AIDS TREATMENT NEWS #233, October 20, 1995
John S. James

* On November 6 the committee will discuss the NDA (New Drug Application, or request for marketing approval) for tablets and oral solution for lamivudine (also called Epivir, or 3TC). The meeting will begin at 8:30 a.m., and be open to the public all day, with public testimony from 11:30 to noon.

* On November 7 the committee will consider the NDA for saquinavir (Invirase), a protease inhibitor developed by Hoffmann-La Roche. Invirase is likely to be the first protease inhibitor to be approved. This meeting also will also begin at 8:30 a.m. and be open all day, with public testimony from 11:30 to noon.

* On November 8 the committee will look at the results of confirmatory trials of stavudine (Zerit, or d4T). Stavudine has already been approved, but with restricted "labeling," or indications for use. This meeting will be during the morning only, beginning at 8:00 a.m., with public testimony from 10:00 to 10:30.

There will be a closed session November 8 in the afternoon to consider proprietary or trade-secret information. Stavudine will NOT be discussed at the closed session; we do not know what drug or drugs will be.

All three meetings will be in the Maryland Ballroom of the Quality Hotel, 8727 Coleville Rd., Silver Spring, Maryland (about three blocks from Silver Spring Station, on the Washington Metro "Red Line"). Persons making reservations should mention the FDA meeting, as the hotel has a group rate of $89 per night.

Members of the public wishing to speak at any of these three meetings should call Lee Zwanziger or Elizabeth Ortuzar at 301/443-4695, by October 31.

You can always find out about upcoming hearings of the Antiviral Drugs Advisory Committee by calling the FDA Committee Management Office hotline, 800/741-8138, or 301/443-0572; the 5-digit code for the Antiviral Drugs Advisory Committee is 12531. This hotline has information even before it is published in the Federal Register.

Comment

Meetings of the Antiviral Drugs Advisory Committee usually include more detail about the drugs than is presented at professional conferences. And FDA analysts, who have studied the NDAs (New Drug Applications, thousands of pages each, which are not usually released to the public), critique the presentations of the company researchers. Their meetings, therefore, can be the most in-depth source of information available about new drugs.

Sometimes one or more community representatives or activists are appointed temporarily, for a single meeting, to FDA advisory committees. We have heard that there is much pressure of people trying to get on for one or the other of these three days.

Our understanding of the major issues is as follows:

* Lamivudine (Epivir, 3TC). Glaxo-Wellcome is asking the FDA for an indication for AZT plus lamivudine as initial combination treatment for HIV in persons with a CD4 (T-cell) count of zero to 500. This combination has shown good results in viral load and CD4 counts; a longer "confirmatory trial," now going on, is looking for clinical endpoints (death or AIDS progression) in persons with CD4 counts between 50 and 250.

Some activists are unhappy that the clinical-endpoint trial does not cover the entire 0-500 CD4 range the company is requesting in the labeling. The problem is that it is hard to measure clinical progression in persons with CD4 counts over 250, since very little clinical progression occurs at high CD4 counts. (Those under 50 were excluded apparently because of an earlier belief, now widely considered to be erroneous, that it is hard to see much effect of drug treatment in those with CD4 counts that low; this may have been true when treatments were less effective than those now being studied.)

Our concern is that the AZT plus 3TC combination does appear to be a reasonable treatment possibility for a physician and patient to consider at almost any CD4 count -- and restricting the labeling will create hardship by making it difficult to get the drugs paid for. CD4 boundaries are arbitrary, mostly inherited without much thought from old trials designed years ago. If this combination slows disease progression in those with counts from 50 to 250, there is no reason to believe it will suddenly stop working because the count is 40 or 300 instead.

* Saquinavir (Invirase). This drug probably qualifies for accelerated approval, based on surrogate-marker results showing superiority of combinations including saquinavir to standard treatment -- and the existence of large, ongoing clinical-endpoint trials to confirm the surrogate-marker data. But there is concern that the dose which will be recommended -- the standard dose which has been tested in large trials -- is lower than the most effective dose. This could be a problem because too low a dose of a drug can lead to faster development of drug resistance by the target organism.

On the other hand, saquinavir seems to cause HIV drug resistance relatively slowly, even at the current dose -- and to cause less cross resistance (resistance to other protease inhibitors, even though the virus has never seen them) than other protease inhibitors do. If this is true -- and we will know better after listening to the experts debate at the meeting -- it would argue for approval. But in either case, unless the danger is very great, we think the drug should be approved, with warnings if necessary. Many people do not have time to wait for the newer formulation of saquinavir which is designed to deliver higher doses, or for new doses, combinations, or treatment strategies to be tested. They should be allowed to make informed treatment decisions now.

* Stavudine (Zerit, d4T). Our understanding is that this meeting will focus on whether Bristol-Myers Squibb has met the requirements of confirming the accelerated approval of stavudine. New recommended uses for this drug will be discussed at a later meeting, not at this one.

[Stavudine note: Some activists have talked to a number of people who reported sleep disturbances when taking stavudine; usually the problem was solved simply by taking the drug earlier in the evening, not at bedtime. This information does not appear in the official product literature, possibly because less serious side effects are often not reported by clinical-trial volunteers, who may fear losing access to the drug. Stavudine may be taken without regard to meals; the two daily doses should normally be used 12 hours apart.]

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