By Jessica Long, B.S., R.A.C., Regulatory Associate II/Submissions Specialist at Cato Research
“Before you judge a man, walk a mile in his shoes.”
― Cherokee Proverb
Judgment has nothing to do with this post; seeing things through a different perspective has everything to do with it. There are many guidances on the content of granular electronic Common Technical Document (eCTD) sections, but many authors new to eCTD find it difficult to find guidance on best practices. When in doubt, put yourself in the shoes of a reviewer at the regulatory agency to which you are submitting and use that perspective to help structure documents that clearly present relevant information, as well as ensure intuitive future searches for data. Readers will find a U.S. slant to this post, as the bulk of my submissions are to the FDA, but the principles apply to nearly every other regulatory authority as well. A quick search will locate comparable regional guidances to the ones I have provided.
For the past several years, Refuse-To-File (RTF) decisions have been on the rise from FDA. The timelines provided in PDUFA legislation require that reviewers plow through mountains of data quickly in an effort to shorten the time to market for pharmaceuticals. Reviewers have the equivalent of tons of information thrown at them. In the old days of regulatory submissions, the volume of paper for a single New Drug Application (NDA) submission was enough to fill up four or more semi-trailers. In those days, reviewers spent a great deal of time checking things in and out of the document control room at FDA and shuffling through mounds of paper just to find needed material.
These days, the life of a reviewer is easier. Data arrives electronically and is always easily accessible in a reviewer’s computer. eCTD organizes data into higher level summaries supported by more detailed data. Reviewers can start with the summaries and navigate between documents using either the pre-defined eCTD structure or, in many cases, by the use of inter-document hyperlinks. With this in mind, what is the most effective way for authors to produce documents optimized for eCTD format?
I find myself often asking ‘What Would a Reviewer Want’ (WWRW) as I try to assist document authors with more complex issues that might not always have clear-cut answers. It never hurts to gain some fresh perspective.
Know the Specs
Take time to familiarize yourself with the current specifications for Portable Document Format (PDF). While most submission documents are PDFs, much of the requested format must be built into the Word version. Be sure to share these specifications with any vendors from which you might receive submission deliverables. For example, if you are using a nonclinical vendor, you’ll want to ensure the final study report received is submission-ready, per the specifications for PDF. Many publishers charge extra for remediation of documents and it can be difficult, if not impossible, to fully remediate PDF documents.
Create an Overall Table of Contents
When planning your submission, start by determining which documents are necessary and go ahead and map them out in the eCTD. Knowing what will be submitted and where it falls in the CTD is essential to cross-referencing between documents. Additionally, applications often have multiple authors to cover multiple disciplines. It is essential that all authors understand and are in agreement with what will be submitted. By now, most authors are familiar with the structure of the CTD, but there is a misconception that a document must be present in your application for every section in the CTD. This is not true. If a section of the CTD does not apply to your application, there is no need to submit a document stating that the section does not apply. Reviewers will note the absence of a document in that section and infer that there is no data for it. For FDA, refer to the Comprehensive Table of Contents (CTOC) guidance to organize necessary documents based upon their placement in the eCTD structure. This tool can also be used to assist with version control and can be handy as you track documents through review cycles.
I often see companies who restructure their existing Investigational Medicinal Product Dossier (IMPD) into the various Module 3 sections. Occasionally, I am asked why we need more granular sections, when, in some sections, additional granularity is optional. First of all, when we speak of granularity in the eCTD context, what we’re really referring to is how we’re going to break information up into separate documents. Will we have an entire 3.2.P document? Or will we have many – 3.2.P.1.1, 3.2.P.1.2, etc. – all as individual documents? The advantages of working at a higher level of granularity (3.2.P.1.1 as opposed to 3.2.P) become apparent over the life cycle of the application, as new information becomes available and documents are amended. Section 3.2.P.8.1 is OFTEN amended, as new stability data is available all the time. Having a separate 3.2.P.8.1 document prevents you from having to resubmit all the data from other sections every time you have new stability information. It is important that all authors are familiar with the level of granularity being used so they understand how to cross-reference other sections.
Is too much of a good thing a bad thing? It can be when it comes to granularity. In Module 1, in particular, if you have attachments to meeting packages; it might be best to go ahead and merge them with the PDF for the package. In sections where the CTD does not provide a structure for additional granularity, multiple documents end up floating in the same section and will not always stay in the same order as other documents are updated over the life cycle of the application. Plan carefully and use your best judgment when submitting attachments separately from the document to which they belong.
Use Templates for Authoring
If your organization does not already utilize eCTD templates, consider investing in some. There are many templates available for use, along with industry-specific toolbars designed to make authoring easier. The use of templates is an excellent way to ensure consistency between document authors and can save time formatting the document for eCTD.
Use a Style Guide
The use of a style guide is another way to create consistency between authors. Style guides can address the use of abbreviations, how certain documents will be cited, fonts, headers and footers, style headings in Word, terminology, the citation of publications, etc. A corporate style guide that aligns with the format specifications of the regulatory agency(ies) to which you are submitting can be a useful tool in assessing a vendor’s ability to produce submission-ready documents.
Of Bookmarks and Word Styles…
On the left side of a PDF document, there is a bookmark section that should match the document Table of Contents. Generally, these bookmarks are generated through the use of styles and headings in Word. It is important to use styles consistently throughout your Word document to facilitate the generation of bookmarks from a PDF rendering tool. The Acrobat plug-in available for Microsoft Word 2010 allows you to select which styles and headings are used in the creation of bookmarks. Authors must be careful with any information cut and pasted into their document, as style information from external sources can be brought with it, creating inconsistency within a document.
To link or not to link?
This is the time I most recommend authors ask themselves WWRW? It might seem helpful to fill every paragraph with links so the reviewer can easily access the hard data your summary documents are citing. However, excessive hyperlinking can make a document more difficult to read. It also takes time to generate all those internal cross-references and can make the eCTD submission expensive to publish. Sometimes it is inevitable that the same piece of information might be cited multiple times on the same page. In those cases, an author might only link the first instance of the citation on each page.
In addition, it’s important to consider HOW you will cite something. Often times, we know exactly to what we might wish to refer, but if someone else will be responsible for creating hyperlinks in your document, the citation should make it clear to what the text should be linked. Be specific.
Also, understand that inter-document hyperlinks are just that; between PDF documents. It is not possible to link to an entire eCTD node. If, for example, Section 184.108.40.206 contains five studies, make sure you cite the individual study to which you wish the text to be linked. If you wish to refer to all five studies, list them out, one after another, so each study can be linked.
Whatever convention you decide to follow in making references, be consistent.
Also important is to consider how the lifecycle of documents will be managed. This is a discussion that goes hand in hand with deciding how granular your documents should be. The argument for greater granularity is that in eCTD, when you update a section, the appropriate way to manage the lifecycle for that section is to ‘replace’ the previously submitted document with the updated one. This is performed using an operator attribute within the backbone of the submission. While there is an option to ‘append,’ FDA has stated they prefer this function is not used (it might be going the way of the dodo in publishing software before too long). What this means is that if you decide to go less granular and, for example, submit an entire 3.2.P section as opposed to breaking it up, every time you make an update, you’ll have to resubmit the entire 3.2.P document (even if you only changed 3.2.P.2.1). This becomes costly from a publishing perspective. Unfortunately, once granularity has been set within an application, it can be difficult, if not impossible to change.
Review, Review, Review!
In this industry, we’re used to checking things many, many times to ensure the quality. It is sometimes easy, however, to get so caught up in review of the content of these documents that we forget to have someone review for formatting and styles. Once the document has been rendered into a PDF for submission, any inconsistencies become very difficult to work around, so it’s always a good idea to leave the style/formatting check for after all content changes have been finalized. Then, of course, once the documents have been published for submission, it’s critical to check the individual submission files to make sure bookmarks and hyperlinks are functional.
There are a lot of things to remember when authoring for eCTD, but if you set your goals around making sure documents are well-organized, concise, and consistent, you’ll be off to a good start. From there, place yourself in the role of reviewer and ask yourself what you would want if you were required to read all this information.
Cato Research has extensive experience with regulatory filings. Please visit our website for a list of services.