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MYLAN DIAZEPAM APPROVAL WAS DELAYED BY FDA SO THAT SIMULTANEOUS APPROVALS COULD BE GRANTED, MYLAN CONTENDS; BARR LABS, BARRE NATIONAL TESTIFY ALSO

Executive Summary

Mylan's diazepam ANDA was deliberately delayed by FDA for one month so that three generic firms could receive approval on the same day, Mylan VP-Scientific Affairs Cheryl Blume, PhD, told a House Commerce/Oversight Subcommittee May 11 hearing on the ANDA approval process. Mylan's diazepam ANDA review was "done a month before our approval was actually granted and we were told we were being held up because two other companies [ were] coming behind and the agency wanted to have all the drug approvals avow on the same day," Blume testified. Mylan, Zenith and Parke-Davis received same-day approvals of diazepam (Roche's Valium) on Sept. 4, 1985. Preventing FDA from inventorying ANDAs for simultaneous approvals could be one of the first reforms to emerge from the House investigation of the generic drug approval process. Same-day approvals for competitive ANDAs have been relatively common since passage of the Waxman/Hatch Act. HHS drew attention to the simultaneous diazepam approvals, for example, with a press conference at which then-Secretary Margaret Heckler touted the cost savings of generics. The diazepam ANDA was one of five applications by Mylan that the company believes was consciously delayed by FDA reviewers. The other alleged delays related to applications for clonidine, clorazepate, ibuprofen and haloperidol tablets. Mylan did not specifically cite the reason for approval delay of its haloperidol ANDA, but noted that they shared a first approval with Searle in June 1986, despite the fact that the Mylan ANDA was submitted nine months before Searle's. Mylan Chairman Roy McKnight testified to the House subcommittee that approval of the firm's ANDA for clorazepate "was delayed in order to enable a brand new, untested company, Able Labs, an earlier access to the market." Mylan was "told by an FDA employee that the decision was made entirely to accelerate the ANDA for Able Labs," Blume said. "Evidently," Blume claimed, "Dr. Seife [director of the Generic Drugs Division] had indicated that he wanted Able to receive this approval because they were a very small company, had not yet manufactured prescription drug products, and they needed this large market base to initiate their business as a prescription generic drug distributor." In testimony May 10, former FDA superviory chemist Charles Chang said he "sometimes tried to help some of the smaller companies" by assigning their applications to speedier FDA reviewers (see related story p. 10). Mylan maintained that Able Labs' manufacturing facilities had not met FDA Good Manufacturing Practice (GMP) requirements before obtaining their ANDA approval for clorazepate in June 1987. The company described a May 1986 inspection report that found significant GMP problems and informed the committee that another inspection was not performed until 1988. Able Labs has not been cited in any of the information papers or indictments filed in connection with the Baltimore grand jury's investigation of charges of favoritism in the generic drug approval process. Able contends that it is not involved in the grand jury investigation and that the Congressional request for the company's compliance records and ANDA "jackets" is related only to the company's ANDA for conjugated estrogens and the associated circumstances of FDA's policy shift on approval requirements for conjugated estrogens. Able Labs was actually the second company to receive approval for clorazepate: American Therapeutics received the first approval on June 9, 1987, followed by Able Labs on June 26 and Mylan on July 7. Information filings against FDA reviewer Charles Chang with the Baltimore federal court allege that he received bribes from American Therapeutics. The May 11 hearing marked the first public disclosure that the subcommittee's investigation, and resulting investigations by the HHS Inspector General and the Baltimore grand jury, were initiated on the basis of evidence of ANDA review irregularities gathered by Mylan. Mylan approached the subcommittee with evidence of favoritism in June 1988 after hiring private detectives to investigate "possible illegal gratuities to Charles Chang . . . who appeared to be the source of most of the irregularities involving Mylan applications," Subcommittee Chairman Dingell (D-Mich.) noted in his opening remarks. "Their gamble paid off when they were able to obtain photographs and other documentry evidence which strongly suggested Mr. Chang was receiving gifts of considerable value from generic drug firms," Dingell said. McKnight alleged that, beginning in 1985, Mylan was subjected to "open animosity" from the Generic Drugs Division, during which time the division "took a number of unwarranted actions that were extremely damaging to our marketing position." Approval requirements "were being routinely and arbitrarily modified from one company to another during the approval process [and] chemist reviewers were making unreasonable and often repetitive requests for information, slowing down our approvals unnecessarily," McKnight claimed. The CEO asserted that the company brought its concerns about the approval process to Seife, but that he "steadfastly refused" to intervene "with his employees in order to rectify the situation . . . and became increasingly hostile toward Mylan." McKnight reported that the company then was told in March 1987 by a "former agency chemist reviewer . . . that we had been singled out for discriminatory treatment; that other firms were being favored with expedited reviews and approvals in exchange for gratuities and payoffs; and that there was a concerted effort to delay and obstruct Mylan's applications." McKnight said that "a few weeks after" the March 17 meeting, "we confirmed an earlier rumor that Mr. Charles Chang . . . had openly declared his hostility to Mylan in a meeting before his own staff [and] went so far as to instruct his reviewers to 'lose jackets,' 'slow down reviews,' and fabricate excuses in order to prevent Mylan from receiving approvals." In support of its allegations Mylan cited, among other things, the review of its application for clonidine. Noting that Chang was in charge of the chemistry review for clonidine, the company reported that it submitted an ANDA for the drug in November 1984 and received approval in June 1987, while review for a combination clonidine/chlorthalidone product, conducted by another chemistry reviewer, was completed between May 1986 and February 1987. McKnight said that when its clonidine application was "nearly ready for chemistry approval . . . it was unexplainably reassigned to a second reviewer who began the entire review process all over again. When that second reviewer finally informed us she had recommended approval, her boss Charles Chang let our application sit on the shelf for two months and then reassigned it to a third reviewer who began the entire process once more." Par was the first company to obtain a clonidine approval, receiving ANDA clearance on Nov. 22, 1985. However, three other companies obtained approvals before the expiration date of Boehringer Ingelheim's patent on Catapres: Biocraft, on March 20, 1986; American Therapeutics, on May 27, 1986; and Danbury on July 1, 1986. Former Par VP Ashok Patel is among those indicted by the grand jury for bribing an FDA official ("The Pink Sheet" May 1, T&G-1). Discussing the review of its ANDA for ibuprofen, McKnight said that the company was "well positioned to receive a first approval," but that it lost its lead because it was not notified when FDA decided to ask all applicants to conduct an additional bioavailability study on use of the drug with food. Mylan said that it was the first to submit the originally required bioavailability study in the fasting state. The company was eventually sixth to reach the market with a generic version of the non-steroidal anti-inflammatory. Mylan estimates that it lost $ 10 mil. in potential ibuprofen sales from not gaining the first approval it believes it would have otherwise obtained. Mylan also complained that the food study was required for ibuprofen, but not for generic competitors to its branded triamterene/hydrochlorothiazide product (ITALICS)Maxzide. Mylan also alleges that FDA has been "retaliating" against the company for bringing the charges of favoritism to the subcommittee by not granting the company approval to manufacture products in its Puerto Rican facility. "We believe that the Generic Drugs Division is holding up approvals because they believe Mylan started this investigation and that this was one way to retaliate. As a matter of fact, after the subcommittee probe began and it was widely rumored that Mylan had blown the whistle, we were told by an agency employee, Mr. Walter Kletch, that we would never get approvals for Puerto Rico," McKnight testified. Kletch refused to testify before the subcommittee on May 3, citing his Fifth Amendment rights. Retaliation by FDA is apparently one of the major concerns of the subcommittee. Dingell questioned all those testifying (Mylan, Barr Labs and Barre National) about fear of retaliation and emphasized that he would contact FDA Commissioner Young about the potential problem. "Previous testimony and other information available to this subcommittee suggests that the fear of retaliation by Mylan and others who may be asked to testify in front of this subcommittee is based on a realistic reading of the situation at FDA," Dingell said. "Today, I will personally inform Commissioner Young that any retaliation by any FDA employee against the firms or individuals who testify before us will not be tolerated. Further, he will be asked to explain, in detail, the steps he intends to take to assure that Mylan and those other firms testifying today and in the future are not the victims of any further discrimination," he added. In a May 11 letter to the subcommittee, a Barr attorney reported that an FDA inspector arrived at the generic manufacturer's primary manufacturing facility that afternoon. Lawrence Fox (D.C. firm Bishop, Cook, Purcell & Reynolds) said the firm had been inspected during the summer of last year with no letter of adverse finding resulting from the inspection. In a May 12 letter to FDA Acting Deputy Commissioner James Benson, Dingell said he had received "a disturbing report indicating possible retaliation by the FDA against Barr Laboratories." Citing "the gravity of the situation," Dingell demanded that FDA supply "a list of all non-clerical FDA employees who had advance knowledge that Barr was to be inspected" by the close of business on May 12. Dingell also asked that those employees "be made available for interviews" during the afternoon of May 15. Barr Labs' testimony focused on FDA's denial of the firm's ANDA for conjugated estrogens, because of a decision midway through the review to require blood level studies. The firm believes it has been the subject of retaliation by the agency due to a lawsuit stemming from the conjugated estrogens review. As an example, the company cited its approval in November for erythromycin 500 mg enteric coated tabs. The company maintained that review of pending applications for two lower strengths of the antibiotic have been intentionally held up (see related T&G, this issue). Barre National President Max Mendelsohn, in his testimony, said that he did not fear any retaliation by the agency for testifying. The company's regulatory affairs director, James Allen, however, testified that he was worried. Allen indicated that he felt reviews were held up when the firm previously complained agency about irregularities in approval practices. (PARAGRAPH)Barre National testified about review of three drug products that received untimely and/or unusual reviews: lactulose syrup, haloperidol and diphenhydramine cough syrup. Mendelsohn said that the company was asked to submit additional information on numerous occasions after being told that the application was essentially approvable. The firm noted in its testimony that the subcommittee had specifically asked it to discuss the three drugs. Barre National said it was attending the hearing "because of the subcommittee's invitation and not through our solicitation." Mendelsohn emphasized that the reviews were irregular, but that the company could not "demonstrate on the basis of information known to us that the company was the object of discriminatory treatment by any FDA official or employee." Mendelsohn added that he "and others at Barre National believe that the great majority of its 75-80 approved applications and numerous application supplements have received timely and reasonable FDA reviews." Dingell declared that he "see[s] that this is a very serious matter . . . that it is going to ultimately require legislative activity on the part of this committee which will address the abuses." Rep. Wyden (D-Ore.) commented that he "find[s] it incredible that so many of the policies in this generic drug division seem to be sort of made up as they go along," and said he "looks forward to working with the chairman in forming legislation."
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