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BARR LABS ACCUSES FDA OF CONTINUING TO MISPLACE APPLICATIONS: CONJUGATED ESTROGENS CORRESPONDENCE IS LATEST LOST LETTER; NO BARR ANDAS APPROVED

Executive Summary

Barr Labs continues to accuse FDA of purposeful misplacement of its submissions and correspondence. The generic firm is waging a campaign to keep outside attention focused on alleged FDA retaliation for the firm's role in bringing ANDA approval improprieties to light. In a April 12 letter to FDA Acting Commissioner Benson, Barr Labs refers to FDA's recent misplacement of a letter regarding generic conjugated estrogens as "the latest 'lost document' [that] should demonstrate to you that there is a pattern of inexcusable discrimination." Barr's letter was written by outside counsel Lawrence Fox (Bishop, Cook, Purcell & Reynolds, Washington, D.C.). The "lost document" filed with the agency in mid-March requested FDA's opinion as to whether its Notice and Opportunity for a Hearing on the proposal to withdraw ANDAs of conjugated estrogens rated "BP" (bioinequivalent) applies to Barr's ANDA applications for "AB"-rated (bioequivalent) estrogens. Barr filed the original letter with FDA's Dockets Management Branch, Fox noted. Two weeks after its submission "on March 29, FDA informed Barr that Dockets Management had no record of the original letter, and requested that Barr resubmit it." Fox added: "Given Barr's public outcry concerning lost documents, can anyone believe the continued loss of material is accidental?" Barr is pressing Benson to "eradicate FDA's retaliation" against the Company. "Although FDA has been expressly warned by Chairman John Dingell [House Energy & Commerce Committee] that retaliation against Barr would violate [regulations], the Agency's discriminatory treatment of Barr continues unabated to this day," Fox declared. Barr sent copies of its retaliation complaints to Dingell, HHS Assistant Secretary for Health James Mason, HHS Inspector General Richard Kusserow, FDA General Counsel Margaret Porter, First Assistant U.S. Attorney Gary Jordan, and to a number of senators. Barr's attorney acknowledged that "viewed individually, each specific incident of FDA's inequitable treatment might be attributed to indifference or incompetence as opposed to retaliation for Barr's criticisms of the agency, including Barr's testimony before the House Oversight Subcommittee and its lawsuit against the agency [regarding its conjugated estrogens applications]. However, the evidence...leads inescapably to the conclusion of retaliation." As "direct evidence" of reliation, Fox pointed to FDA's "for cause" inspection of Barr's manufacturing facilities which was initiated on the same day that the company testified before the subcommittee on May 11. Fox noted that Dingell determined that possible explanations for FDA adding Barr to the inspection list included "malice, confusion, overreaction or some combination of these." "FDA has not approved a single Barr ANDA since the company criticized FDA in testimony before" the Dingell subcommittee, Fox noted. The attorney pointed out that since the hearing FDA "has approved 41 ANDAs, none submitted by Barr." Fox calculated that the "odds of Barr not receiving a single ANDA are approximately 25 to one." To arrive at this figure, Fox assumes that as of May 11, "there were a total of 1,000 ANDAs pending at the agency, of which at least 75 had been submitted by Barr." The other public complainer, Mylan, has received only one ANDA approval since the company testified against FDA at the same May hearing, Fox noted. Mylan received its last generic approval on June 9, 1989. Barr's counsel stated that "the odds of neither Barr nor Mylan receiving one of the 33 approvals since Mylan's last approval are approximately 165 to one." To arrive at that ratio, Fox assumes that as of June 9, "there were 1,000 pending ANDAs, of which at least 150 had been submitted by Barr and Mylan." The counselor noted that "adding Mylan, another whistleblower, to this calculation forecloses any cause but retaliation." Mylan is also believed to be having difficulties with an NDA application. The company has been trying to crack Marion Merrell Dow's lock on sucralfate. Mylan is reputed to be tied up with the agency on protocol difficulties in its attempt to submit a full sucralfate NDA. Mylan has a good track record in using full NDAs to get into protected markets. It was the first company to compete with SmithKline's Dyazide in the triamterene/hydrochlorothiazide market after receiving NDA approval for the Maxzide different dosage combination. In support of the contention of retaliation against Barr, Fox notes the loss of a pilot plasma bioequivalence study for the firm's conjugated estrogens ANDA which was sent on March 17, 1989 to then-FDA Commissioner Young. Former FDA Division of Generic Drugs Review Support Branch Chief David Rosen testified about that incident before a July 27 closed session of Dingell's subcommittee. According to just-published testimony of that House hearing, Rosen said that he did not become aware that the submission went to Young's office until over two months later. The FDAer pointed out that although Young had requested that the study be sent to him, "it is not normal for information, to be reviewed in context of an ANDA, to be sent to the Commissioner's office." The original submission arrived in the Division of Generic Drugs at the same time that a resubmitted version was sent in to the division, Rosen said. In Barr's letter, Fox noted that the resubmission also "was lost." The subcommittee asked Rosen: "To your knowledge, is it true no FDA official at the June 16 meeting [with Barr] was aware the June 9 submission had been made initially?" Rosen responded: "It was because of the reference, how it was referred to in Barr's counsel's letter. It was referred to as a letter to Mr. Terselic [acting director, generic drugs division] without any other specifics." Rosen outlined what happened to the submission in a June 21 memo to the ANDA file, which was included as an exhibit to Barr's April 12 letter. Rosen explained that apparently Bishop, Cook & Purcell had intended that the submission, which was addressed to Terselic, be hand delivered to him. However, most submissions are addressed to the director, but are not actually seen by the director "if it is identified as being related to a specific application," he said. Apparently, the submission had the ANDA file numbers on it. Therefore, the study went through the normal processing channels -- to the Division of Bioequivalence. Incidences of delays in the review of Barr ANDAs or non-approvals are also acts of retaliation, according to Fox. For example, Barr met with FDA in September to discuss the progress of these ANDAs ("The Pink Sheet" Sept. 18, "In Brief"). In one incidence, Fox said, FDA "assured Barr that there was 'no problem'" with its methotrexate ANDA in August, and in October "FDA informed Barr that the ANDA was 'nonapprovable.'" The reason, Fox said, is "FDA misquoted and then misapplied an FDA regulation to Barr." He charged that FDA has yet to retract its "mistake." Fox also discussed events surrounding the review of a Barr ANDA application for erythromycin estolate oral suspension. Fox said that FDA informed Barr in June that the only requirement left for approval was acceptable stability data, which Barr subsequently submitted. He noted that "the agency committed to expedite [this ANDA] because of FDA's laboratory testing errors." FDA then granted the "reviewer's request to withdraw from reviewing Barr's application solely because it was Barr's, Fox said. The ANDA was then reassigned to another reviewer who was on vacation "causing a further delay of one and one-half months." FDA approved the stability data, but then requested data on Barr's manufacturing facility, which, Fox said, Barr had submitted almost a year earlier. The attorney noted that at a Jan. 19 meeting between Barr and FDA, agency officials explained that its request was "for a supplement was really a requirement that Barr conduct a new bioequivalence study or, alternatively, seek a waiver for such a study." Fox contended that "your people when confronted with their error, 'interpreted' the letter rather than admit their error." Regarding Barr's ANDA application for erythromycin delayed-release tablets, Fox said that FDA Center for Drug Evaluation and Research Director Carl Peck informed the company in May that its product was bioequivalent. Then in August, according to Fox, Peck said he was going to "re-review" the ANDA, and in November, he denied the application citing the need for another bioequivalence study.
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