We have received inquiries about FDA's Nov 25, 1992, approval of atovaquone, a drug for treating mild to moderate Pneumocystis Carinii Pneumonia (PCP) in patients who are intolerant of trimethoprim-sulfamethoxazole (TMP/SMX), the standard therapy. PCP is a potentially life-threatening infection that often afflicts AIDS patients, whose depleted immune systems can make them highly vulnerable to opportunistic infections. PCP is one of the most common opportunistic infections.
The following can be used to answer questions.
In November 1991, atovaquone was made available under a Treatment Investigational New Drug (IND) protocol. Treatment IND regulations allow drug developers to provide pre-approval access, under certain circumstances, to experimental drugs that are designed to treat serious or life threatening conditions for which there are no satisfactory alternative treatments. As with all new drugs, drugs that are granted treatment IND status must be shown to be safe and effective through controlled clinical tests before marketing approval is granted.
On September 23, 1992, FDA's Antiviral Drugs Advisory Committee, a panel of outside experts, recommended approval of atovaquone based on data from two pivotal clinical trials involving 582 patients at multiple sites. These trials were conducted in the United States, Canada and Europe. The data from these trials were jointly reviewed by FDA officials and Canadian Health Protection Branch of the Canadian Department of National Health and Welfare.
Each pivotal study compared atovaquone to one of two existing therapies -- TMP/SMX and injectable pentamidine.
The results of the study comparing atovaquone to TMP/SMX indicated that patients' sustained improvement in clinical symptoms -- a definition of a successful therapy -- occurred about the same rate (62 percent versus 64 percent, respectively).
More of the patients who received atovaquone had to be removed from the trials because they did not respond to therapy, than of the patients who received TMP/SMX (17 percent versus 6 percent). There were 16 deaths in the atovaquone treatment group, the majority of which were due to PCP and bacterial infections, as compared to six deaths in the TMP/SMX treatment group, where only one death was attributed to PCP. However, only 9 percent of patients who received atovaquone prematurely discontinued therapy due to side effects, versus 24 percent of patients who received TMP/SMX. Side effects were generally mild and included rash, nausea, diarrhea, headache, vomiting and fever.
The results of the pentamidine comparative study indicated that 57 percent of patients who received atovaquone reported clinical improvement compared to 39 percent of patients treated with pentamidine. Twenty-nine percent of patients in the atovaquone treatment group did not respond to therapy compared to 19 percent of patients in the pentamidine treatment group.
There were 10 deaths in atovaquone treatment group compared to 12 deaths in the pentamidine treatment group. PCP, either alone or in combination with other factors, including bacterial infections, was the cause of death in six patients treated with atovaquone and five patients treated with pentamidine. Seven percent of patients receiving atovaquone discontinued treatment due to side effects compared to 41 percent of patients who received pentamidine.
Due to the higher mortality in patients who received atovaquone in the TMP/SMX comparative trial, atovaquone was approved only for patients who cannot tolerate TMP/SMX.
Atovaquone's U.S. approval coincides with its approval by the Health Protection Branch of the Canadian Department of National Health and Welfare. Atovaquone will be marketed by Burroughs Wellcome Co. Research Triangle Park, N.C., under the trade name Mepron.