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ANDA REVIEWS BY NEW DRUG EVALUATION OFFICE CHEMISTS ARE BEING PHASED OUT; GENERICS OFFICE IS "REFUSING TO FILE" ONE-IN-THREE ANDAs SUBMITTED

Executive Summary

FDA's Office of Generic Drugs is phasing out the assignment of ANDA reviews to chemists in the agency's new drug evaluation offices. The assignment of ANDAs was started 18 months ago as a temporary rescue program to help the generics office catch up with the large backlog of pending ANDAs. FDA Generic Drugs Office Deputy Director Douglas Sporn reported at an April 15 meeting of the National Association of Pharmaceutical Manufacturers (NAPM) in Bethesda, MD, that FDA sent over the "last set" of ANDAs for review by the NDA review chemists in February. Altogether, Sporn noted, NDA chemists reviewed 470 ANDA applications under the program. With the backlog in pending ANDAs significantly reduced and the generics office at "almost full staff," Sporn explained, "we've decided that we can't ask for help from" the NDA review offices, "so that is going by the wayside." The FDA generics office now has 42 reviewing chemists on its staff, up from less than 30 in 1990. The new chemists are getting a "standardized training program before they go to the chemistry review branches where they get additional training," Sporn said. ANDA reviewers will also be "going out in the field on pre- approval inspections" where they will "have a chance to interact with field investigators and district offices," Sporn reported. FDA officials at the NAPM meeting pointed to the upward trend in the number of applications approved in recent months and the declining backlog as indications of the productivity gains made by the generics office. The agency cleared 28 ANDAs in March, a high since the industry investigations began ("The Pink Sheet" April 6, p. 4). However, Sporn noted, the office's productivity may face some new challenges. One will be the loss of the help from the NDA reviewers. The other major challenge will be a new requirement that ANDA reviews be assigned randomly to office chemists. The random assignment procedures will be instituted by the generics office in June under a mandate from the HHS Inspector General ("The Pink Sheet" March 23, 1992, p. 6). Branch chiefs in the generics office currently have the discretion to assign applications based on workload as well as the expertise of the available chemists. Under the new procedures, the oldest application pending will get the highest priority and be randomly assigned to the next available reviewer. While the new IG procedures are designed to assure fairness, Sporn said, they will reduce the efficiency inherent in having experienced chemists review applications for the same or similar products. With six or seven chemistry reviewers in each of the branches, "it is entirely possible that the same drug product could go to these different chemists" who "may not have seen that type of drug product before" and therefore "won't be as productive." Trying to maintain consistency in the review of the same products among different chemists "will also be a challenge for us," Sporn observed. An ongoing problem in terms of office productivity, Sporn said, has been the lack of microbiological expertise among the staff. Although the overall number of unreviewed applications pending more than 180 days has dropped "dramatically" over the past year, Sporn noted that the absence of microbiologists at the generics office has been a sticking point in addressing backlogs among injectable products. Currently, microbiological aspects of the review are being farmed out to the new drug reviewing offices. Sporn said that, on average, this process has been taking "over 230 days from the time we send an application over...to the time it comes back to us." An effort to recruit a microbiologist for each of the generics office's chemistry review divisions is now underway, although finding a qualified microbiologist "to come to work for the government has not been easy," Sporn said. "If we can get those people on board and trained, then I think we'll have a much better opportunity to see those applications pending over 180 days go down much more." Generics office staffer Gordon Johnston reported that the number of applications which the office is refusing to file has increased significantly over the past few months. During 1991, the agency was sending back about 20%, Johnston said, noting that since December the rate has increased to about one in three. Under the policy, announced in a letter to industry by Center for Drug Evaluation & Research Director Carl Peck in June 1990, the agency conducts an initial review of ANDAs to make sure that critical components are included before accepting the applications into the review cycle. Generic Drugs Office Director Roger Williams elaborated on the FDA requirements regarding ANDA completion in a follow-up letter to industry in November 1991. Johnston noted that most of the applications are being returned to sponsors due to their failure to follow the basic instructions contained in Williams' letter. The most common reasons for refusing to file ANDAs, Johnston said, are the failure of firms to include adequate: [] [] patent and exclusivity information [] [] authorization for the drug master file [] [] and/or blank master production records. Lack of DMF authorization has been "one of most consistent omissions" over the past few months, Johnston said. Noting that a letter of authorization "that is dated and signed from the DMF holder." Johnston explained that either "we don't get an authorization at all" or the authorization "is from a marketer or chemical supply house where it is being accessed" and not from the DMF holder itself. Firms also frequently do not file information on patents that are still in effect or on the exclusivity awarded, he said. In the case of master production records, Johnston explained that either none is submitted or the production record "really is blank," including no information, for instance, on the size of the batch the firm intends to produce. In other cases, he noted, the master record provides for more than the allowed 10-fold scale-up in batch size compared to the biobatch. Williams reported to the generics group that he has seen no real expression of support either within FDA or from outside for the concept of "batching" ANDA reviews for applications from different sponsors for the same drug. Batching of approvals was among proposals suggested to the agency by Rep. Dingell in April 1990 as a means of expediting the review of ANDAs for "blockbuster" drugs coming off patent. FDA Mid-Atlantic Region Director Richard Davis urged the generic manufacturers to have a "product development report," detailing "exactly what you did in the development of your product," ready for FDA investigator review during pre-approval inspections. In particular, he praised the utility of a "unique" version of a product development report called a "problem analysis report" recently submitted to FDA inspectors by one company. The report outlined what the management of the company had identified as problems in the development of their process and application and how those problems had been solved, Davis said. Because the inspected firm had addressed problems before FDA found them, "that was a very easy inspection to do," Davis said, explaining that "the company had done its homework -- we were in there and out of there in a few hours." Office of Compliance Director Daniel Michels concurred, saying that the companies with product development reports find "that it makes their life easier and more comfortable to know that they've done the job right the first time." He added that he advocates the use of product development reports because "I don't want to have the Office of Generic Drugs wasting its time on poorly prepared or inaccurate or fraudulent applications" or to risk "exposure of the public to questionable product." Davis noted that, while FDA encourages product development reports, they are not required under current Good Manufacturing Practices and therefore cannot be listed as deficiencies on inspection forms. He acknowledged that this error has been made in the past, and he has taken steps to correct it.

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