This is a case study of how Amgen manages a major electronic Common Technical Document filing. It focusses on tools and processes developed and refined from 2005 to present. During this time, Amgen has filed three original Marketing Applications with an operational goal of submitting these simultaneously in four major regions (US, Canada, EU and Australia). Since operations groups exist in a fluid environment defined by evolving technology, it is important that these tools and processes adapt to meet the changing landscape of regulatory publishing.
The electronic Common Technical Document (eCTD) format provides an opportunity for regulatory operations groups to gain significant efficiencies through the standardisation and automation of publishing processes. In order to take advantage of this opportunity, it is important to first identify what kinds of tools are needed. Some of these tools are elementary: a Document Management System (DMS), Portable Document Format (PDF) authoring tools and eCTD construction software. Some of these tools are specialised and will aid in the automation of processes: authoring templates and PDF plug-ins.
A DMS is the foundation of any regulatory submission whether the final format is paper or electronic. Such a system should provide version control for auditing purposes, a centralised location for each submission and should utilise a “lock out” feature that prevents changes to final documents without notifying the publisher.
Amgen publishing works with what are termed as “submission-ready” PDF files created from word processing source files provided by the authors. To create these documents, software or print drivers are needed to convert the word processing files into PDFs. There are a number of tools available for this task; one that makes use of various heading styles, caption styles and other template features in the source files to create navigational elements, is highly recommended.
An eCTD submission can be created by manually coding the required Extensible Markup Language (XML), but the complexity of the actual code behind an eCTD submission makes the need for eCTD construction software apparent. Construction software will create the XML code, manage the required metadata, create folder structures and allow for life-cycling management of documents, but those are just the basic expectations. In addition to these features, the programme should allow multiple users to access the same submission simultaneously and have a feature that enables cloning of a submission in order to take full advantage of the resources available during a global filing. The importance of multiple-user access becomes clear when the structure of Amgen’s global publishing team is examined. Amgen currently uses the US submission structure as the base, portions of which are cloned by regional publishers throughout the global filing timeline. This ability to repurpose submissions eliminates a large amount of rework and aids in creating a consistent submission across regions.
Another key component in creating successful submissions is creating and managing global authoring templates. When creating these templates, regional differences must be considered. Putting region-specific information such as a license number or a proprietary product name in the header of a document can mean the difference between a regional publisher being able to use a document as-is or having to reprocess the file to remove the offending information. Proper use of templates affords other benefits as well. As authors become familiar with a standard set of formatting tools, such as macros and styles, publishers spend less time dealing with corrupted documents or tailoring the formatting to accomplish a standard appearance. A consistent document style, the “look and feel” of a file, creates a coherent interface for reviewers across files, modules and applications.
There are a number of third-party manufacturers who provide software solutions that aid in the creation and publishing of PDF files. Amgen utilises a number of these products to aid in the publishing process, including software that can create and manage bookmarks, automate intra and inter-document linking, perform basic quality control checks across one or more files and set standard document settings such as open options, inherit zoom magnification, fast web view and PDF version. Although these items may seem small when examined individually, a macro view of the entire publishing process makes the benefits obvious.
While the development of software tools available to an operations group is largely determined by product vendors and economic realities, the processes that make use of the tools are almost entirely controllable. There are certainly limitations around any proposed changes in processes: how nimble is the organisation, will other business partners be amenable and are the proposed changes realistic. However, significant benefits can be reaped if processes are efficient, scalable and flexible.
Amgen’s publishing group is made up of several regional groups that can be categorised into two major sub-groups: component publishing and submission publishing. How and when these groups interact with authors as well as each other is a large part of the publishing process.
The responsibilities of authors and publishers should be clearly defined and accepted. Use and ownership of templates, formatting duties and quality of source documents are some of the major areas that must be defined. Establishing an agreed upon and mutually beneficial set of standards requires early planning and open communication.
When publishers and authors interact at Amgen, it is with the understanding that publishers are responsible for technical aspects of the submission while authors manage content-related issues. Authors are asked to make use of global templates in the central DMS location, while the publisher formats these source documents. Publishers and authors open communication channels early to discuss such critical items as hand-off dates, construction of documents from multiple files, standard syntax of hyperlink references and final approval of published documents. The publishing also provides support to authors on technical issues.
Component publishers are the first line of contact for an author. Primary component publishing responsibilities include formatting source files, generating PDFs from those files, creating intra-document navigational items and gaining author approval of component published documents. Once these tasks are completed, approved “submission-ready components” are delivered to submission publishers.
Main responsibilities of submission publishers include: tracking documents, ensuring all required documents are present in the DMS, building documents in the eCTD construction software, applying standard leaf titles and filenames, post-publishing tasks (such as inter-document linking) and managing comments received during final team review of the completed submission.
Typically, one submission publisher is assigned to a product per region, but for a major filing, this model is not always effective. During a major filing, a publishing lead is established for each region of interest, and the lead is given the flexibility to assemble a team of submission and component publishers as needed. Since the US submission is used as the base for all other regions at Amgen, most of the component publishing is handled by the US team. Regional component publishers take responsibility for region-specific documents.
During the most recent filing at Amgen, for example, the US submission team utilised four module submission publishers: one for Modules 1 and 2 and one for each technical module (Modules 3-5). Five component publishers were assigned to the project: one for Module 2, one for Module 3 and three for Module 5, due to the size of this module. For Module 1, the submission publisher also took component responsibilities due to its relatively small size. Because the studies in Module 4 were finalised before many of the other documents, the submission publisher was able to component publish these files. In this particular submission, many Module 3 documents were completed far enough in advance that the Module 3 submission publisher also served as the Module 2 component publisher. In total, eight publishers (component and submission) filled eleven roles; (the total number of roles and individuals can be adjusted depending upon need, timelines and resources). Once the team structure was established, regularly scheduled meetings between all regional leaders as well as individual regional team meetings were held to track progress towards completion and discussion of any issues encountered.
There are a number of finalisation steps that take place after the submission is published and before it is submitted to the regulatory agency. Although these steps may seem minor, they can take a significant amount of time, and adequate planning is required to ensure a successful submission.
Current Amgen process requires a team review of the final published submission. This review period is an opportunity to take one last look to ensure that all documents are present, correct versions are included and documents reside in their expected locations within the eCTD. A review panel of appropriate size, one large enough to include major contributors but small enough to avoid unnecessary or repetitive comments, should be determined based on varying needs of a particular submission. The review panel convened in this example included representatives from the global regulatory team responsible for reviewing the overall submission, technical module leaders from functional areas to review the technical modules and related summaries, and submission publishers to review technical aspects. This review was performed in stages as individual modules were completed. Staggering the review period provided the module submission publishers time to incorporate comments received and allowed the regional publishing leads to clone completed modules earlier which granted them more time to make regional adjustments, including the production of a paper dossier, if necessary.
Once final team review comments are received and incorporated by submission publishers, final validation procedures are performed. Quality control plug-ins are used to take a high-level look at the entire submission. Checksums are generated using built-in functionality in the eCTD construction software, or a separate application, and the final submission is validated in each region. Virus scans are performed on the final submission, which is then sent to the regulators on an appropriate media format.
Thus far, the discussion of Amgen’s publishing processes has focussed on the US filing. While regional publishers follow a similar process, there are certain challenges to consider; the earlier those challenges are identified and addressed, the greater the chance for efficient and successful submission. Major issues include timing of regional filings, cloning structures and regional differences.
The timeline for each region should be established early on in the process. It should be realistic and should gather input from all functional areas. This timeline should be based on past efforts and adjusted to compensate for changes in technology and process improvements.
Changes in technology and process during the period discussed have allowed for a greater degree of simultaneous work across regions and targeted cloning of the base submission. The eCTD construction software allowed for more than one submission publisher to work on the same application at the same time, reducing the overall timeline for construction. This reduction in time allowed modules to be completed earlier, and as a result, other regions were able to clone the submission in phases rather than waiting to clone the entire application. This early and targeted cloning allowed regional publishers to begin any required modifications at an earlier point in time and freed resources that could be put towards the remaining modules.
Early completion of modules on a global scale allows more resources to be directed towards regional differences. Although the idea of the eCTD is to enable the reuse of technical modules across each region, the reality is different. For example, the US makes use of Study Tagging Files in Module 5; regional portions of Module 3 contain different information globally; certain regulatory authorities prefer different locations for some Module 3 information; some regions request additional information that would not be submitted elsewhere. Examining the overall submission table of contents and identifying where these differences exist, especially eCTD location differences, can allow these issues to be addressed before publishing begins or avoided entirely.
Every process has room for improvement, and Amgen’s process is no different. As the DMS software improves, better integration with the eCTD construction software can develop. Global publishers can take better advantage of time differences and standardisation of publishing processes across regions to create a nearly continuous production cycle. As submission formats continues to evolve, we also move closer to the goal of full reuse of technical modules. These are but a few of the areas in which improvements can be made, but an operations group must be able to adapt to the changing submissions landscape in order to take full advantage of new technologies and develop processes that will lead to a successful simultaneous global filing.