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Executive Summary

A generic conjugated estrogens product could reach the market by mid-1993, Barr Labs President Edwin Cohen told a Furman Selz generic drug conference April 14 in New York City. Barr is "still in discussions with the agency" on its ANDA for conjugated estrogens (Wyeth-Ayerst's Premarin), Cohen said. "I have every reason to believe that if ours is not the first, it should be among the very, very first ones out there." FDA's Generic Drugs Advisory Committee agreed on standards for determining bioequivalence to Premarin at a February 1991 meeting. At that time, Office of Generic Drugs Director Roger Williams, MD, estimated that a generic conjugated estrogens product would take two years to reach the market ("The Pink Sheet" March 4, 1991, p. 9). Barr has been pursuing a generic conjugated estrogens since 1987, when it filed an ANDA for the product. The company's application was turned down in 1989 when FDA decided that the previously used standards for approval of conjugated estrogens ANDAs were not adequate. FDA proposed withdrawing conjugated estrogens ANDAs held by Duramed, Zenith, Chelsea, and several other firms in February 1990. The last generic conjugated estrogens was recalled by Zenith in April 1991 ("The Pink Sheet" April 1, 1991, T&G-13). With the recovery of its position as the sole supplier of the hormone replacement therapy, Wyeth-Ayerst has seen its Premarin sales double during the last two years. Worldwide Premarin sales reached $569 mil. in 1991 ("The Pink Sheet" April 13, p. 9). [EDITORS' NOTE: In a story on Wyeth-Ayerst's 1991 results in the April 13 issue of "The Pink Sheet," Premarin's position in the estrogen replacement market was twice referred to as a "monopoly." While the generic versions of conjugated estrogens have been forced off the market until they can meet FDA's current standards for approval, Premarin competes in the same class with a number of estradiol and estrone products.] FDA's handling of Barr's conjugated estrogens application led to accusations from the generic firm that the agency was "retaliating" against the company for its role in aiding the generic drug investigations. Barr filed suit against FDA over the application. At the Furman Selz meeting, however, Cohen exhibited a changed attitude toward FDA. He praised the agency's recent efforts to clarify standards for conjugated estrogens bioequivalence. "We feel now, for the first, time FDA has clearly and concisely put in writing all of their demands on this product," he said. The agency "is beginning to speak more clearly" in the generic review process in general, Cohen added. Barr's most-recently submitted ANDA, he said "was a better, more complete application than went down the time before, not only because of our efforts but because FDA is beginning to speak more definitively on what their demands really are." In addition to conjugated estrogens, the Barr exec cited controlled-release narcotic analgesics as an example. "We've had some serious problems with the agency" over the narcotics, Cohen said. "We did things that we thought were correct, and we found that they wanted much more than we had done even though it was not clearly spelled out for us when we moved forward on these projects." Barr has in the past cited delays in approvals of its controlled-release applications as additional evidence of unfair treatment by FDA. While Barr's controlled-release applications "are languishing," Cohen expressed optimism that the company would ultimately see approvals. In the meantime, Barr is "doing process validation" on "half-a-dozen" products now, Cohen said. Barr currently produces a controlled release erythromycin, the equivalent of Warner-Lambert's Eryc. Expanded availability of generic controlled release products will contribute to the trend towards higher priced generics, Cohen said. Barr's average price for generics today is $65 per 1,000, he noted, compared to an industry average of less than $10 per 1,000 thirty years ago. In the future, "generic drugs are going to keep a less traditional range of discount off brandname drugs," Cohen said. Generic firms will experience "escalation of cost, improvement of profit margins...[and] less competition" as regulatory and technical barriers to entry continue to increase, he predicted. Brandname prices, meanwhile, will "continue to rise" despite congressional pressure to hold them down, Cohen maintained. His remarks reiterate a view of increasing generic prices expressed by one of the leading data services in the drug industry, Pharmaceutical Data Services ("The Pink Sheet" March 16, p. 9). Generic controlled release products are one of two areas of "opportunity" being explored by Barr, Cohen said. The second is "questioning the validity of certain patents." Barr challenged Miles' patent for the quinolone antibiotic Cipro (ciprofloxacin) at the start of November, Cohen said. The basic Cipro patent runs through 2004; NDA exclusivity expires in October. Cipro "is a product that falls right into our product line. We are a major producer of antibiotic and anti- infective drugs," Cohen said. Barr has lodged two other patent challenges, Cohen noted. The company has an approved ANDA for tamoxifen (ICI's Nolvadex). Barr's challenge of the tamoxifen patent, which expires in 2002, was heard in court in late 1990. The judge has not yet ruled, Cohen noted. The generic firm also has launched a widely-publicized patent challenge against Burroughs Wellcome's Retrovir (zidovudine, AZT) ("The Pink Sheet" April 22, 1991, T&G-4). NIH granted Barr a license to AZT in July ("The Pink Sheet" July 22, T&G-5). "We have a number of products that we're looking at that may also go that same way," Cohen added. In the manufacturing compliance area, "I think we've reached a corporate mentality that says that we have to hit the target" set by FDA, Cohen said. "It's a moving target," he added, but "we're working at it literally 24 hours a day and actually seven days a week." An FDA inspection last autumn led to the issuance of two FD- 483 adverse observation reports. The company also was threatened with an injunction if it did not come into compliance. At that time, Barr reiterated its allegations of retaliation by FDA. The firm had some congressional support ("The Pink Sheet" Nov. 11, p. 15). At the Furman Selz meeting, however, Cohen said: "We are not looking for continued confrontation with the agency. What we're really looking for is accommodation. Hopefully we're moving in that direction." Characterizing some FDA actions as "overcontrol" of the industry, Cohen said, "I think the agency has become sensitized to that. I think that the pendulum is beginning to move back to the center...The trick is not to fight it, certainly not to fight it too hard. You have to go with the flow." "We are making progress," Cohen continued. "People are beginning to listen. I am hopeful that relationships between the agency and the industry will continue to improve and to clarify." Barr is "in a very very strong position to gain" from increased ANDA approvals, Cohen maintained. The company has ANDAs for over 50 different drugs pending, he said. Barr's last approval was for methotrexate in October 1990. Several other generic firms gave the Furman Selz meeting an update on the number of ANDAs they have pending. Biocraft VP- Controller Brian Snyder said that his firm has approximately 50 ANDAs pending. The company has had four approvals so far this year, and expects as many as eight more products by year end, he said. Marsam VP Judith Arnoff said that the generic injectable firm has 21 products with ANDAs pending and is "currently undergoing a number of preapproval inspections." Lemmon President William Fletcher said that his firm, a subsidiary of Teva, has 36 ANDAs pending for 25 different products. Lemmon has had four approvals so far this year.

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