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:
- Document type definitions (the submission format "rulebook")
- Style sheets (formats and styles used to view the XML backbone)
- Submission metadata (information 'tags' associated with applications and documents and used within the XML backbone)
- The XML backbone, which replaces submission-level and module-level tables of contents.