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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
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ISSN # 1052-4207

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