Protease Inhibitors at FDA Advisory Hearings

[Note: This writer was unable to attend the recent meetings of the FDA advisory committees, due to the flu. AIDS treatment writer Mark Mascolini helped with the research for our coverage of the protease inhibitor and nucleoside analog combination meetings.]

On February 28-March 1, four separate one-day meetings of FDA advisory committees took place at two different sites near Washington, D.C.

FDA advisory committees consist of outside experts (not FDA employees) who meet when requested and advise the FDA on drug approvals and related issues. While the FDA does not have to follow the recommendations of the committees, it almost always does. These meetings are important because they usually present more information and analysis about a potential new treatment than is available from any other public source. (Most FDA advisory committee meetings are open to the public, at least in large part, although sometimes closed sessions are scheduled to review confidential proprietary data.)

The Antiviral Drugs Advisory Committee, which reviews most AIDS drugs seeking marketing approval, held three of the hearings -- on recommendations for indinavir (Crixivan(R), Merck's protease inhibitor); ritonavir (NORVIR(TM), Abbott's protease inhibitor); and also on usage of AZT/ddI/ddC, in view of new data from major clinical trials. Also, the Endocrine and Metabolic Drugs Committee met separately (at the same time as the indinavir hearing) to review the request for approval for human growth hormone to treat AIDS-related wasting. This article reviews the hearings on the two protease inhibitors; the human growth hormone hearing is examined in a separate article, below, and the meeting on new recommendations for use of the older drugs will be covered in a later issue of AIDS TREATMENT NEWS.

Indinavir (Crixivan) -- Merck's Protease Inhibitor

The March 1 indinavir hearing was the smoothest of the four meetings, mainly because Merck & Co. had the data and trials it needed to support the recommendation it was asking for.

Merck was seeking (and has now been granted) clearance to market indinavir under the FDA's "accelerated approval" regulations. Accelerated approval allows an HIV treatment to be approved based on CD4 count and viral load improvements in clinical trials -- provided that larger trials are in place to also prove clinical benefit to patients, such as longer survival or fewer opportunistic infections.

About 2,000 volunteers have now taken indinavir at the currently accepted dose (800 mg every 8 hours); 600 have taken this dose for at least six months, and 250 for at least a year. The main safety concerns have been an increase in bilirubin (but without evidence of liver toxicity), and kidney stones or related symptoms in less than three percent of patients. The most common (but less serious) side effects are rash, dry skin, and altered sense of taste.

Merck reported results of several trials, and they are consistent with what was known before. More information on specific trial results (some of which were never presented publicly before this meeting) is available through NATAP, the National AIDS Treatment Advocacy Project; for contact information, see "FDA Hearings: For More Information," below.

While drug interactions are much less of a problem with indinavir than with ritonavir, indinavir does have important interactions several other drugs. Dose adjustments are required in some cases; other drugs cannot be used at all with indinavir.

At the end of the day, the Committee recommended accelerated approval for indinavir -- recommending combination treatment when possible, but with an option for indinavir alone for people who cannot tolerate the nucleoside analogs.

Ritonavir (NORVIR) -- Abbott's Protease Inhibitor

The February 29 meeting on ritonavir was more difficult than the indinavir meeting. It was followed by a private late-night meeting between Abbott and the FDA, during which final agreements were negotiated. On the following day, Abbott distributed a letter announcing that it would conduct trials to provide certain additional data; and the FDA announced that ritonavir would be approved.

The reason the Committee meeting was difficult is that while Abbott came in with the best results so far for any HIV treatment -- clear evidence that the drug substantially reduced the risk of death and of opportunistic infections in a major trial -- other important information was unavailable. For example, there is little information on safety or efficacy beyond six months, which is especially worrisome for a drug with important safety concerns. There are no pediatric data. Information is inadequate on how well the drug works in people with earlier stages of HIV infection (the trial which showed clinical benefit was only open to those with CD4 counts under 100).

There were many different ideas on the Committee, and much discussion, about what proof was needed for efficacy in earlier disease. The issue is that the accelerated approval regulations require subsequent trials that show direct clinical benefit to patients, to eventually back up the early approval which is based on improvements shown in blood tests, like CD4 count and viral load. But it has always been very difficult -- and is now almost impossible -- to prove delayed disease progression in persons with high CD4 counts, because it will take many years for enough volunteers to get sick to provide statistical proof of benefit, and people are unwilling to stay on the same treatment that long while better treatments are becoming available. (The proposed "symptom reduction trials" to get around this problem -- see AIDS TREATMENT NEWS #228, #229, and #231 -- have not caught on at this time, probably because while they could provide clinical proof of benefit quickly, they would not
provide long-term balance of ris
ks and benefits, especially for asymptomatic patients.)

The compromise that seemed to win wide acceptance at the FDA advisory meeting was a long-term surrogate marker (CD4 and viral load) and safety study, which would use the clinical endpoints of illness and survival primarily to assure safety, while using CD4 and viral load changes to test for durability of response to the drug. The private meeting that evening built on this idea, with Abbott agreeing to "provide long-term follow-up safety and clinical endpoint data from ongoing studies M94-247 and M94-245 to assess the comparative clinical efficacy and safety data in patients with advanced stage disease versus patients with early stage disease." Also, Abbott agreed "to provide data from a study in patients with higher CD4 cell counts (>100 cells/microliter) looking for durability of response by evaluating CD4 response, HIV RNA response and safety from a study comparing ritonavir to ritonavir+saquinavir." And Abbott agreed "to participate in a clinical study to define the safety and
clinical efficacy of ritonavi
r in pediatric patients."

With these agreements in place, the FDA sent Abbott an approval letter "for the use of ritonavir in combination with nucleoside analogs or as monotherapy for treatment of HIV infection when therapy is warranted." The labeling (information for physicians) will describe the evidence on which the approval is based, and the limitations of this evidence for late-stage and also for early-stage HIV disease.

Ritonavir Comment

The key issue for the Committee seems to have been the balancing of risks and benefits in early disease, especially because the drug has important safety issues and no long-term safety data. The resolution which resulted left physicians and patients with maximum flexibility in the use of this drug. We believe this decision was the right one -- but that the success of this drug will depend on Abbott's ability to educate physicians, pharmacists, and patients on how to use ritonavir correctly, and on the company's continued ability to rapidly conduct the research on which this education must be based.