Today, the eCTD format remains the only globally approved and ICH-recommended standard. While it has been in use for more than 15 years, it is the mandated submission format for drug applications within Europe, the US and Australia, Canada, China, Great Britain, Gulf Cooperation Council, Japan, Jordan, Oman, South Africa, Switzerland, and Thailand. An overlooked but important component of eCTD is the ability to navigate around and between documents (Hyperlinks). Other countries are in the process of transitioning to using digitized CTD in their journey to full eCTD, using more formalized structures like NeES or other formats such as ASEAN (Association of Southeast Asian Nations) CTD (ACTD), for example, Singapore. Again, hyperlinks are an important means to navigate around these dossiers.
Hyperlinks come into play long before the eCTD is created, as they are integral to all electronic documents that ultimately reside within the CTD structure. For instance, all clinical and non-clinical study reports, process development, formulation, and manufacturing documents to name a few, all have some degree of hyperlinking. When all of these documents are brought together into the eCTD they must have the same look and feel and follow a consistent set of rules.
In this post, we analyze this often trivialized requirement in order to provide a comprehensive best practice on hyperlinking and the processes that an organization needs in place to prevent expensive rework in the creation of the final eCTD or electronic equivalent. We also provide a summary of Health Authority guidance around cross-referencing and hyperlinking (both business and technical), and a list of the FDA’s validation criteria related to hyperlinking.
Hyperlinking for Optimal Submission
In eCTD (electronic Common Technical Document) submissions, cross-referencing (hyperlinks from one area of submission content to another) are crucial for organizing the information in a structured and clear manner. However, Health Authorities have not provided extensive guidance on the proper use of hyperlinks.
To optimize your submissions for reviewers, a holistic approach to cross-referencing is important. Any organization submitting eCTDs should develop and document a set of hyperlinking principles. In this post, we’ll share best practices from experienced regulatory experts. At a general level, best practices include:
- Cross-referencing should be used to link related information across different sections of the submission. This can include references to supporting documents, such as clinical study reports, or related sections within the same document.
- Cross-referencing should be done using hyperlinks, rather than manually referencing page numbers or section headings. This ensures that the links are accurate and will work correctly when the submission is viewed electronically.
- Cross-referencing links should be clear and easy to identify. Normally, this involves displaying hyperlinks in a blue font.
- Cross-referencing links should be tested to ensure that they work correctly and navigate to the correct location. This is particularly important when the submission is viewed on different platforms or with different software applications. Often, hyperlinks can be confirmed as valid by tools within publishing software, but software alone can’t confirm that links are directing the viewer to the correct destination.
- Cross-referencing should be used consistently throughout the submission. This includes using the same terminology and formatting for links, and ensuring that links are used appropriately and do not lead to redundant information.
- Generally, when a cross-reference with the same destination is repeated multiple times on the same page, only the first mention of the destination is hyperlinked per page. Also, when the cross reference and destination are on the same page, there is no need to hyperlink the cross-referenced text.
- In general, it is best to use hyperlinks judiciously and only when they provide value to the information being presented. While there is no specific number of hyperlinks that can be considered “too many,” it is important to ensure that the use of hyperlinks does not distract from the main content of the submission or make it difficult to navigate.
- Hyperlinks should be clearly labeled and easy to identify, using consistent terminology and formatting. Avoid using hyperlinks that are too long or too short, as these can be difficult to read and understand.
Cross-references can occur within a document (usually created by the author) or between documents (usually created by a submission publisher). In both cases, those responsible must have both technical training and an understanding of your organization’s standards and best practices.
Some recommendations related to specific hyperlinks that should be created routinely include:
- Provide inter-document hyperlinks between the cover letter and all documents that it references.
- Provide an intra-document cross-reference/hyperlink anytime the text refers to a section, table, figure, appendix, etc., that is not on the same page.
- Provide links from the TOC to all headings, tables, figures, references, and appendices
- Provide inter-document hyperlinks between the summary documents in module 2 and the documents referenced in module 3, module 4, or module 5.
- Provide a hyperlink from literature citations to the list of references at the end of the document, or to the list of references in Module 2.7.5. If the publication itself is provided as a PDF in Module 3.3, Module 4.3 or Module 5.4, provide a further hyperlink from the list of references to the document.
Within Your Organization
You should develop a hyperlinking standard in collaboration with all stakeholders, which should be periodically reviewed and updated. It should cover document types including product information, clinical studies, non-clinical studies, and formulation and manufacture. Often clinical and non-clinical studies reports are published by a different group than the eCTD. But also remember that the final eCTD sections are often reviewed by different groups and if you have reworked a group’s hyperlinks I can guarantee they will object.
Don’t forget good document navigation is not just limited to hyperlinks. All pdfs have the navigator pane which is derived from the source documents structure. So make sure your initial document templates are in good order and are being used. Without good document structure, it is very difficult to ensure good quality and precise links within your documents.
A clear hyperlinking standard applied to all documents means that you remove a significant overhead when repurposing regulatory applications. This could be as simple as reusing modules 2 to 5 for a second-tier eCTD initial submission or producing a completely different digitized CTD format. The point is that if the hyperlinks are consistent and the document structure remains largely unchanged you can very quickly produce a cascade of new product applications or variations.
Summary of Agency Guidance
|Reference and Page
|Appendix 2: The eCTD SubmissionLinks CTD cross-references can be supported in the eCTD through the use of hyperlinks. Links among objects in the eCTD submission should be relative. The intention is to make the eCTD submission self-contained. All literature references introduced by the applicant should be included in the submission. One can always point to a file. The capacity to point to a specific location within a file depends on the linking technology. Different formats allow for the use of different linking technology.
|Appendix 3: General Considerations for the CTD ModulesIntroduction Documents that are provided in the different modules should be formatted as defined by the ICH Common Technical Document. There should also be consistency in the way navigational aids are provided. Within each document, bookmarks and hypertext links from the table of contents should be provided to all tables, figures, publications, and appendices.
Hypertext links should be provided throughout the body of these documents to aid efficient navigation to annotations, related sections, publications, appendices, tables, and figures that are not located on the same page. CTD cross-references can be supported in the eCTD through the use of hyperlinks. If a list of references is included at the end of a document, there should be hypertext links to the appropriate publication.
|Appendix 4: File Organization for the eCTD
File: 2/27-clin-sum/synopses-indiv-studies.pdf Comment These synopses should already be located in the Clinical Study Reports in Module 5 and should not, therefore, be repeated in Module 2. It is considered sufficient to provide hyperlinks from the listing of the studies, located here, to the locations of the synopses in Module 5.
|Appendix 7: Specification for Submission FormatsHypertext Linking and BookmarksHypertext links throughout the document to support annotations, related sections, references, appendices, tables, or figures that are not located on the same page are helpful and improve navigation efficiency. Relative paths should be used when creating hypertext links to minimize the loss of hyperlink functionality when folders are moved between disk drives. Absolute links that reference specific drives and root directories will no longer work once the submission is loaded onto the Agency’s network servers.
|Cover letters contain pertinent information which aid communication within the review process. It is recommended that the cover letter include the following information: • Regulatory description of the submission, including appropriate regulatory information, and any desired hyperlinks to submitted information
|Reviewers Guide A reviewers guide10 is beneficial when accompanying an original NDA, BLA, or combination product11 application. The reviewers guide should include a high-level overview of the submission with hyperlinks to submitted information.
|3.1.11 Regenerative Medicine Advanced Therapy (RMAT) Designation Currently there is no Module 1 section for RMAT designation requests. Therefore, please place the RMAT designation request in section 1.12.4 and provide a hyperlink in the cover letter to the request.
|3.5.1 Tabular Listing of All Clinical Studies The tabular listing of all clinical studies should be provided as a single PDF file in section 5.2 of the eCTD. For ease of review, hyperlinks to the referenced studies in m5 should be provided.
|Combination ProductsQuality information on the combination product as a whole (not the separate constituent parts) should be located in 3.2.P with appropriate hyperlinks to 3.2.R.
|Section 3.2.P.3 ManufactureAs applicable, this section may hyperlink to unique device constituent manufacturing information in 3.2.R.
|2.9.7 Bookmarks and Hypertext LinksNavigation through an electronic submission is greatly enhanced by the appropriate use of bookmarks and hypertext links. ICH Q&A number 53 states, “It is expected that any document that has a Table of Contents (TOC) will have bookmarks (see the eCTD specification for details). Documents without TOCs should have bookmarks included where it aids in the navigation around the document content. For example, a 4 page document summarising findings could require bookmarks to aid navigation. However, a 300 page file containing a single data listing might not require bookmarks as there is no further internal structure. Please consult regional guidance documents for further details.In general terms, bookmarks and hyperlinks should be used to aid navigation. The overuse of hyperlinks may confuse rather than help assessors and may cause problems later in lifecycle management. However, hyperlinks back to previously submitted documents are welcome as well if pointing to the correct location.
|2.12 Technical Baseline ApplicationsIt should be clearly stated in the cover letter of the “baseline eCTD sequence” that the content of the previously submitted dossier has not been changed, only the format. There is no need for the NCAs or EMA to assess baseline submissions and hyperlinks between documents are not needed. The submission type reformat should be used in the envelope for the baseline sequence.
|3.6.4 Provision of Synopses of Individual StudiesIt is acceptable either to include copies of the synopses for each study in eCTD section 2.7.6 or to provide hyperlinks to synopses located in Module 5 without providing copies in section 2.7.6. In either case a Listing of Clinical Studies should be provided and this should include hyperlinks to the first page of each synopsis.
All authorities accepting eCTD apply validation criteria which include the validation of hyperlinks. This is often in a broken link error message. These errors are often not catastrophic for the submission but give the wrong impression if not fixed and some agencies will write to or even reject submissions from persistent offenders.
Validation tools like IQVIA eSubmission Validator, Lorenz eValidator, and Extedo EURS validator were used exclusively by certain authorities in years gone by, however, agencies generally no longer recommend a tool preferring to provide validation criteria. The important thing is to ensure the validation tool you are using has the most up-to-date validation criteria for the authority you’re submitting to, to ensure you get all of those broken links. A best practice is to try and use two validation tools, the one from your publishing vendor and perhaps one other, however many companies now rely only on their vendor’s tool as buying and maintaining some of these tools is expensive. Below is an example of the FDA validation criteria:
Reference  defines a set of technical problems that the FDA’s validation tools automatically detect. Other Health Authorities may include similar technical checks.
- Broken links (5200) Medium
- Link has non-existent named destination or page (5202) Medium
- Multiple action hyperlink (5203) Medium
- External hyperlink (5205) Medium
- Inactive hyperlink (5210) Medium
- Non-relative hyperlink (5215) Medium
The FDA and other Health Authorities place high importance on proper cross-referencing in eCTD submissions, as it helps to ensure that the information in the submission is clear, well-organized, and easy to navigate. This can best be summarized by a comment I heard years ago from an FDA reviewer: “If you were the reviewer, would you be annoyed if there was no hyperlink?” However, I have also heard the opposite “Why bother, as I know the eCTD structure” by a nameless European Agency representative, in jest.
-  International Conference on Harmonisation Of Technical Requirements For Registration of Pharmaceuticals for Human Use, Electronic Common Technical Document Specification V 3.2.2 16-July-2008
-  US Food and Drug Administration, eCTD Technical Conformance Guide, November 2022
-  Harmonised Technical Guidance for eCTD Submissions in the EU (V5), February 2022, EMA, Harmonised Technical Guidance for eCTD Submissions in the EU
-  US Food and Drug Administration, Specifications for eCTD Validation Criteria, Version 4,4 2022-05-11
-  European Federation of Pharmaceutical Industries and Associations (EFPIA), Global ICH eCTD Adoption, December 2021