX-SL Approval Recommended ***** Basic Science and Clinical Trials: Interview with William Paul, Director of the Office of AIDS Research by John S. James 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. ***** AIDS Clinical Trials: Why They Have Recruiting Problems by Bruce Mirken One of the functions of a publication such as AIDS TREATMENT NEWS is to provide information about clinical studies of new treatments. Often those of us who report on AIDS trials hear that potentially important studies are having trouble enrolling the number of volunteers needed. The problem is quite common. Ronald Mitsuyasu, M.D., director of UCLA's Center for Clinical AIDS Research and Education, a major southern California clinical trial site, comments that "the majority of our trials take a lot longer than anybody expected to enroll. My guess is that this is what's happening across the country." In fact, Dr. Mitsuyasu says, "very few" UCLA AIDS trials enroll on schedule. This is a significant problem. Collection of needed data can be greatly delayed. Worse, if trials are underenrolled, or if the factors that cause people not to enroll also lead large numbers of volunteers to drop out or "cheat," either by lying to get into the study or by not following the trial regimen, the result could be data that is of little or no value, even though produced at great expense. Obstacles to enrollment in AIDS trials generally fall into one of two broad areas: The publicity or outreach efforts used to recruit prospective volunteers, and the design of the trials themselves. Publicity and Outreach The news releases, flyers and other materials designed to publicize trials vary widely in content and quality. Some that we have seen are excellent, giving a clear description of the treatment being studied, what is known about it thus far and the nature of the research being announced, in language that nonscientists (which includes most of the writers and editors likely to make use of this material) can understand. Others are problematic at best, omitting key information or so mired in jargon as to be incomprehensible to most lay people. Mark Bowers, who until recently recruited potential trial participants as Clinical Outreach Coordinator at HIV Care, the research division of St. Francis Memorial Hospital in San Francisco, puts some of the blame on what he calls the drug companies' "proprietary, closed-mouthed attitude" about new compounds. "On the one hand they want to recruit their study. On the other hand, they do not want anybody else to know they are doing it, and they do not want the slightest amount of information to be leaked out to the public." This reluctance to release data developed in-house on a prospective drug, Bowers says, at times made it difficult for him to give potential volunteers the information they needed to feel safe in the study. Another apparent obstacle to publicizing trials is the lack of clear guidance from the FDA on what publicity materials should or should not say, which may lead some trial sponsors to err on the side of caution by not saying much at all. Jennifer Fernandez, Product Communication Manager for Immune Response Corporation, the company developing the Salk Immunogen therapeutic HIV vaccine, calls the FDA's rules "a real gray zone." The formal FDA regulations which lay out procedures for informed consent, the responsibilities of Institutional Review Boards, etc., say nothing specific about publicity for trials. The only written rules the Agency has, according to spokesman Arthur Whitmore, is in the form of a one and one- quarter page "guidance document"--a notch below a formal regulation in the bureaucratic pecking order--titled, "Advertising for Study Subjects." The document deals specifically with advertising, making no mention of other forms of publicity such as news releases. The general principles contained apply across-the-board, Whitmore says, but in conversations with him and with Richard Klein of the FDA's Office of AIDS, it appears that relatively little thought has been given to the news releases that treatment publications, the gay press, and mainstream media outlets often rely on for basic information about new studies. The basics are relatively straightforward: Publicity materials should be reviewed by an Institutional Review Board, which should treat them as an extension of the informed consent process. They should not be inaccurate, misleading, or claim that an experimental drug has been shown safe or effective. The document then goes on to state, "Generally, the FDA believes that any advertisement to recruit subjects should be limited to: "1) The name and address of the clinical investigator; "2) The purpose of the research and, in summary form, the eligibility criteria that will be used to admit subjects into the study; "3) A straightforward and truthful description of the benefits (e.g., payments or free treatment) to the subject from participation in the study; and "4) The location of the research and the person to contact for further information." The language is quite vague: How much detail, for example, is appropriate in a description of "the purpose of the research"? A great deal of information which might be of interest is not included, such as information about the study drug, its believed mechanism of action and the results of prior research. It does not seem unreasonable to speculate that fear of putting too much detail into an "advertisement" may account for the sketchiness of some press releases announcing trials. "I think for the most part people in the Agency do not interpret this [document] word-for-word or really narrowly," Klein explains, emphasizing that the idea is to make sure that information is accurate and that no one is misled into thinking they are taking a drug that has been proven effective when it is still experimental. Unfortunately, the Agency has not put this sentiment in writing. Once publicity materials have been developed, getting the word out can become a problem, particularly when there is little budget for paid advertisements. Treatment publications reach one segment of potential volunteers, as does the gay press, which sometimes runs announcements of studies. But many potential candidates for HIV/AIDS trials are not reached by these publications, and information about studies that are recruiting rarely finds its way into mainstream media outlets which might reach a broader audience. Women, People of Color, and Other "Underserved Populations" For years activists have complained about the underrepresentation in AIDS clinical trials of women, injection drug users, and people of color, despite the fact that these groups represent a large and growing proportion of AIDS cases. These complaints have often centered around the worry that drugs are not being tested on a population that is representative of those who will actually use them, and that potentially important information about a given drug's activity and toxicities may be left undiscovered. And in addition to that consideration, it appears that a substantial pool of potential volunteers is being left largely untapped. Jeannett Ickovics, Ph.D., of the Yale University School of Medicine, has studied both participants and non-participants in AIDS trials at the Nathan Smith Clinic, the location of Yale's AIDS Clinical Trials Unit. Her findings, the bulk of which have not yet been published, raise a number of issues. Of patients in the clinic who were not enrolled in a trial, 35.3% had not heard of clinical trials at all, and 55.6% did not know that the clinic had an ACTU [AIDS Clinical Trial Unit]. But 56.9% said they would be willing to participate in a study if asked. In a clinic where much of the recruitment for trials happens through individual physicians telling individual patients about studies which may be of interest, 72.5% had not yet been asked. Latinos, and also current or recent injection drug users, were least likely to have been asked to participate. Significantly, Ickovics' study of those who were trial participants suggests that common stereotypes branding certain groups as being unreliable study participants are false. "Neither sex, race nor history of injection drug use were associated with non-adherence to medication regimen," she writes. Even so, "Injection drug users are often excluded from clinical trials by inclusion criteria that explicitly (e.g. no active drug users) or implicitly (e.g. high standards for liver function tests) eliminate them from clinical trials." Jeff Getty, a treatment activist who volunteers at the Center for AIDS Services in Oakland, California, in addition to being a member of ACT UP/Golden Gate, says that clinical investigators frequently are unwilling to accommodate the needs of the people with whom he works, many of whom are women, people of color, or people with a history of injection drug use. Before many of these individuals can even think about joining a study, Getty explains, "they have a lot of pressing needs that need to be met in terms of housing, shelter, paying their bills. They need help with things like transportation and child care, and even a small reimbursement. If you think rich peoples' time is money, look at poor people." For people who are barely making ends meet, the cost of transportation across the bay to San Francisco, where the majority of nearby studies occur, and of arranging child care for the time involved, can be an insurmountable obstacle. Trial sponsors, Getty complains, have only rarely made an effort to accommodate such needs--and never do so for popular studies of treatments perceived as "hot" in the community. "There is an unspoken prejudice that's quietly there, keeping women, the poor and IDUs out of these studies," Getty argues. "There are thousands of people in the East Bay who could be in these studies, but they are not." Although there has been some progress in increasing the numbers of women and minorities in trials, and even though the FDA is on record as encouraging such inclusion, there is clearly more work to be done in this area. Study Design Issues Of course, all the publicity, outreach and accommodation of financial and other barriers in the world will not attract people to a trial whose design is inherently unappealing to patients or whose inclusion/exclusion criteria shut out too many potential volunteers. This is another longstanding complaint of the activist community, one with which many researchers at least partly agree. Sometimes a study's design keeps out the very people researchers need to recruit. One of the clearest examples of this occurred about a year and a half ago, in what eventually became an important study of recombinant human growth hormone as a treatment for wasting syndrome. After nearly a year of recruitment, the study was enrolling at a painfully slow pace. The problem turned out to be the exclusion criteria, which among other things barred anyone taking either d4T or 3TC, both drugs that were not yet approved but were available to many patients via either large-scale clinical trials or expanded access. After activists successfully lobbied to have the exclusions dropped, the enrollment problem disappeared. The motivation for such exclusions is usually a desire for "clean" data, uncluttered by the "noise" which might be produced by other drugs--particularly unapproved ones, about which less may be known. But in this case the trial's designers had failed to consider the fact that wasting is generally a manifestation of late-stage disease, and people with wasting were likely to have already gone through all of the approved drugs and moved on to the newer ones. They were barring the very patients who most needed and wanted the treatment they were studying. Greg Dubs, Ph.D., has seen the issue of trial design from two angles: As Project Director of the recently-completed Stanford NAC trial, and as a person with HIV who has himself tried unsuccessfully to get into studies as a volunteer. The culprit in his case, he argues, has been needlessly restrictive entry criteria. Dubs says his platelet count, which varies between 72,000 and 90,000, has disqualified him from "almost 90% of the studies, because they always ask for platelets over 100,000... And yet my platelet count has essentially no clinical significance whatsoever. It has been stable for five years." Sometimes, he argues, those criteria exist for no good reason. "I've sat in so many protocol discussions where I questioned a criterion, and the reason that criterion had been put in place was not through any rational process, but because they had taken it from another protocol." He is particularly critical of those antiretroviral studies--still fairly common--that insist on patients with relatively low CD4 counts who either have never taken antiretrovirals or who have only very limited experience with them. Such an approach, he argues, is absurd in a city like San Francisco where--except for those who have chosen not to take antiretrovirals at all and who thus would have no interest in such a study--the vast majority of HIV patients with low CD4 counts have been on AZT or its cousins for some time. By putting out exclusion criteria that few can meet, Dubs says, "all you are doing is finding out who can lie well. They never study how many people lie to get into their studies." Dr. Mitsuyasu agrees that inclusion criteria are frequently too narrow. "I'm not going to try to defend that policy, because in most cases I can't," he comments. "The reason for doing it is to make the drugs look good... You are going to see the biggest change in naive patients." Another unhappy result, he adds, is that potential volunteers get discouraged if they repeatedly fail to meet the entry criteria for studies they would like to participate in. "Sometimes they don't come back," he says. A related issue is the continuing prevalence of study designs that in the view of many do not fit into the real-world needs of patients. As the consensus grows that combinations of antiviral agents--most likely with periodic changes to ward of viral resistance--are the most effective treatment strategy, long-term monotherapy trials become less and less attractive. Bowers takes the argument a step further. "It will soon be perceived by a sizable segment of the activist community... that denying anybody the opportunity for combination therapy from the get-go is unethical. The best evidence that we have today shows that combination therapy started at the earliest possible moment provides the longest and most reasonable benefit, and it is unethical to deny anyone that, just as it is unethical to do long-term placebo-controlled studies." Bowers argues that study designs must evolve more rapidly in order both to attract volunteers and to produce results that reflect the way doctors and patients treat HIV/AIDS in the real world--making more allowances for combinations of drugs and pragmatic adjustments in treatment over time. In a recent position paper, Project Inform founder Martin Delaney argued, "we should consider going to war against anyone planning to run long-term studies which include the possibility of randomization to a monotherapy arm, unless there are clear provisions to move such unlucky patients to better therapy at the first sign of returning virus levels." Such an attitude, he added, probably means confrontation with common drug-development strategies and with the FDA, "since meeting Agency requirements is the principal reason companies are doing things that way." The FDA's Klein insists that "the Agency encourages, to the extent that they can, combination therapy--they are working with the ICC [the Intercompany Collaboration for AIDS Drug Development, which is testing drug combinations]--but it's not for the Agency to dictate how people do research." Mitsuyasu agrees that the Agency is becoming "more responsive," but says it still has trouble keeping up with the changing science in the field. Perhaps most disturbingly, many, including Dubs and Mitsuyasu, say they detect a growing malaise among PWAs when it comes to volunteering for trials. "Even before we screen them we are having trouble getting people to call," Mitsuyasu notes. "Patients are almost burnt out, and maybe somewhat pessimistic about what trials can do for them." ***** Valacyclovir Study Stopped -- Worse Survival by John S. James In an unexpected setback for Burroughs-Wellcome -- but one which might turn into good news for people with AIDS -- a study of valacyclovir was stopped early because patients assigned to that drug had worse survival than those in either the low dose or high dose acyclovir arms, which were intended as control groups for the valacyclovir treatment. Valacyclovir is a prodrug of acyclovir -- meaning a drug which turns into acyclovir inside the body. Its advantage is that higher doses can be absorbed orally than when acyclovir itself is given. Therefore, doses which would otherwise require intravenous acyclovir can be given orally with valacyclovir. Burroughs-Wellcome has focused recent development work on valacyclovir rather than acyclovir, because the patent on acyclovir will soon run out, and that drug will become generic -- meaning that it will be inexpensive for the purchaser, but not very profitable for the company. The study which was stopped, called ACTG 204, had been run by the AIDS Clinical Trials Group (ACTG) with support from Burroughs-Wellcome. The purpose was to see whether valacyclovir could help to prevent CMV disease in persons with advanced HIV infection (CD4 count under 100). Due to ethical problems with using a placebo in such a study, low dose and high dose acyclovir regimens were used for control (comparison) groups. High-dose acyclovir has been shown to prevent CMV disease in organ-transplant patients (who have immune deficiencies due to immune-suppressive drugs taken to prevent rejection of the new organ); but prior attempts to use it to prevent CMV disease in AIDS have not been promising. The theory behind ACTG 204 was that the higher dose possible with valacyclovir might provide a practical treatment to prevent CMV disease. But this study was stopped on February 13 because there were more deaths in the valacyclovir arm than in either acyclovir arm. No one knows why this happened. But we have learned that volunteers assigned to the valacyclovir arm were on the drug for less time than those assigned to the acyclovir arms. And the main cause of death -- progression of HIV disease -- seemed to be similar in all the arms. Comment This study may stimulate research in use of acyclovir to increase survival by persons with late-stage AIDS. Since those assigned to acyclovir lived longer than those assigned to valacyclovir, either the acyclovir was helping, or the valacyclovir was hastening death, which seems unlikely. One possibility is that the valacyclovir dose was too high for this patient population, leading to side effects and interruption of treatment, resulting in more time off drug in the valacyclovir arm. The acyclovir arms may then have shown a greater survival effect because of greater time on treatment, or greater consistency of treatment. A recent epidemiological study using the MACS (Multicenter AIDS Cohort Study) database suggested that "consistent use of acyclovir at a dose sufficient to suppress herpetic recurrences (that is, 600 to 800 mg/day) has a clinically significant effect on prolonging survival in a well-characterized cohort with extensive previous exposure to herpesvirus infections" (D.S. Stein and others, "The Effect of the Interaction of Acyclovir with Zidovudine on Progression to AIDS and Survival," ANNALS OF INTERNAL MEDICINE, July 15, 1994, pages 100-108) --finding that consistent use, not high dose, seemed to matter. The same study also found the effect in late-stage disease -- another finding consistent with ACTG 204. There have also been negative results. For example, two studies presented at the recent Human Retroviruses conference in Washington, D.C., failed to find a survival benefit of acyclovir. But it also appears that neither of them can rule out a benefit, due to certain limitations of those studies. We hope to learn more about what happened in ACTG 204 at the semi-annual ACTG meeting next week. We especially want to know how the two acyclovir arms compared, and any details in the differences in outcome among the valacyclovir, high-dose acyclovir, and low-dose acyclovir arms. And we want to see how researchers and physicians interpret this very unexpected result. ACTG 204 might accidentally have been the controlled study needed to focus research interest in acyclovir and survival -- with the valacyclovir arm unintentionally providing the control. This interpretation will be supported or contradicted as more information becomes available. ***** AZT: Pediatric Study Changed After Worse Monotherapy Survival A government study of treatment for children with symptomatic HIV infection was stopped early after those treated with AZT alone showed worse survival than those in at least one of the comparison treatment groups. ACTG 152 compared AZT alone, ddI alone, and the combination of AZT plus ddI, for treating children from three months to 18 years old who had little or no prior anti-HIV treatment. The trial was double blind, meaning that neither the patients nor the doctors treating them knew who was in which group. But for ethical reasons, a special committee called the DSMB (Data Safety Monitoring Board) periodically unblinds such studies in secret, so that in case there is a major difference between the treatment arms, the study can be stopped or revised so that patients are not left on the worse treatment. In this case, the DSMB recommended that the AZT- only arm be discontinued, but that the other two arms continue because the survival difference between them is not great enough to meet the statistical test required for stopping that part of the study. Because the study is continuing, the DSMB will not say which of the other two arms looks better at this time, since doing so could bias the results and seriously harm the study. Unless a DSMB stops or changes a study, it says nothing. ACTG 152 will reach its scheduled end later in 1995, at which time all the data will be available to be analyzed. Comment This result -- a difference large enough to stop the trial early -- was unexpected. We may not be able to know what it means until the study stops later this year. There are many possibilities. One is that those assigned to the combination treatment did better than those assigned to a single treatment alone -- and that the survival difference was unexpectedly great because HIV disease can progress faster in children than in adults. We hope to learn more at the ACTG meeting next week. A major question, which may need to wait until the end of the study, is the effect of age differences in this result. Children three months old may react differently to treatment than those 17 years old -- even if Congress lumped them together when it mandated "pediatric" trials at the expense of adult research. Age-related analysis will be important for developing treatment recommendations for children of different ages, for understanding what this result may say about treatment of adults, and for guidance about when and how adult data can reliably be used to guide treatment for children. ***** Kaposi's Sarcoma: DOX-SL Approval Recommended The FDA's Oncologic Drugs Advisory Committee voted eight to zero to recommend that DOX-SL be given accelerated approval for treatment of AIDS-related Kaposi's sarcoma (KS) in patients who have failed conventional treatment. Under accelerated approval, the company will be required to conduct additional research, continuing after the drug is approved. The committee had previously voted ten to zero against approving DOX-SL without requiring the further research -- and some earlier critical votes were close. (Some newspapers got the story wrong, and erroneously reported that the committee had rejected the drug.) AIDS TREATMENT NEWS was not at the February 14 hearing; the best report we have seen was in BioCentury, a weekly faxed newsletter published by BioCentury Publications Inc., San Carlos, California. Apparently the committee was unhappy with data analysis provided by the drug's developer, Liposome Technology Inc., and based the approval recommendation on the FDA's analysis. Comment Although this case ended well, it illustrates an ongoing problem with the current drug-approval system. Each advisory committee -- in this case consisting of cancer experts, not AIDS experts -- sees many approval applications over the years, and has developed its own "corporate culture" for judging them. This corporate culture can include an accumulation of in-group or academic criteria, each of which may have been useful in making some decision in the past, and which then become institutionalized. When a major pharmaceutical company which is well-accustomed to doing business with a particular committee brings a new drug before it, this ingrown academic or committee culture is not a problem; it may even be a benefit. Everyone knows the rules, and the rules can improve over time. But a smaller biotechnology company, which may have a single product, is likely to be coming before the committee for the first time, having seen only one new-drug application -- its own. It is at a serious disadvantage because it has no background in the nuances of the committee. And the committee cannot easily compensate for this inexperience, because its members have little background in the company, its people, or (often) its technology. This can and does lead to the mistaken rejection of important drugs which clearly benefit patients. The FDA saved the day in this case, as it has done in some other cases before. The problem is that we should not have to keep our fingers crossed for the system to work. Changes in personnel, or just bad luck, could lead to the kinds of delays which people with AIDS routinely suffered in the early years of the epidemic. It is easier to point to a problem than to suggest a solution. Perhaps the FDA could develop a body of knowledge, based on past experience with its committee system, to help committee members avoid certain perennial mistakes. ***** AIDS TREATMENT NEWS Published twice monthly Subscription and Editorial Office: P.O. Box 411256 San Francisco, CA 94141 800/TREAT-1-2 toll-free U.S. and Canada 415/255-0588 regular office number fax: 415/255-4659 Internet: aidsnews@igc.apc.org Editor and Publisher: John S. James Reader Services and Business: Richard Copeland Thom Fontaine Tadd Tobias Statement of Purpose: AIDS TREATMENT NEWS reports on experimental and standard treatments, especially those available now. We interview physicians, scientists, other health professionals, and persons with AIDS or HIV; we also collect information from meetings and conferences, medical journals, and computer databases. Long-term survivors have usually tried many different treatments, and found combinations which work for them. AIDS Treatment News does not recommend particular therapies, but seeks to increase the options available. Subscription Information: Call 800/TREAT-1-2 Businesses, Institutions, Professionals: $230/year. Nonprofit organizations: $115/year. Individuals: $100/year, or $60 for six months. Special discount for persons with financial difficulties: $45/year, or $24 for six months. If you cannot afford a subscription, please write or call. Outside North, Central, or South America, add air mail postage: $20/year, $10 for six months. Back issues available. Fax subscriptions, bulk rates, and multiple subscriptions are available; contact our office for details. Please send U.S. funds: personal check or bank draft, international postal money order, or travelers checks. VISA, Mastercard, and purchase orders also accepted. ISSN # 1052-4207 Copyright 1995 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.