AIDS TREATMENT NEWS No. 052 - March 11, 1988
On February 16 the U.S. Food and Drug Administration (FDA) and
the National Institute of Allergy and Infectious Diseases
(NIAID) approved the first-ever "treatment IND" for early
release of an AIDS treatment--trimetrexate with leucovorin for
pneumocystis. The AIDS community rightly welcomed this step
forward--the first AIDS use of the FDA's widely publicized "new
rules" intended to allow physicians to use promising drugs
before full approval for commercial sale, in cases of serious
or life-threatening illnesses. If it works as intended, the
new approval should save many lives.
Unfortunately the trimetrexate ruling also contains a tragic
flaw which will almost certainly result in many deaths of
others who could be saved.
On October 15, 1987 The New England Journal of Medicine
published a major article on a new treatment for pneumocystis
(Allegra and others, 1987). Trimetrexate, an experimental
anticancer drug, had been found to be 1500 times more powerful
than trimethoprim, part of a standard treatment, for inhibiting
an enzyme obtained from the protozoa which cause pneumocystis.
The dose of trimetrexate required to treat pneumocystis is
potentially lethal; but an antidote, leucovorin, can be used to
rescue human cells. Protozoa, such as pneumocystis, cannot use
A trial of the trimetrexate/leucovorin combination with 49
patients found clearly better survival than would have been
expected for those patients with standard treatments. And the
new drug combination had very few side effects; only one of the
49 patients had drug intolerance serious enough to require
discontinuing the treatment. Most significantly, the
trimetrexate treatment saved 11 of the 16 patients who could
not use either of the standard therapies (intravenous bactrim
or pentamidine), either beca use they had severe side effects
or because they had been ineffective.
The New Approval: Who Can, Who Cannot Qualify
Under the new approval announced February 16, the NIAID will
provide trimetrexate only for patients who have shown "a severe
or life-threatening adverse reaction to the approved therapies"
(quote from FDA/NIAID press release). The drug, available only
from the NIAID, will NOT be provided for patients for whom
standard therapies have merely proven ineffective--but not
caused severe or life-threatening toxicities. These patients
will be left to die.
This ruling flies in the face of the recommendation of the
eleven physicians who wrote the October 15 article in the New
England Journal of Medicine. Their abstract concludes "that
the combination of trimetrexate and leucovorin is safe and
effective for the initial treatment of pneumocystis pneumonia
in patients with AIDS and for the treatment of patients with
intolerance or lack of response to standard therapies".
A spokesman for Warner Lambert, the manufacturer of
trimetrexate, said that the restriction (against using the drug
when all standard treatments had failed to work, though they
had not caused a severe or life-threatening reaction) was an
FDA decision; it had been explained to him once but he didn't
recall the rationale. A spokesman for the FDA gave two
reasons. First, the drug had not been approved; clinical tests
had not been completed. Second, it is not a drug to be used
lightly, as it was potentially lethal unless leucovorin was
also administered. When we asked how these reasons applied
when the only alternative was the death of the patient -and the
trimetrexate/leucovorin combination almost never had side
effects severe enough to cause its use to be discontinued--he
had no meaningful answer but suggested we talk to the NIAID,
which developed the protocol (with the help of the FDA, which
approved it). He did say that individual cases might be
considered under an emergency treatment IND--an option we
believe unlikely to happen in actual hospital practice,
especially since physicians would be applying for something
explicitly not allowed in the new NIAID/FDA protocol. He also
said that the question of whether to expand the conditions
under which physicians could use the drug was now being
considered by NIAID.
NIAID said, however, that the exclusion of patients for whom
all standard treatments failed was an FDA decision. NIAID is
now working on "protocol 30", which is designed for these
patients; we have not seen protocol 30 since it has not yet
been released, but it is part of a series of protocols designed
for scientific use, not treatment access, so presumably it will
have selection criteria which exclude many patients for whom
trimetrexate treatment would be medically indicated.
We do not know why these patients were excluded from the
treatment IND (which is designed for treatment access), since
no one involved will take responsibility for this decision.
The best guess is that the reason for it was to force a
selected group of the patients affected into protocol 30. Most
of the others will end up in the morgue.
The public had no input this decision, hidden in the fine print
of the first AIDS-related treatment IND, which was announced by
surprise at the time of two major meetings where it was
important for the FDA to look good. Persons with AIDS, and as
far as we know their physicians, also had no input. Unless
compelling new information has developed since last October--
information unknown to the press offices of either the drug
manufacturer or the FDA--this access restriction could only be
called a ghoulish decision to deny trimetrexate to pneumocystis
patients for whom all other available treatments have failed--
despite the clear recommendation of the world's leading experts
on the trimetrexate treatment, based on their published
evidence. The press, which usually only rewrites official news
releases on medical-treatment stories, largely missed what
The February 16 NIAID/FDA press release saw the matter as
"'Today's action reaffirms FDA's commitment to broaden early
patient access to promising experimental treatments for AIDS,
AIDS-associated conditions and other life-threatening
diseases,' said FDA Commissioner Dr. Frank E. Young, PhD.
'Thanks to this effort with NIAID, trimetrexate's increased
availability to those people with AIDS who could potentially
benefit from it brings us another step forward in treating one
of the most devastating infections seen in AIDS.'
"NIAID Director Dr. Anthony S. Fauci said, "This treatment IND
will allow us to offer an important treatment alternative to
severely ill patients who cannot tolerate the standard therapy.
It is also an example of how NIH is meeting one of its major
goals--enabling community physicians to select the most
appropriate therapies for their patients with AIDS.'"
(Note: We should add that aerosol pentamidine treatment--also
highly safe and effective, though not yet approved--should be
another treatment option. But even at San Francisco General
Hospital, which developed the treatment and knows it better
than anyone else, red tape and institutional fears of using a
non-approved treatment have kept it out of reach of many
patients. The October article on trimetrexate did not discuss
Physicians who want details on this distribution of
trimetrexate /leucovorin can call an NIAID hotline, (800)
426-7527, except from Michigan where the number is (800)
833-0014, between 8AM and 8PM EST, Monday through Friday. We
asked at FDA whether physicians should start paperwork in
advance, as the drug might be needed in an emergency. We were
advised that the most important thing was to keep patient
records up to date, as physicians must prove that there had
been severe or life-threatening reactions to the standard
treatments before obtaining the trimetrexate.
Carmen J. Allegra, M.D., Bruce A. Chabner, M.D., Carmelita U.
Tuazon, M.D., Debra Ogata-Arakaki, R.N., Barbara Baird, R.N.,
James C. Drake, B.S., J. Thayer Simmons, M.D., Ernest E.
Lack, M.D., James H. Shelhamer, M.D., Frank Balis, M.D., Robert
Walker, M.D., Joseph A Kovacs, M.D., H. Clifford Lane, M.D.,
and Henry Masur, M.D. Trimetrexate For the Treatment Of
Pneumocystis Carinii Pneumonia In Patients With the Acquired
Immunodeficiency Syndrome. The New England Journal of
Medicine, volume 317, pages 978-985, October 15, 1987.