The end of paper submissions looms closer, and requirements for Standardized Study Data go into effect. What does that means for industry?
Under section 745A(a) of the FD&C Act, no earlier than 24 months after FDA issued the final guidance on December 2014, “Providing Regulatory Submissions in Electronic Format – Submissions Under Section 745A(a) of the Federal Food, Drug ,and Cosmetic Act”), NDAs, ANDAs, BLAs, new DMFs, new BPFs, and drug/device combination product applications filed under section 505 subsection (b), (i) or (j) of the FD&C Act or under section 351 subsection (a) or (k) of the PHS Act, must be submitted electronically in a format that FDA can process, review and archive. The requirement takes effect for commercial IND submissions at least 36 months after final guidance issuance. The requirement does not apply to devices regulated by CBER under section 745A(b), or to noncommercial INDs (products not intended for commercial distribution, investigator INDs, expanded access INDs).
The guidance documents triggering the above cited effective dates are published. Guidance describing the requirements were published in two parts: the first specifies overall submission standards, and the second describes standards specific to clinical and nonclinical study data:
- FDA final guidance, “Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications” was published in May 2015. Therefore, as of May 15, 2017, submissions described above that are not submitted electronically and those electronic submissions not in a format the FDA can process, review and archive, will not be filed/received. Commercial INDs must comply with the requirements by May 15, 2018.
The guidance describes additional requirements, including:
- Obtaining a pre-assigned application number
- Following the FDA eCTD Table of Contents Headings and Hierarchy and the guidance “Granularity Document: Annex to M4: Organization of the CTD (October 2005)”
- Use of the FDA ESG for transmission (submissions smaller than 10GB)
- Submitting only FDA fillable forms with electronic signatures
The FDA compiled the list of specifications and supportive files for eCTD submissions into a single document, eCTD Submission Standards. The document contains the accepted file formats, supported versions, dates that support begins/ends, dates the requirement begins/ends and hyperlinks to the regulatory references. The eCTD Submission Standards are periodically updated on the FDA Electronic Common Technical Document (eCTD) web page.
- FDA final guidance, “Providing Regulatory Submissions in Electronic Format – Standardized Study Data”, issued December 2014, went into effect for ANDAs, NDAs, BLAs on December 17, 2016. Data from studies with a start date after December 17, 2016 must conform to the standards. The requirement goes into effect for commercial INDs on December 17, 2017. The FDA may refuse to file (RTF) or refuse to receive (RTR) a submission containing study data that does not comply.
The FDA compiled a set of standards into a single location for sponsors to identify all data exchange standards, file formats and terminology standards supported in the FDA Data Standards Catalog. The catalog contains accepted file formats, supported versions, dates that support begins/ends, dates the requirement begins/ends, and hyperlinks to the regulatory references. The catalog is periodically updated on the FDA Electronic Common Technical Document (eCTD) web page and on the FDA Study Data Standards Resources web page.
Enforcement: Technical Validation.
For standardized study data requirements, at the time of submission, the FDA will determine if the clinical and non-clinical study(ies) within the submission must comply with the standardized study standards based on the start date. In order to perform the assessment, the FDA added validation for study data to the technical validation criteria performed during the technical validation process. Therefore, the FDA will reject a submission for failure of technical validation criteria.
A Technical Rejection Criteria for Study Data document is published on the FDA Electronic Common Technical Document (eCTD) web page and on the FDA Study Data Standards Resources web page.
- A trial summary (TS) dataset containing the study start date is present for each clinical and nonclinical study. Regardless of when the study started, beginning December 17, 2016, if the TS dataset is missing from submissions containing study data in Modules 4 or 5, the submission will be technically rejected. During technical validation, FDA will look at the study start date in the TS dataset. The study start date is defined as the earliest date of informed consent. If the study start date is after December 17, 2016, study data not in the format specified in the Data Standards Catalog, will result in a technical rejection of the submission.
- For studies starting after December 17, 2016, a Demographic (DM) dataset and a define.xml file is present for Module 4 nonclinical data. A Subject level analysis (ADSL) dataset and a define.xml is present for Module 5 clinical data. If these files are missing, the submission is technically rejected.
In both cases, a rejection notice in the form of a third acknowledgement is sent via the ESG, and it will specify an error number. The sponsor should refer to the technical rejection criteria for study data document to obtain the details of the error and the required corrective action. The technical contact listed in the application will NOT be notified. Technical validation usually occurs quickly, but the FDA is allowed 3 days; therefore, the sponsor should monitor their ESG account until the third acknowledgement arrives.
There are two additional technical validation criteria which do not result in technical rejection:
- Correct STF file-tags must be used for all standardized datasets.
- For each study, no more than one dataset of the same type is submitted. Use lifecycle operators (new, replace, append, delete).
In the instance described above, since the submission was not uploaded onto the FDA server (i.e., not received), a receipt date was not established. When the submission is corrected, either the same sequence number, or a new sequence number may be used.
Premier Consulting has longstanding experience with the FDA, including involvement with more than 1100 FDA meetings. For assistance with achieving the new FDA electronic filing standards, contact us.
Associate Director of Submissions
Granularity Document: Annex to M4: Organization of the CTD (October 2005)
The following documents are periodically updated on the FDA web pages specified below:
- eCTD Submission Standards
- Data Standards Catalog
- Study Data Technical Conformance Guide
- Technical Rejection Criteria for Study Data