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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

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AIDS TREATMENT NEWS reports on experimental and 
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Treatment News does not recommend particular 
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ISSN # 1052-4207 

Copyright 1995 by John S. James.  Permission granted for 
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