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How to cut time and cost by re-using already submitted documents.
Increasing drug-development costs, patent expirations, and fewer blockbuster drugs in the pipeline are forcing life-science companies to find faster, more cost-effective ways of getting new drugs approved and onto store shelves.
The worldwide shift toward the Common Technical Document (CTD) submission format promises a standardized global approach, while its electronic version, the eCTD, offers the functionality of digital-document management, manipulation, and storage. Both can streamline and speed the drug approval process.
Although industry has been anticipating these submission process changes since 2003, many drugmakers have been slow to make the transition to the eCTD. As a result, busy regulatory operations managers and staffs are being forced to face a stiff learning curve, and some eCTD technical advantages are being lost due to the lack of planning and understanding.
This article examines cross-application linking, an eCTD feature that allows sponsors to submit some required documents and data once and then refer back to those items in later eCTD applications or submissions. This means, for example, that sponsors building a New Drug Application (NDA) can link back via the extensible markup language (XML) backbone (by placing a "virtual" leaf element in the directory tree) to protocol, Chemistry, Manufactory, and Controls (CMC), or pharmacology and toxicology information already submitted and reviewed in the product's Investigational New Drug (IND) application. The link is seamless from the reviewer's viewpoint–with only the leaf title indicating that the document resides in an earlier eCTD submission. The sponsor can eliminate submission publishing and validation costs by substituting a reference link for the full document.
Because the CTD is a submission format, the content requirements for an IND, NDA, Marketing Authorization Application (MAA), or any other regulatory submission do not change. The format does, however, organize the required documentation into smaller chunks of information called "granules" that are 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.
Whereas the CTD is a paper submission that is hand-delivered, the eCTD is an XML-based version that is sent through electronic media or secure regulator gateways. Among the advantages of electronic transmission, management and storage, the eCTD allows sponsors to link to documents within and across previously filed submissions and applications. This feature can save time and the cost of publishing and maintaining a submission or application, but only if properly set up and managed from the start of the product IND eCTD application.
The primary technical components of the eCTD, which reside in the XML "backbone", are:
Planning is key
According to a 2008 survey by ISI, INDs were the most anticipated submission for 2009, with two-thirds of the companies surveyed in Phase I development reporting that they planned to file an IND last year. A majority of the 216 survey respondents (63%) were emerging companies with fewer than 250 employees.
The US Food and Drug Administration advises sponsors to submit INDs in eCTD format to facilitate review and life-cycle management throughout the product portfolio lifespan. Strategy is the key to getting the most out of IND eCTD submissions, and there needs to be a good understanding of how the IND fits into product development and global marketing plans so that documents can be harmonized to accommodate 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. FDA and the European Medicines Agency have suggested that those new to the eCTD process seek expert help for submissions (see Figure 1).
Figure 1: Investigational new drug (IND) applications lead the way in planned submissions. BLA is biologic license application. NDA is new drug application. Source: ISI.
Moving from an IND to an NDA
There is no one-size-fits-all approach to IND building. Each application must consider long-term product uses and global marketing goals, so that submission documents can be created that easily flow within the application or across applications of the same drug product. Regional regulatory issues such as granularity and content requirements should be considered at the planning stages to gain the maximum utility and flexibility because the IND eCTD becomes the foundation for future regulatory submissions and applications. By leveraging the regulatory similarities and consistencies across target documents, sponsors can develop a cohesive strategy that will save time and money in the submission-publishing phase by taking advantage of eCTD cross-application referencing capabilities.
Cross-application linking is possible within the following eCTD submission combinations:
Cross-application functionality currently is outside the scope of EU eCTD specifications, however, and it is not yet available for BLAs submitted to FDA's Center for Biological Evaluation and Research (CBER). FDA is encouraging sponsors to build submissions that use the cross-reference linking capabilities of the eCTD format to reduce submission size, lessen redundancies, minimize errors, and improve life-cycle management over the product's application lifespan.
IND documents that will typically be reused in an NDA application include:
However, Clinical Study Reports (CSRs), or components of CSRs, are far more granular in the IND than in the NDA (in this case, for example, documents should not be cross-referenced). When making reference decisions, sponsors need to remember that one of the key drivers in making the cross-application linking function work is determining whether or not the granularity will change from the original IND submission to the NDA submission. If there are differences in the level of granularity, it will not work. FDA encourages sponsors to incorporate communication with regulators (firstname.lastname@example.org) into the submission planning stage to gain additional information and to test sample cross-application links before submission (1).
Using the right tools
As sponsors develop a proactive plan that will set up documents for reuse and life-cycle management chores throughout a product application, they must also seek appropriate submission publishing tools to ensure proper integration of cross-application linking and associated life-cycle changes into the submission process. Before taking advantage of the cross-application linking benefits, sponsors need to have a capable eCTD tool or a vendor that does.
Whether compiling eCTDs in-house or outsourcing submissions, sponsors should ask:
Linking across applications
Cross-application linking is an important timesaving feature of an eCTD because it allows a sponsor to reuse 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 life-cycle management ability increases efficiency for the publisher and aids in the consistency of information presented throughout the product application portfolio. In addition, because the XML backbone is a common format across all eCTD applications, sponsors building an NDA can use cross-application linking through a leaf title that references back to the IND document without republishing that document in the NDA submission.
For this function to work, a reviewer's software must be compatible with the sponsor's submission building tools. To ensure that the two systems will work together, FDA is urging sponsors to set up a cross-referencing compatibility test with reviewers (by e-mail at email@example.com) before the submission is sent (1). In general, FDA uses "ind" as the prefix for IND; "nda" as the prefix for NDA; "mf" as the prefix for Drug Master Files, and so forth. However, FDA has reported that failed links are a common cause of confusion and delay as the reviewer is left to research or query grayed out leaf titles in the eCTD viewer (1).
The following is a list of instances in which cross-application linking works best:
Dos and don'ts
As discussed, the biggest "do" is to include FDA when planning and setting up cross-reference links in a submission or application to avoid problems that could lead to delays or refusals to file. Other important issues include:
Managing the product's life cycle
As sponsors work to develop a proactive plan that will set up documents for reuse and management chores throughout the life of the product, they must also find submission-publishing tools to ensure the proper integration of cross-application linking and associated lifecycle changes into the submission building process. Life-cycle management capabilities are enhanced by the eCTD granular format, allowing submissions to become ongoing as documents, and data can be submitted as it becomes available for an application or submission type.
"New," "append," "replace," and "delete" are operation attributes within the eCTD XML backbone that allow sponsors to replace only granules of information that need replacing. The cross-application linking function makes sure that changes made to any document in one application are also changed in all referencing submissions and applications.
Navigating challenges and pitfalls
Granularity is a key indicator of the ability to cross-reference documents across multiple submissions. However, granularity can be challenging when the level of granularity differs between the two applications. For example, the clinical documents in an IND typically are more granular because each 1572 and each investigator CV would be a separate PDF file. Although this granularity model makes it much easier to maintain life-cycle management in the IND, it may make it more cumbersome to link back from the NDA. In the NDA, on the other hand, quality documents are more granular because more CMC changes occur that require those documents to be upgraded or replaced. Other potential life-cycle problems include:
In today's shrinking economy, life-science companies are looking for ways to cut costs, improve efficiency, and reduce time to market. With eCTD deadlines looming in the world's major marketplaces, sponsors must embrace eCTD submission formats. The good news is the eCTD format has built-in functionality that can help simplify and improve submission building and life-cycle management chores across all product lines. The caveat is, however, that the submission builder has to understand timesaving eCTD features such as cross-application linking and plan for their use before submission.
To best use cross-application linking functionality, sponsors need to have a plan that:
A September/October 2006 impact report released by the Tufts Center for the Study of Drug Development revealed that the companies best at organizing and executing the drug development process earn a billion-dollar advantage over their slowest competitors, bringing products to market 17 months faster. This research underscores the value of learning to squeeze the most out of tools and processes, and the importance of taking advantage of timesaving eCTD features, such as cross-application linking.
Michelle Perez is a manager of global regulatory consulting operations at ISI, which has offices in North America, Europe, and Asia, firstname.lastname@example.org
1. C. Robinson-Kuiperi, A New Look at eCTD Lifecycle Management: How Mapping from NDA back to IND Can Streamline Submission Lifecycle Chores, presented at the 2009 DIA conference (San Diego, CA).