SECTION 1: FUNDAMENTALS

Q1. What is the eCTD?

The Electronic Common Technical Document (eCTD) is the international standard format for submitting pharmaceutical regulatory applications to health authorities. It is the electronic implementation of the Common Technical Document (CTD) — a harmonized structure for organizing the technical and administrative information required in drug marketing authorization applications, investigational applications, and other regulatory submissions. The eCTD format was developed under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and is defined by the ICH M2 Expert Working Group. It provides a standardized, navigable, and lifecycle-manageable format that both sponsors and regulatory agencies can use efficiently.

Q2. What is the difference between the CTD and the eCTD?

The CTD (Common Technical Document) refers to the internationally agreed-upon organizational structure for regulatory submission content — the framework of modules, sections, and subsections that defines what information must be submitted and how it should be organized. The eCTD is the electronic implementation of that structure. While the CTD can theoretically be submitted in paper format, the eCTD specifies the technical standards for presenting the CTD content electronically: the XML backbone, the file formats, the folder structure, the metadata, and the lifecycle management mechanisms. In practice, "CTD" and "eCTD" are often used interchangeably because most major markets now require or strongly prefer electronic submission.

Q3. What are the five modules of the CTD/eCTD?

The CTD is organized into five modules:

• Module 1 — Administrative and Prescribing Information: Region-specific documents such as application forms, proposed labels, patent certifications, and cover letters. This module is not internationally harmonized — its content varies by jurisdiction.
• Module 2 — CTD Summaries: High-level overviews and summaries of the full technical data, including the Quality Overall Summary (QOS), the Nonclinical Overview and Summaries, and the Clinical Overview and Summaries. This is often what regulatory reviewers read first.
• Module 3 — Quality: Chemistry, Manufacturing, and Controls (CMC) data covering drug substance and drug product characterization, manufacturing processes, specifications, analytical methods, and stability data.
• Module 4 — Nonclinical Study Reports: Full reports of pharmacology, pharmacokinetics, and toxicology studies conducted in vitro and in animal models.
• Module 5 — Clinical Study Reports: Full reports of all human clinical studies, including bioavailability, pharmacokinetic, pharmacodynamic, efficacy, and safety studies.

Q4. Which regulatory agencies require eCTD submissions?

eCTD is required or strongly recommended by most major global health authorities, including:

• FDA (United States): eCTD has been mandatory for NDAs, BLAs, ANDAs, and INDs since May 2017 (with some small business exemptions). The relevant regulation is 21 CFR Parts 312 and 314.
• EMA (European Union): eCTD is required for all centralized procedure applications and is the standard for national and mutual recognition procedures.
• Health Canada: eCTD is accepted and increasingly required for New Drug Submissions (NDS), Abbreviated NDS, and Clinical Trial Applications (CTAs).
• PMDA (Japan): eCTD is required for new drug applications and has been the standard since 2008.
• TGA (Australia): eCTD is required for prescription medicine registration submissions.
• MHRA (United Kingdom): Post-Brexit, the MHRA accepts and requires eCTD for marketing authorization applications.
• NMPA (China), ANVISA (Brazil), CDSCO (India): These agencies are at varying stages of eCTD adoption and acceptance.

For global submissions, sponsors should consult the most current guidance from each agency regarding specific timelines and requirements.

Q5. What is the ICH M2 guideline?

ICH M2 is the guideline developed by the ICH M2 Expert Working Group that defines the technical specifications for the eCTD. It covers the XML backbone specification, Document Type Definitions (DTDs), the folder and file naming conventions, metadata requirements, and the operational model for managing the lifecycle of a submission. The most current iteration is ICH M2 eCTD Specification v4.0, which introduced significant enhancements over the earlier v3.2.2 specification, including improved lifecycle management, support for structured data, and better alignment with modern XML standards. Sponsors should always confirm which specification version is accepted or required by their target regulatory agency.

SECTION 2: TECHNICAL STRUCTURE

Q6. What is the eCTD backbone and why is it important?

The eCTD backbone is an XML file (typically named index.xml or its equivalent) that serves as the structural skeleton of the entire submission. It defines the hierarchical organization of the submission, identifies every document included, assigns each document to its correct position in the CTD module/section/subsection hierarchy, and records the lifecycle operation associated with each document (new, replace, append, delete). The backbone is what allows regulatory agencies' submission processing systems to automatically parse, validate, and navigate the dossier. Without a valid, well-formed backbone, a submission cannot be processed electronically — which is why backbone integrity is one of the first things validated by both agency technical screening tools and AI-assisted review systems.

Q7. What file formats are accepted in an eCTD submission?

The primary file format for narrative documents in an eCTD submission is PDF. Agencies have specific requirements governing PDF quality: files must be text-searchable (not scanned images), must have bookmarks for longer documents, must have working hyperlinks for cross-references, and must comply with specific PDF version requirements. The FDA, for example, specifies PDF/A compliance for archival purposes in certain contexts. In addition to PDF, structured data may be submitted in XML format (e.g., for product information, SPL labeling in the US), and study data are increasingly submitted in CDISC standards formats — SDTM (Study Data Tabulation Model) for raw clinical data and ADaM (Analysis Data Model) for analysis datasets. Sponsors should always consult the current agency technical specifications, as requirements evolve.

Q8. What is the eCTD folder and file naming convention?

The eCTD specification defines a strict folder structure and file naming convention that must be followed precisely. Files must be named using lowercase alphanumeric characters, hyphens, and underscores only — no spaces, special characters, or uppercase letters are permitted. File names must be unique within a submission sequence and must not exceed 64 characters. The folder structure mirrors the CTD module hierarchy: a top-level folder for the sequence number, with subfolders for each module and then progressively deeper subfolders for sections and subsections. Deviations from these conventions can cause processing failures at the agency level and are a common source of technical validation errors.

Q9. What is a submission sequence and how does it work?

A submission sequence is a discrete, numbered submission event within an application's lifecycle. Every time a sponsor submits something to the agency under a given application number — whether it is the original application, an amendment, a response to agency questions, or an annual report — it is assigned a sequential four-digit sequence number (0000, 0001, 0002, and so on). The first sequence (0000) is always the original submission. Subsequent sequences represent lifecycle transactions. Each sequence contains its own XML backbone that identifies which documents are new, which replace previously submitted documents, and which prior documents remain in effect. This sequential structure allows both the sponsor and the agency to track the complete history of the application over time and reconstruct the "current view" of the dossier at any point.

Q10. What are eCTD lifecycle operations?

Lifecycle operations are the mechanisms by which the eCTD manages changes to the submission over time. The four core lifecycle operations are:

• New: A document being submitted for the first time in a given section.
• Replace: A new version of a previously submitted document that supersedes the prior version. The new file replaces the old one in the current view of the dossier.
• Append: Additional content added to a section that supplements but does not replace existing content.
• Delete: Removes a previously submitted document from the current view of the dossier. Used with caution, as deleted documents remain in the historical record but are no longer part of the active dossier.

Correct use of lifecycle operations is critical for maintaining the integrity of the submission history. Errors in lifecycle operations — such as failing to replace an outdated document or incorrectly deleting a required section — are among the more serious technical deficiencies that eCTD validation tools are designed to catch.

Q11. What is the difference between eCTD v3.2.2 and eCTD v4.0?

eCTD v3.2.2 has been the dominant specification for most of the history of electronic submissions and remains the current standard for the majority of agency submissions worldwide. eCTD v4.0 is the next-generation specification published by ICH M2, offering several significant improvements: a modernized XML schema (moving from DTD to XML Schema Definition), enhanced support for structured and machine-readable content, improved lifecycle management capabilities, better support for multiple regional variations within a single submission, and greater alignment with modern regulatory information management concepts. As of early 2026, the FDA is in the process of transitioning to eCTD v4.0, and sponsors should monitor FDA and ICH guidance for updated timelines and requirements. The EMA has its own transition roadmap that sponsors should consult directly.

SECTION 3: SUBMISSION TYPES AND APPLICATIONS

Q12. What types of submissions are made in eCTD format?

eCTD is used for a wide range of submission types, including but not limited to:

• IND (Investigational New Drug Application): US submission to initiate clinical trials.
• NDA (New Drug Application): US marketing authorization for small molecule drugs.
• BLA (Biologics License Application): US marketing authorization for biologics, including vaccines, blood products, and gene therapies.
• ANDA (Abbreviated New Drug Application): US marketing authorization for generic drugs.
• NDS/SNDS (New Drug Submission / Supplemental NDS): Canadian marketing authorization applications.
• MAA (Marketing Authorization Application): EU and UK marketing authorization applications.
• CTA (Clinical Trial Application): EU application to initiate clinical trials.
• JNDA (Japanese New Drug Application): Japanese marketing authorization.
• Annual Reports, Safety Reports, and Post-Approval Submissions: Ongoing lifecycle management submissions after initial approval.

Q13. Are eCTD requirements the same for all submission types?

No. While the overall CTD structure applies broadly, agencies have specific expectations for different submission types. An IND, for example, does not require the full complement of Modules 3, 4, and 5 that an NDA would contain — early INDs may include only limited CMC information and preliminary nonclinical data. The FDA has published specific guidance documents for each submission type detailing what content is required. Similarly, a generic drug ANDA has different CMC and clinical requirements compared to an innovator NDA. Sponsors should always consult the agency's current format guidance for their specific submission type and not assume that what was required for one submission type applies universally.

Q14. What is a Type I, Type II, or Type III drug master file (DMF), and how does it relate to eCTD?

A Drug Master File (DMF) is a confidential submission to the FDA that provides detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of a drug. DMFs are not applications in themselves but are referenced by sponsors in their NDAs, ANDAs, or INDs to avoid disclosing proprietary manufacturing information in their own submissions. DMFs submitted to the FDA must also comply with eCTD technical standards. The holder of the DMF submits it in eCTD format, and the referencing sponsor includes an authorization letter in their submission allowing the FDA to reference the DMF during review.

SECTION 4: VALIDATION AND QUALITY

Q15. What is eCTD validation and why does it matter?

eCTD validation is the process of checking a submission against the technical specifications defined in the applicable eCTD standard and agency guidance to confirm that it is structurally complete, technically compliant, and processable by the agency's review systems. Validation is typically performed using specialized software tools — either commercial products or agency-provided tools such as the FDA's Comprehensive Table of Contents Heading and Hierarchy (CTOC) checker. Validation checks include backbone XML well-formedness and validity, correct lifecycle operation usage, file naming compliance, folder structure correctness, PDF technical quality, and completeness of required metadata. A submission that fails technical validation may be refused for filing before agency reviewers ever look at the scientific content, making validation a critical step in the submission preparation process.

Q16. What are the most common eCTD technical errors?

Common technical errors encountered in eCTD submissions include: incorrect or duplicate file names, file names containing spaces or illegal characters, backbone XML that is not well-formed or does not validate against the DTD/schema, incorrect lifecycle operations (e.g., using "new" when "replace" is required), broken hyperlinks within PDF documents, non-searchable PDFs (scanned images submitted without OCR), documents placed in incorrect CTD sections, sequence numbering errors, missing required metadata attributes, and PDF files that do not comply with agency-specified PDF version or compliance standards. Many of these errors are preventable through the use of eCTD authoring and validation software prior to submission.

Q17. What tools are available for eCTD authoring and validation?

A range of commercial software platforms support eCTD authoring, compilation, validation, and publishing, including Veeva Vault RIM, EXTEDO eCTD Manager, Lorenz docuBridge, Amplexor/Amplexus, and others. These tools provide templates aligned with CTD structure, automated backbone generation, lifecycle operation management, built-in validation against agency specifications, and PDF compliance checking. The FDA also provides free validation tools including the eCTD Validation Criteria and the Substance Registration System. Organizations should ensure that their chosen authoring tool is updated to reflect the current agency specifications and that staff are adequately trained in both the tool and the underlying eCTD standards.

Q18. What is a Refuse to File (RTF) action, and how can eCTD errors cause one?

A Refuse to File (RTF) action occurs when the FDA determines, within 60 days of receiving an NDA or BLA, that the application is sufficiently incomplete that substantive review cannot begin. While RTF decisions can be triggered by scientific deficiencies, they are also frequently triggered by technical and administrative deficiencies — including eCTD formatting errors, missing required sections, and document quality failures. An RTF resets the entire review clock and can delay a program by six months to a year or more. Preventing eCTD-related RTF actions through rigorous pre-submission technical validation is one of the most straightforward ways a regulatory affairs team can protect its development timeline.

SECTION 5: REGIONAL CONSIDERATIONS

Q19. Are there regional differences in eCTD requirements?

Yes, and these differences are important. While the CTD structure is internationally harmonized, the eCTD technical implementation has regional variations. Module 1 content is entirely region-specific. The FDA has specific requirements for study data standards (CDISC SDTM and ADaM), study tagging files (STF), and the Study Data Reviewer's Guide that are not required in the same way by the EMA. The EMA requires an eAF (electronic Application Form) that is specific to EU submissions. The FDA requires structured product labeling (SPL) in XML format for prescription drug labeling. The PMDA has its own Module 1 requirements and regional formatting expectations. Organizations submitting globally must maintain a clear understanding of how to adapt their core eCTD dossier to meet each jurisdiction's specific requirements.

Q20. What is the EU Clinical Trials Regulation (CTR) and how does it affect eCTD for clinical trial applications?

Regulation (EU) No 536/2014 (the Clinical Trials Regulation, or CTR), which became fully applicable in January 2023, introduced a new framework for clinical trial applications in the EU. Under the CTR, sponsors submit CTAs through the Clinical Trials Information System (CTIS), the EU's centralized portal for clinical trial management. While CTIS uses its own structured data submission format rather than a traditional eCTD backbone, the Investigational Medicinal Product Dossier (IMPD) — which corresponds roughly to the CTD Modules 3 and 4 content for an investigational product — is still submitted in a CTD-aligned format. Sponsors transitioning from the prior EU CTA system (under Directive 2001/20/EC) to the CTR framework should consult current EMA CTIS guidance, as the technical submission requirements are meaningfully different from a traditional eCTD workflow.

Q21. What is the FDA's Study Data Standards requirement, and how does it relate to eCTD?

The FDA requires that clinical and nonclinical study data submitted in NDAs, BLAs, and ANDAs be provided in CDISC (Clinical Data Interchange Standards Consortium) format. Clinical data must use SDTM (Study Data Tabulation Model) and ADaM (Analysis Data Model) standards. Nonclinical data must use SEND (Standard for Exchange of Nonclinical Data). These study data packages are submitted as part of Module 5 of the eCTD, accompanied by a Study Data Reviewer's Guide (SDRG) and a Dataset Reviewer's Guide (DSRG) that orient FDA reviewers to the data structure. Non-compliance with CDISC data standards can trigger Technical Rejection Criteria (TRC) and effectively prevent the FDA from accepting a submission for review. The FDA's Study Data Technical Conformance Guide provides current detailed requirements.

SECTION 6: LIFECYCLE MANAGEMENT AND POST-APPROVAL

Q22. How is the eCTD used after initial approval?

The eCTD is not only a submission format for obtaining initial approval — it is also the framework for managing the entire lifecycle of an approved product. Post-approval, sponsors submit a continuous stream of eCTD sequences for various purposes: labeling updates (Prior Approval Supplements, Changes Being Effected supplements), CMC changes (manufacturing process modifications, new manufacturing sites, stability protocol updates), annual product quality reviews, Periodic Safety Update Reports (PSURs) or Periodic Benefit-Risk Evaluation Reports (PBRERs), Risk Management Plan (RMP) updates, and responses to post-marketing commitments or agency requests. Each of these is submitted as a new sequence in the same eCTD application, maintaining the complete, auditable lifecycle record of the product's regulatory history.

Q23. What is a "current view" in eCTD lifecycle management?

The current view of an eCTD submission is the reconstructed state of the dossier at any given point in time, reflecting all lifecycle operations applied up to that point. When a document is submitted as "new," it appears in the current view. When a subsequent sequence submits a "replace" operation for that document, the replacement appears in the current view and the original is superseded (though still preserved in the historical record). The ability to maintain and audit the current view is one of the core administrative advantages of the eCTD over paper submissions — both the sponsor and the agency can always determine exactly what the definitive, up-to-date version of any section of the dossier is, without physically sorting through paper amendments and supplements.

Q24. What happens to eCTD submissions if a product is withdrawn from the market?

If a product is withdrawn from the market — whether voluntarily by the sponsor or at agency request — the eCTD application record is not deleted. The regulatory history of the product, including all submission sequences, agency correspondence, and the complete lifecycle of the dossier, is retained by the agency as a permanent regulatory record. The sponsor may submit a withdrawal notification as a new sequence in the application. In some jurisdictions, certain post-marketing obligations may continue even after market withdrawal, requiring additional submissions. Sponsors should consult agency-specific guidance on the administrative process for withdrawing a marketing authorization.

SECTION 7: EMERGING TRENDS AND FUTURE OF eCTD

Q25. How is AI being applied to eCTD submissions?

Artificial intelligence is increasingly being applied across the eCTD submission lifecycle. AI-powered review agents can validate eCTD backbone integrity, perform cross-document consistency checks across modules, automate compliance validation against FDA and EMA submission checklists, flag outdated guideline references, identify missing required sections, and prioritize deficiencies by regulatory risk. Natural language processing enables these systems to understand document content contextually — not just structurally — catching substantive inconsistencies (e.g., mismatched efficacy data between Module 2 summaries and Module 5 study reports) that purely structural validators would miss. As these tools mature, they are expected to move upstream into the document authoring process, providing real-time compliance guidance as regulatory writers draft submission content.

Q26. What is the future of eCTD — are there newer standards on the horizon?

The transition to eCTD v4.0 represents the most significant near-term evolution in the standard, bringing modernized XML architecture and improved support for structured and machine-readable content. Looking further ahead, there is growing discussion within the ICH and regulatory community about moving beyond document-centric submissions toward more data-centric regulatory exchange — where structured clinical, quality, and safety data are the primary submission artifact rather than narrative PDF documents. Initiatives such as the FDA's Data Modernization Action Plan, the EMA's IDMP (Identification of Medicinal Products) implementation, and the broader push toward regulatory information management (RIM) reflect this directional shift. The long-term vision is a regulatory ecosystem where machine-readable data flows directly between sponsors and agencies, enabling faster, more efficient, and more transparent regulatory review.

Q27. What is IDMP and how does it relate to eCTD?

IDMP (Identification of Medicinal Products) is a set of ISO standards (ISO 11615, 11616, 11238, 11239, 11240) that define a structured, globally harmonized way of identifying medicinal products — their substances, pharmaceutical products, packaging, and regulatory authorizations. The EMA has been implementing IDMP as part of its electronic product information initiative, requiring sponsors to submit structured product data in IDMP-compliant XML format. IDMP data does not replace the eCTD dossier but complements it by providing machine-readable product identification information that can be used across regulatory databases, pharmacovigilance systems, and supply chain management. Sponsors submitting to the EMA should familiarize themselves with the current IDMP implementation timeline and technical specifications.

SECTION 8: PRACTICAL GUIDANCE

Q28. What should an organization do to prepare for its first eCTD submission?

Preparing for a first eCTD submission requires investment in several areas: selecting and implementing appropriate eCTD authoring and validation software, training regulatory affairs staff on both the eCTD technical standard and the agency-specific requirements for the target submission type, establishing internal document quality standards (PDF technical requirements, naming conventions, hyperlinking standards), and developing a submission project management process that builds in adequate time for eCTD compilation and validation before the submission date. Organizations making their first submission to a particular agency are strongly encouraged to request a pre-submission meeting to discuss the agency's specific technical expectations and to utilize any agency-provided technical validation tools to pre-check the submission prior to filing.

Q29. How should organizations manage eCTD submissions across multiple global markets?

Global lifecycle management of eCTD submissions requires a well-organized regulatory information management (RIM) strategy. Organizations should maintain a master global dossier aligned with the ICH CTD structure, from which regional variations can be derived for each jurisdiction. A RIM system — whether a commercial platform or a well-structured document management system — should track the status of each document in each regional dossier, record the history of submissions and approvals in each market, and facilitate the efficient adaptation of core dossier content to meet regional requirements. As the product lifecycle evolves, changes to the global dossier must be assessed for their impact across all markets, and the appropriate submission sequences must be filed in each jurisdiction according to its specific requirements and timelines.

Q30. Where can organizations find the most current eCTD guidance?

The authoritative sources for eCTD guidance include:

• ICH Website (ich.org): ICH M2 guideline and eCTD specification documents.
• FDA Website (fda.gov): Electronic Submissions Gateway (ESG) guidance, Study Data Technical Conformance Guide, eCTD Validation Criteria, and submission type-specific format guidance documents.
• EMA Website (ema.europa.eu): eCTD guidance documents, eAF guidance, CTIS guidance for clinical trial applications, and IDMP implementation resources.
• Health Canada (canada.ca/health-canada): Guidance on eCTD submissions for Canadian regulatory applications.
• PMDA (pmda.go.jp): Japanese eCTD submission guidance.

Given how frequently these requirements are updated, regulatory affairs teams should subscribe to agency update notifications and conduct periodic reviews of their submission procedures against the latest available guidance.

This FAQ is intended as a general educational reference and reflects publicly available information as of early 2026. Regulatory requirements change frequently. Organizations should always consult current agency guidance and qualified regulatory affairs professionals when preparing specific submissions.