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PARKE-DAVIS' AMSIDYL SUBMISSION LACKS TWO WELL-CONTROLLED CLINICAL TRIALS TO SUPPORT FIRST-LINE THERAPY USE IN NON-LYMPHOCYTIC LEUKEMIA -- FDA PANEL

Executive Summary

Parke-Davis' Amsidyl (amsacrine) clinical data for acute nonlymphocytic leukemia includes only one well-controlled study demonstrating equivalent efficacy to daunorubicin therapy in terms of complete responses, FDA's Oncologic Drugs Advisory Committee concluded at its Sept. 10 meeting. The committee did not vote on whether to recommend approval for the Parke-Davis NDA for amsacrine use in combination with standard antileukemic agents. The company was seeking an indication as first-line induction therapy in adults with acute nonlymphocytic leukemia. However, the panel did address specific questions on the adequacy of two clinical studies submitted in the NDA. One of the studies was a Parke-Davis trial of 397 leukemia patients, who ranged in age from 18-50 years old. Of those patients, 261 were from the U.S.; the rest were Europeans. The other study, which was considered problematic by FDA reviewer Grant Williams, MD, and the advisory committee, was conducted by the National Cancer Institute's Southeastern Cancer Study Group (SEG) and involved 363 leukemia patients over the age of 50. Williams, a reviewing medical officer from FDA's Division of Oncology and Pulmonary Drugs provided the committee with FDA's perspective on the studies. He maintained that the amsacrine NDA "supplies one trial with borderline evidence of efficacy and one trial with no supporting evidence." Regarding the company study, Williams said he thought "the trial did show [efficacy] with regard to complete response and survival. However, I think proof of efficacy was somewhat borderline as based on the 95% confidence intervals of CR [complete response] rate and historical considerations." The FDAer continued: "I think the SEG was clearly not equivalent, and I don't think that efficacy is established in the trial." "We should not compromise the drug approval standard for cancer drugs by allowing approval on the basis of unduplicated evidence of equivalence to a standard drug," Williams said. Parke-Davis Senior Director-Clinical Oncology Charles Kowal, MD, reported that the primary efficacy parameter measured in the studies was complete response rate, while secondary parameters included survival, time to complete response, and duration of complete response. In the company trial, patients were randomized to receive either a regimen of amsacrine, Ara-C (cytarabine), and thioquanine (AAT) or a regimen of daunorubicin (Cerubidine), Ara-C, and thioquanine (DAT) for one or two induction courses. In the SEG study, patients were randomized to receive amsacrine and Ara-C (AA) or daunorubicin and Ara-C (DA) during induction. Kowal noted that Parke-Davis did a literature review to evaluate daunorubicin's contribution to complete response rates, and the firm found that daunorubicin-based treatment generated complete responses in about 45% of nonlymphocytic leukemia patients. This estimate was used as a base to compare the relative efficacy of amsacrine-based therapy. * In the Parke-Davis study, amsacrine-based therapy (AAT) was responsible for complete responses in 50% of patients versus a 46% complete response rate for daunorubicin-based therapy (DAT), Kowal said. However, the SEG study showed complete response rates of 37% in the AA regimen compared to 43% in the DA regimen. When combined the average complete response rate for the two amsacrine-based regimens was 44% compared to the average response rate of the two daunorubicin-based therapies of 45%. In its questions to the panel, FDA noted that the complete response (CR) rates from the Parke-Davis study are "sufficient evidence that the CR rate with AAT is at worst equivalent to the CR rate with DAT." However, when asked by FDA whether there was "substantial evidence that amsacrine contributes to the CR rate of the AAT regimen," the committee voted five-to-two, with one abstention, that there was not substantial evidence. In presenting his analysis of the Amsidyl studies, committee discussant David Ahmann, MD, Mayo Medical School, stated: "I am not convinced in my own mind that there is a great deal of proof that amsacrine adds to this particular regimen of AAT." Ahmann said that "the DAT versus the AAT in the [Parke-Davis] trial was comparable in most parameters." However, he questioned the role of amsacrine "in this situation." Ahmann suggested that a trial of Ara-C and thioquanine versus amsacrine, Ara-C and thioquanine "could prove the fact" that amsacrine contributes to the drug regimen. He added that amsacrine "produced a little more toxicity at least with respect to...maintaining patients on blood products and antibiotics because of infectious or hemorrhagic complications." Although the committee members generally agreed that the Parke-Davis study provided evidence that the amsacrine-based therapy and the daunorubicin-based therapy are equivalent first-line treatments for acute nonlymphocytic leukemia, they felt that the SEG study could not be considered a supportive study. Asked by FDA whether the SEG study, which showed a 6% lower CR rate with the amsacrine regimen, was a "well-controlled study demonstrating the efficacy of amsacrine in combination with cytarabine for primary induction therapy of ANLL," seven committee members voted that the SEG study was not well controlled with one member abstaining. Ahmann commented that he did not believe that the SEG study was well-controlled "due to the number of the data sets that have been lost...23% unevaluable...which is way too high." Ahmann said he "personally" could not support approval of amsacrine for first-line treatment based on the clinical data in the submission. However, he pointed out that "the drug does have activity and one could also make an agrument for availability in terms of treating patients who are refractory to other drugs." Amsacrine has been available through Group C distribution to refractory nonlymphocytic leukemia patients. FDA Office of Drug Evaluation I Director Robert Temple, MD, said he assumed "the committee would welcome further attempts to look at the Group C data that have been collected involving somewhere over 500 patients to see whether there is potential evidence for use in refractory relapse disease. * At the same meeting, Adria presented the final results of four studies on the efficacy of Idamycin (idarubicin) in combination with other antileukemic drugs for the treatment of acute nonlymphocytic leukemia. Adria did not request a committee vote. The NDA was filed in August 1989. During a preliminary review of available data at FDA's Oncologic Drugs Advisory Committee meeting on Feb. 2, a consensus was reached among committee members that the Adria drug was as effective as Wyeth-Ayerst's Cerubidine. Committee member Robert Capizzi, MD, had emphasized at the time that the opinion was contingent on FDA's analysis of the final data ("The Pink Sheet" Feb. 5, T&G-4). Adria presented an update of trial results in April. The three American trials and one Italian trial compared idarubicin in combination and cytarabine (Ara-C) to the standard ANLL therapy combination of daunorubicin and cytarabine. The single-center trial at Sloan-Kettering Memorial Cancer Center, studying patients 60 and under, found that the complete response rate in idarubicin patients was 78% (51 of 65), compared to 58% (38 of 65) in daunorubicin patients; the study found that the survival rate of idarubicin patients was better than that of daunorubicin patients. Sloan-Kettering was the smallest trial, and the only one of the four that was terminated before completion. The early termination stemmed from findings that idarubicin was significantly more effective than daunorubicin. Adria Senior Director-Medical Research Richard Gams, MD, who presented the trial results, reported that Sloan-Kettering has since adopted idarubicin as the hospital's standard induction therapy for ANLL. A multicenter trial by the Southeastern Cancer Study Group (SEG) found complete response rates of 69% in (77 of 111) idarubicin patients, compared to 55% in daunorubicin patients. However, in that study, Gams noted that the survival curve was "certainly unfavorable to patients treated with idarubicin." Adria's own multicenter trial found a 67% complete response rate (68 of 101) in idarubicin patients, compared to 58% (66 of 113) in daunorubicin patients. Survival rates were " significantly better" in idarubicin patients. Neither the SEG nor Adria studies set an age limit for adult patients. The Gimema (Italy) trial on approximately 250 patients over 55 found equivalent complete response rates -- around 40% with both idarubicin and daunorubicin -- and roughly equivalent survival rates, Gams said.
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