eCTD Regulatory Submissions: Hints & Common Mistakes to Avoid

The electronic common technical document (eCTD) is the standard format for submitting applications, amendments, supplements, and reports to FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Understanding eCTD requirements and successfully applying them to your submissions is critical. However, these requirements are not always intuitive, and headaches can occur when documents do not fit seamlessly into the permitted eCTD structure. When this happens, Sponsors can be faced with making last minute changes, putting timelines at risk. Worse still, the entire submission could be bounced back by the FDA which is known as a technical rejection.

eCTD Structure

In the past, paper submissions were a way of life for anyone submitting an application to the FDA. Unfortunately, paper submissions are bulky, hard to store, and inefficient to assemble, update, and review. In order to eliminate these issues and speed the review process, the FDA now requires electronic submissions for most applications. Since May 5, 2018, all submissions for new drug applications (NDAs), Abbreviated NDAs (ANDAs), Biologics License Applications (BLAs), Commercial Investigational New Drug Applications (INDs), and Master Files are required to follow eCTD specifications. There are many nuances to the eCTD, but in its simplest terms, the eCTD is a standardized arrangement of documents that allows for the consistent and comprehensive presentation of information within a submission. eCTD submissions include 5 parts, termed modules, with each containing a specific type of information.

• Module 1 (not technically part of the CTD): region-specific administrative information
• Module 2: manufacturing, nonclinical, and clinical overviews and summaries
• Module 3: detailed manufacturing information
• Module 4: nonclinical study reports
• Module 5: clinical study reports

Chemistry, Manufacturing, and Controls (CMC)

As anyone who has written an IND or marketing application knows, the CMC modules (module 3 and summaries in module 2) are expansive and can be tedious and time-consuming to complete. Because more documents typically mean more “cooks in the kitchen,” it is tempting to combine permitted sections in an effort to streamline the management of authors and versions. However, the granularity of CMC sections should be written with the entire life cycle of the submission in mind. For instance, if you decide to consolidate module 2.3 (Quality Overall Summary), any updates to drug substance sections will require the resubmission of this entire module rather than just the pertinent information. As a general rule, a more granular structure should be considered in order to avoid issues throughout the lifecycle of the application. The “M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use” can be used as a reference to determine the permitted granularity.

Clinical Study Reports

Even experienced teams can encounter problems when determining the best way to structure a clinical study report (CSR) within the eCTD. Should it be submitted as a single document? If splitting it up, what is the proper way to group the sections? The eCTD structure for Module 5 follows the levels outlined in “The Comprehensive Table of Contents Headings and Hierarchy.” Although legacy CSRs can be submitted as one document, the current recommendation is to divide CSRs into sections: synopsis, report body, and individual appendices (i.e., Section 16 of the CSR separated to 3^rd level headings). Preparing a CSR in this format allows reviewers to more easily navigate the large amount of information, leading to more efficient reviews. In addition, by dividing the report into sections, changes can be more easily tracked, as the entire report does not need to be replaced if only one section is updated.

Report Numbering

Every study report, both nonclinical and clinical, is required to have a study ID and title inserted into the submission. As such, it is important to ensure that all reports have a unique ID associated with them prior to sending to your publishing team. This typically becomes an issue when study data spans across multiple reports, such as an initial clinical study and associated population PK analyses. If a population PK analysis is being conducted for a specific clinical study, the population PK report should receive a unique study ID to ensure that the analysis is distinct from the general clinical study report. This also helps to ensure that any cross references in summary sections are clear as to the content being referenced.

Annual Reports

Back in paper days, the annual report was often written as a single document; however, the current granularity in “The Comprehensive Table of Contents Headings and Hierarchy” outlines multiple sections for annual reports. While it may be tempting for Sponsors to continue authoring the annual reports as one document, the structure of the eCTD does not easily allow for this approach and can lead to validation errors, putting the application at risk of a technical rejection. If written as a single document, publishers may attempt to avoid validation issues by placing the annual report within a single node corresponding to one of the annual report sections (e.g., Summary for Nonclinical Studies). However, this approach risks confusion during the review, as the content will not properly align with the node description.

Hyperlinking

One of the most common issues that publishers encounter is attempting to hyperlink to a section and realizing that the section either does not exist or that it cannot be linked. Some of this is due to typographical errors during document authoring; however, many instances occur due to a lack of understanding by the authors of what content can actually be linked. As a general rule, hyperlinks can only be made to individual documents and not to section folders. For example, a frequent mistake when hyperlinking is referencing a section that is of a higher level of granularity than that to which the documents are written. Some examples include:

• Referencing the module for single dose toxicity studies (i.e., 4.2.3.1) rather than the specific study
• Referencing module 3.2.P.3 as a whole rather than the specific relevant section(s) (e.g., 3.2.P.3.1)

The “Comprehensive Table of Contents Headings and Hierarchy” and “M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use” can be used to determine permitted levels within an application. In order to make the publishing process as efficient as possible, it is important for writers to ensure that each document has undergone adequate quality control review to verify that all cross-referenced sections exist prior to sending them to the publishing team.

Conclusions

The preparation of eCTD applications requires substantial planning, organization, and resources. To limit the number of issues that arise during publishing, a few key questions should be considered:

1. Is the document or application prepared in a way that allows for the most efficient review and navigation?
2. If a change is needed, can the relevant section be easily replaced without impacting the structure of the application?
3. Is each document written so as to easily fit into the eCTD structure?
4. Do all hyperlinks reference a valid target document?

Even if you have years of experience with regulatory submissions, small changes in guidances or specifications can have significant repercussions. Prior to starting your submission, you should meet with your publishers to discuss the submission plans and determine the best organization for your program. As there are slight differences between eCTD versions, it is also important to discuss the preferred eCTD version with your publishers prior to preparing your application. If you have any questions, the best option is to reach out to your publishing team, as they will have the resources and experience to direct you down the right path. Contact Allucent today to learn how we can assist with your next submission.

Additional Resources

• Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
• The Comprehensive Table of Contents Headings and Hierarchy (FDA)
• The eCTD Backbone Files Specification for Module 1
• M2 eCTD: Electronic Common Technical Document Specification (FDA Guidance for Industry)
• M4 Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use (FDA Guidance for Industry)
• M4E: The CTD – Efficacy (FDA Guidance for Industry)
• M4Q: The CTD – Quality (FDA Guidance for Industry)
• M4S: The CTD – Safety (FDA Guidance for Industry)
• M4S: The CTD – Safety Appendices (FDA Guidance for Industry)