FDA Antiviral Advisory Committee Meeting to Consider ddC, ddI, Markers

On April 20 and 21 the Antiviral Drugs Advisory Committee, a
panel of outside experts set up by the U. S. Food and Drug
Administration (FDA), will meet in Bethesda, Maryland, outside
Washington D. C. This meeting, scheduled to begin 8:30 a.m. April
20, and 7:30 a.m. April 21, at the Bethesda Ramada Inn, is open
to the public.

On the first day the committee is scheduled to discuss:

* ddI, now an approved AIDS treatment, which was recommended
for approval by the same committee in July 1991, and approved in
October;

* The use of T-helper cells as a "surrogate marker" to show
if a drug for HIV infection is working in a clinical trial; and

* Whether to recommend approval of ddC. This issue will
also be discussed on April 21.

New data on ddI is expected to be released either at the
committee meeting, or at the Washington, D. C. meeting of the
AIDS Clinical Trials Group (ACTG) the week before. The purpose
of the ddI section of the meeting will be to evaluate whether T-
helper cell increases have proven reliable as a basis for
evaluating efficacy of nucleoside-analog drugs (such as AZT, ddI,
and ddC) used for HIV treatment. The committee had previously
recommended ddI for approval partly on the basis of T-helper
counts seen in a major clinical trial.

The most important part of this meeting will of course be
the discussion of ddC, since the issue at hand is whether or not
ddC should be approved.

Comment

Although no one knows what will come out of this meeting,
the prevailing opinion, unfortunately, is that the committee will
not recommend approval of ddC. As a single drug, ddC appears to
be inferior to AZT, at least in the short term. And some members
of the committee feel that there is less urgency for this
approval than there was in the case of ddI, since now there are
two antiretroviral drugs approved (AZT and ddI), instead of only
AZT.

The real interest in ddC is for use in combination with AZT,
which has become a de facto standard of care among many leading
AIDS physicians. The only published study on this combination
use showed extremely good results (see "ddC Background," AIDS
TREATMENT NEWS #145, February 21, 1992). But this study, called
ACTG 106, was fairly small, and was not designed to test the
efficacy of the combination; it was designed to test dosage and
safety of this use. What happened is that the combination was
found to work much better than anybody had expected.

A larger study designed to test the efficacy of the
combination (ACTG 155) is ongoing now, but no data has been
released. Apparently the advisory committee will not be allowed
even a peek at this data -- a very limited look so that they can
see whether or not the results of ACTG 106 are being confirmed --
which was allowed earlier for the same committee's evaluation of
ddI. (Researchers are almost always unwilling to release release
results while a trial is going on, for fear that volunteers would
conclude too early that one treatment looked better than another,
and drop out of the trial before conclusive evidence was
obtained.)

Two other issues may be involved:

* A new trial, ACTG 175, is testing this combination vs.
other treatments (AZT plus ddI, AZT alone, and ddI alone) for a
different group of patients -- those with T-helper counts between
200 and 500. This study, expected to enroll over two thousand
volunteers, will use a substantial fraction of the resources
available for clinical trials of AIDS treatments, and will
probably take over two years to produce any results. But it is
likely to be a cash cow for the participating institutions. If
AZT plus ddC becomes a generally accepted standard of care for
HIV infection, ACTG 175 might need to be discontinued. Could
institutional self-interest have contributed to the unusual
resistance to this combination treatment?

* Hoffmann-La Roche, the developer of ddC, has announced
that it will modify its expanded-access program for this drug, to
allow it to be used in combination with AZT, for some patients.
Since the drug will be more available than before through this
program, the advisory committee may conclude that approval is
less urgent.

But expanded-access programs, while a great advance over no
drug at all, do have drawbacks. They are not really "free," even
if the drug is free; requirements for medical care and laboratory
work usually exclude public clinics and uninsured patients. And
such programs almost always have strings attached, taking control
of treatment decisions away from patients and their physicians.

Expanded access developed as an alternative to drug approval
because a number of leaders who are influential on this issue
consider it immoral to sell a drug without full proof of
efficacy. But they have less problem with giving the same drug
to the same patients for free. The resulting politics has led to
a dysfunctional system, with no vision for its improvement.

What should be done? We believe that ddC should be approved
quickly, with appropriate documentation ("labeling"), provided
that the currently-existing data from ACTG 155 confirms the
results of ACTG 106. Let patients and their physicians decide
whether or when to use the combination treatment. There is
already enough information to support rational decision-making
under uncertainty, which is what physicians normally do. And
little is lost if we "never know" for sure if the combination
treatment is best, since even this combination leaves much to be
desired, and will become obsolete as soon as a truly good
treatment becomes available.

For the long term, we need to start now with proper planning
and management of the whole HIV treatment-development effort. Do
we really need to have each new drug tested two or three times
because of arbitrary dividing lines of T-helper counts under 200,
200 to 500, and over 500? Should we spend much of the money and
other resources available for AIDS clinical trials over the next
several years for developing treatments which everybody knows are
mediocre at best? It is already clear that ACTG 175 will show
that the combination therapies are better than the single-drug
treatments The main question this study will answer is how long
it will take to get the required statistical proof.

We should approve ddC now and move on, to develop better
drugs for the future.