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FDA WITHDRAWING THREE PAR ANDAs AND 25 VITARINE ANDAs VIA ADMINISTRATIVE RULEMAKING PROCEDURES; ATI SUES AGENCY OVER CHLORZOXAZONE RESCISSION

Executive Summary

FDA plans to withdraw three ANDA approvals from Par and 25 ANDA approvals from Vitarine by publishing the proposed withdrawals in an upcoming Federal Register notice. In an Aug. 23 "Talk Paper, FDA said it "will be formally proposing withdrawal proceedings for a number of [the two companies'] previously approved ANDAs, which would essentially end their permission to make these drugs." FDA said that the "withdrawal proposals will be published in the Federal Register soon." Par and Vitarine will have 30 days following the rulemaking to request a hearing on the proposed actions. FDA has been considering several ways to take punitive action against generic firms found guilty of wrongdoing. In a July 28 memo to HHS Secretary Sullivan, FDA Commissioner Young offered two possible approaches -- administrative rulemaking procedures that would allow companies to submit comments, and legislation to expand FDA's enforcement authority. The latter is being pursued by HHS and FDA. The agency recently rescinded Par and American Therapeutics' ANDA approvals for chlorzoxazone (McNeil's Parafon Forte), because of good manufacturing practice deficiencies. FDA explained that the approvals were issued "in error" since the GMP information had been available before the approval letters were issued in June ("The Pink Sheet" Aug. 7, p. 3). American Therapeutics has since filed suit against FDA for the action. FDA notified Par on Aug. 22 that the agency would soon propose the withdrawal of the company's ANDAs for Orphengesic (orphenadrine citrate), Orphengesic Forte, and generic Maxzide (triamterene/hydrochlorothiazide) "on the grounds that these ANDAs contain untrue statements of material fact." On the same day, FDA told Vitarine that the agency would seek to revoke 25 ANDA approvals "on the same grounds," the "Talk Paper" notes. FDA told the two companies that the letters were "only meant to be a preliminary notice of the actions FDA intends to take." FDA noted in the letters that the agency's "investigations are continuing and [FDA] may propose to withdraw approval of additional ANDAs." FDA said that it "may specify additional grounds for withdrawal, such as violation of Current Good Manufacturing Practices (CGMPs)," when the notice of opportunity for hearing is published in the Federal Register. Both companies had previously ceased distribution or recalled the products targeted by FDA. Par recalled the three products in July after it discovered that samples of the products had been switched during an FDA inspection of the plant ("The Pink Sheet" July 31, p. 15). The Vitarine ANDAs include 25 dosage forms or ANDAs of 13 products, 12 of which had been recalled in May. That recall was in response to the revelation that two Vitarine scientists had submitted SmithKline's innovator product in the place of Vitarine's generic Dyazide for bioequivalence studies and that batch sizes for other products had been overstated in ANDA filings ("The Pink Sheet" July 3, p. 13). In an Aug. 23 statement, Vitarine said that "for many of its products, including some on the FDA's list, [the company] has already submitted data to the FDA adequate to correct any material misstatements in the ANDA[s] at the time of approval." Vitarine said it plans to argue that although there may have been some falsification of data in the ANDA applications, the company has since taken steps to provide new bioequivalence data on the products that would allow the agency to immediately reinstate any withdrawn ANDA approvals. Par also plans to submit new bioequivalence data on Orphengesic and Orphengesic Forte, but may not take any remedial action on its generic Maxzide due to poor performance in sales, the company said. The Vitarine ANDAs to be withdrawn include: baclofen tabs 10 and 20 mg; cephadrine caps 250 and 500 mg; cephalexin caps 250 and 500 mg; cephalexin tabs 250, 500 and 1,000 mg; cephalexin oral suspension 125 mg/5 ml and 250 mg/5 ml; clindamycin caps 50 and 75 mg; desipramine HCl tabs 10 and 150 mg; doxycycline hyclate caps 50 and 100 mg; hydrochlorothiazide 50 mg/triamterene 75 mg tabs; indomethacin ER 75 mg caps; indomethacin caps 25 and 50 mg; meclofenamate sodium caps 50 and 100 mg; mefenamic acid caps 250 mg; Orphenadrine Compound tabs (aspirin 385 mg, caffeine 30 mg, orphenadrine citrate 25 mg); Orphenadrine Compound Double Strength tabs (aspirin 770 mg, caffeine 60 mg, orphenadrine citrate 50 mg); tetracycline HCl cap 250 and 500 mg; and trimipramine maleate caps 25, 50 and 100 mg. As a result of the actions, FDA is bracing itself for several lawsuits. At an Aug. 24 breakfast with reporters in Washington, D.C., FDA Commissioner Young said: "I know that for some of the actions I am taking now, I will see the agency sued." Young admitted that "we do not have the authority" to remove drugs and set penalties "to show that crime does not pay." He said that FDA's authority "will be tested to see whether the actions that [the agency is] taking are appropriate." So far, only American Therapeutics has brought suit against FDA. The company challenged the rescission of the chlorzoxazone ANDA in a suit filed in Washington, D.C. federal court Aug. 22. American Therapeutics' lawsuit contains many of the same arguments outlined in an Aug. 9 letter to FDA on the chlorzoxazone ANDA rescission ("The Pink Sheet" Aug. 14, p. 3). FDA has not yet responded to the letter. In the lawsuit, American Therapeutics maintains that FDA does not have the legal authority to "rescind" ANDA approvals and is violating the Administrative Procedures Act and the Constitution by not providing the company with due process. The company is asking the court to declare that FDA's Aug. 3 letter is null and void and that its chlorzoxazone ANDA is lawfully approved. American Therapeutics is also requesting that the court enjoin FDA from rescinding any other of the company's ANDAs "unless the requirements of the FD&C Act, the APA, and the due process clause of the Fifth Amendment to the Constitution are followed." The generics firm concedes that FDA has the authority to withdraw ANDA approvals under the FD&C Act. Quoting the regulation, American Therapeutics noted that the HHS Secretary may withdraw ANDA approval if "on the basis of new information before him, evaluated together with the evidence before him when the application was approved, the methods used in, or the facilities . . . are inadequate to assure and preserve its identity, strength, quality and purity." However, American Therapeutics asserted that FDA must provide written notice and the opportunity for a hearing prior to revoking an approval. American Therapeutics also pointed out that the HHS Secretary may immediately rescind an ANDA if the secretary finds that the product represents an "imminent hazard." However, American Therapeutics noted, the company still has to be provided with the opportunity for an expedited hearing. In addition, American Therapeutics questioned the material facts upon which the rescission is based. FDA told the company in its rescission letter that the action was based on a June 23 FD-483 inspection report. The company points out that "only five of the 33 items on the Form FD-483 were related to ATI's production practices." Furthermore, the company said that it notified FDA's New York field office on Aug. 3 of "corrective action it had taken to address the concerns reflected in the [report], including all five items relating to manufacturing practices and procedures." Par has indicated that it will not take legal action to restore its chlorzoxazone ANDA, or the three ANDAs that FDA proposes to withdraw. The company said it has agreed to cease marketing of chlorzoxazone "while questions concerning Par's compliance status are outstanding." In an Aug. 10 response to the rescission action, Par took a conciliatory approach. The company said that while it "regards the action asserted by [FDA] in [its] Aug. 3 letter as a legal nullity, Par does not intend to add further to either [FDA's] burdens or to its own." However, in the letter, Par reminded FDA of "assertions" made by FDA Center of Drug Evaluation and Research Director Peck at Rep. Dingell's July 11 hearing that Peck "had personally reviewed Par's ANDA file and satisfied [himself] of the safety and effectiveness of its 500 mg chlorzoxazone product." Par suggested that the motive for FDA's rescission of the ANDA stemmed from pressure put on the agency by Dingell. "We recognize the extraordinary burdens presently carried by the FDA, including the criticism leveled on July 11 by Congressman Dingell at a public hearing challenging the propriety of this ANDA," the letter states. Par has said that it is complying with the agency as much as possible. Two weeks ago, at the FDA's request, Par ceased shipments of all of its solid dosage form products to review on a case-by-case basis whether the products were in accordance with ANDA specifications ("The Pink Sheet" Aug. 21, p. 15). The company said that beginning on Aug. 21, it has resumed shipments of some of its products. Par said that its review is expected to take anywhere from a couple of weeks to two months. Meanwhile, due to the slowdown in production, Par has been forced to lay off about 150 employees, including production personnel, laboratory chemists, and office personnel.
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