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FDA HAS BACKLOG OF ABOUT 200 PRE-APPROVAL INSPECTIONS IN PLANTS OUTSIDE U.S.; FDA MANAGEMENT PLAN ASKS DISTRICTS TO ESTABLISH CADRE OF EXPERIENCED INSPECTORS

Executive Summary

FDA currently has a backlog of around 200 pending pre-approval inspections for foreign firms listed on NDAs and ANDAs, FDA International Programs Staff Deputy Director Peter Smith told a "Commissioner's Industry Exchange Meeting" on the agency's pre- approval inspection program in Cherry Hill, N.J. Oct. 22. Smith noted that the "extremely high" number of pending foreign pre-approval inspection assignments reflects a sharp decline in the number of foreign inspections the agency was able to conduct in FY 1991 (ending Sept. 30). FDA conducted only about 120 foreign drug inspections during the past year compared to over 200 in FY 1990. Smith attributed the decline to Congressional delay in finalizing an FDA budget, which prevented trips from being planned last fall, and the outbreak of the Persian Gulf war in January, which "essentially ended our travel for five or six months." While his office is "now trying to work down the backlog," Smith noted "that is difficult" as investigators and analysts have to be borrowed from the district offices, which are burdened with their own pre-approval inspection workload. In general, he explained, the "high priority" applications "are getting done" while inspections for lower priority applications are being delayed. Smith joined Commissioner Kessler and a large panel of officials from agency headquarters and field offices to discuss the pre-approval program with industry representatives at the Cherry Hill meeting. Three additional "commissioner exchange" meetings are scheduled to be held on the pre-approval program: in San Franciso on Nov. 13, in Puerto Rico on Nov. 22, and in Chicago on Nov. 26. The meetings are intended to provide industry with information on the pre-approval inspection program and to allow a forum for industry input. The agency is considering holding additional "commissioner exchange" meetings on other topics including direct- to-consumer advertising, nutrition labeling, combination products, and safe medical device act issues. Smith said that the agency is making an effort to mirror domestic pre-approval inspections by sending a team including an investigator and a field laboratory analyst to conduct the inspections abroad. Where possible, he noted, the agency will try to use the same investigator/analyst team for all firms, both foreign and domestic, listed on an application. An FDA review last year of 600 NDA and ANDA applications found that "57% had one or more foreign firms" listed, Smith noted. "That could be a raw material or active ingredient supplier, or it could be the entire dosage form, or a company that provides laboratory services." Smith emphasized that the agency has "had some problems" during pre-approval inspections with "many of the firms overseas who have been in good general GMP compliance." In terms of foreign inspection findings, he said, "GMP and pre-approval generally does not seem to be equal." He added that FDA will not generally reinspect suppliers listed on applications which have been inspected and cleared within the past three or four years for the same or similar products. FDA has been taking steps to resolve the handling of pre- approval inspections in the three countries with whom the agency has a Memorandum of Understanding (MOU) providing for mutual recognition of inspections conducted domestically, Smith noted. FDA sent an inspection team to Canada during the summer to conduct demonstration pre-approval inspections on a handful of ANDAs pending from that country, he explained, and will be conducting a training course for the Canadian Health Protection Branch in November. An investigator/analyst team is now in Sweden doing joint inspections with the Swedish government. A team of FDA headquarters officials will be going to Sweden next month to revise the MOU to cover the pre-approval workload. FDA will be following the same approach in Switzerland, Smith explained, adding that "probably by early next year, things will be in order as far as the MOUs go." FDA officials at the meeting emphasized that industry can play a role in expediting the pre-approval inspection process by eliminating unnecessary and unprepared plants and suppliers from applications. Center for Drug Evaluation and Research (CDER) Deputy Director Gerald Meyer noted that a recently reviewed ANDA referenced 21 drug master files (DMFs) including one for the drug substance and 19 for packaging components. The generics office informed the sponsor that, as "any of these could delay the application," redundant ones should be removed, Meyers explained. The FDA panel outlined a number of steps the agency is taking to streamline the application inspection and review process. FDA Deputy Associate Commissioner for Regulatory Affairs Gary Dykstra noted that his office recently released a formal "management plan" giving operating instructions and detailing responsibilities for the pre-approval inspection program. The plan describes procedures that have been worked out between the field and headquarters for inspection planning and scheduling, reporting of inspection information, and tracking of corrections ("The Pink Sheet" Oct. 7, T&G-14). The plan calls for the districts to select "an experienced person to coordinate and manage the district's work under" the pre-approval program. The principle duties of the position, the plan explains, will be "to manage assignments, facilitate the rapid completion of assignments, and to provide a focal point for communications between the district" and other district offices, CDER and industry concerning the program. The plan also calls for the districts to establish a cadre of experienced investigators and analysts specifically designated for handling the pre-approval inspection workload. FDA Mid-Atlantic Region Director Richard Davis has been designated as overall program manager with responsibility for running and monitoring the plan. Dykstra said Davis "is the one who, on a day-to-day basis, is in contact with all of the other district offices, making sure that this plan is being implemented in an orderly and reasonable way." Davis told the meeting that continued improvement in communications between the field and the reviewing offices will be his top priority in running the program. He noted, for instance, that FDA is currently working on developing and implementing "a single field/headquarters database using some of the best computer technology that is available." New equipment for the system will be installed "in another couple of months" at six regional computer centers in the field. By the time these centers are set up, Davis said, "we expect to have already developed a field/headquarters database for the NDA/ANDA pre-approval inspection program." This database would put the field offices on line with the Office of Compliance and the CDER reviewing offices. Monitoring and improving consistency in field office handling of the pre-approval inspection program will be another top priority. Davis said that his office has recently helped organize a week-long advanced training course which will be given to the program's managers and inspection cadres. The course "is one of the best that the agency has ever put together" and includes both expert FDA investigators and industry speakers on "the problems that we have had out there," Davis said. Another goal will be designing and implementing a formal field-wide quality assurance program covering the pre-approval inspection work. FDA Office of Generic Drugs Director Roger Williams pointed to efforts underway at his office to streamline the review process. He noted, for instance, that his office has just completed barcoding of "all our applications in the center." That effort has resulted over the past few months, Williams explained, in the barcoding of 35,000 jackets. Each of the reviewing staff has also been assigned a barcode, he noted. Williams pointed out that the generics office has been making "dramatic progress" in reducing the backlog of pending ANDAs and supplements and in speeding up the rate of application approvals ("The Pink Sheet" Oct. 14, T&G-9). The generics director emphasized, however, that his office is "still approving applications that came in" before the "watershed" crisis period began in May of 1989, and "before all of the initiatives that we are talking about here today" were put in place. With higher quality applications now coming in, Williams said, "there is still substantial reason to think that things are going to continue to get better."
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