Meeting Agency eCTD Expectations for Efficient Navigation

Edward S. Tripp, July 13, 2010

As the industry and regulatory authorities moved to electronic submissions, one of the goals was to make the review process more efficient. The goal of greater efficiency and more timely review, led the regulatory authorities to establishing navigation expectations for reviewing the submission and its documents on line. The expectation is that the e lectronic documents are highly navigable; however, meeting this expectation places a greater burden on the applicant to create properly formatted content with maximum efficiency.

Submissions for a New Drug Application or Marketing Authorization are massive collections of documents, often exceeding a half a million pages. A single Clinical Study Report, included in a Submission to the Food and Drug Administration (FDA), often exceeds 25,000 pages. To put that in perspective, it is a single document that is 20 times larger than the unabridged, complete works of William Shakespeare.

The Burden is on the Applicant

In today’s electronic submission environment, applicants must not only provide clearly understandable scientific and technical content, but additionally they must provide the means to navigate within a document and across documents. The general expectation is that a reviewer can quickly and easily move throughout a document, jump to tables and figures, as well as quickly link to supporting information and supporting documents. The more effectively an applicant can aid the reviewer in navigating the submission and document content, the less time it will take to review the material submitted. The burden on the applicant is not only to provide the navigation in the authoring of the submission content, but also to review and verify that the bookmarks and hyperlinks are accurate prior to submission.

Expectations from FDA can be found in “Guidance for Industry, Providing Regulatory Submissions in Electronic Format — Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications, Revision 2, June 2008.” Section II Q states “For documents with a table of contents, provide bookmarks and hypertext links for each item listed in the table of contents including tables, figures, publications, references, and associated appendices.” Additionally, “Navigation efficiency is also improved by providing hypertext links throughout the body of the document to supporting annotations, related sections, references, appendices, tables, or figures that are not located on the same page.”

This is, however, not specific to FDA in that similar language can be found in the “ICH eCTD Specification V 3.2.2”, 16-July-2008, in Appendix 7: Specification for Submission Formats; Hypertext Linking and Bookmarks. Therefore, whatever agency is receiving an eCTD submission, the navigation expectations are similar. The European Medicines Agency also issued “Practical Guidelines Relating To Non-eCTD Electronic Submissions.”The Non-eCTD Electronic Submissions (NeeS) also specify a level of bookmarks and navigation, although somewhat less intensive. “In general, hypertext links are encouraged within the non-eCTD electronic submission, to facilitate swift navigation around the dossier, but should not be overused. The non-eCTD electronic submission should be structured and links provided in such a way as to ensure that the reviewer is constantly aware of the overall structure and narrative flow of the dossier.” Therefore, regardless of the electronic format for a submission, the applicant should provide a level of navigation that facilitates review.

Start with a Quality Word Document

While these are expectations for PDF documents, the author can improve document quality and reduce the likelihood of a costly rendering failure by providing the underlying formatting and navigation in the Microsoft Word document. Using a properly formatted and structured Word document will improve the rendering process when the PDF document is prepared for submission. Additionally, starting with a navigable, properly formatted Word document will reduce the time required to manually add navigation to the PDF document.

What are the implications on an organization preparing documents for inclusion in a biologic or pharmaceutical electronic submission to a regulatory authority? First, authors must be trained on the agency expectations. An author must understand that a sentence that includes a reference similar to “as shown on Table 37”; should include a hyperlink to the table referenced, unless the table appears on the same page. Authors also need to understand the expectation that Tables, Figures, Publications, References and Appendices should be included in the Table of Contents of the document.

This education should be extended to the reviewers and approvers of the submission documents so that they can verify structure, as well as content, of the document. Next, authors will need to be trained in how to insert a Table of Contents (TOC), and what styles to use for headings, and how to caption tables and figures consistently. If you don’t establish consistent templates for the majority of your documents, there can be significant time lost reformatting the content for an updatable TOC.

There are other items that require the creation of training and training materials as well. For example, it is important to determine if separate Table of Figures, Table of Tables and Table of Appendices will be require for all documents or only if the number of these items exceeds a certain threshold?

Microsoft Word is a powerful yet, versatile tool, but with that comes inherent complexity as functionality is often located several menus deep, requiring a considerable training investment in order to use properly. Consider the steps to establish a hyperlink for a document entry where you want to link to “Table ## - Results” from “see Table ## - Results” reference.

For this example I will use Microsoft Office Word 2007. First, the Table and an associated caption must be created. At the point in the document you want the table, click on the Insert Ribbon, Table and use one of the Microsoft Word options to create the table. Fill out the table with the appropriate content and formatting. Next, click on the References Ribbon, Insert Caption, in the caption dialog box select Table for the Label field, then in the Caption field type any additional description.

For this example I will enter “– Results” after the displayed table number. Now I can type my content discussing the results and at the end of the paragraph type “see.” In the Captions Group of the References Ribbon select Cross-reference. In the Cross-reference dialog box select Table in the reference type field, Entire Caption in the Insert reference to field and check insert as hyperlink. Now select the “Table ## - Results” from the list box. The Cross-reference tool can also be found on the Insert Ribbon. Note that once Microsoft Office Word 2007 creates a caption and a reference to the caption, it will automatically update the numbers of both to match as other captioned content is added to the document.

Example 1: Microsoft Word Cross-reference dialogue box. The dialogue box must be launched every time you link a cross-reference in the document and while open, prevents navigation and editing within the document.

Complete Document Review

One last check is required. Is the referenced content on the same page as the referencing paragraph? This verification must be done on completion of the document, as inserted content may cause repagination. On completion of the document, a page by page review for references should be made. If a reference link needs to be removed, because it appears on the same page, select the link, right click, select Edit Field and uncheck hyperlink to paragraph for that link.

Although this is a very versatile function, it requires training, and can interrupt the thought process of your content expert. Alternatively, many companies employ document editors or word processors to post process authored documents and to add the appropriate reference. Either way, once complete, the document must be reviewed. The final review should include a review for content, format, and navigability where each reference is checked for an appropriate link and that the link takes the reviewer to the appropriate content. This can result in a very lengthy review process for large documents with numerous tables, figures and appendices.

Automation is an Alternative

One function computers are ideally suited for is to automate repetitive, complex, and time consuming processes. There is now a product available that addresses the issue of creating cross references in Microsoft Word documents. DocXtools™ from Microsystems will specifically address this time consuming task of creating and verifying document navigation. The software integrates with Microsoft Office Word 2003, 2007 or 2010.

DocXtools scans the document for potential cross references and cross reference candidates; the result of the scan will be a display of all possible candidates and targets in the task pane. The results can be filtered by type, such as Tables, Figures, Appendices or Equations. For example, if you filter on Table references, only the Tables found in the document will display.

DocXtools can be configured to auto link exact matches or offers an easy and intuitive process for linking one or more cross reference candidates to the cross reference target. Navigation to the candidate or target is provided and a check mark will appear next to the cross reference candidate to indicate it is properly linked.

This functionality will expedite both the authoring and the review processes. Rather than verifying links while reading the document, reviewers can use DocXtools to scan the document and then examine the two column list for missing, broken or invalid links. Working in the task pane, the reviewer can easily navigate throughout the document to identify, verify and rebuild all remaining broken references. Using automation to scan and assess cross references will significantly reduce the time spent during the document review process and improve the accuracy of the cross reference links. Additionally, the interface is intuitive, reducing the amount of time it takes to train usersintuitive, reducing the amount of time it takes to train users.

Example 2: Microsystems DocXtools cross-reference task pane discovers all cross-reference candidates and targets and can either auto link exact matches or provides a process for linking multiple candidates at once. Additionally, while working in the task pane you can navigate and edit within the document.

Reduce Burden, Focus on Core Competency

Agency expectations for navigating electronic submission documents place an additional burden on sponsor organizations versus paper submissions. Fortunately, the reward of a more efficient and timely review of submissions and submission documents can result in huge rewards for the sponsor. The challenge is to reduce the added burden and allow scientific and technical content experts to focus on those activities that are considered company core competencies. Automation of time-consuming processes will improve efficiency of document creation and review, while freeing up key resources for higher value activities. Additionally, companies can benefit from more consistent and easier to review submission content.

There are a number of document assessment, cleanup and problem-solving tools within DocXtools software. Considering the amount of time organizations spend building and re-building links within Clinical Study Reports over the course of a year, the cross reference functionality alone justifies consideration of this product.

Edward Tripp is President of Edward S. Tripp and Associates Inc., a consulting firm specializing in Management Consulting in Document Management, e-Submissions and HL7 standards for the Pharmaceutical and Device industries. Previously, Ed’s 36 year career with Abbott Laboratories spanned the areas of Quality Assurance, Manufacturing, Engineering, Research and Development and Regulatory Affairs.

Ed is past Chairman of the PhRMA Electronic Regulatory Submissions Working Group, Liaison to the PhRMA Information Management Policy and Coordinating Committee (IMPACC). He is a member of HL7 and co-Chair of the Regulated Clinical Research Information Management (RCRIM) Work Group, co-Chair of the HL7 Domain Experts Steering Division and member of the HL7 Technical Steering Committee.

Ed earned his B.S. in Chemistry from North Carolina Wesleyan College. He can be reached at edward.tripp@estripp.com.