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Electronic Submissions to Regulatory Authorities

Electronic Submissions to Regulatory Authorities

This article is written to serve as a brief overview of the electronic submission process for regulatory documents. Further detailed guidance can be located at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064994.htm

Electronic submissions? eCTD? Module placement? What does this all mean?

Many professionals within the industry have a broad understanding of the process, but are not aware of the full-extent, details and the requirements behind the process.  The process is so intricate that the FDA has eighteen (18) Guidance documents on the process.  Included in this article are just some of the detailed steps and consideration for electronic submissions.

The eCTD is defined as an interface for industry to agency transfer of regulatory information while at the same time taking into consideration the facilitation of the creation, review, lifecycle management and archival of the electronic submission.

The objectives of eCTD submissions is to group common documents from multiple submissions into specific sections for ease of access for review and approval of the specific medical product. 

The creation of the five (5) module electronic database and subsections defining the placement of electronic Common Technical Documents (“eCTD”) for regulatory agency submission was instrumental in the success we appreciate today. The eCTD program designates the specific format of modules, sections and documents to be used by a Marketing Authorization Applicants for a medical product for human use in the United States, European Union and Japan (the parties of International Conference on Harmonisation (“ICH”)

The eCTD submission process is an interface for industry for agency transfer of regulatory information.  It is designed as a categorized database and folder structure within the FDA (and other Regulatory Agencies).  The database consists of five (5) main modules (see Figure 1), which are broken down into multiple sub-sections where the documents are assigned during the publishing process and submitted regulatory agencies through an electronic portal.  The complete list of subsections is extensive, so only a snippet is shown in Figure 2 as an example.

Figure 1

Figure 2

Document Approval Process

This process varies at different pharmaceutical companies, and Clinical Research Organizations (“CRO”).  The final, proposed submission documents may be provided to a Project Manager, a Regulatory Affairs Specialist, or possibly to a Publisher directly, depending on the individuals subject matter expertise. Subsequent to document approval,

Publishing the Submission Package (Dossier)

The publishing process electronically “builds’ the submission package typically as a pdf dossier to be submitted through the Electronic Submissions Gateway (“ESG”) for the FDA and Health Canada or can be submitted to other regulatory agencies through other electronic portals, or as an email attachment.

History of Electronic Submissions

‘Action is the foundation of all success.” – Pablo Picasso, Spanish Artist

With advancing technologies of document creation and processing, it was logical to replace the time-intensive paper submission process with an electronic process.  Version 1.0 of eCTD was introduced in 1999.  Although relatively successful, the main benefit was to set a foundation in which to build. 

Advances of the Internet, connectivity and program interfaces have been invaluable tools to assist in the building of eCTD submission packages, or dossiers. The ease of which documents can be shared, edited and published has significantly reduced the time, effort and thus cost of regulatory submissions.  The history of the development of the eCTD process could fill volumes. Following is a brief description of this history.

Version 2.0 of eCTD – an upgrade over the original CTD – was finalized on February 12, 2002, and version 3.0 was finalized on October 8 of the same year. In August 2016, Version 3.2.2 was released on July 16, 2008.

A Draft Implementation Guide for version 4.0 of eCTD was released in August 2012. However, work stalled on the project. An additional Draft Implementation Guide was released in February 2015[5] Draft specifications and guides were issued in April 2016 by the ICH and the FDA, followed by a May 13 ICH "teleconference to discuss the guidance and any questions and clarifications needed."

U.S.

On May 5, 2015, the U.S. Food & Drug Administration published a final, binding guidance document requiring certain submissions in electronic (eCTD) format within 24 months. The projected date for mandatory electronic submissions is May 5, 2017 for New Drug Applications (NDAs), Biologic License Applications (BLAs), Abbreviated New Drug Applications (ANDAs) and Drug Master Files (DMFs).  Starting May 5, 2018. Additionally, Commercial Investigational New Drug Applications (INDs) and Master Files must be submitted using eCTD format.

E.U.

In February 2004, the European Union Based released their eCTD version 3.2, and following in June 2008 version 3.2.2 was implemented, which is still in use.

The E.U. and its European Medicines Agency (“EMA”) began accepting eCTD submissions in 2003.  and in February 2015, the EMA announced it would not accept paper application forms for products applying to the centralized procedure beginning 1 July 2015.  The EMA verified on that date that it would no longer accept "human and veterinary centralized procedure applications" and that all electronic application forms would have to be eCTD by January 2016.

In October 2003, the European Union (EU) In February 2004, the European Union released their eCTD version 3.2. using the International Conference on Harmonisation (“ICH”), outlining the electronic exchange standard for regulatory information submissions for Sponsors and Agents marketing authorizations for medicinal products.  It applies the ICH Common Technical Document (CTD), the ICH M2 specifications to the European region and supplements this with the European Module 1 (http://esubmission.ema.europa.eu/eumodule1/index.htm).  In July 2008, version 3.2.2 was implemented providing minor editorial corrections after Step 4 approval and sign-off (http://estri.ich.org/eCTD/eCTD_Specification_v3_2_2.pdf).

EMA eSubmission Guidance for veterinary medical products, has also been developed (http://esubmission.ema.europa.eu/tiges/vetesub.htm).

Post-Publishing Review

“It’s not over until it’s over.” – Yogi Berra, American Baseball Player

Ahh, the overused quote from the master of simplicity.  However, Mr. Berra seemed to hit the nail on the head more often than we care to admit.  Anyone that has suffered (yes, I say ‘suffered’) through an eCTD submission process understands that there always seems to be one more requested revision; one more person to review; one more format change, or one more change to document placement.  Often the authors are so close to the data and document content, that results are transcribed incorrectly to the submission documents, or material is omitted.  This is common and nothing short of multiple reviews by multiple pairs of eyes can prevent these last-minute changes. 

Understandably, if working with a CRO or vendor company to make submissions, additional reviews and publishing efforts will increase submission costs.

After revisions are made, the edited document can be re-published in the final submission package.  Until the document is submitted through the portal, and Acknowledgements of Receipt received, revisions are always possible.

Sponsor Obligations, Responsibilities and Best Practices

Legal Responsibility

An important point to remember, is that Sponsors are ultimately legally responsible for the content, data and documents submitted to the regulatory authorities.  Meeting regulatory agency-imposed deadlines is important!  Therefore, it is essential to provide proposed final documents to the submitting department, or company in a timely manner to allow for rereview, reapproval and republishing of the submission package.  Every client wants an exception when documents are provided late, but if the Sponsor does not adhere to given submission timelines, deadlines may be missed to due caseload, bandwidth, or other factors of the submitting company/department.

Further, Requests for Information (“RFI”) from a regulatory agency are significant because of the impact they impose on the  review/approval timeline.  They are preventable.  Often, when a RFI is received from a regulatory agency the reader of the request experiences an “A-ha moment” and immediately understands the request.  They may say to themselves, “Yes, I should have explained the impact of this variable better.” or something to that affect.  Anticipate any ambiguity of the regulatory agency approver by having multiple people, in varying positions, read and review proposed final submission documents.  They may question a term or phrase that will be understood by the reader, but often if it is unclear to anyone, the text may require a slightly better explanation, or additional information provided.

Document Transfer

Documents are provided to the submission and publishing departments in various ways; as email attachments, zipped folders, through company SharePoint sites, File Transfer Protocol (“FTP”) servers, or even via USB-flash drives and discs.  The important takeaway is that they’re provided in the agreed upon format. 

Document Templates

“You don’t have to reinvent the wheel, just attach it to a new wagon.” – Mark McCormack, American Lawyer

It is recommended that document templates be created for each type of regulatory document submitted as they are drafted.  Certainly, it would be cumbersome and unnecessary to produce templates of document types that will not be required but having the templates of previous submitted documents will reduce production time for subsequent submissions and ensure that the proper content is included. 

It is not extraordinary for the same FDA Project Manager to be assigned to the same Sponsor for multiple product submissions, contingent on the medical therapeutic area.  Once it is known that a particular project manager prefers a specific format, use this in your template and make note of this preference.

Payment Obligations

Referring to a previous point, the Sponsor is ultimately responsible for missed deadlines, and lack of response to regulatory agencies.  A CRO, or other vendor has every right to withhold further performance if financial considerations are not met by the Sponsor for worked already performed.  Often, timelines can be re-negotiated to ensure that work continues, but re-negotiations are a courtesy and not required by a CRO, or the vendor company.