Call to Activists: Focus Needed on Early Human Research

The main obstacle today to better AIDS treatments is early
in the drug-development pipeline. Hundreds of potential
antivirals are coming out of laboratories and being published in
leading journals, but almost none of them move further, through
FDA-required animal toxicity tests and into early human trials.
Once a potential drug shows biological activity in humans (by
decreasing viral measures, or raising T-helper cells, etc.) , it
would likely get enough attention to be developed appropriately.
But without such data, a drug is usually ignored, because: (1)
the scientists who developed it cannot finance clinical research;
(2) pharmaceutical companies consider many factors other than
medical or scientific ones in deciding whether to develop an AIDS
drug; (3) the public has little consistent interest in a chemical
which has never been tested in humans; and (4) the Reagan-Bush
administrations did not take responsibility for managing the
research effort. The resulting catch-22 -- no interest since
there is no data, no data since there is no interest -- has
blocked development of almost all potential AIDS drugs, and is
still blocking them today.

With the new administration, this critical problem could be
fixed, allowing new treatments to come into use quickly if
appropriate. As soon as there is evidence that a drug works very
well, it is likely to move exceedingly rapidly into wider use.
But if the same drug is never tested in people, or is only tested
for toxicity in HIV-negative volunteers, the necessary evidence
will not exist, and the drug will probably be delayed
indefinitely.

The big danger now is inertia, because no force is yet
available to make the changes needed. Pharmaceutical companies
are interested in short-term gain from drugs already on the
market or soon to be there. Most influential AIDS researchers,
even when supported largely by federal grants and contracts, also
have business ties with these companies -- a situation which has
long distorted research policy and prevented potential new drugs
from being fairly considered. The Washington, D. C., AIDS policy
organizations have not historically included research issues in
their "corporate culture," and might not be able to challenge the
research community when necessary; yet these organizations will
manage the articulation of the AIDS consensus which will go to
the Clinton transition team and administration. Some candidates
now discussed as potential "AIDS czar" have avoided treatment
issues, apparently due to unwillingness to challenge their
scientific colleagues. In short, all the conditions are in place
for a nightmare of business as usual, which could leave us, in
several years, about where we are today -- with no major new
antivirals and little advance in AIDS treatment except for
refinements in the use of AZT, ddI, and ddC.

AIDS activists can make the difference, by never letting the
most critical issues in drug development be ignored. So far,
however, early drug development is scarcely on the table among
activists. It has been easier to focus on more immediate
concerns, such as conditions for expanded access, or equity in
access to clinical trials. These issues are also important, but
without better drugs, they will not save many lives.

The facts about excellent candidate drugs not getting into
the development pipeline, or not proceeding coherently to the
first tests of antiviral activity in humans, have been public
knowledge for years. Yet this issue has received little
attention until now, because until this month there was no chance
of resolving it successfully. Such a pervasive, systemic
malfunction cannot be repaired without national commitment and
high-level involvement and support. The FDA could not solve the
problem by itself; neither could the NIH; neither could any
private organization. The necessary national mobilization would
have required engagement and cooperation of higher Federal
officials, which was not available.

Our biggest enemy today is the inertia of 11 years of
Federal AIDS mismanagement. What can defeat it is an ongoing
determination to bring the most critical problems into the light
of public and professional attention, to keep them there as long
as necessary, and to insist that they be addressed. AIDS
activists must take the lead in exposing the seriousness of
neglecting the flow of new drugs into early clinical development.

* * *

Note: The following is our submission to the National
Commission on AIDS, which is preparing recommendations for the
new president and Congress. The Commission requested that these
statements, which were due November 23, include specific
recommendations to the executive and legislative branches.

Better AIDS Drugs: The Biggest Obstacle

To improve AIDS/HIV treatment and save lives of those
already infected, the greatest need by far is better
antiretroviral drugs. And the main reason progress in new drugs
has been so disappointingly slow concerns obstacles near the
beginning of the drug "pipeline" -- in the late preclinical and
early clinical stages of drug development. This part of the
development process has been overlooked, not because of
scientific disagreements but because of systemic political and
commercial snafus. It urgently needs more attention:

* Because of improvements by the FDA, the blockage near the
end of the drug pipeline has been greatly reduced; ddI, ddC, and
now d4T have been made available. The problem is that no major
anti-HIV drugs are now in the pipeline, except for some, like tat
and protease inhibitors, which are still very early in clinical
trials. Therefore, no important advances are likely from the
mainstream drug-development pipeline for at least several years.

(An FDA press release dated October 19, 1992 said that the
FDA had "received" more than 500 IND applications "to test drugs
or biologics that may have potential in treating AIDS and other
HIV-related conditions." But when the press release listed
"potential AIDS therapies publicly acknowledged by their sponsors
to be under study," it had to stretch considerably to include any
anti-HIV drugs. The following is the FDA's list of "INDs for
experimental antiviral agents": compound Q, N-butyl DNJ,
ribavirin, ddC, beta interferon, d4T, and AZDU. None of these is
likely to be a major advance in HIV treatment, and some appear to
be dead. Vaccines, which can also be HIV treatments, are listed
separately; but there is considerable debate about whether any
therapeutic vaccine has shown clinical benefit or is ready for
large trials. And as for the drugs the FDA could not name
because they had not been publicly acknowledged by their
sponsors, none could have progressed to large human trials
without being well known. In short, no important HIV drugs will
emerge for some time. The image of hope and competence projected
by the press release is an illusion.)

* Dozens if not hundreds of potential anti-HIV drugs or lead
chemicals have been produced in university and other
laboratories, tested in viral cultures or in animals, and
published in major, peer-reviewed journals. Usually development
stops there, since no one involved has the money to finish the
preclinical development required or to begin human tests. Since
no public agency takes responsibility for shepherding these
compounds into further development if justified, they usually
wait indefinitely unless some pharmaceutical company picks them
up -- unlikely when there is no data on biological activity in
humans.

* The existing AIDS trials networks (ACTG, CPCRA, CBCT) are
focused on a later stage of research. Today they are often
conducting dubious trials because they have no compelling drugs
to study.

* Some people believe that the National Cooperative Drug
Discovery Group program (NCDDG-HIV) is addressing this problem.
We have not attended their meetings, but we hear that they focus
on theories of rational drug design -- which clearly will be the
ultimate future of drug development, but so far has not been
effective for AIDS. (Much of the focus is on improving high-tech
tools such as computer imaging systems, but the drugs produced
with those tools have not worked.) For the current epidemic, we
also need empirical development of the most promising leads
available, even those resulting from chance discoveries instead
of high-tech science. But this work is undervalued because it is
usually routine and not glamorous.

* The bottom line is that we are suffering a serious
imbalance in research, because the drugs which most need
attention now for saving lives are not well positioned to build
the constituency needed to motivate their continued development.
Drugs which are already marketed, or almost ready for marketing,
can develop industrial, medical, and public constituencies.
Rational drug design generates both industrial and academic
support. But no constituency champions a drug developed by one
scientist or academic team, with no pharmaceutical sponsor, and
with no human tests.

Recommendations

* The executive branch must take responsibility for
proactively shepherding critical drugs through the development
process -- not just wait for some pharmaceutical company to move.

* The U. S. National Cancer Institute has shown that
government can successfully carry out early human drug
development when necessary. Both legislative and executive
branches should expand this work.

* The executive branch should set up a medical research
ombuds office, where anyone who knows about research snafus of
any sort can report them, and can expect to get action when
appropriate. Most of the problems which block clinical trials or
other research are red-tape accidents which could be cleared up
by a few phone calls from an office with the president's
authority behind it. When broader policy issues are involved,
the office should research and prepare recommendations for the
executive branch, for Congress, and for foundations, companies,
and other private organizations.