Taking advantage of the eCTD's cross-application feature, linking from NDA back to IND.
Life science companies in today’s shrinking economy are looking for ways to maintain growth in the face of imminent patent expiration, growing generic competition, and escalating drug development cost. One way an increasing number of sponsors are cutting expenses and time to market is by transitioning to the electronic Common Technical Document (eCTD) format right from the Investigational New Drug (IND) application. The eCTD has a number of features that can speed up submission publishing and review times, including cross-application linking capabilities that allow sponsors to submit a document just once and refer to it as many times as necessary in subsequent submissions and applications.
Focusing on the IND as a product application starting point (and the typical beginning of the clinical trial period), this article will address eCTD structure and functionality and outline the possibilities and pitfalls of building a submission strategy that takes advantage of the cross-application linking feature to achieve the following: • Cut publishing and review times in the NDA; • Improve submission and lifecycle management functions across all product applications.
The eCTD: ICH Format Designed for Efficiency
The Common Technical Document (CTD) was developed by the International Conference on Harmonization (ICH) and is fast becoming the preferred or required submission format by regulators in the world’s major marketplaces and beyond. Since July 2003, the CTD has been mandated for marketing and post-marketing applications in Europe, Japan, and Canada. The Food and Drug Administration (FDA) has required eCTD submissions since 2008, and the European Medicines Agency (EMEA) wants all Centralised Procedure applications in the eCTD format by the start of 2010. Although the industry has been bracing for change for some time now, many drug makers are making the transition to eCTD just ahead of regulatory deadlines. The result is that often many of the eCTD technical advantages are lost due to the lack of planning and understanding, as companies struggling with unfamiliar formats and processes fail to effectively plan for the product lifespan.
The CTD is a submission format, so it does not change the content requirements for the IND, New Drug Application (NDA), Marketing Authorization Application (MAA) or any other regulatory submission. It does, however, allow sponsors to more efficiently manage submission publishing, transmission and lifecycle chores, in part by organizing required information into smaller chunks or “granules” that are more easily assembled and managed over the application’s lifetime. These granules are placed into a rigid, well-defined folder structure that allows sponsors and regulators to take a more consistent and harmonized approach to submission building and review. The “e” in the eCTD denotes a change in transmission methods – the CTD is a paper submission that is hand-delivered, while the eCTD is an XML-based version that is submitted via electronic media or directly through secure regulator gateways. Among the advantages of electronic transmission, management and storage, the eCTD allows submission builders to map to documents within and across all submissions and applications. This feature can save on time and cost, but only if properly set up and managed from the start of the product IND application.
IND: Planning is Key
According to a survey conducted in 2008 by ISI, a longtime global regulatory submission consulting firm, INDs are the most anticipated submission for 2009, with two-thirds of the companies surveyed in the Phase I stage of development saying they plan to file an IND this year. A majority of the 216 survey respondents (63%) were emerging companies with fewer than 250 employees.
However, in order for sponsors to get the most out of their IND eCTD submissions, there needs to be a good understanding of how the IND fits into the product lifespan and a clear vision of global marketing strategies so that documents are harmonized in a way that will accommodate all present needs and future uses. This important step should not be overlooked, as regulators worldwide have cited a lack of eCTD experience and planning for a myriad of submission mistakes and delays, and many are suggesting that those new to eCTD seek expert help.
Planning Your IND
The eCTD format provides a platform for time savings and future product growth by giving sponsors the ability to re-use and lifecycle previously published and submitted documents both within a single submission and across all product applications. However, in order to effectively leverage the cross-application linking feature, sponsors need to have a plan:
• Identify product lifecycle and global submission goals prior to IND
• Make granularity decisions that support the flow of documents across applications (IND though NDA) and across regions (US to EU)
• When building the NDA, ask regulators to test all cross-application links
• Get expert help to access best practice eCTD strategies and processes
• Remember, there is no one-size-fits-all solution, so plan separately for each product
IND to NDA Strategies
There is no cookie-cutter approach to IND building, as each application needs to consider long term product uses and global marketing goals so that submission documents can be created to easily flow within the application or across applications in support of the same drug product. Regional regulatory issues such as granularity and content requirements should be considered at the earliest stages in order to gain the maximum utility and flexibility as the IND eCTD becomes the foundation for the future regulatory marketing application. By effectively leveraging the regulatory similarities and consistencies across target documents, sponsors should be able to develop a cohesive strategy that will save time and money in the submission publishing phase by taking full advantage of eCTD cross-application referencing and mapping capabilities.
As sponsors work to develop a proactive plan that will set up documents for re-use and lifecycle management chores throughout the life of the product, they also must actively seek out appropriate submission publishing tools and advice to ensure the proper integration of cross-application linking and associated lifecycle changes into the submission building process. IND documents that will typically be re-used in an NDA application include:
• M5- Protocol
• Investigator CVs
• Form 1572s
• M4-Nonclinical data
• M3-CMC or Quality information
“It’s important to ensure files are in the correct placement so that reviewers know where to find information quickly and easily,” FDA Regulatory Information Specialist Connie Robinson-Kuiperi said during the June 2009 Drug Information Association Webinar titled The New Look at eCTD Lifecycle Management: How Mapping from NDA to IND can Streamline Submission Lifecycle Chores. “Proper placement also supports lifecycle management and cross-application linking functions.”
Cross-application linking is an important timesaving feature of an eCTD because it provides the ability to both re-use submission documents and to apply granular document updates (either during the building of the current submission or while applying a lifecycle attribute in a future sequence) to all linked occurrences elsewhere across related product applications. This lifecycle management ability increases efficiency for the publisher and aids in the consistency of information presented throughout the product application portfolio. And because the XML backbone is a common format across all eCTD applications, sponsors building an NDA can utilize cross-application linking via a leaf title that references back to the IND document (without actually having to republish that document in the NDA submission).
To regulators viewing the submission, this link is seamless with only the leaf title giving a clue that the document resides in an earlier application. Of course, in order for this function to work correctly, the reviewer’s software must be compatible with the sponsor’s submission building tools. To ensure that the two systems will work well together, the FDA is urging sponsors to set up a cross-referencing compatibility test with reviewers before the submission is finalized and sent.
A 2006 study released by the Tufts Center for the Study of Drug Development shows that companies best at organizing and executing the drug development process earn a billion-dollar advantage over their slowest competitors and bring products to market 17 months sooner. This research underscores the value of learning to squeeze the most out of your tools and processes, and the importance of taking advantage of time-saving eCTD features, such as cross-application linking, to streamline NDA building work by referencing back to documents already published and filed in the product IND.
Michelle Perezis Principal Consultant of Regulatory Consulting Services at ISI, which has offices in the North America, Europe and Asia. She can be reached at firstname.lastname@example.org
• The ISI 2008 Emerging Biopharmaceutical Pulse Survey; Image Solutions, Inc.
• Preparing Compliant eCTDs; Regulatory Affairs Professionals Society (RAPS)
• Fastest Drug Developers Consistently Outperform Their Peers, Generating Substantially Higher Revenue and Cost Savings ; Tufts Center for the Study of Drug Development; September/October 2006 Tufts CSDD Impact Report
• DIA Webinar: The New Look at eCTD Lifecycle Management: How Mapping from NDA to IND can Streamline Submission Lifecycle Chores; June 4, 2009; Michelle Perez, ISI, Connie Robinson-Kuiperi, FDA-CDER