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Executive Summary

FDA field offices have recommended against NDA/ANDA approval in 40% of cases following requests for concurrence from agency headquarters six months into the agency's new pre-approval inspection program, FDA Mid-Atlantic Region Director Richard Davis told a Food and Drug Law Institute workshop Sept. 13 in Washington, D.C. Davis reported that as of Aug. 22, six months after the new pre-approval procedures were established, district offices have received 347 requests for concurrence from the Center for Drug Evaluation and Research (CDER) and have recommended approval in 211 cases -- 154 without performing an inspection and 67 after an inspection. The pre-approval program at FDA now calls for field evaluation of sponsors or their suppliers and contract labs, and concurrence prior to approval of applications. Pre-approval inspections under the new procedures may be requested by agency headquarters or conducted at the district office's discretion. Among the 347 approval requests, FDA district directors determined that an inspection was needed in about half, or 180 cases. * In those instances where the district offices decided to conduct inspections, the field recommended against approval for over two-thirds (123) of the applications. Each recommendation against approval, Davis maintained, was based on the finding of "significant" problems with the application or current good manufacturing practices (CGMPs). Davis explained that "many" of the approval recommendations given without a pre-approval inspection involved drug testing laboratories conducting analytical assays, bulk drug suppliers or contract packaging plants. Davis noted that although an explicit timeframe is not specified in a recently issued compliance program formalizing the new pre-approval inspection procedures, the field has a self-imposed 30-day deadline for completing inspections. The FDAer said that the districts expect to meet this timeframe "90% of the time." The compliance program spelling out the new pre-approval inspection procedures was finalized by FDA headquarters and sent out to the field in late August. The program specifies that once an application is considered "approvable" by headquarters, the district director will receive written notification to which a response is expected in 10 days. The district may concur with the approval without conducting pre-approval audits, may recommend withholding the approval, or may conduct a pre-approval inspection. The review program, Davis commented, thus places the field offices directly "in the information loop" of the new drug approval process. Davis explained that some of the "new approaches" spelled out in the program have been implemented by the field during the past six months, while others are being implemented with the issuance of the program. Areas receiving more intense scrutiny under the new program will include clinical production facilities and laboratory analytical procedures, the FDA official noted. One "significant" new approach specified in the program, Davis pointed out, is the provision for on-site FDA collection of samples from biobatch or clinical production batches for agency methods validation review and "profile" analysis. Davis explained that agency collection is intended to: eliminate the recurrent problem of delays by companies in shipping samples to the field offices; allow collection and testing of research batch samples; and eliminate the possibility of sample substitution. In a written update of the pre-approval inspection program prepared for the FDLI meeting, Davis pointed out that the agency will conduct audits of bio/clinical batches at the time it collects these samples. These audits will involve an evaluation of the production and control processes used for the bio/clinical batches, along with a comparison to the full-scale production processes and control procedures. "This means that every new drug application will be audited at least to a limited extent by the field office," Davis noted in the update. Profile analysis will also be done by certain specified FDA laboratories on the samples, which will be recorded on a computer and available for later comparison with production batches, Davis explained. The analysis will serve as a "surveillance tool," he stated, and significant differences in profiles of the same drug may trigger an inspection to determine the reasons for these differences. The analytical procedures, for example, Davis noted, will detect changes in formulations, suppliers and manufacturing processes "which might have occurred without FDA approval." FDA's pre-approval inspection program will cover NDAs, ANDAs, some supplemental applications and certain INDs including Treatment INDs. It was initiated by the agency to respond to compliance problems uncovered during the generic investigations. The overall objectives of the new program, FDA explained, is "to assure that establishments involved in the manufacturing, testing or other manipulation of new drug dosage forms and new drug substances are thoroughly investigated through on-site inspections...and through laboratory testing of products, including evaluations of the adequacy of analytical methodology." Agency inspectors will look for "compliance with CGMPs and conformance with application commitments." Davis commented that they will expect to see a "substantial connection" between the manufacture of bio/clinical batches and finished product. Pre-approval inspections, the program notes, will include evaluation of the establishment's compliance with CGMP requirements, including coverage of the specific batches used to demonstrate bioequivalence. Inspectors will also ensure that the establishment has "adequate facilities, equipment, procedures and controls to manufacture the product in conformance with application commitments." In addition, inspectors will audit the accuracy of biobatch manufacturing and testing information submitted with the application and collect samples of biobatches from bioequivalence testing labs. Under the pre-approval inspection program, CDER will assign inspections for NDAs and ANDAs covering narrow-therapeutic-range drugs, new chemical entities and generic versions of the 200 most-prescribed drugs. In addition, CDER will assign pre-approval inspections when a "plant and/or dosage form has not received a satisfactory inspection within the past two years, and when the application is the initial one for the applicant regardless of inspection history." Also, CDER may assign inspections when its review of an application "discloses discrepancies warranting investigation," the document states. For supplemental applications, CDER will require pre-approval inspections when the application provides for "major changes, such as a new facility or process." The pre-approval inspection program, however, does not cover biologicals, which are already covered by the Establishment Licensing Application requirement for market approval. * According to the recently issued program document, FDA's Center for Drugs will request inspections for investigational drugs: when the IND is a Treatment IND or Treatment Protocol; when the facility used to manufacture investigational drugs is a contract manufacturer; when there is "information available...that inspection is warranted to protect the health of patients"; and when the IND sponsor requests cost recovery. The directive specifies that Treatment IND pre-approval inspections be completed by district offices within 10 days after agency notification. This is required in order to meet the 30 day review timeframe mandated for Treatment INDs, the program explains. "In order to adequately protect patients' health," the document states, "a comprehensive evaluation must be conducted within this 30-day period. Consequently, districts must complete inspections within 10 calendar days after receipt of assignments." FDA's field offices also will be consulted by CDER when an application is about to be approved. "Such consultations," the compliance program explains, "are designed to allow districts to exercise judgment as to whether pre-approval inspections should be conducted, and to provide other information that should be taken into account by CDER before approving applications." A key element of field participation in the application review process will be assuring that process validation is complete prior to product distribution, Davis told the FDLI meeting. While validation of non-sterile products is not required prior to approval, Davis emphasized that investigators will be evaluating validation protocols during the pre-approval audits and reviewing validation regarding bio/clinical batches. Where full validation of final production processes has not been completed at the time of the inspection, applicants will be contacted by the field to assure validation is complete prior to product distribution "if you do not contact us first," the FDA official said. The program calls for the use of inspection teams "highly skilled in drug manufacturing and analytical technology" for the pre-appproval work, including, where feasible, the field chemist involved in the lab validation of the product under review. Davis noted at the FDLI meeting that the field has trained an additional 160 investigators and analysts during the past two months and that more advanced training is being planned. The field has made a commitment, Davis said, to "quickly assign and conduct" follow up inspections of plants when the company has notified the District that problems uncovered during audits of the application have been corrected. In turn, he said, the district offices "will promptly notify the Center for Drugs when necessary corrections have been made and that the field concurs in approval."



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