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.

Background 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 leucovorin.

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 happened here.

The February 16 NIAID/FDA press release saw the matter as follows: "'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 aerosol pentamidine.) 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.

References 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.