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Introduction to the components of the CTD within the eNDA folder structure.
The CTD is an industry wide initiative that has been developed by the International Conference on Harmonization (ICH). The initiative grew from the concept that global filings could be harmonized across ICH regions (Japan, the United States and Europe) in order to reduce the time and resources. This overview provides a brief description of the CTD components and illustrates how it should be presented within the eNDA folder structure.
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Electronic Submissions (eSubs) have evolved as the preferred method for submitting the huge amount of documentation and data required for marketing approval of a new compound in the US. Many organizations see the opportunities for efficiency and are constantly improving their eSub processes so that products can be taken to market more quickly. However, this is not a simple task. Organizations continue to grapple with evolving standards and emerging tools and technologies that automate compliance with those standards. Because the scope of a market application is so large, it includes information that is compiled from many sources throughout the R&D organization. Many people impact the submission process and many are impacted when standards for submission deliverables change. This issue continues to be one of the biggest challenges for companies to address.
The idea of electronic regulatory submissions for the pharmaceutical industry started in the early 1990's with CANDAs (Computer Assisted New Drug Applications). CANDAs represented the industry's first attempt to deliver electronic documents and data to the agency for review and approval of a new drug application. However, because there were no standards for CANDAs, each submission was built by a sponsor using whatever tools and technology they felt were most appropriate. This meant that sponsors shipped entire systems to the US FDA (United States Food and Drug Administration) (hardware and software) and each reviewer had to be trained on the system being used to present the submission. As a result, reviewers had multiple machines on their desks and no two submissions were alike. Reviewer training was application specific and sponsors were responsible for developing training aids that assisted the reviewer in navigating the submission.
In 1997, the FDA issued the first guidance for electronic regulatory submissions [Archiving Submissions in Electronic Format]. This guidance represented the first standards for electronic submissions but only addressed Items 11 and 12 (case report tabulations and case report forms) of the U.S. NDA (New Drug Application). It enabled sponsors to submit the tabulations and case report forms in PDF (Portable Document Format). These sections represent a significant portion of NDA documentation so the benefits of not submitting electronically were immediately apparent to sponsors and agency.
In 1999, the agency published [Regulatory Submissions in Electronic Format; General Considerations & Regulatory Submissions in Electronic Format; New Drug Applications] guidance on electronic submissions, which addressed the remaining sections of the NDA or BLA and also offered an update to the guidance for Items 11 and 12. The guidance outlined the requirements for submitting datasets in SAS Transport file format instead of PDF. This format offered reviewers the ability to receive data, replicate analyses and query data more efficiently. This component of the electronic submission signaled the first real shift from "electronic paper" to truly electronic, data driven submissions.
During this same time period, the International Conference on Harmonization (ICH) had been continuing to develop standards for the structure and format of global submissions. As a result, the Common Technical Document (CTD) guidance was drafted by ICH and implemented by the various regions beginning in 2001. The US FDA issued a draft guidance in 2001 [Submitting Marketing Applications According to the ICH-CTD Format - General Considerations ] that enabled sponsors to submit content organized according to CTD but formatted according the electronic submission file/folder format. This transition approach to new market applications is commonly referred to as the "hybrid" submission. Sponsors were now able to author content in CTD format, map it to the traditional electronic New Drug application (eNDA) folder structures, and thereby continue to submit electronically.
The ICH was also working on a specification for submitting global CTDs in an electronic format, also known as the electronic Common Technical Document, or eCTD. The specification includes content in PDF format but adds a new dimension to the electronic submission arena by including an XML backbone for navigation. The XML (eXtensible Markup Language) file is used to store metadata about each component of the submission. This metadata will be used by a review tool to facilitate various presentations of the submission content. Though some metadata was required in previous electronic submissions to support searches using PDF Title fields, this is the first time that the metadata is used to show relationships of individual submissions across the lifecycle of a market application. The focus on the creation of the backbone and the development of correct metadata has lead many organizations to spend significant time defining and understanding lifecycle management.
There are numerous approaches to submitting regulatory submissions. Sponsors can submit paper NDAs, electronic NDAs, hybrids, paper CTDs or eCTDs. However, each of these approaches requires certain expertise and commitment from an organization to support. For example, an eCTD is not just a market application. It begins with the submission of an eIND and extends to market approval and beyond. An organization must have internal and/or external capabilities to support the longer-term maintenance of submissions that are part of the eCTD. With eCTD, the submission is no longer viewed as a one-time event. Rather, it is a constantly evolving process of collecting information and building relationships between components of information that tell the story of the submission. In the future, this holistic view of the submission will offer more efficient reviews but in the present, organizations continue to struggle with the nuances of the evolving standards and how best to align processes to support them.
The prevalence of XML in the regulatory submission arena is expected to continue to grow. The industry is already witnessing many initiatives that are investigating and developing standards for submitting content in XML format. For labeling, the SPL or Structured Product Labeling represents an attempt to break down an important component of the submission into identifiable chunks of information that can be collected and represented in many ways. This is true for documents and data. CDISC (Clinical Data Interchange Standards Consortium) continues to examine data standards that may someday be submitted in XML format.
The evolution of eCTD and the convergence of initiatives such as SPL and CDISC, signal the shift of electronic submissions toward more data driven applications that reviewers will be able to navigate more efficiently. Development of these standards also provide an opportunity in the future for the agency to compare data across multiple applications so trends can be analyzed and potential safety issues can be identified more rapidly.
"Archiving Submissions in Electronic Format - NDAs (62 FR 49695, September 23, 1997)"
Regulatory Submissions in Electronic Format; General Considerations; January 27, 1999
Regulatory Submissions in Electronic Format; New Drug Applications; January 27, 1999
Guidance for Industry; M4: Organization of the CTD
Submitting Marketing Applications According to the ICH-CTD Format - General Considerations; November 2001
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