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Executive Summary

Syntex' Cytovene (ganciclovir) should be approved for the treatment of cytomegalovirus retinitis in AIDS patients, provided that a number of Phase IV studies are conducted, FDA's Anti-Infective Drugs Advisory Committee unanimously agreed at its May 2 meeting. The committee voted eight to zero in favor of approving the drug, with one member abstaining. The panel recommended several Phase IV studies that had been suggested by FDA, including a comparison to foscarnet, a comparison to intravitreal ganciclovir with zidovudine (AZT), and studies in other cytomegalovirus (CMV) diseases. In addition, the committee proposed that Phase IV studies be conducted in pediatric AIDS patients with CMV retinitis and that studies look at long-term safety of the drug, particularly bacteremia associated with I.V. administration. The ganciclovir NDA is based almost entirely on compassionate use data. The drug has been available under a compassionate use protocol since 1984 and was cleared for Treatment IND status in November 1988. The Treatment IND, sponsored by the National Institute for Allergy and Infectious Diseases (NIAID), was pursued after the anti-infective advisory committee recommended against approval in October 1987. In remarks to the committee, FDA Antiviral Division Medical Reviewer Sandra Kweder, MD, emphasized that FDA feels the drug should be approved despite the lack of standard, double-blind controlled studies. "We don't have a single traditional pivotol Phase III efficacy study on which to assess the effect of ganciclovir in the treatment of AIDS patients with CMV retinitis . . . In spite of this, the direction of the data is apparent -- we can see that the direction of the data in all of the studies that we've reviewed thus far supports the efficacy of ganciclovir," Kweder said. Among the data presented to the committee were results from the original compassionate use protocol, results of a subset of compassionate use data collected at the Jules Stein Eye Institute (University of California, Los Angeles), and data on 58 patients collected by Douglas Jabs, MD, Johns Hopkins University School of Medicine. FDA indicated that it found the Jabs results particularly convincing because, unlike most of the open use data, a number of controls were instituted to limit potential bias, such as fixed schedules for exams. In the 58 patients examined by Jabs, the median number of days to progression of CMV retinitis for patients treated with ganciclovir was 71 days, while the median days to progression for a matched group of untreated patients was 29 days. FDA reported that median days to progression in the Jules Stein data base was 51 days for the 25 ganciclovir treated patients and 26 days for a matched group of 21 untreated patients. In the original compassionate use protocol, 111 patients received ganciclovir induction therapy, 70 of which then received maintenance doses of the drug. Disease in patients receiving maintenance therapy progressed 145 days after the induction period, compared to 37 days post-induction in patients not receiving maintenance therapy. Voicing his approval recommendation, committee member Calvin Kunin, MD, Ohio State University, commented: "I believe I speak for most members of the committee that we hope that this kind of a situation will not occur again. When you have a potentially useful agent, the data should be obtained in an appropriate way so that any intelligent human being could understand what was done. Obviously, we have to approve it. We can't deny it, but there is a lingering bitterness on my part in regard to how this data was accumulated." Summarizing FDA's view on Phase IV studies, Kweder outlined a number of issues the division wants addressed in post-marketing studies, including: (1) "a direct comparison of ganciclovir and newer, alternative anti-CMV agents, [such as foscarnet], in the treatment of CMV retinitis as such agents begin to try to establish their own efficacy"; (2) "the study of combined regimens of ganciclovir and zidovudine or other antiretroviral agents deserves further attention, and this may include administration of ganciclovir by alternate routes, such as intravitreal administration or oral administration"; (3) "studies should absolutely include evaluation of the long-term effects of ganciclovir administration on survival"; and (4) "the continued study of ganciclovir in the treatment of other CMV-related illnesses is warranted, both in persons with AIDS and other end organ diseases, such as colitis and esophogitis and particularly in transplant patients with their own manifestations of this infection." Syntex is planning a controlled study of invitreal ganciclovir v. placebo in CMV retinitis patients who have had to discontinue I.V. ganciclovir therapy because of neutropenia. Cytovene is not currently used with AZT because they both cause neutropenia, which appears to be increased with concommitant administration. Because the invitreal formulation is not systemic, it presumably would not increase AZT-related neutropenia. A number of other trials that would address the suggested Phase IV requirements are also being planned or underway. The National Eye Institute has funded Johns Hopkins to conduct studies in eye diseases and Jabs, a Johns Hopkins researcher, reported that the university has prepared a protocol for a foscarnet v. ganciclovir study. Also, Syntex and NIAID are currently conducting a study in AIDS patients with peripheral retinitis. Other ganciclovir studies underway include a CMV prophylaxis trial in transplant patients, a study in gastrointestinal CMV, an active control study in CMV pneumonia, and two studies looking at the combination of ganciclovir and granulocyte macrophage colony stimulating factor (GM-CSF) to see if GM-CSF can reduce the neutropenia associated with ganciclovir. Syntex is working on one of the GM-CSF studies with Schering. The study will enroll patients who have experienced neutropenia with ganciclovir and randomize them to receive either ganciclovir plus GM-CSF or ganciclovir plus placebo. The other study, conducted by NIAID, compares ganciclovir alone to ganciclovir plus GM-CSF in patients receiving initial CMV retinitis therapy.

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