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This month sees Europe make its move towards electronic submissions harmonization, but is it ready?
In 2005, the heads of the European medicines agencies agreed that all EU member states must have the infrastructure and processes in place to handle only electronic Common Technical Document (eCTD) format electronic documents by an agreed second half of 2009 deadline. The rationale behind the move was to successfully support the related decision-making processes for medicinal products within the EU.1 Now, all companies submitting electronic applications for medicinal product marketing authorization must be eCTDready; this month sees the mandate issued by the EUropean Medicines Agency (EMA) come into effect.
(Getty Images/Yuri Arcurs)
One of the main reasons behind the EMA's drive for electronic submissions is to encourage paperless submissions; thus reducing the high cost and inefficiencies associated with paper applications. "A paper submission for marketing authorization of a medicinal product easily fills 150 binders and more," explained Dr Barbara Jentges, Managing Director at PhACT GmbH, a regulatory consulting and training firm based in Switzerland.
The EMA has now reinforced its commitment to electronic submissions by mandating the use of the eCTD format for the centralized procedure of all electroniconly submissions. "From here on in, noneCTD format electronic submissions will be rejected. Although paperonly submissions may be accepted as an alternative, this type of submission may lead to significant handling and review issues," Jentges added.
So what does this mean to industry and regulators? Submitting a marketing authorization application electronically should be simpler and more efficient compared with the effort required to compile a paper submission, which requires copying, packaging, shipping, archiving and so on.
Theoretically, electronic submissions should be simpler. Some people may find the idea hard to swallow, but they're going to have to come around to that way of thinking soon — the era of electronic submissions is now upon the pharmaceutical industry and it will probably eventually lead to the full phasing out of paper submissions for all medicinal product marketing authorizations.
To understand how to achieve eCTD compliance, one must first understand the eCTD itself.
"An eCTD is the electronic submission of registration files that are organized according to the version 3.2 of the ICH eCTD specifications... an eCTD is the submission of (mostly) PDF leaf documents, stored in the eCTD directory structure, crucially accessed through the XML backbone (index.xml) and with the files integrity guaranteed by the MD5 Checksum."2
Sounds confusing "Ultimately, the idea behind eCTD is to harmonize the standard of electronic-only submissions and provide an electronic submission documentation that can be easily navigated and archived by both applicant and reviewer," Jentges summarized. "One of the key challenges for the applicant is the preparation of 'eCTDcompliant documents'."This includes, for example, the creation of PDF v1.4 files only, as this is currently the only PDF version that is compatible with the regulatory authority systems. All pages of the document must also be textbased, rather than imagebased, and a number of navigation tools, such as hyperlinking and bookmarking, must be implemented to make documents searchable. "So if you have scanned documents of text, then these need to be converted to text-based PDF files using Optical Character Recognition," Jentges clarified.
"Producing an eCTD is going to be far from simple. Of course, this procedure will allow industry and regulators to archive and access submissions at the click of a button, and that is a big benefit," she added. However, the implementation of eCTD will require companies to install a suitable information technology infrastructure and to alter the processes they already have in place to produce marketing authorization applications. Furthermore, once a company has become eCTD compliant and is ready to submit the appropriate documents for European review, they must then consider the differences across EU member states as well as across different continents. "For example, US eCTDs require the provision of study tagging files for each preclinical and clinical study report," advised Jentges.
"But that's not all; we have special challenges within the EU itself," she remarked.
In a separate interview with Pharmaceutical Technology's Angie Drakulich,3 Jentges admitted that there's still some way to go: "An EU eCTD Implementation Survey4 that covered the period from July 2007 to June 2008 revealed that 28% of the authorities did not specify when they will be ready to accept eCTDs."
"The eCTD has set off an avalanche towards paperless submission," concluded Jentges. If the EU is looking towards an electronic future for all marketing authorization submissions, then drug manufacturers are going to have to familiarize themselves with the new processes, sooner rather than later.
Dr Barbara Jentges discussed the challenges faced by the regulators and pharmaceutical industry today, as well the new procedures for electronic submissions, during the 2nd Vetter Drug Management Leadership Conference, held in Germany (September 2009).
Dr Barbara Jentges is Managing Director at PhACT GmbH in Duggingen/Basel (Switzerland). email@example.com
1. EMA, EMEA Implementation of Electronic-Only Submissions and Mandatory eCTD Submissions in the Centralized Procedure: Statement of Intent (2008). www.ema.europa.eu
2. EMA, What is eSubmission? (2009). esubmission.ema.europa.eu
3. Pharmaceutical Technology, Q&A With Compliance Expert Barbara Jentges (2009). www.pharmtech.com/jentges
4. eCTD Implementation Survey Report: v3.0-20090626 (Heads of Medicines Agencies). www.hma.eu