PDF Hyperlinking within the eCTD

The use of hypertext links in eCTD submissions to aid navigation within and between PDF documents is commonplace. Along with the use of bookmarks, links can play a vital role in accelerating and facilitating the eCTD review process. Whilst an eCTD will not necessarily fail technical validation if hyperlinks aren’t created correctly, validation tools should still show errors where this is the case, reporting a failure to comply with eCTD best practice rules.

eCTD Validation Criteria v3.0 (which will come into force September of this year) states that:

            “The applicant should make every effort to address these areas [failure to comply with best practice criteria] before the eCTD is submitted to the agency.  The applicant should be prepared to include justification for any Best Practice criteria not met in the submission cover letter/reviewer's guide.”

The best practice criteria address some of the link formatting issues which any eCTD publisher will face. These will be addressed in the sections which follow.

When to link

The use of links within and between documents submitted in eCTD format is an important consideration for any submission publisher. There is no absolute rule set in stone which determines how many links should be created in any document, but the eCTD spec. v3.2.2 states that:

            “Hypertext 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.”

The purpose of hypertext links, then, is to help the reviewer navigate through and between documents, and so this should always be in the mind of the publisher. Links to sections on the same page, for example, might not help the reviewer at all, and so such linking is merely an unnecessary waste of time.

Link Properties

The properties associated with any link are governed by the eCTD validation criteria v3.0 and the eCTD specifications v3.2.2. They are as follows:

16.BP2

PDF Files

Hyperlinks within documents, or between documents within the same sequence, have a valid target

This means that each link in any PDF included as part of an eCTD submission (a single sequence) must open to a valid document, or section within a document, within that sequence. A link must not be broken. For example, if the name of a document within the eCTD changes, all links (if not corrected) directing to that particular document will break.

16.BP4

PDF Files

Hyperlinks to targets within documents in a different sequence in the same application have a valid target

As above, but this refers to links to documents which are located within a different eCTD submission belonging to the same application (i.e. with a different eCTD sequence number).

16.BP9

PDF Files

All PDF hyperlinks are relative

A link will be relative if its path recognises only the folders and files which are included in the overall eCTD structure. If the link path contains the drive name and folders which sit outside the eCTD structure, the link will break. This is because the drive and folder setup outside the eCTD folder structure will be specific to your computer, and so the agency’s computer will not be able to follow the same path.

For example:

If a link appears as follows: ..\..\..\m1\eu\10-cover\emea\emea-cover-lou then its path relates only to those folders included within the overall submission structure. It is therefore a relative link.

If however, the link path is: Mark\Submissions\calcium\0002\m1\eu\10-cover\emea\emea-cover-lou then it relates to folders (namely “Mark” and “Submissions”) which sit outside of the overall eCTD structure, and so the link will not work on the agency’s computer. This link is said to be “absolute”.

16.BP6

PDF Files

All bookmarks and links are set to "inherit zoom"

The “inherit zoom” property means that when the link is used, the reviewer’s view settings (i.e. the page zoom level) for the PDF document will not change. Some settings will change how the PDF is viewed, which could slow the reviewing process.

Link Appearance

The eCTD specifications state that a link may appear either with a thin line appearing around the text, or with the link text turned to blue:

Blue text should be used where the document has been created in a Word Processing tool such as MS Word and rendered to PDF. A thin line should be used where this is not possible, for example where a scanned document is being included in a submission (although scanned documents should undergo OCR, it may still not be possible to change the link text to blue).

How do I change the properties of my document hyperlinks?

Adobe Acrobat will let you change properties of document links, however there are numerous Adobe Acrobat third party plug-ins which will enable your submission publishers to change the properties of hyperlinks within eCTD submission documents by batch. Such applications will save hours of document publishing time. Some eCTD publishing tools will also automatically change such properties (and other document properties, e.g. document open properties) when publishing the eCTD.

If you would like any advice choosing the right software for your needs, please feel free to visit our website at www.apexregulatory.co.uk and contact us by phone or using our contact form and we’ll be glad to help.

Document Granularity within the eCTD Structure

Deciding where a document should begin and end is one of the key considerations when drafting certain documents which are to be submitted as part of an eCTD submission. For the most part, the eCTD structure allows no legroom when deciding where and how to include a document as part of an eCTD.  For example, your Cover Letter (section 1.0) and Application Form (section 1.2) cannot be submitted as one merged PDF document in either section.

In some sections of Modules 2 and 3, there is some scope to choose how to submit your documents. For example, it is possible to submit one document in 2.3 which covers all CTD sections below this level; or you may submit one document per CTD section (e.g. 2.3.S.1, 2.3.S.2…). The second approach is said to be the more “granular” approach as documents are broken down into smaller sections. Document granularity, therefore, means the level into which documents are broken down for submission. The screenshot below displays the documents which can be submitted at more than one level.

Also, it is possible to submit documents such as QP and GMP certificates separately (per certificate) or merged together.

Similarly, in Modules 4 and 5, study reports can be submitted either with all appendices attached to the study itself, or as separate documents within the same document section. The latter may be preferable in the case of documents which, when combined with annexes, would exceed the applicable size limits for individual files.

Before deciding the appropriate granularity for your documents, it’s worth considering some of the practical eCTD implications of adopting either approach.

For example - You decide to submit a complete 2.3 QoS section as one document in your initial eCTD sequence. If at some point you need to update only section 2.3.S Drug Substance, it would not be possible to submit in the new sequence only the updated Drug Substance section. This is because it’s not possible to replace a complete 2.3 with only a 2.3.S – If you were to do this, all of the other non-Substance related data (e.g. 2.3.P, 2.3.A and 2.3.R) would be deleted from the eCTD current view. You would therefore have to update the entire 2.3 document with only the changes made in 2.3.S, and replace the ‘old’ 2.3 document in the eCTD.

The real advantage to this ‘less granular’ approach is that the overall number of documents to be submitted will be kept to a minimum, improving the manageability of the CTD sections.

There are however, quite a few disadvantages to this approach…

The first major disadvantage is the potential for more linking and bookmarking in sections which have not been updated but are still submitted as part of the greater ‘complete’ document. This may well increase the time it takes to publish a submission.

Secondly (and probably most importantly), where sections will be authored by more than one individual, updating only one document could lead to possible errors or omissions and an overall delay in the authoring process.

Thirdly, this approach provides more scope for publishing error. For example, if in your initial submission you submit three QP Declarations submitted as a merged document, one of which subsequently needs to be updated, your submissions specialist will need to: be aware of which certificate has been updated, delete the old certificate within the originally submitted PDF and insert the new certificate in its place, then replace the old document in the eCTD outline. If the certificates had been submitted separately there would be no need to manipulate the documents, but only to replace the old document in the eCTD outline.

Lastly, the time it takes to review the dossier will be longer if currently approved sections are included in the eCTD dossier. The reviewer will need to know which sections have been updated, and scroll through the pages of sections which haven’t.

You should consider various things carefully before deciding which method to adopt:

Is the dossier particularly large and complex?

Is there a need for multiple Drug Product or Drug Substance sections?
How often will the dossier need to be updated?

Without considering the particulars of any individual scenario, my preferred approach is to submit documents in a more granular fashion. In this way the potential for authoring and publishing errors is kept to a minimum, and one of the overall ideals of eCTD – that the dossier should be easy to review – is achieved.

If you would like advice regarding document granularity, or any other eCTD issues, please visit us at www.apexregulatory.co.uk, contact us using our contact form, or give us a call on the number at the top of the site.