Call for Action: Community Consensus on Treatments Needing Development

Recently a number of AIDS treatment stories have appeared in
the press. Most of this news is good, although sometimes there is
less to it than meets the eye. Yet critical problems remain. This
article shows how community organizations can help to overcome
the perennial problem of the lack of development of major new
drugs.

The bad news is what isn't happening. Most policy problems
in AIDS stem from lack of national coordination, lack of anyone
responsible for developing, implementing, and monitoring coherent
national strategy. In treatment development, there is no public
office able to investigate any potential treatment (regardless of
who owns it, or its stage of development), select those few which
are most critical for the public interest and most urgently need
attention, identify obstacles to their speedy development, and
place those obstacles on the national agenda. As a result, the
most important drugs today are failing to move into the
clinical-trials pipeline. Unless we act now to invest in the
future, little will come out over the next two to three years
except ddI and ddC -- important new options, yes, but not enough by
themselves to prevent many deaths.

Ideally, some official body with well-respected medical and
scientific leadership and staff would have done this job for the
last ten years. It would take time, however, to bring any such
group into being, and it would be difficult to assure its
independence from the problems of the past. But there is an
alternative which could be started immediately, and would in some
ways be better than an official body.

By working with the organizations and the networking which
already exist, we can develop community consensus -- among PWA
groups, advocacy groups, front-line physicians, research
organizations, and others -- on which potential treatments are most
important, and what must be done to move them forward. While such
an effort would not have the automatic authority of a government
body, it could in practice have even more influence. Official
reports often collect dust on library shelves, because they have
no constituency. But the process of building a consensus also
builds a constituency for carrying it out.

Is Anyone Doing This Already?

Several existing or proposed bodies are concerned with
setting AIDS treatment research priorities:

* The ACDDC (AIDS Clinical Drug Development Committee).
This committee within the ACTG (AIDS Clinical Trials Group) meets
four times a year to divide drugs into four priorities: high,
medium low, and not recommended for clinical trials at this time.
The meetings are closed, and we do not know the committee's
operation in detail, but there have long been serious concerns
about drug priorities within the ACTG.

About two years ago, a physician trying to get a drug into
the ACTG system said that the drugs were taken up by the
committee in no particular order. Usually at least one of the
drugs proposed would provoke argument among the competitive
scientists, and once the time for the meeting had elapsed, all
the other proposals behind it in the queue were put off for the
next meeting, months away. While we have never seen an ACDDC
meeting, this scenario rings true, in that a committee charged
with setting priorities could hardly pre-prioritize without
raising questions about the need for the committee's existence.

We question whether a committee meeting four times a year,
with busy members presumably supplied with stacks of paper to
inform them about the decisions they are to make, is the best way
to set priorities for treatment research. In almost every other
aspect of human affairs, a new idea needs a "champion" to push
it, or it will not progress. Without an ongoing relationship with
the advocate, committees almost always reject important new
ideas, because of political dynamics. It is easy to score points
by criticizing a novel proposal, but dangerous to become
identified with something unfamiliar.

For this article, we picked the three drugs that we would
most recommend for urgent attention: hypericin, TIBO derivatives,
and HPMPC (see below). The most recent list of ACDDC priorities
which we have obtained -- through the December 1989 meeting --
included none of these three in any category, suggesting that
none had been considered by that time; we have heard that one or
more have been given high priority since. (For TIBO derivatives,
the first paper was not published until February 1, 1990;
however, study results usually circulate in the scientific
community for months before publication.)

The ACTG is built on investigator-initiated research. Almost
all of its principal investigators have consulting arrangements
with pharmaceutical companies (usually not disclosed), in
addition to their Federal grants or contracts. It seems unlikely
that a drug would come to the ACTG (and therefore to the ACDDC
within it), unless it has a sponsoring pharmaceutical company,
and that company was ready to move the drug and had decided to
seek Federal help in doing so.

The ACDDC, as an advisory body of the ACTG, presumably
considers only drugs which the ACTG could test. It does not seek
out new drugs (even if they are not yet ready for clinical
trials, or are not commercially viable, and/or if their owner is
busy elsewhere or does not want to bother with an AIDS drug) and
then mobilize whatever resources are needed, including public
pressure, to get them tested quickly. Yet this is what needs to
be done.

* The ARAC (AIDS Research Advisory Committee). This group,
to include people with AIDS, is part of the proposed "parallel
track" system published last month in the Federal Register (see
article on parallel track in AIDS TREATMENT NEWS #104, June 1).
If parallel track is accepted, after the 60-day period for public
comments, then the ARAC will be a major advance; for the first
time there will be an official body able to take an integrated
approach in deciding which drugs are important. (Pharmaceutical
companies cannot do so, because each will only promote its own
products; and the FDA usually does not compare different drugs,
but says "yes" or "no" to each drug separately, based on
paperwork placed in front of it.)

But the ARAC has not yet met. And even if parallel track is
accepted and the system works perfectly, it will focus primarily
on drugs well along in clinical trials and ready for parallel-
track access. Yet today the biggest bottleneck seems to be the
business negotiations which occur as a promising compound
finishes its pre-clinical development and moves into human trials
for the first time. At that stage, an organization focused only
on parallel track can do nothing.

* HIV/AIDS Biomedical Research Priorities document. Over 45
major AIDS and health organizations have endorsed 15
recommendations to the U. S. National Institutes of Health on
AIDS/HIV biomedical research priorities (see article in AIDS
TREATMENT NEWS #104, June 1). This important effort embodies the
kind of consensus building which is needed. We are suggesting a
companion effort, to develop consensus on specific treatments
which need public and professional attention to facilitate their
progress through the research system. The May 17 document does
not mention any treatments. Both kinds of efforts are needed.

* New ACT UP list of potential treatments. ACT UP/New York
is preparing a list of drugs and treatment approaches which the
ACTG has not researched. The pre-publication draft we have seen
lists dozens of drugs and classes of drugs, mostly high-tech
approaches to treatment, some of which we had not heard of.

The research to create this list is exactly the kind of
effort needed to develop community consensus on a research
agenda. The information comes from scientist, physicians, and
others with specialized knowledge. The activists make sure that
priorities reflect the interests of persons with AIDS or HIV,
above those of companies with products to sell, or of
professionals with careers to advance.

Even harder than preparing the initial list will be setting
priorities. We believe that this effort should focus on finding a
short list, perhaps five to ten treatments most needing public
and research attention -- not on trying to rate or categorize every
treatment suggested.

Treatment Examples Show Unmet Needs

Since U. S. media coverage of AIDS research usually consists
of rewriting official press releases, most of the public believes
that the slow pace of treatment development primarily reflects
the scientific difficulty of the problem, and appropriate medical
caution. In fact, business and administrative problems cause most
of the delays in treatment development. Glaring past examples
include aerosol pentamidine, used to prevent pneumocystis, and
fluconazole, an important new antifungal. These cases are not
unusual; most drugs suffer similar delays, only there is less
publicity about what happened. (A few drugs have been developed
rapidly -- for example, the initial approval of AZT, and the
progress of ddI since last summer.)

In the cases of aerosol pentamidine and fluconazole, the
delays occurred after considerable human experience with the
drugs in question was already available. But the biggest problem
today seems to be the obstacles to taking a promising compound
from pre-clinical laboratory and animal studies into the first
human trials and then into early efficacy studies. The three
drugs below were not picked as examples of delays -- indeed they
are progressing faster than most. They do show how much could be
gained if there were a public voice to insist that the most
critical potential treatments be expedited, not left to usual
procedures.

* Hypericin. This chemical, in human use in Europe as an
antidepressant and long used in herbal medicine, has been
extensively covered in AIDS TREATMENT NEWS starting August 26,
1988 (issue #63). It works very well against HIV in the test
tube, and against other retroviruses in animals. A community-
based study in San Francisco, using available herbal extracts,
showed sustained T-helper improvements in those who started with
high T-helper counts (the average baseline value was over 500);
these patients were not using any other antiviral. But with the
very small hypericin doses in the herbal extracts now available,
most of those with low T-helper counts (mean under 200) continued
to show T-helper declines. P-24 levels did decrease or become
negative in four of six patients, but they were also using AZT,
which might have caused the improvement. (For more information
about this study, see AIDS TREATMENT NEWS #96, February 2, 1990.)
Another study of the herbal extract found no significant
improvement in T-helper counts or p24 levels, whether or not the
extract was combined with AZT (see AIDS/HIV Experimental
Treatment Directory -- published by AmFAR -- December 1989, page
35).

However, the herbal preparations contain very low
concentrations of hypericin; animal studies suggest that larger
amounts of the chemical are needed. Animals can tolerate large
doses of pure hypericin, suggesting that people might be able to
do so (long-term human tolerance of low doses is already
established through the history of use of the herbal extracts).
And hypericin works very differently than AZT; it is not a
nucleoside analog (like AZT, ddI, and ddC). Therefore if it does
work in people as an anti-HIV treatment, it could open a new
world of therapeutic options, used either alone or in combination
with AZT or other drugs.

All this, except for the community studies of the herbal
extract, was known two years ago, and was published in a leading
journal (Proceedings of the National Academy of Sciences, USA,
July 1988). But because of the lack of effective national
mobilization for AIDS treatment development, this very promising
compound had to go through the usual procedures: finding
investors, chemistry research to improve methods for synthesis,
creation of a large enough batch so that the same supply could be
tested in animals before begin given to humans, and toxicity
tests in animals. According to the February 19 issue of FDC
Reports (The Pink Sheet), hypericin was being tested in monkeys
at that time (February 1990), and if all went well, could begin
human efficacy testing in late 1990, with filing for an NDA
(permission from the FDA to market the drug) in early 1993, "if
the drug shows 'dramatic' efficacy and lack of toxicity in
humans." (And if no ordinary problems develop in business,
administration, personnel turnover, etc.)

By the standards of business as usual, four and a half years
from the first published laboratory report of antiviral activity
to application for the NDA is fast. But if the nation would
mobilize to save lives, it could have been done many times
faster, without undue risk. Once the drug looked promising,
enough could be extracted from plants, or synthesized by the
already-known procedures, for animal tests for acute toxicity,
then small, efficient human tests of safe doses for short-term
evidence of efficacy (p24 decrease, T-helper improvement, weight
gain, decline of AIDS-related symptoms, etc.) If the drug showed
clear signs of working, then an all-out effort would be justified
to solve any supply problems, get the treatment to those who had
no other alternative, continue collecting data on long-term
toxicity, begin combination trials with AZT, and begin trials to
establish conclusive proof of efficacy. Note that despite its
speed, this approach to developing key drugs would cost little
until a drug was all but known to work, at which time money would
be easy to raise.

What we are suggesting here is not very different from what
in fact was done with AZT, ddC, and ddI. The early phase I
trials, in theory designed to test for toxicity and determine
maximum tolerated dose, in fact also provided the efficacy
information which motivated larger trials. But the early human
testing of all three of these drugs depended on a single
individual -- Samuel Broder, M. D., who has since been promoted to
director of the National Cancer Institute (NCI). Since Broder now
has other duties, new drugs are not following expeditiously from
preclinical work into clinical trials. We suspect that the
fundamental problem is that new drugs have not yet built
(bought? ) a constituency within the AIDS research establishment.
The lucky chance of the right individual in a strategic position
(the NCI has more power than pharmaceutical companies to overcome
Federal obstacles in early stages of clinical trials) temporarily
masked the major weakness and bottleneck in the whole U. S. drug-
development process -- the lack of movement of promising compounds
through completion of preclinical development and into trials.
With Broder no longer in position, this stage in the AIDS drug-
development process has largely shut down. But the public has not
noticed, because the problem is at the beginning of the
clinical-trials pipeline, so its practical effects are delayed.
Only a year or two later does the public become aware that the
new drugs are not there.

When government experts say that there are no new antivirals
ready to test, most people accept their statements on faith,
because few have been prepared to challenge them. But the AIDS
community can do its own investigation, by networking among
organizations and individuals with many different talents and
skills. With our own consensus about which treatments most
urgently need public attention, we can discuss options like
hypericin when experts say that no new drugs are ready. Sometimes
the experts may be right. And sometimes they may be protecting
themselves, as bureaucrats often do, by providing standard
answers suggesting that whatever is already happening is all that
could or should be done.

* TIBO derivatives. This class of drugs was developed in
Belgium, by researchers using a process of intelligent trial and
error to create new anti-HIV drugs. The first report, published
in Nature on February 1 of this year, especially concerned one
compound called R82150.

Laboratory tests showed that the drug was effective against
HIV in extremely small concentrations -- 31,000 times less than the
dose which harmed cells (compared to 6,200 for AZT). Then in
another test, dogs were given in a single dose a thousand times
the amount expected to be effective, with no harm. Finally, six
healthy people volunteered to take the drug, and no toxicity was
found.

On May 16 the U. S. National Institute of Allergy and
Infections Diseases (NIAID) distributed a reply to ACT UP/New
York, which had strongly criticized NIAID's ACTG research system.
ACT UP had urged that TIBO derivatives be tested, but NIAID
replied that they were not yet ready for clinical trials.

We find it hard to understand how a drug which appears to
have a huge margin of safety, and which has already been given to
humans, is not ready for clinical trials -- especially when there
is so urgent a need for new anti-HIV drugs. We suspect that this
drug "is not yet ready for clinical trials" because the business
and administrative arrangements are not ready.

A small clinical trial has in fact started in Europe. If the
United States, with more AIDS cases and also more research
resources than any other country, is behind in the development of
some of the most important treatments, no one would be surprised.

By building a community consensus on the most important
priorities for development, we can focus on the critical drugs
and make sure that all necessary resources are available for
their development. Without community input, it will take many
years for drugs like R82150 to become available.

* HPMPC. This chemical, now being developed by Bristol-
Myers, acts against CMV and herpes (not against HIV). HPMPC was
discovered in Belgium by a team which included one of the
researchers who discovered the TIBO derivatives. Technical
articles about HPMPC have appeared in journals for several years.

Much of the research on HPMPC has tested it for herpes, but
in AIDS the most important use may be for treating CMV
(cytomegalovirus), which can cause blindness, or other serious
infections. Two drugs, ganciclovir and foscarnet, are already
used for CMV, but both have drawbacks.

In the laboratory HPMPC is active against human CMV in very
small concentrations, .04 micrograms per milliliter. Yet a
toxicity study found that mice could tolerate up to 200
milligrams per kilogram per day.

One animal study (abstract #751) was presented last
September at ICAAC (Interscience Conference on Antimicrobial
Agents and Chemotherapy), an annual conference on new
antibiotics. Animals cannot be infected with human CMV, so a
related virus, murine cytomegalovirus, was used in mice instead;
experience with foscarnet had indicated that this animal model
might help predict which drugs would be useful for human CMV
infection. The study compared ganciclovir, the only CMV drug
approved in the United States, with HPMPC. Ganciclovir reduced
viral titers in blood and organs by 10 to 100 times, during the
21 days of the test. HPMPC reduced the titers by 100,000 to
1,000,000 times (to undetectable levels) in four to six days.

Another study presented at the same conference (abstract
#739) reported that laboratory tests with cell cultures suggested
that infrequent dosing might be effective.

In all the animal studies we have seen, the drug has been
administered by injection (or applied topically to herpes
lesions); one paper found some efficacy with oral administration
of a related drug (HPMPA), but large doses were necessary,
suggesting that oral availability might be poor.

Supply problems are unlikely for HPMPC, as at least three
papers have published methods for making it.

We do not know the current status of HPMPC at Bristol-Myers;
pharmaceutical companies seldom release details about their
preclinical drug development. Apparently the next step is for
Bristol-Myers to complete preclinical tests, obtain an IND
(permission for human testing) from the FDA, and begin clinical
trials.

We do not know whether or not development is moving rapidly.
There does seem to be considerable enthusiasm for this drug among
the few medical and research professionals who are familiar with
it. On the other hand, there may be a limited market -- for CMV
because the infection does not need treatment except for persons
with immune deficiencies, and for herpes because there is already
a well-established treatment, acyclovir.

Under the U. S. system of drug development, companies which
have exclusive rights to even vitally important drugs have no
obligation to do anything with them; the public interest has no
place in the decision. The FDA can bring pressure informally if
it wants to, because companies must stay on its good side. But
the law requires the FDA to keep much of its information secret,
so usually the public does not know what is happening until there
are clinical trials, which are hard to conceal. Often it is
difficult to know whether a drug is being actively and
effectively developed, or whether there are unnecessary
obstacles. Fortunately, some companies have done much more than
they had to in support of the public interest. Perhaps the
remaining problems will be ameliorated by the growing belief that
the lives of persons with AIDS are worth saving.

* Other treatments. While preparing this article we made a
list of treatments which might deserve high-priority, expedited
development. We made no attempt to be complete; for example, we
omitted some important drugs like ddI and ddC, which are already
in high-profile development. Also, we did not include non-drug
treatments such as nutrition or exercise in this particular list.
The treatments are in alphabetical order.

This list should show that there are many treatments which
need to be investigated, and it may suggest leads that others
will want to pursue:


AS101 (for HIV)
AzdU (HIV)
Azithromycin (MAI; toxoplasmosis)
ddC or ddI in combination with AZT (HIV)
Compound Q (HIV)
d4T (HIV)
Diclazuril (cryptosporidiosis)
G-CSF (a colony stimulating factor)
Glycyrrhizin (HIV)
HIVIG, or other passive immunotherapy (HIV)
HPMPC (CMV; herpes)
Hypericin (HIV)
Imuthiol (immune modulator)
Itraconazole (many fungal infections)
KS secret treatment
Levamisole (immune modulator)
Milk antibodies (cryptosporidiosis)
NAC (HIV, indirectly)
Oxophenarsine (HIV -- see 1989 Montreal conference
abstract #M. C. P. 133)
Peptide T (treatment for neurological effects of HIV)
Sulfolipids (HIV)
TIBO Derivatives (HIV)
Vaccines: Salk, HGP-30, some others (HIV)
The Next Step


The way to develop community consensus on which treatments
need a public voice to assist and expedite their development is
through expanding discussions among PWA, advocacy, physician, and
other organizations. No one needs to play gatekeeper to designate
who is or is not part of this process; treatment investigation is
labor intensive, and it is clear who is doing the work. People
usually start by investigating treatments which interest them,
and bringing what they find to others. Leadership emerges
spontaneously, without formal machinery.

Such discussions are already going on; for example, ACT UP
groups in several cities (including New York, San Francisco,
Boston, Providence, and Washington, DC) now have treatment
committees. PWA coalitions have long been interested in
treatments. Front-line physicians and community-based research
organizations are primary sources of information -- as well as
friendly researchers in academia, government, or industry. This
work is not new. More people need to become involved, however,
and let each other know what they are doing. Also, we should
discuss specific goals for this effort -- for example, do we agree
that we should reach consensus on a few high-priority treatments,
and then focus on expediting their development?

Many people are ready to contribute money or other resources
to research, but are stopped by the confusing jumble of so many
voices advocating so many different approaches and directions.
Potential investors or contributors cannot find information they
can trust, because those close enough to the research to evaluate
it usually have personal interests in the decisions or personal
loyalties to those who do. A public process of dialog and
consensus, centered in organizations interested in treatment of
patients instead of commercial or professional promotion, could
provide a clear context in treatment research and open the door
for those ready to apply their talents and energies.