FDA is receiving numerous inquiries concerning recommendations by the Antiviral Drug Products Advisory Committee on dideoxycytidine (ddC), an experimental therapy for treating patients at advanced stages of infection with the AIDS virus.
On April 21, a majority of the committee, a panel of outside experts, recommended that FDA approve ddC for use in combination with zidovudine (AZT), an approved treatment for people with AIDS. However, the committee recommended against ddC's approval as monotherapy in treating AIDS patients who are intolerant to, or who have not responded to AZT and didanosine (ddI) -- the other approved therapy for AIDS.
The committee made its recommendations after reviewing data and analyses presented by FDA reviewers, clinical researchers from the National Institute of Allergy and Infectious Diseases (NIAID) and representatives of the drug's manufacturer, Hoffmann-LaRoche Inc. of Nutley, N.J. The data presented involved several studies, some of which examined ddC's use as a single agent, and others that looked at it in combination with AZT therapy.
In determining ddC's effectiveness as monotherapy, the committee considered a study conducted jointly by Hoffmann-LaRoche and the AIDS Clinical Trial Group (ACTG) of NIAID, that compares AIDS patients treated with ddC to similar patients treated with AZT. This study, designated N3300/ACTG 114, indicated that the patients given AZT did better than patients on ddC in terms of their length of survival and the avoidance of serious opportunistic infections.
In their presentation before the committee, researchers for Hoffmann-LaRoche contended that data from this study as well as other large-scale ddC protocols suggested that some patients on ddC did appear to derive some quality of life benefits from the drug -- for example, weight gain. The committee was interested in these data, but not convinced that these benefits were clear and well substantiated. Therefore, the committee determined, after a careful assessment of the risks and potential benefits, that an approval for ddC monotherapy was not warranted at this time.
The committee considered several small studies that dealt with the efficacy of combination ddC/AZT therapy. These studies compared patient groups given combination ddC/AZT therapy to patient groups treated with AZT. The majority of these studies used only groups containing patients who had not previously been treated with AZT.
The results of these trials indicated that the combination therapy had a beneficial effect in some patients. This effect was gauged through measuring patients' CD4 helper cell levels. CD4 helper cells are white blood cells important in the immune system that are destroyed by the AIDS virus. Healthy individuals normally have CD4 helper cell counts of 1,000 or more, while those at advanced stages of AIDS infection usually have counts of 200 or less. Both FDA and its Antiviral Products Advisory Committee have agreed with many researchers that an increase in CD4 cell counts can indicate a beneficial effect on a patient's immune system.
The results from these studies were augmented by data from a study by AZT's manufacturer, the Burroughs Wellcome Co. of Research Triangle Park, N.C. This randomized study produced results consistent with those found in the smaller Hoffmann-La Roche studies.
The committee in its recommendation concluded that data from these studies, when considered together, warranted FDA's approval of ddC for use in combination with AZT. The committee emphasized, however, that since most of the ddC/AZT combination therapy trials involved patients who had not previously received AZT therapy, the approved indication for combination ddC/AZT should be limited to patients who had similarly not been treated with AZT. The benefits of ddC/AZT combination therapy need to be studied in persons already treated with AZT, according to the committee, before its indication can be extended to this group.
The committee strongly urged that ACTG 155 -- a large ongoing double-blind, randomized clinical trial which compares patient groups on combination therapy with patient groups being treated with either AZT or ddC -- should continue. Some interested parties had asked that the codes helping to ensure that objectivity of the trial be broken, so that clinical data gathered so far can be analyzed. The committee argued that such action would be premature and would irrevocably harm an chance to acquire reliable efficacy data on ddC/AZT combination therapy.
Although the committee's recommendations for approval are not binding upon FDA, they will be given a very serious consideration in the agency's review of the new drug application for ddC. The amount of time needed to consider an advisory committee's recommendations varies widely depending on a number of factors, but FDA intends to act quickly in its evaluation of this drug and has devoted extraordinary resources to this effort.
In the meantime, the drug is being made widely available, through a series of protocols sponsored by Hoffmann-LaRoche, to physicians treating AIDS patients and others at advanced stages of infection with the AIDS virus who cannot participate in controlled clinical studies of the drug. Physicians interested in these protocols can contact the company at 1-800-ddC-21HIV, Monday through Friday, from 9 a.m. to 8 p.m., Eastern Time.
FDA regularly calls on its 40 advisory committees to address specific issues or problems concerning FDA-regulated products.