eCTD: The Format Every US Submission Has to Arrive In

The electronic Common Technical Document (eCTD) is the format FDA requires for drug and biologic submissions. It is the electronic implementation of the CTD structure: a fixed folder tree, plus an XML backbone that tells the reviewer what every file is and what it does to the submission that came before.

The five modules

• Module 1: regional. Country-specific administrative content. Forms, cover letters, labelling, patent information. This is the module that differs between FDA, EMA and PMDA.
• Module 2: summaries. The quality overall summary, the nonclinical and clinical overviews.
• Module 3: quality. CMC. Drug substance, drug product, manufacture, controls, stability.
• Module 4: nonclinical study reports.
• Module 5: clinical study reports.

Modules 2 to 5 are common across regions. Only Module 1 is rewritten per authority, which is the whole point of the CTD.

Datasets belong in Modules 3, 4 or 5. They do not go in Modules 1 or 2.

The backbone is the submission

The part people underestimate is the XML backbone. It is not packaging. It carries a lifecycle operation for every file:

• new, a document appearing for the first time
• replace, superseding an earlier document
• append, adding to one
• delete, withdrawing one

Get the operations wrong and the reviewer sees the wrong version of a document, or two versions with no indication which is current. The content can be perfect and the submission still fails technical validation.

This is why a sequence is cumulative. A submission is not a snapshot; it is the current state produced by applying every sequence in order.

When it is mandatory

• NDAs, ANDAs and BLAs, and their amendments, supplements and reports: mandatory since 5 May 2017.
• Commercial INDs, meaning those intended to support marketing: mandatory since 5 May 2018.

Non-commercial INDs, including most investigator-initiated and expanded access applications, are outside the requirement.

A submission that should be in eCTD and is not will be refused to file.

v4.0

FDA has supported eCTD v4.0 for new NDAs, BLAs, ANDAs, INDs and master files since 16 September 2024. It replaces the folder-based structure with a controlled vocabulary and a message-based exchange, and it allows a document to be reused across submissions by reference rather than copied.

v3.2.2 remains in use. The migration is not automatic, and a v4.0 sequence cannot simply be appended to a v3.2.2 lifecycle.