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Executive Summary

FDA is encouraging NDA sponsors to respond to reviewer requests for additional case reports and data tabulations within 30 days. According to a new FDA staff manual guide, the agency will not extend the time period for an NDA review if the information is submitted within 30 days. However, if the sponsor takes longer to answer the data request, FDA may consider the data a "major amendment" to the application and allow itself more time for review. "lf an applicant delays beyond 30 days in submitting clinical case reports or tabulations requested by the FDA, review time will be extended for an amount of time equal to the time from the request to the submission, rounded up to the next month," the guide states. The staff manual guide outlines FDA policy regarding time frames for new drug and antibiotic reviews established in the revised NDA regs published earlier this year ("The Pink Sheet" Feb. 25, p. 3) FDA issued the document along with nine draft guidelines for NDA submissions. "The guidelines," FDA explained in a June 25 Federal Register notice announcing their availability and soliciting comments on them, "are intended to assist applicants in complying with the requirements of the regulations." The draft guidelines cover the format and content of the NDA summary (Docket No. 85D-0247); chemistry, manufacturing, and controls section (Docket No. 85D-0243); nonclinical pharmacology/toxicology section (Docket No. 85D-0244); human pharmacokinetics and bioavailability section (Docket No. 85D-0275); microbiology section (Docket No. 85D-0245); andstatistical section (Docket No. 85D-0246). The remaining guidelines discuss NDA and antibiotic formatting, assembly and submission (Docket No. 85D-0248); submission of an archival copy in microfiche (85D- 0250), and postmarketing adverse drug reaction reporting (85D-0249). The guidelines and staff manual guide (No. CDB 4820.2.1) may be obtained by by writing the Center for Drugs and Biologics, FDA, Rm. 13B-05, 5600 Fishers Lane, Rockville, MD 20857, or by calling (301)443-6060. Requests should identify the guidelines by docket number and the staff manual guide by its number. The documents are designed as "walk through" guides detailing the kind of information required in an NDA and the format in which the information should be submitted to the agency. The guides also clarify some of the questions raised by the language of the regulation. For example, in the guideline for postmarketing reporting of adverse drug reactions, FDA explains that there are two ways to determine a significant increased frequency of serious adverse reactions, which triggers the 15-day reporting requirement. Under the "arithmetic approach," significant increase is defined "as a doubling of reports of serious, labelled ADRs from one reporting interval (comparative time) to the next (current reporting interval) after an appropriate adjustment for change in drug use has been made." Under the "statistically based approach," significant increase is defined "as an observed number of reports in the current reporting interval that exceeds the upper 95% confidence interval," which is based on the "observed number of reports in the comparisons interval adjusted for drug use." The agency noted that the arithmetic approach "is conceptually simple, but may result in more 15-day narrative reports being submitted to the FDA than the alternative statistical approach." The staff manual guide describes several types of "major" amendments and the approximate times the agency expects the review would be extended for each. The guide explains that "the review period will be extended only for the time estimated to be necessary to review the new information and may not be extended more than 180 days." Under the old NDA rules, submission of a major amendment immediately reset the 180-day review clock. Under the new policy guidelines, for example, a "full new analysis" of clinical studies, without new data, "will call for a 60-day extension. Data from new studies accompanied by case records or tabulations may call for a 90-120 day extension." Up to an additional 180 days may be needed if "an NDA-sized amount of data were submitted such as might occur when new data to support an additional claim are provided," FDA said. Explaining the time frames, the document notes that "the division director has discretion in determining the length of any extension," although the numbers specified in the guidelines "should be used except in unusual circumstances." The guideline states that when more than one amendment is submitted, each to a different reviewing discipline, review time extensions will run concurrently. "For example," the agency explains, "for a clinical amendment that calls for a 90-day extension, and a chemistry amendment that calls for a 60-day extension, 90 days is added to the review clock, not 150 days." However, FDA adds, if multiple amendments are submitted to the same discipline, the time added will be cumulative, up to a maximum of 180 days. The staff manual guide also sets time periods for mfrs. to respond to approvable and nonapprovable letters. The agency is requiring mfrs. to respond to approvable letters within 10 days. If the sponsor responds by informing FDA that it intends to amend the application, the agency will automatically extend the review period by 45 days from the date the amendment is submitted. Failure to respond to an approvable letter within the 10-day period will be considered by FDA as a "request by the applicant to withdraw the application."

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