PI Perspective #17

December 1995     View PDF     En español

FDA Committee Recommends Approval of Three New Drugs

The FDA Antiviral Drugs Advisory Committee met in early November and recommended that 3TC (also known as lamivudine and Epivir) and saquinavir (also known as Invirase, the Roche protease inhibitor) be approved under the accelerated approval guidelines. The Advisory Committee also recommended d4T (also known as stavudine and Zerit) for full approval based on the superiority of d4T over AZT in delaying progression to AIDS (see PI Perspective #16 for results).

The Committee recommended that 3TC be approved for use in combination with AZT both for people who have or have not previously used antiviral drugs. They also recommended approval for use in the pediatric population, despite the fact that pancreatitis was seen in some children. Taken together, these are the broadest approval indications yet given for any antiviral drug under the accelerated approval guidelines. The required confirmatory trials are being conducted in people with advanced disease, but not in people with higher CD4+ cell counts, leading to complaints from some that the drug would be sold to people in whom it’s clinical benefit would not be confirmed. However, the Committee was convinced of the need to make the drug more widely available because of the 3TC combination’s powerful impact on surrogate makers. The combination’s increase in CD4+ cells and reduction in viral load (by PCR testing) was substantially better and longer sustained than in any previous antiviral drug trial. In defending its lack of a confirmatory trial in people with higher CD4+ counts, the sponsor argued that it would be difficult or impossible to recruit and keep people with higher CD4+ counts in a such a trial. Proving the clinical superiority of the combination in this population would require putting half the treatment group on what most people feel would be an inferior or at least less active single drug or combination. Moreover, with new and even more active combinations including protease inhibitors likely to be available very soon, it seemed unlikely that people would be willing to stay on the AZT + 3TC combination for the two or more years required by such a trial.

A key question left unanswered by this and other recent trials is “What is the best time to begin this or any other antiviral therapy?” Earlier studies had argued that therapy was appropriate anytime a person’s CD4+ count fell below 500, but this view is now widely considered unproven. Many people with 500 or lower CD4+ counts seem stable and perhaps in little need of therapy, while some others with counts above 500 experience rapid decline and could possibly benefit from earlier intervention. But this is a question about the use of any antiviral drug and not an issue unique to the use of AZT + 3TC. The issue is being examined in a number of other studies about to get underway, testing whether high viral load (PCR) levels are a better indicator of when to start treatment, independent of CD4+ counts.

On November 7, the Advisory Committee also recommended that the Roche protease inhibitor saquinavir (600mg three times a day) be approved for use in combination with any of the approved nucleoside analogues in people with advanced HIV disease (people with fewer than 300 CD4+ cells) who are failing other therapies. Data presented by the FDA showed that people who took saquinavir with a nucleoside analogue or combination of nucleoside analogues that they had not taken previously received greater antiviral effect compared to people who just added saquinavir to their current nucleoside analogue regimen or who stayed on the original regimen. Citing lack of data, the Advisory Committee rejected the sponsor’s request to also approve the drug for use as monotherapy for people with advanced HIV disease who are intolerant to existing therapies.

Anticipated Approval and Availability of New Therapies for AIDS
Therapy	Approval	Filing In Pharmacy
3TC Saquinavir Indinavir Ritonavir Nevirapine Delavirdine Doxil	11/95 11/95 1–2/96 2–4/96 1–3/96 1–3/96 9/94	11/95 1–2/96 3–5/96 3–6/96 4–6/96 4–6/96 1–2/96

One concern raised by many people at the meeting was the admission that only a very small amount, less than 4% of the amount taken, of the current version of saquinavir was being sustained in the blood. This is because a liver enzyme very rapidly clears the drug from the blood. In this formulation, the drug is only mildly active. Some people feared that using it might lead to rapid development of resistance which might affect other protease inhibitors as well (see the related article Project Inform Resistance Meeting). An improved version of saquinavir is already in clinical trials and should be made available sometime during 1996. Many observers concluded that people who had run out of other therapeutic options need not be concerned by this issue and should go ahead and use the drug if they need to. Those not in immediate need of better or changed therapy might be better off waiting for the arrival of the improved formulation or one of the other two protease inhibitors expected to be approved in early 1996.

On November 8, the Advisory Committee recommended that d4T be granted full approval based on the results of a confirmatory study which showed d4T to be superior to AZT for people with between 50 and 500 CD4+ cells and who have had at least 6 months prior AZT therapy. d4T was granted accelerated approval in June, 1994. The confirmatory results for d4T, which correspond with the drug’s impact on surrogate markers such as CD4+ cells, should give clinicians more comfort in prescribing this drug as there is now clear cut benefit over continued AZT use.

The FDA must now act on the Committee’s recommendations in order for saquinavir to be available in pharmacies and this is expected within the next two months. 3TC was approved as the PI Perspective was in production and should be in pharmacies by the time you read this. Saquinavir access might take a little longer, perhaps reaching pharmacies early in 1996.

HIV Infection & “Managed Care”

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