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Executive Summary

Approximately one-third of all ANDA deficiencies leading to first non-approvable letters were the result of incomplete or missing submissions in the area of chemistry and manufacturing, according to an FDA survey of 45 ANDA submissions. Of 795 ANDA deficiencies listed in first non-approvable letters sent to the sponsors of the 45 ANDAs, approximately 250 (or 32%) were the result of missing data relating to tests and procedures in the chemistry and manufacturing sections of ANDA submissions, the study showed. The preliminary results of the survey of 45 randomly selected ANDAs that generated at least two non-approvable letters from Jan. 1 to May 31 were released at an FDA sponsored workshop on ANDA submissions on Sept. 24. Office of Generic Drug's Deputy Director of Chemistry Robert Jerussi called the number of omissions "staggering." The survey was conducted by FDA economist Priscilla Prunella. In the case of raw materials testing, for example, over two thirds of all deficiencies were the result of absent tests and/or specifications. "Every ANDA that I looked at had missing or incomplete information," Prunella told the workshop. FDA identified 1,175 deficiencies in the 45 ANDAs. Office of Generic Drugs Acting Deputy Director Douglas Sporn emphasized that the ANDAs chosen for the study, although randomly selected," reflected quite a few reviewers" and were representational "in terms of dosage forms and what comes in the door here." Sporn noted that "the bulk of ANDAs have to go through at least three cycles before they are approved." He added that FDA "would very much like to see a greater portion of approvals come out in the first and the second cycle." For the purposes of the study, the 1,175 deficiencies were characterized according to the major category of deficiency, the type of deficiency, the reason for the deficiency and the specific problem area involved. Preliminary findings of the study showed that deficiencies in the chemistry and manufacturing sections of the ANDAs analyzed accounted for 82% of the deficiencies in the first non-approvable letters sent to sponsors. Labeling deficiencies were next, accounting for 13% of deficiencies in first non-approvable letters. Among the 650 chemistry and manufacturing deficiencies that turned up in first non-approvable letters, inadequate raw material testing data (26%), insufficient stability test data (17%) and poor submissions covering analytical procedures (11%) were the three areas associated with the most deficiencies. Raw material deficiencies alone accounted for 166 of the 795 total deficiencies cited in first non-approvable letters. Speaking at the workshop, Office of Generic Drugs Acting Director Bruce Burlington explained that the study grew out of the agency's pressing need to expedite the ANDA approval process. "We have a substantial inventory of unreviewed ANDAs [of] around 1,200," Burlington said. "One of the major problems was that ANDAs tend to be resubmitted," Burlington continued. "As a consequence, we asked the Office of Planning and Evaluation to conduct a formal study. [We wanted] to look and see what are the problems identified and find a forum in which we could transmit that information to the industry." Burlington noted that not one of the approximately 4,000 ANDAs that have been submitted to the agency since 1984 has received an approval on the first try. Similar errors of omission were cited by FDA officials working in ANDA review areas not addressed by the study. FDA Division of Bioequivalence Director Shrikant Dighe, PhD, noted that assay validation "is one area where FDA is finding glaring deficiencies," including "incomplete or inadequate data on sample stability." Speaking on protocols and procedure guides, Generic Drugs Division Deputy Director Kent Johnson pointed out the industry's "underuse of the guidance program." In response to a suggestion that some of these deficiencies might be the result of individual reviewers "pet questions," or "reviewer nit-picking," Generic Drug Division Deputy Director-Chemistry Robert Jerussi replied that he questioned "maybe 1%" of all the deficiencies cited in the study. Jerussi stated that "industry is not meeting its stability commitments in general." Center for Drug Evaluation and Research Director Carl Peck described the workshop as a "nuts and bolts meeting" designed to help generic companies conduct their regulatory business with the agency. "The solution to getting applications approved is better applications and better reviews," Peck said. "This agency and this industry must and will do better." Peck said that FDA now "has a strong program for receiving and reviewing ANDAs." The agency, he added, "will insist [that generic firms] have better and more complete applications."

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