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Technical Rejection of a Regulatory Submission

While accuracy and completeness are essential in regulatory submissions, technical and structural compliance are initial hurdles for those in the drug manufacturing industry. A surprising number of drug applications are rejected for technical issues. 

A 2019 FDA study of applications submitted between 2016 and 2018 indicates that more than 20% of all applications received by the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) contain technical errors.  Specifically noted were formatting issues and errors in electronic common technical document (eCTD) module preparation, which are two of the top reasons for Refuse to File responses. FDA experts present this data for transparency to support industry regulatory affairs professionals in their quality metrics evaluations.

As of 2018, FDA has adopted the eCTD as the standard format for drugs and biologics applications, including both investigational and marketed products. The eCTD is defined by the separation of information and data into individual modules as outlined in the ICH M4 Common Technical Document.  The intent is to provide a standardized format that sponsors use globally and create a simpler process for submission review, although this does not guarantee a simplified submission development process. 

The 2019 FDA study identified the most common error in the Study Tagging File (STF) structure as follows:

  • Error 1735: Correct STF file-tags must be used for all standardized datasets and corresponding define.xml files in required sections

A follow-up study in March 2021 noted the updated Technical Rejection Criteria (TRC) requiring standardized study data upon implementation. Based on the updated criteria, the FDA will not accept an electronic submission that does not have study data in compliance with the required standards specified in the FDA Data Standards Catalog as of September 15, 2021.

As the FDA continues to fine-tune the eCTD Technical Conformance Guide to best represent their expectations, submission processes are becoming better defined. Bringing attention to these updated criteria for validation of submissions and the need to maintain consistent and compliant formatting is another way they give industry feedback.  

It should also be noted that CDER and CBER have differing expectations based on the application type and the specific module being validated.  The centers may define individual phased approaches for any criteria being implemented. For example:

  • Per CBER, rejection criteria will not be applied until March 15, 2023 for non-clinical studies.

Many industry experts lean on commercially-available systems to ensure compliance of submissions but home-grown solutions can be developed and revised to meet the TRC. Maneuvering commercial or developed eCTD preparation tools requires experienced professionals with knowledge of FDA requirements and expectations.  Building a compliant submission package is our business. 

Contact a Partner today to discover how FlexPro achieves regulatory compliance and gets it right the first time.  

Written by Nancy Watts, BS, RAC, Director of Regulatory Affairs at The FlexPro Group.

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