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FDA GENERIC DRUG INSPECTIONS WILL BE COMPLETED "WITHIN 12 WEEKS," COMMISSIONER YOUNG PREDICTS; 20 ADDITIONAL FIRMS GETTING NOT-FOR-CAUSE INSPECTIONS

Executive Summary

FDA's generic drug re-reviews and manufacturing facility inspections will be completed "within 12 weeks," Commissioner Young said at an Aug. 24 press briefing. "We think that within 12 weeks, the review of" 30 pioneer drugs and "close to 300 generic copies" will be accomplished, Young predicted. The drug product review will involve "almost 2,000 different samples," he added. In addition, FDA "will have looked at, by inspection, the plants" of 31 generic manufacturers, including a number of brandname companies that also manufacture generics, Young said. The agency began for-cause inspections of 11 generic houses in May ("The Pink Sheet" July 17, p. 11). On Aug. 23, FDA announced that it is expanding the effort to include routine inspections of another 20 "leading producers of generic drugs." The commissioner has set an ambitious schedule for FDA. However, public attention to the issue will not fade as quickly as 12 weeks. The announcement of additional criminal allegations, including indictments of two more FDA employees, are expected from the U.S. attorney in Baltimore, and the legislative process of establishing new safeguards and remedies for the agency will keep generic drug concerns in the public eye. In addition, hearings before Rep. Dingell's Energy & Commerce/Oversight Subcommittee are tentatively set for Sept. 11 and 29. Officials of Par, Vitarine, and Bolar reportedly were invited, along with U.S. Attorney General Richard Thornburgh. In an Aug. 23 "Talk Paper," FDA said it "has begun comprehensive inspections of 20 leading drug companies that manufacture generic products." The agency explained that the inspections were not initiated on a "for-cause" basis. FDA said that the inspections "are not a result of allegations of wrongdoing [but represent] a further effort by the FDA to assure the public of both the safety and efficacy of the generic drug supply in the U.S." The 20 firms "were selected in large part because of their large numbers" of approved ANDAs, FDA added. The agency is planning to conduct chemical testing to compare the 20 firms' production samples to their bioequivalence test samples and to reference drug samples, FDA said. The plant inspections will also "examine good manufacturing practices (GMPs) at the 20 firms . . . and at their various manufacturing sites" to check that bioequivalence and stability data submitted in their ANDAs "are valid and relevant to the commercially marketed products," the agency explained. The added inspections are also intended to "confirm and update FDA's routine inspections" for compliance with manufacturing process and product specifications listed in the ANDAs, the agency said. As with all inspections, regulatory action will be taken "as appropriate if violations are encountered." Inspection of the 20 firms' plants differs from the previously announced inspections of 11 generic manufacturers, in that the 11 were "targeted" for "potential problems," FDA explained. Those companies targeted in April for inspections were Able, American Therapeutics, Barre-National, Bolar, Par, Pharmaceutical Basics, Quad, Superpharm, Vitarine, Watson Labs, and Zenith. FDA has not disclosed the names of the 20 companies that will be included in the latest round of generic inspections. FDA emphasized that its investigation "has uncovered no evidence to indicate that there are any unsafe or ineffective generic drugs on the market." Young said at the press briefing that he "would not recommend" that patients switch from generic to brandname products. "Any person who's on a prescription drug [should] not be summarily taken off when you just have suspicions about safety because a lot of times you have difficulty switching out of a drug," he advised. The American Pharmaceutical Association, in an Aug. 24 statement, urged the public "to discuss directly with their pharmacist questions or concerns they may have about generic drug products and their appropriate use." The association said it "cautions against impugning the integrity of the many generic drug companies and their quality products because of the wrongful actions of only a few companies." Nonetheless, APhA added that it "supports the enactment of legislation" to increase FDA resources for "oversight of the drug approval process and the generic drug industry." On Aug. 18, HHS Secretary Sullivan announced that he would submit a legislative proposal to Congress "to strengthen and broaden the department's authority to act promptly against any improper activity in connection with the applications for approval of drugs" ("The Pink Sheet" Aug. 21, p. 13). In an Aug. 22 letter to the American Academy of Family Physicians, APhA Exec VP John Gans maintained that "it is obvious that there are patients for whom" a generic product "is appropriate, and equally obvious that there are patients for whom switching between products from different manufacturers is inappropriate." Gans was replying to AAFP's proposed policy against a "blanket approval of generic substitution" ("The Pink Sheet" Aug. 14, T&G-7). Gans said APhA had "serious concerns" about AAFP's proposal in that it "does not take into account the role of the pharmacist in addressing general concerns of drug product selection and shows a remarkable lack of knowledge about the drug distribution system." For example, Gans continued, if AAFP members are concerned that "there is no way of knowing" that a patient's medication has been switched, they need only "to call their patients' pharmacists." The APhA letter also took issue with several AAFP statements. Contrary to an AAFP comment linking drug bioequivalence to equivalent amounts of inert compounds, Gans said: "bioequivalence has nothing to do with the inert ingredients." Regarding AAFP's questions as to whether equivalent blood levels of drugs assure therapeutic equivalence, Gans remarked: "The measurement of bioequivalency is a direct measure of potential therapeutic outcome." Furthermore, Gans maintained that AAFP's "criteria for avoiding the use of multi-source products in certain types of diseases and patients (i.e., elderly females but not elderly males) seem both arbitrary and poorly based in science. References to support these assertions are not provided." In short, he concluded, AAFP's report "incompletely, and in some cases inaccurately, informs the academy's members about the very important and complex issue of appropriate use of multi-source drug product selection in quality cost-effective health care." Gans offered to have APhA address AAFP delegates on the subject "prior to . . . voting on such an important" proposal. APhA also commended the investigation by Rep. Dingell (D-Mich.) and his House Commerce/Oversight Subcommittee and the actions taken by FDA since the investigation's disclosures "to prevent a repeat of such wrongdoings in the future." In an Aug. 24 letter, Gans told Rep. Dingell that the association supports legislation to authorize FDA "to impose major legal and financial penalties for proven criminal activity, even if such activity does not result in an unsafe or ineffective drug product being approved." Gans added that FDA's financial support should be increased "so that sufficient resources can be applied to the drug approval process to minimize the chance of future unethical behavior among FDA staff." A group of 17 West Coast physicians and health professionals has asked FDA, in an Aug. 23 citizen's petition, to schedule a new bioequivalence hearing. The petition called on the agency to sponsor "an open hearing on bioequivalence, therapeutic equivalence, and overall safety and efficacy of generic drugs." Such a hearing would constitute a rerun of the three-day bioequivalence hearing held by the agency in 1985 in the aftermath of Waxman/Hatch. The group is asking FDA to hold a second hearing in order to reconsider generic drug issues in light of the current situation. The petition recommends that the hearing review the "procedural mechanisms for curtailing abuses of the ANDA approval process by generic drug manufacturers," the petition states, as well as conduct a "systematic scientific and regulatory review" of all ANDAs approved since enactment of the 1984 Waxman/Hatch act. "The entire process for judging bioequivalence, therapeutic equivalence and safety" of generic products is "seriously flawed," the petition maintains. The group seems to imply that FDA should scrap its current system of reviewing generics based on bioequivalence studies in favor of a system that would require proof of therapeutic equivalence. The petitioners are asking FDA to require generic drug sponsors to demonstrate "that they can and will meet their burdens of proof under 21 U.S.C. 355(j)(2) and generate and provide data pursuant to the requirements of the Act." The Waxman-Hatch Act rules embodied in that section of the code encourage FDA to approve ANDAs unless there is insufficient evidence to meet approval requirements. The West Coast group suggests that the hearing focus in particular on generic drugs "intended for use in the treatment of depression, asthma, heart disease, epilepsy, diabetes mellitus and psychoses." Drugs for these conditions were cited as inappropriate for generic substitution in a recent report by the American Academy of Family Physicians ("The Pink Sheet" Aug. 14, T&G-7). The petitioners also asked that a moratorium be placed on all ANDA approvals "for a period of at least one year" to allow FDA time to complete its review of the process and formulate new regulations. "Continuing to approve generic drugs prior to fully evaluating the weaknesses in the current system is socially, medically, and morally indefensible," the petition declares. UCLA Psychiatry Professor J. Thomas Ungerleider, MD, chairs the committee signing the petition. He was one of seven physicians to petition FDA in 1985 to replace all then-extant bioequivalence guidelines with more stringent regulations. Counsel for the petitioners is Michael Sonnenreich (Washington, D.C. firm Sonnenreich & Roccograndi). Sonnenreich, a frequent counsel for physician groups questioning generic quality, is also legal counsel to Medicine in the Public Interest (MIPI). That group has contended that equal availability of products in the bloodstream does not ensure therapeutic equivalence. The American Association of Retired Persons accused MIPI with spreading "anti-generic propaganda" and alleged it was "supported by brandname industry funds."
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