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ESTROGEN PELLETS AVAILABILITY UNDER COMPASSIONATE INDs SHOULD BE DISCONTINUED AS A LAST RESORT TREATMENT FOR MENOPAUSAL SYMPTOMS -- FDA ADVISORY COMMITTEE

Executive Summary

Compassionate INDs making estrogen pellets available as a last-resort treatment of menopausal disorder should be terminated for safety reasons, FDA's Fertility & Maternal Health Drugs Advisory Committee unanimously agreed at its Jan. 14 meeting. Summarizing the hazards unique to the use of the pellets, committee chair Carolyn Coulam, MD, Methodist Hospital of Indiana, noted "the risk of bleeding and infection, the lack of information on release rates, difficulty in reversibility of the drug, increased feasibility of overdosage of the drug, and increased risk of non-compliance or safety measures [such as] the addition of progestin." FDAer Phill Price, MD, Fertility & Maternal Health Drugs Group, voiced the agency's concurrence with the committee's conclusion. "With potentially serious safety concerns and alternative drug modalities available," Price said, "the division feels these INDs should be terminated and alternative methods adopted to treat women who may need higher amounts of estrogen." After being marketed in the U.S. for decades, estrogen pellets were the subject of reg letters in 1977 from FDA asking manufacturers to cease production. Two companies, Bartor and Progynon Associates, currently have NDAs pending for estrogen pellets. Progynon bought the estrogen product from Schering in January 1983. There are approximately 15,000 patients are being treated under compassionate INDs, said Price. According to Price, Schering submitted an NDA for compressed estradiol pellet as a treatment for prostatic carcinoma, but was unable to provide supportive data. Progynon, after obtaining Schering's pellet, submitted retrospective biopharmaceutical data to FDA. However, the agency concluded that "essential serum data" was missing, Price said. Bartor's NDA for its estrogen pellet product, Estrapel, was first presented to the advisory committee in 1978. The panel recommended against approval and requested additional information including estradiol serum levels and effects on endometrial hyperplasia, Price noted. Estrapel's NDA came before the committee again on Oct. 23, 1980. The committee determined that there was "insufficient evidence from well-controlled studies to evaluate the efficacy" of the pellets and recommended that dose-response studies be done, Price added. Bartor later conducted a randomized, placebo-controlled study, which was submitted in December 1983 and again in December 1986. The study was found to be unacceptable and Bartor was sent a non-approvable letter in October 1987, Price said. After the October 1980 committee meeting, FDA agreed to allow patients to be treated with estrogen pellets under compassionate INDs. In recommending termination of the INDs, Price noted FDA's regulation: "an investigational plan or protocol(s) may be terminated if there is not a reasonable or bona fide scientific plan to determine whether or not the drug is safe and effective for use." The committee, while acknowledging that subcutaneous estrogen pellets have health risks, also agreed that they have potential utility for those individuals who cannot use oral or transdermal estrogen products. Coulam noted that "if somebody wants to bring forth to the FDA a proposal for a new strong IND or NDA, then that would certainly be reviewed by the FDA. But to continue it as [it has] been done for eight years, without information coming in, is not the best way."
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