In a recent review, I summarized the underlying reasons contributing to delayed market entry for 51 product applications submitted to CDER between 2009 and 2012.1 Reasons cited in the complete response letters issued for these applications covered a number of areas, including safety, efficacy, regulatory, labeling and quality related issues. Quality- related issues were one of the most prominent reasons for delay of market entry with deficiencies being cited in 20/51 (39%) of applications. GMP inspection failures and data deficiencies contributed equally to the quality citations. The prominence of quality-related issues in the delay of product approvals emphasizes the importance of robust quality programs in drug development. Understanding what elements have posed as hurdles in past development programs will help a sponsor avoid these pitfalls in the future.
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GMP inspection failures
Although the specific reasons for GMP inspection failures were not provided in the complete response letters, one can glean from FDA Warning Letters issued to manufacturers that anything related to assuring the quality and control of manufacturing processes can be a contributing factor. Some common deficiencies cited in warning letters include failure to follow Standard Operating Procedures, failure to document critical steps, and failure to establish procedures controlling critical components of the manufacturing processes in the first place. Such deficiencies cause the FDA to question whether the manufacturing process has been thoroughly developed to ensure that product will be consistently manufactured to meet the quality, strength, purity and potency parameters defined in the marketing application.
Data quality issues
Data quality deficiencies leading to delays in marketing approval identified by the survey were primarily due to problems with data generated by others, although it is possible for sponsor- generated data to also be at fault. The data discrepancies were identified either during formal FDA audits or during review. Deficiencies related to data generated by others were due to either insufficient information in cross-referenced applications (e.g. Drug Master Files (DMFs) or Reference Listed Drug (RLD) applications) or deficiencies in data obtained from other groups and included in the application (e.g. acquired through corporate partnerships or generated by contract research organizations (CROs). Examples of deficiencies in cross-referenced applications include situations where the referenced application does not reflect current regulatory standards and when the data does not support the proposed use in the new application (e.g. additional compatibility testing may be needed to accommodate use of a container closure system with a new drug formulation). Deficiencies in the data acquired from others included lack of source data verification and manipulation of data after database hardlock.
Observed triggers which caused suspicion of the data included datasets not reflecting information in eCRFs, errors in SAS datasets and unexplained changes between interim and final study reports. These deficiencies caused the FDA to question the reliability of the safety and/or efficacy data submitted for the proposed product.
The role of the quality program in preventing delays in product approval
The above observations offer many insights into how quality programs contribute to efficient product development and approval. These examples emphasize the importance of quality management throughout the lifecycle of a product and that it touches all disciplines involved—CMC, nonclinical and clinical. Prevention through careful planning and oversight is the tool that can reduce the incidence of such deficiencies.
Prevention has many faces. When considering the GMP facility inspection failures cited above, careful attention to process development, pre-selection vendor qualification audits, and regular post-selection monitoring increase the confidence a manufacturing site’s GMP capabilities. Establishing quality agreements prior to initiating manufacturing activities provides a formal framework outlining the expectations for the activities being conducted also provides some control over the use of contracted facilities and is recommended by the FDA when contract manufacturers are engaged.2 Similar tacks can be used when dealing with CROs and when considering potential corporate partners. Implementing these controls would have helped prevent some of the data deficiencies cited above.
When considering the data quality issues identified in the complete response letters, formal data audits prior to regulatory submission places the sponsor in the driving seat for addressing the deficiencies rather than being relegated to a reactive mode responding to FDA queries. Datasets should always be checked against source data and confirmed to be readable prior to submission. Formal report audits should include comparison between interim and final reports as well as the data contained within the report itself. If any inconsistencies are identified during these audits, they should be corrected or explained in the application itself. Such steps would have likely prevented or reduced the impact of the data deficiencies cited above.
Implementing these quality strategies won’t solve the fact that product development is complicated and often requires adjustments during maturation. But these suggestions can help greatly reduce the opportunity for controllable errors that lead to unnecessary delays in product approval.
1 Allio TC. FDA Complete Response Letter Analysis: How 51 Companies Turned Failure to Success. FDAnews. Falls Church, Virginia, 2013.
2 FDA Guidance for Industry: Contract Manufacturing Arrangements for Drugs: Quality Agreements, 2013.
Theresa Allio Ph.D. has 10 years’ experience in drug development, including service in academia, industry and the FDA. She started her career at Vertex Pharmaceuticals, serving a key regulatory role on the Incivek and Kalydeco development teams. While at the FDA, she served as a nonclinical reviewer and as support staff for the Pediatric Advisory Committee. She currently works as a regulatory officer at the National Institutes of Health (NIH). Note, the views presented in this article are the author's own and do not necessarily represent those of the NIH.