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Executive Summary

FDA's slowdown in ANDA approvals has been due to increased scrutiny and to a loss of chemistry reviewers and not to involvement in the review process by the head of the agency's Center for Drug Evaluation and Research, CDER Director Carl Peck, MD, told House Oversight Subcommittee Chairman Dingell (D-Mich.) on July 19. "The [generic drug] review process did not come to a halt as a consequence of my involvement in the reviews," Peck maintained. "However, the impact of giving increased scrutiny to applications and the loss of a number of chemistry review staff resulted in a decrease in the total actions produced by the office and a significant reduction in the number of approvals." Peck -- with CDER Deputy Director Gerald Meyer and Office of Generic Drugs Director Roger Williams, MD -- was replying in writing to questions sent to FDA June 25 by the subcommittee following a June 5 subcommittee hearing ("The Pink Sheet" June 10, p. 10; July 15, T&G-2). The subcommittee asked Peck why he insisted on personally "re- reviewing approvals," whether it was "a prudent use" of his scarce time and whether there was "no one else . . . who could have done this work." Peck responded that in May 1989 then-Commissioner Young asked him to "personally assume the final sign-off authority for all ANDAs" because "it was imperative to demonstrate the FDA's commitment at the highest levels of management to address the issues surrounding" the generic drug crisis. Peck maintained that "the utility" of his re-review "was demonstrated" both in affirming proper approvals and in identifying deficiencies requiring the return of ANDAs for further "data or division-level review." Peck's re-reviews were particularly useful, he said, regarding ANDAs whose "approval was accompanied by a request for resolution of scientific/medical issues not resolvable" by the Bioequivalence Division. For example, Peck continued, FDA's "review staff had observed an excess incidence of dizziness and fainting spells" in volunteers in a bioequivalence study receiving the generic, test version of the antihypertensive prazosin (Pfizer's Minipress). The review staff disagreed "as to whether this was medically significant," Peck said. "Upon close examination and further analysis, I determined that this product would be unsafe for approval, as the product was clearly absorbed more rapidly than the innovator's product, resulting in clinically significant episodes of low blood pressure and cardiovascular shock." He said he therefore "concluded the generic version was bioinequivalent to the innovator's product." Peck said his personal involvement in ANDA reviews lasted from May to October 1989, when Commissioner Young and he "agreed that although the crisis was continuing to unfold, we thought that we understood enough about its direction that I could redelegate immediate responsibility to a new team of managers." Asked why FDA has not required SmithKline Beecham to reformulate the antihypertensive Dyazide due to the product's poor and variable bioavailability, Peck answered: "Even though we know that the product is poorly bioavailable (an issue which is addressed in the labeling), there is no specific safety or efficacy issue which would provide us with the authority to demand a reformulation. There are already fully bioavailable combinations of hydrochlorothiazide and triamterene on the U.S. market; clinicians can prescribe those as readily as Dyazide." In response to a separate question, Peck confirmed that since the generic scandal broke, Bolar is the only firm that has contested an ANDA withdrawal. The firm resisted withdrawal of its ANDA for generic Dyazide, which was approved based on a bioequivalence study involving a fraudulent product switch. "To date, FDA has found 169 products covered by ANDAs to be supported by untrue statements," Peck said. "Of these, the agency has withdrawn approval of 59 products," 45 of which "were withdrawn after the firms requested withdrawal and 14 were withdrawn after a NOOH (notice of opportunity for hearing). Of the 14 withdrawn after an NOOH, 13 applicants subsequently withdrew their requests for hearing and only one, Bolar, continued to contest the withdrawal," he explained. Of the remaining 110 products supported by untrue statements, FDA has issued 35 NOOHs and "must still issue NOOHs for 75 products." The subcommittee also asked whether legislation would "simplify the withdrawal process." Because "it is clear that the withdrawal process (including any appeal to the courts) takes a long time," during which "a product of questionable safety and effectiveness" can remain on the market unless it poses an imminent hazard, Peck said "we would be pleased to work with departmental and administrative legislative staffs and the Congress to develop legislation to increase our ability to protect the public health." Rep. Dingell is cosponsoring legislation that authorizes FDA to quickly withdraw product approvals. Peck indicated that, until FDA's fraud policy is final, the agency will continue reviewing applications in order of submission regardless of whether a sponsor has committed fraud in a previous application. Peck acknowledged that FDA counsel David Adams has indicated that the agency has the authority to skip over applications whose sponsors have been tainted with fraud. The subcommittee asked how the agency justifies "review of applications of such pervasively corrupt firms as Bolar at the expense of honest firms." Peck acknowledged that FDA "feels it has the authority to implement the proposed [fraud] policy with respect to deferral" of reviews of suspect firms' applications. However, he said, the agency has "offered the public an opportunity to comment prior to implementation" and considers it "more appropriate to follow through on our offer to consider public input on the policy prior to its implementation." The report by outside consultants led by the American Pharmaceutical Association's Arthur Kibbe criticized what it called FDA's practice of issuing "policy by podium" since such edicts could be "incorrect, misleading or ambiguous." In answer to a question about that practice, Peck said the agency has taken several steps to address such concerns. The management of the generic drugs office "reviews all material to be presented by the staff to industry," he said, and policy statements "receive close scrutiny" for accuracy and clarity. Office management and staff "readily respond to inquiries from industry regarding documentation required in an application," he added. Williams explained that five FDA officials are now authorized to sign off on ANDA approvals, including himself, Peck, Meyer, CDER Deputy Director for Medical Affairs Bruce Burlington, MD, and Office of Generic Drugs Deputy Director Douglas Sporn. However, Williams said he has signed off on "almost all" generic approvals since October 1990. In response to another question, the generic office director said he disagreed with the conclusion of Kibbe consultants that the office's chemists are inadequately trained. However, he acknowledged, FDA has identified areas "in which their training could be improved." Consequently, he said, the office has established a review training branch headed by John Simmons, PhD, formerly with the Cardio-Renal Drugs Division. Meyer was asked why the subcommittee should "have any confidence" in his "ability or will" to correct the generic drug regulatory "mess" in light of CDER's "negligent or worse" management. In response, Meyer pointed out CDER's "notable accomplishments during this same period": accelerated reviews for life-threatening and seriously debilitating illnesses, expanded access programs, and the "significant reductions in the center's backlog of overdue NDAs." Regarding generic drugs, he continued, Peck and Meyer personally reviewed every approval recommendation early in the crisis. Although the Kibbe consultants characterized the re- reviews as causing an unnecessary bottleneck, Meyer explained: "we felt our personal involvement was necessary to restore confidence in the review and approval process in view of the serious charges that had been leveled against the" Generic Drugs Division. Meyer said he and Peck meet weekly with Williams and Sporn "to discuss the progress that has been made and the problems that have arisen in the office," and they meet "regularly with Compliance, Regulatory Affairs and field management on the issues surfaced by the newly instituted pre-approval audits."

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