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Executive Summary

FDA may require generic firms to submit full-term stability test data with ANDAs due to the failure of many generic manufacturers to meet stability testing and reporting commitments, Generic Drugs Division Deputy Director (Chemistry) Robert Jerussi cautioned the National Association of Pharmaceutical Manufacturers mid-year meeting on June 7. Based on the agency's review of annual reports from generic manufacturers, Jerussi observed, "it seems fairly obvious that a number of companies are not living up to the commitments they made in order to get their ANDA approvals." Problems, he said, include reports containing no stability data whatsoever, a lack of room temperature stability data at 18 and 24 months, and the absence of stability data when changes in formulation are made. The deputy director of FDA's generics division pointed to the failure of some generic firms to make complete submissions and to follow up on ANDA commitments as among the "disturbing practices commonly followed by applicants that must change immediately and permanently." Jerussi warned that "continuation of this behavior" by industry could lead FDA to significantly tighten its stability filing requirements. Possible actions that could be taken by the agency, the generics official suggested, include a requirement that full-term data be submitted before approval, or that expiration dates be set "at the date of the last data we have, i.e., if you miss your first commitment to supply the data, we assign you the three-month dating [on which] you were approved. If you miss your second set of data you get assigned the date supported by the first set, probably 6 months to one year in most cases." Also, FDA is finding in its review of annual reports that changes are being reported that require a supplement to the ANDA. Although the agency is considering more vigorous enforcement, Jerussi said that "for now, we are putting a notice in our letters to you when we discover such an incident, advising you not to place batches into interstate commerce that have used the reported change until approval of a supplement is obtained." FDA sent a letter to all NDA and ANDA holders and applicants on June 1 to notify generic firms that the agency will be cracking down on incomplete generic applications by checking them carefully before filing and returning those that are submitted with incomplete or missing data ("The Pink Sheet" June 4, p. 15). For example, the letter said that ANDAs will be returned if they do not contain at least three months of accelerated stability data, and completed batch records on stability and bioequivalence study lots. The letter also alerted industry that, based on the frequency of the problem in the past, FDA will be closely reviewing annual reports to ensure that stability commitments are being met and that manufacturing changes are getting appropriate clearance. Jerussi acknowledged that industry is not "fully to blame for slipshod submissions practices." He suggested that FDA "aided in the development of this learned behavior" by essentially saying to industry: "'don't worry about what you submit, we'll work with you and try to get you an approval any way'." However, he noted, "no longer do we have the luxury of offering such an uncritical helping hand." A key part of his job, the generics division deputy director told the generics manufacturers, is "to help you learn a new behavior." FDA has been spelling out the new generics division policies in a series of guidances intended to help standardize industry and agency application and review practices. Almost two dozen have now been issued. FDA formally announced the availability of the guides in the June 1 letter to industry. Jerussi repeated a request made in the letter for industry to bring to FDA attention any instances where the agency's advice or instructions appear to be inconsistent. He cited reworking as one area where agency advice has been inconsistent in the past. A policy guide will appear slowly, he noted. * Office of Generic Drugs Acting Director Bruce Burlington emphasized that the main bottleneck in ANDA reviews currently is in the chemistry area. Burlington noted productivity among generics division chemistry reviewers has declined due to the loss of some highly productive reviewers and more careful review procedures currently in place. The three or four action a day pace set by some reviewers in the past, Burlington maintained, "represented too many to both do an accurate review and to adequately document the administrative record that would show people what had happened to that review." Among the 16 chemistry reviewers that are carry overs from the 1988 period, Burlington said, productivity has declined from about 23 actions a month to 17 actions per month. However, he said, "we don't think that is an unreasonable accommodation given all the other impositions that have happened in terms of developing responses to numerous inquiries from industry, from Congress, and from within the agency to continue to investigate the problems that have occurred with the generic drugs review program." The primary chemistry review staff has had a net increase of about six full time equivalent positions since the 1988 period, Burlington reported. One focal point in addressing the application backlog problem, Burlington noted, is to reduce the number of major revision cycles in which applications are involved. He noted that applications have been averaging almost four such major amendments before approval. The agency is currently conducting a survey of defects in applications that took several cycles over the past few years, Burlington said, and will share the results with industry in the effort to get applications through in one cycle. The generics office is also putting an effort into developing a format guidance similar to that for NDAs. "The format guidance will materially assist our reviewers in reviewing applications more quickly," Burlington explained. The acting generics division director noted that FDA "finally got up into double digits in terms of original application approvals last month" with 12 approvals. Burlington reported that there are now 1,127 ANDAs and AADAs pending, compared to about 800 in 1987. At that time, the agency was processing about 50-70 applications per month, compared to a current rate of 40, he said. Exacerbating the problem, Burlington pointed out, is the estimated 185 products that will become available for generic competition over the next five years, "many of which are blockbusters. We have reason to think we may get around 50 applications per product -- that is 10,000 applications." The supplement inventory has also grown from about 1,500 pending supplements in 1987-88 to over 3,300 at present, Burlington noted. The message from the inventory numbers, the generics official said, "is that we have a serious mismatch between the work we are taking in and the work we are putting out, and we need to do something about it." Burlington pointed out, however, that there are "bookkeeping issues that make the system look worse than it is." He noted, for instance, that a recent Alert List contained 57 facilities "which are responsible for a large number of applications that even if we are near or at completion of review we can't clear until the company comes into compliance." A procedures guide is now being developed, Burlington said, to "send non-approvable letters that will highlight the compliance problems as the cause for non-approval." The letters will allow companies to focus their resources on problems and clear FDA's books of those applications. * Commenting on the status of the Generic Drugs Advisory Committee, Burlington noted that candidates have been evaluated and availability checks are now underway. The agency expects to put together a package of nominations and send them to HHS over the next few weeks. The department is expected to act quickly, Burlington said, allowing for a meeting of the committee during the fall. Among questions that the generics office would like to see addressed by the committee, Burlington explained, are "specific questions on bioequivalence and broad questions on what our scale-up policy should be." Jerussi pointed to scale-up along with fast-track handling of blockbuster drugs as two issues currently generating significant debate in setting the new FDA policies. Dingell has been recommending that there should be a fast track review of generic copies of major volume drugs coming off patent as a health care cost reduction measure. The agency is also closely reevaluating antibiotic filing requirements and significant changes in this area are being considered, Jerussi said.

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