ANDA APPROVALS FOR 50-60 APPLICATIONS ARE CLOSE, GENERICS DIRECTOR WILLIAMS TELLS NAPM; ANDA BACKLOG STANDS AT ABOUT 1,000, DOWN FROM 1,200

FDA may have as many as 50-60 ANDAs ready for approval that are awaiting final clearance from the field, Office of Generic Drugs Director Roger Williams, MD, said at a June 6 session of the National Association of Pharmaceutical Manufacturers' mid-year meeting in Washington, D.C. Applications "either have to have a product-specific inspection or the field has to say they don't need a product specific inspection. That process sometimes takes weeks and maybe even months depending on the priorities that the field is confronted with," Williams said. "We might have 50 or 60 applications that are ready to be approved, and they're being held up because they're awaiting a field inspection." Some applications are being held because the sponsor is "one of the special firms that we're holding approvals for, the fraud firms, or there's something else going on in the field that's holding up that application." He added that if the process "moved forward rapidly we might have another 20 or 30 or 40 applications approved right now." In May, the agency approved six ANDAs but an equal number of approvable applications were held up awaiting clearance from field inspectors, Williams said. The field inspection stage "was a particular problem for us in May," Williams said. "It's disappointing to us, we feel we could have another six or seven [approvals] if all the inspectional processes had been completed." He added: "I think it's a particular example of how these field inspections, which are going to be rigorous, have added another [approval] rate limiting step to the process." Asked about field staff assertions that their work does not hold up approvals, Williams said that may be so over the long term, but "on a month to month basis, we think it's holding it up." He added: "We felt that in May it definitely held up about seven approvals." FDA may "catch up and have a little bolus [of approvals] in June" but "we just don't know where those field inspectors are going to be at any one time or what they'll be called in to look at." Questioned whether FDA headquarters staff has the authority to direct field inspectors to give priority to applications nearing the approval stage, Williams said no, but "we feel the way to resolve that issue is high quality communications between us, the field and compliance [personnel]." He continued: "We meet with people with Office of Compliance weekly to see what's coming through our pipeline and we've also worked very closely with the field." The situation is "not a command issue, it's a communications issue." Despite having only six ANDA approvals last month, Williams pointed to several "hopeful trends." He suggested the general goal of moving to about 20 approvals per month, as suggested at Rep. Dingell's (D-Mich.) hearing the day before, is "realistic" although "it's just hard to know where things are going to be a year from now." There is "no question about it that the approvals have gone from 100s per year down to about 60 or 70 last year. It's been painful," Williams said, but one of the "hopeful signs that we think we're seeing in the Office of Generic Drugs..... is that already this year by May, which is five months of the year, we already have about 52 approvals." Williams also said that in 1990, "approvals were running about five to 10 a month, we think they're running about 10 to 15 a month now." On the ANDA backlog, he reported that "we've gone down from about 1,200..... to about 1,000 sitting in the queue, this is current to April of '91." The numbers for May are "a little better still," Williams said. "So we hope that we'll see a gradual decrement and I think in the not too far future we might approach the 800 that it was before the crisis and we even hope that it will get better than that." The office has made "even better progress" in working through the backlog of supplements. As of May, "we're down to about 2,400 to 3,000 supplements [in the backlog]. So we've gone from a high of over 3,500 down to about 2,400. That obviously is a substantial decrement." Williams remarked that "one of the things that came out in the hearing yesterday is do we just pay lip service" to the requirement that ANDAs be acted on within 180 days. The agency takes this deadline "very seriously," Williams said, reported that the number of applications awaiting action for more than 180 days has gone from a high of 600 to about 430. "So again, we think we've made substantial progress." Regarding Sen. Hatch's (R-Utah) suggestion at the Dingell hearing that FDA be given six months to make substantial performance improvements, Williams responded: "I see the office staff..... making an incredible effort." The staff "would like to see that goal being met and I think a goal of 15-20 [approvals monthly] is a very realistic expection for us, but I hesitate saying [that specifically in] six months we're going to have 20 approvals a month," even though "we're out there making that commitment." Williams pointed out that the generics office has hired 13 chemistry reviewers over the past several months, bring the total to 33. The office has FDA authority to bring the chemistry review staff to 45. "Another thing we're going to try to do is go back to our pattern of having workshops with you. "We're planning a workshop now to deal with the scale-up issues," Williams informed the NAPM members. Williams outlined some more "aggressive" strategies being explored to help "in resolving our backlog and our delays," including the concept of a "one-shot review." One idea "that's kind of ticking away in my mind, and believe me there's nothing that I can commit to now about it, is more the concept of a one-shot review," he said. "The way I think about that is there might be some way to develop a managerial strategy so that..... you work very closely with a firm as they're responding to that first nonapproval letter, with the objective being that the next response is an approval letter." Williams acknowledged: "Right now that might seem like a big fantasy, given all the [review] cycles and the lengths of the cycles, but if we could implement something like that I think it would cut our review times down dramatically." Noting that FDA just recently published a Federal Register notice seeking comment on approaches to a monograph system for generic drugs ("The Pink Sheet" June 3, p. 10), he cautioned that "it's a very challenging concept." Williams said he was "not so sure" that the monograph approach would move approvals through more rapidly. Updating progress on other issues, Williams predicted that "all of the guidances and requirements" regarding testing of generic conjugated estrogens will be in place "by the end of this year." He told the NAPM members that "I'd like to have you help me adhere to my goal..... [of having] "generic formulations out in a couple of years." Williams called the Generic Drugs Advisory Committee's work on conjugated estrogens a "success." In February, the committee recommended that conjugated estrogens' bioequivalence should be demonstrated by both rate and and extent of absorption, and that companies should be given an option to perform either single or multiple dose studies ("The Pink Sheet" March 4, p. 9). Williams said a draft guidance on conducting the clinical studies has been forwarded to the advisory committee and "we have asked them for comments by June." In addition, the office expects to have final "compendial standards out by..... mid-fall of this year," Williams said. He added that he is working "vigorously" on the specific scientific issues related to use of metered dose inhalers for generic products. In addition, FDA's fraud policy "is coming out of the agency and there's a projected implementation date of the end of this month," Williams said. Declining to give details of the policy, Williams said only that the "basic principle is that it will defer review until everything gets back into the right shape at a particular company." Provisions of the earlier proposed fraud policy included a requirement that fraudulent product applications must be replaced with new applications and could not be corrected via supplemental information ("The Pink Sheet" Dec. 24, p. 11).