Why AIDS Drug Development Has Failed

Francisco AIDS Foundation public policy forum on research
issues, 8/23/94.]

The Problem

The recent Yokohama conference was badly reported in the
press. Behind the gloom and doom on AIDS treatments, much
valuable science was overlooked. AIDS Research is improving,
and good work is finally being done; but drug development, a
very different process by different people, is still a
disaster. Why?

If you ask scientists, most will say that the lack of
treatment progress results from the biological difficulty of
the problem, of controlling the HIV virus. This is true --
but not the whole story. The lack of progress also results
from systematic human mistakes. Yes, if the biology of
stopping HIV were easy, even the crippled effort we have
today would have already been successful. A hard problem
means that we have to do better to succeed.

But there are political reasons why it has been difficult or
impossible to successfully raise the alarm. And the same
political obstacles are stopping progress today.

Medical Research Progress -- Where It Comes From

Almost all medical advance in the past, and still today,
comes not from rational calculation or design, but from the
unexpected, the unpredictable, the unknown. And the unknown
first comes into view without a major corporate,
professional, or political constituency behind it. But today,
the process of mainstream drug development creates such high
barriers and obstacles -- regulatory, financial, legal, and
other -- that only the largest companies, with a major
corporate commitment, can progress over them.

This means that the new ideas and information that come to
doctors, scientists, and others through accident and chance
observation -- the very ideas and information that feed
medical progress -- usually cannot go anywhere. No matter
what their intrinsic merit, they cannot move at all to build
the credibility required to crank up the very expensive
processes required today before the first human test. There
is no path which leads over the barriers. So they are stuck
forever.

Hundreds of entirely reputable ideas wait like this, frozen
on display in peer-reviewed journals, or out of public sight
in a scientist's or doctor's mind or in unpublished work.
Eventually, a tiny handful may be picked up by a well-
financed corporate development project. But because of the
great role of the unexpected in medical research, there is no
reason to think that these lucky few are the cream of the
crop. Instead, they are essentially selected at random, based
more on patents, contracts, deals, and personalities than on
perceived merit (however unreliable even the latter is).

As a result, the world has appallingly few shots at a
significant treatment improvement. What is needed is a
rational development path for the hundreds of other good
ideas and proposals, so that they can begin the process of
establishing their credibility, if they merit it. Many
different possibilities would then have a chance at
development. Eventually, the best of them could move into
formal clinical trials.

AIDS Politics: The Unholy Alliance

It's no accident that this reform was not accomplished long
ago.

Start with a big picture, beyond AIDS, beyond medicine. In
any public-policy arena where regulation is involved, there
is usually an ongoing battle between two superpowers, big
business and consumer protection. And public policy is
determined by where the battle line between them ends up.
This battle is the normal and usual process by which we as a
society balance different risks and different benefits
against each other.

In drug development, for AIDS or for other diseases, this
battle proceeds, as elsewhere. But unfortunately, there is
one key place in drug development where the battle does not
work as it should, and instead produces pathological results.
And this key place is the unexpected, the creative, the
chance observations, the new ideas -- which proceed from the
unknown, and form the river which feeds most of the potential
for advances in treatment development, as discussed above.

In this one key area (which is unimportant for the present,
but centrally important for the future) big business and
consumer protection are not in conflict, but instead work
together -- an unholy alliance against new ideas. For very
different reasons, both of these superpowers want the
barriers and obstacles, which any forward movement must
cross, to be set as high as possible. Consumer protectionists
want high barriers to protect the public against dangerous
products and unscrupulous companies; big business wants high
barriers to protect itself against competition by small
business. Big business can pay almost any price; and later,
with a monopoly of an essential drug, raise prices as high as
necessary to get the money back and more.

Whether a potential advance is a major corporate development
project with tens of millions of dollars behind it, or an
accidental observation with no constituency yet, doesn't
matter -- both are treated equally. But the multimillion
dollar corporate effort can (with sufficient merit) overcome
the barriers and prevail, while the new idea which has had no
chance yet to build a constituency or financial support is
stopped cold, usually forever.

This problem has not been solved because both consumer
protection and big business have such a pervasive influence
throughout the AIDS research and service communities. Almost
everybody who is professionally involved worships at one or
both of these altars. Big business funds thousands of
projects by scientists, doctors, and service organizations --
as it should (and small business, incidentally, funds almost
nothing in comparison). Meanwhile, consumer protectionists
dominate policy almost everywhere in AIDS, from our friends
in Congress, to the FDA of course, to AIDS Action Council and
the large service organizations -- which, despite ongoing
pressure from their major donors, have usually refused to
become seriously involved with treatment development. To do
so could jeopardize important relationships that they must
maintain in order to accomplish their service missions.

The end result is that treatment progress is seldom allowed
to happen outside of big-business control. And big business
had no interest in AIDS until AZT made money, and is losing
interest now as ddI, ddC, and d4T are unlikely to ever repay
their development costs. The result? Near-guaranteed
stagnation, which is what we have today, and have had since
the beginning of the epidemic. This is why there has been so
little progress in finding better treatments for HIV, and why
so little relief is in sight.

HIV RNA: New Viral Tests and Their Importance

New viral blood tests, much more accurate than the ones used
before, have recently become available to physicians. These
may provide a partial escape from the bleak drug-development
and political landscapes above. [For background on these
tests, see "HIV RNA: New Blood Test for Individualized
Therapy and Faster Trials," AIDS Treatment News #204, August
5, 1994.]

These tests are important because they can indicate quickly
(within a month, and possibly within days) whether a
particular antiviral treatment is working for a particular
patient. It doesn't matter if the treatment is mainstream,
such as ddI, or "alternative," such as Chinese herbs; if the
virus in the blood is reduced, the tests will show that.

This means that certain new treatments -- those in actual use
by people with HIV, or which can be prescribed by physicians
or otherwise obtained -- now will have a path to begin to
build credibility. Probably the great majority of
"alternative" treatments will be found not to work, and be
largely discarded. But if one patient benefits dramatically
from a treatment (as seen by reduction of virus in the
blood), and then a second, third, and fourth also show a
dramatic reduction, then there will probably be enough
interest to get that treatment into a formal trial, either
through a community-based research organization, or by
finding a corporate sponsor. The potential new treatment will
then be on a development path, instead of left waiting
forever.

This almost never happened before the new tests were
available, since it has been necessary to crank up an
expensive and cumbersome trial before there was any credible
data suggesting measurable benefit in people. Now, the
credible data can start with one person's decision to use an
unproven treatment, not for research but for their own
medical care. If the early data is negative -- the usual case
-- the patient can drop the treatment quickly, and perhaps
try another. And if the data is promising enough, formal
research can follow.