The world is flat.
That is the subject of the Thomas Friedman best seller published around the time eCTD was being implemented in the regions synonymous with economic might – the United States, Europe and Japan. Friedman spoke of an increasingly globalized marketplace where information and commerce are no longer encumbered by historical borders. The book also stressed that those who do not adapt will fall behind.
A harmonized regulatory submission standard is a means of efficiently navigating traditional boundaries to facilitate global trade. The eCTD project has achieved an impressive degree of harmonization and should make even greater strides when the next major version (eCTD v4.0) is implemented. But there are regional differences that must be accounted for as regulatory professionals develop procedures and forecast submission schedules.
Japan’s Pharmaceutical and Medical Devices Agency (PMDA), one of the earliest adopters of eCTD, adheres to a number of unique business rules which create a unique implementation of the eCTD specifications. Information available on eCTD best practices is also limited for this region, primarily due to lower levels of submission activity, compared to Japan’s ICH counterparts.
What do we already know about submitting eCTDs in Japan and what can we expect later this decade as they implement eCTD v4.0?
A Brief History of eCTD in Japan
Japan began accepting eCTD submissions for marketing applications in 2004. Paper copies of the submissions were also required. Regulations changed in 2009, and paper replicas of Modules 3, 4 and 5 were no longer required if applicants submitted an original eCTD.
Data from the Japan Pharmaceutical Manufacturers Association shown here depicts the first decade of eCTD submission activity (original and reference) in Japan and confirms that original submission activity increased after the 2009 regulatory change.
The submission metrics shown apply only to marketing applications. Japan’s clinical trial notification (CTN) is not part of the eCTD program. In this case, Japan is more like Europe. By comparison, Investigational New Drug (IND) applications are accepted in eCTD format in the US.
Japan’s eCTD Lifecycle management is based on individual regulatory activity lifecycle whereas the US and Europe allow for management of the entire product (i.e. application) lifecycle. In short, one application in Japan is one regulatory activity. A single application in the US and Europe is broken into multiple regulatory activities.
The independent, regulatory professional membership organization TOPRA described the logistics of applying for a new indication in Japan.
“If a company wants to file for additional indications for a product, a new eCTD must be created without referring to the original eCTD. The original Module 2 should be included in the new eCTD.”
Japan’s approach to lifecycle management requires the sponsor to perform an action referred to as a pseudo replace in order to repair broken external links. Furthermore, for each new sequence in Japan, the entire XML backbone must be resubmitted with reference to every file that has been previously submitted; the files themselves are not re-submitted.
Module 1 presents another difference between Japan and the US/Europe. Japan has implemented an XML Schema for M1, consistent with the Study Tagging File Specification, to provide data integrity while Document Type Definition (DTD) is used in other regions.
As you can see, there are some very significant differences in the way the eCTD specification is treated in each region. The introduction of eCTD v4.0 will bridge many differences but contrasting approaches will continue.
Japan and eCTD v4.0
As of December 2015, eCTD v4.0, which is based on the Regulated Product Submission (RPS) standard, reached ICH step 4. At this juncture consultation on the standard stops and release of the final guidance documents is imminent.
Japan, the US, Europe and ICH all published draft eCTD v4.0 implementation guides, but implementation will not begin until final guides are issued. Therefore, what we do know is subject to change.
Two-way communication, functionality allowing regulatory agencies to communicate with sponsors by sending an eCTD sequence, is a much anticipated element of eCTD v4.0. Japan will not support two-way communication. Sponsors will need to implement separate correspondence management systems to track communication with the agency.
In eCTD 4, the file-folder structure is no longer relevant. Each region may determine their own structure. Since Japan intends to have sponsors submit CDISC datasets (mandatory as of 2018), the implementation of the Japanese folder structure will not be the same as ICHs, though it may resemble that of other regions that require CDISC datasets such as the US.
Japan does plan to support re-use of documents, another staple of eCTD v4.0, and the guidelines are spelled out in the draft regional implementation guide. However, Japan is waiting to see what other regions do in this area and is reserving the right to reconsider these requirements prior to implementation.
While eCTD 4.0 is on the horizon, PMDA continues to enhance their program and has recently awarded a contract for implementation of a submission gateway that’s scheduled for production in October 2016. It is not clear as to whether the initial gateway system will allow submission of CDISC datasets only, or will also include eCTDs.
Sources who’ve worked closely with PMDA on eCTD submission projects and are familiar with plans for eCTD v4.0 implementation say the new specification won’t be accepted until April 2020. A mandate for eCTD is an additional two years away – April 2022. That projected milestone date signals the completion of the tenuous process of converting paper submissions into electronic format within two decades of eCTD first being accepted in Japan.