FDA amends guidance for three submission types

N. Jay JohnsonSr. Business AnalystTAKE Solutions Inc., Global Life Sciences

Did your organization make a New Year’s resolution to transition to electronic submissions using the eCTD specification? On September 29, 2006, the FDA announced the withdrawal of the guidance for electronic submission of the following three submission types:
• “Providing Submissions in Electronic Format – NDAs” (eNDAs)
• “Providing Regulatory Submissions in Electronic Format – ANDAs” (eANDAs)
• “Providing Regulatory Submissions in Electronic Format: Annual Reports for NDAs and ANDAs” (2003) [Docket Nos. 1999D–0054, 2001D–0475, and 2003D–0364] (formerly Docket Nos. 99D–0054, 01D–0475, and 03D–0364, respectively)

Currently, applicants have three choices when submitting a marketing application electronically:(1) Use the eNDA/eANDA format, (2) use the eCTD format, or (3) use what is called a ‘‘hybrid’’submission (the older eNDA format with the table of contents organized using the newer CTD headings). This variety of choices is confusing and frustrating for the life sciences industry, which is not receiving consistent recommendations about how to submit marketing applications. It is also confusing and frustrating for the agency review staff and has forced the agency to maintain expensive and duplicative processes and systems for receiving and archiving these various application types.

With the recent guidance withdrawal, the FDA has simplified the guidance maze within the industry by exclusively condoning the use of the electronic submissions guidance: “Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.” The eCTD specification has taken center stage at both the FDA and within the industry.

The eCTD guidance sets itself apart technically from the eNDA and eANDA guidance in that the submission’s table of contents is no longer submitted as a PDF file. With the new eCTD standard, the FDA and the international life sciences standards entity ICH (International Conference on Harmonization) introduce a major change to the fundamental structure of the submission by using an XML file as the underlying backbone, which in turn defines and contains the table of contents.

Capitalizing on the acceptance and adoption of XML technology, reviewers and submitters can now easily browse submissions using a common internet browser. Leveraging the power of the XML standard as it is applied to the eCTD specification; dossiers can be viewed comprehensively with each amendment layered against the original submission rendering the lifecycle and documentation of a product as it changes over time in an easily viewable and understandable format. Specifically, using the XML file allows an applicant to update the application’s table of contents automatically as new amendments are filed so that sponsors and reviewers can have access to a real-time, up-to-date, cumulative table of contents. This provides easy and immediate access to all files included in an application, regardless of when they were included or in what submission they are located. This type of flexibility and efficiency has never been previously possible at either the applicant or reviewer levels. Applying the eCTD specification to the XML standard also provides for reusability of the applicant’s submission documents for different regional markets. Five core modules make up the submission, with the first module containing all of the region-specific documentation. Interchanging this first module with another agency’s module allows for efficient re-submission within different markets without having to change the documentation or metadata within the other four modules.

Another advantage is that through the creative use of the XML metadata, the table of contents can be displayed in various ways, allowing for discipline-specific views of an application (e.g., Chemistry vs. Clinical), cumulative lifecycle views showing all documents and their current state, submission-specific views displaying only the delta between submissions, module-specific views, etc., all further promoting review and assembly efficiency. This is especially important for agency review staff and industry’s time to market.

Organizations looking to leverage the advantages gained by moving to electronic submissions will face many challenges, as the undertaking will require a significant amount of resources and dedication to accomplish. After alerting management to the withdrawal notice and subsequently obtaining their buy in, a business and technical strategy should be developed during the initial planning phases.

The business strategy will have much of the same focus and challenges we find in typical scenarios. Participants in the project will need to acquire familiarity with the FDA guidance and be well versed in the supporting guidelines. Business standards will need to be developed to support the shift in paradigm from paper publishing to electronic, which will in turn lead to modifications of business process and, at the lowest levels, department and area standard operating procedures. Key to the strategy will be working to integrate the numerous contributor and author areas making sure that they all still have the appropriate access and control over their deliverables. Establishing and maintaining a communications plan throughout the entire process will ensure that the numerous groups and areas involved have a voice in and throughout the process and can obtain answers to issues and questions as they arise.

The technical strategy will also play a major roll in the transition to electronic submissions as there will be many layers of technology with many tools involved in order to publish a completed submission. The team will have to determine what technology will be necessary and what can be leveraged within the existing environment. Technology which is not currently available within the organization will have to be analyzed with respect to the organization’s information technology department to determine a “buy versus build” investment decision. Is building the tool internally an option, or does the organization’s IT budget demand the integration of an existing product?

When purchasing a tool, have the integration and on-going maintenance costs been considered? Is the tool going to be easily accessible to everyone involved with the eCTD submission? Are there technical considerations as to whether you are a small, single-site organization or a large, multi-regional one? How will any technology changes proposed affect the organization or its efficiency? These questions must be addressed while trying to manage and maximize your organization’s current resources. Remember - once eCTD, always eCTD.

As we begin the New Year, the FDA is recommending that sponsors wishing to submit applications electronically use the most efficient and internationally agreed to formats recommended in their most recent guidance. This will certainly lead to changes within your organization as you adopt the new standard but will also enable dossier control which was never previously possible.

**Excerpts in the above were taken from the Federal Register/Vol. 71, No. 189/Friday, September 29, 2006/Notices, written by Jeffrey Shuren, Assistant Commissioner for Policy.[FR Doc. E6–15966 Filed 9–28–06; 8:45 am]