Today’s post is a round-up of recent eSubmission-related news from the agencies, based on posts from my twitter account, www.twitter.com/kathie_clark. Next time, a roundup of articles and conferences.
The regulatory authorities haven’t put out much in the way of major updates recently, but there have been some updates worth noting:
The individual agencies in Europe have also issued some updates:
As promised, here is an expanded list of posts published recently on my twitter account, this time related to agency news:
There has been a lot going on at the various European agencies in the last few months. This week, we look at some of the announcments and guidance that has been issued across Europe recently.
France: – Caroline AURICHE, Philippe DÜRR and Cécile LEVY from AFSSAPS spoke at EXL Pharma, presenting on Taking the plunge from paper into electronic-only in the EU – the 18-month feed-back experience of «paperlessland» in the French Health Products Safety Agency. AFSSAPS details include:
Germany: The Federal Institute for Drugs and Medical Devices (BfArM) announced that it will accept pure electronic filings (eCTD or NeeS) from mid-February 2010 (previously a full paper copy was required). Only those documents requiring signature will be required in papert.
The BfArM will soon add a section on “electronic filing” to its homepage (www.bfarm.de) to consolidate information The BfArM will be making further announcements closer to the date
Austria: In news passed on from Tim Feldgate of Applied Regulatory Consulting’s blog article Electronic submission available for human use, the AGES PharmMed now accepts, but does not require, purely electronic submissions for human use without additional paper copy, except for those documents that need to be signed: Company letter and application form. eCTD is the preferred standard, and it is the default Nees is only a temporary solution.
Belgium: Federal Agency for Medicines and Health Products advises on automatic emails sent after eSubs uploaded in their system and passed or failed compliance requirements
Belgium: New version of the Belgian agency’s NeeS checker tool: see the agency’s e-Submissions page (you must navigate to the Human Use tab and then the eSubmissions link) (translated from the Dutch) for the file checker and associated documents.
Spain: AEMPS has issued a new version of their NeeS guidance ENVÍO POR PARTE DE LOS LABORATORIOS DE INFORMACIÓN EN FORMATO ELECTRÓNICO A LA AEMPS on December 22nd (in Spanish only.
UK: in The Medicines (Products for Human Use) (Amendments to Fees for Variations) Regulations 2009 , eCTD fees were set at a lower level than other submission types.
UK: E-SUBMISSIONS – Frequently Asked Questions (FAQ) for Vet Meds in the UK has been updated to clarify that the root folder of a Vet Meds eSubmission is part of the submission, and that following the naming conventions for files and folders (with regards to forbidden characters) is important – your submission may be rejected even for use of upper case.
Turkey: Turkish eSubs guidance (in Turkish) has been issued. per Andrew Marr “This is essentially NeeS but with specific file and folder naming in Turkish, with CTD section numbers too. I believe that the final guidance will allow Modules 4 and 5 to use the English folder and filenames.”
Cyprus: the Ministry of Health has issued GUIDANCE FOR PROVIDING REGULATORY INFORMATION IN ELECTRONIC FORMAT SUBMISSIONS. They will accept electronic submissions within the National Procedure, the Mutual Recognition Procedure and the Decentralised Procedure in eCTD or NeeS format. However, the Cover Letter and the Application Form must be submitted in paper with an original signature. The guidance provides information on disk and file formats, packaging and labeling, electronic signature, validation, etc. “The Pharmaceutical Services, Ministry of Health have a strong preference for the submission of electronic regulatory information and sees clear benefits for both regulators and industry.”
Greece: the National Organization for Medicines has posted Instructions for Filing Electronically (translated from the Greek by Google). Human products still require M1-M3 in paper but discourage paper for modules 4 and 5. Vet meds and labeling requirements are also discussed.
Norway: Statens legemiddelverk announced acceptance of / strong recommendation for electronic submissions 1 Jan 2010 (translated from Norwegian by Google).
Sweden: in updates to their Electronic submissions page, MPA prefers “as far as possible be able to work solely with electronic submissions for all medical products.” From the 1st January 2010 the MPA will also accept electronic submissions in NeeS or VNtA formats for veterinary medical products within all procedures.
Bulgaria: the Bulgarian authority has issued an announcement that from 01.01.2010 all types of procedures must be in electronic format -eCTD or NeeS – for all procedure types in Bulgaria (translated by Google). They specify which documents are still required in paper in addition. There is also a Guide for electronic submission of documents eCTD and Nees (this was issued last March). For a more detailed discussion of Bulgaria and eSubmissions, see ForeignExchange Translations blog entry Bulgaria catches up with e-Submissions.
Poland: the Polish agency has announced the acceptance of electronic submissions from 1 January 2010 (Nees, eCTD), with the proviso that certain specified documents must be submitted in paper form, regardless of their submission in electronic form.
P.S. I had previously announced all of this news on Twitter, albeit in abbreviated form. Be sure to follow me on Twitter for timely updates – go to www.twitter.com/kathie_clark to follow me.
As promised, the EMEA released Version 1.4 of the EU Module 1 Specification on schedule in August. The new spec has some changes that will impact eCTD assembly, publishing, verification and viewing software tools. The EMEA has reached out to the vendor community to ensure that they are aware of the changes to ensure that they can modify their products in advance of the required implementation timeline. It’s worth reproducing that timeline here – quoting from EU Module 1 Implementation Guidance:
1. Applicants are advised that, from 1st January 2010, when the new variation regulation comes into force, the EU M1 v1.4 must be used for any eCTD submission for any European procedure that contains grouped variations or is subject to a worksharing agreement. Grouped variation or worksharing eCTD submissions provided from this date using any previous version of the EU M1 specification (v1.0. v1.1, v1.2.1 or v1.3) will not be accepted. All European Regulatory Authorities must therefore be able to accept eCTD submissions built using EU M1 v1.4 from 1st January 2010.
2. Applicants are further advised that, from 1st July 2010, the EU M1 v1.4 must be used for all eCTD submissions for all European procedures, and any eCTD submissions provided from this date using any previous version of the EU M1 specification (v1.0. v1.1, v1.2.1 or v1.3) will not be accepted
The nature of this timeline is related to the most significant change in V1.4: the Specification and DTD have been amended so as to support the New Variations Regulation. The envelope has been reviewed so as to support the different modes of submission for variations: single, grouping and worksharing.
A new envelope element, submission ‘mode’ is now provided for use with variations and line extensions. A related change involves the use of a “high-level” submission number for worksharing submissions and certain grouped submissions. Submission publishing tools will require user interface changes to accommodate these requirements, and publishers will need to be aware of their correct usage. EMEA has also provided a number of sample submissions to illustrate the correct use of these elements.
Another significant change is a new limit on folder path length. The Specification has been amended to update the maximum length for file path. The new maximum length has been set to 180 characters. That is, the overall folder and file name path length starting from the sequence number should not exceed 180 characters, for any file in any module. This is an EU regional requirement, and it is acknowledged that this is less than the ICH agreed overall path length. This may cause issues for anyone using attribute-related folder paths (such as drug substance, indication, etc.) of more than a dozen characters or so. Although this won’t affect sequences already submitted, it will mean that some sponsors may have to modify their conventions in this area (keep in mind that the HAs have said that folder names do not have to actually match metadata in the eCTD backbone).
A few more minor changes:
· The ATC number metadata in M1 has been retired
· A few new values have been added for submission type
· A new stylesheet has been supplied
· Naming conventions for the tracking table have been updated
Sponsors need to prepare to accept and validate updated versions of their publishing tools and will need to work with vendors to ensure that updates will be available in advance of the portion of the deadline that applies to them based on their submission plans. They will also need to update some procedures.
It’s worth reviewing the EU Module 1 V1.4 Release Notes to make sure you understand all the changes…
In other EMEA news, a The NeeS validation criteria v1.0 (a set of technical validation criteria to be applied to all non-eCTD electronic submissions has been drafted. Finally, Practical guidelines on the use of the eCTD format for the Plasma Master File (PMF), for the submission of MAAs for plasma derived medicinal products and medical devices that include a PMF certificate, and for 2nd step procedures, has been released by EMEA.
Rob de Haan, deputy director at MEB, spoke about the status of eCTD at MEB, and also presented a variety of EU statistics, many of them updates from the eCTD Implementation Survey Report published in December of 2008.
MEB now has a full e-working environment (although they make almost no use of their eCTD viewer, for reasons Rob didn’t go into). eSubmissions (eCTD and NeeS) for human medicines are mandatory. Case managers and assessors have secured access to electronic files in a central repository, and thus can work remotely (through Citrix) without downloading files. Veterinary submissions are still on paper. eSubmissions are via CD or DVD now as MEB does not yet have an electronic gateway.
Europe is making slow progress toward the goal of all agencies excepting eSubmissions without paper by the end of 2009. Currently 15 out of 32 agencies are ready (up from 13 six months earlier). Agencies report receiving 54% of all submissions electronically in Q3/Q4 2008, out of a total of 203,941 submissions.
When broken down by submission type, the total percentage by format was as follows:
· 6% eCTD (up from 3% in Q1/Q2)
· 58% NeeS (down from 62% in Q1/Q2)
· 31% Other (down from 33% in Q1/Q2)
[not quite sure why the totals only add up to 95% or why eCTD+NeeS at 64% is much higher than the total of 54% electronic reported in the previous paragraph, but you get the idea!]
At this point, DCP/MRP are about 54% electronic, NP about 50% electronic, and CP almost 100% (see my previous post for EMEA experience).
Rob’s observation is that NeeS will eventually disappear and no longer be accepted by the individual HAs. This won’t happen right away but validation will continue to get tougher, with HAs adding more rules and moving to zero tolerance.
Most agencies really want to move to eCTD, but obstacles remain such as pushback from the sponsors (who sometimes say that NeeS is easier than eCTD). In addition, some regulators don’t want to have to train reviewers and install review tools. Finally, of course, some countries don’t have a legal basis at this time for accepting electronic documents as official or archival copies in lieu of paper, and there is only so much the HAs can do to push legislation.
SwissMedic has issued a package of eCTD related specifications
I have only done a cursory analysis as my day job is a bit overwhelming at the moment. The specification differs notably from the EMEA spec in several areas:
· SwissMedic has issued their own file and folder naming conventions for M1 as of course their M1 contents differ from EMEA
· Module 1 metadata is different, and includes a SwissMedic number and the galenic (dosage) form in both English and other languages, and does not include ATC or procedure type
· The DTD appears to allow M1 to be repeated per galenic form
· The concept of regulatory activity, as implemented in related sequence, is present. However, the concept of first and second level activities is not present as it is in EU/US. For example, a sequence of type na-nas can relate to another sequence of type na-nas.
· The leaf element includes some new attributes such as actuate-list and show-list, and gives a list of values. However, these are not explained or even mentioned in the guidance document.
In other news, EMEA issued their guideline for e-submission for a veterinary medicinal product The guideline specifies the basic parameters required for an acceptable electronic submission, and includes a specification for the folder structure (the granularity) to be used in a basic electronic submission to be known as VNeeS. It does not mention eCTD.
EMEA-EFPIA Information Day 2009, which was held on 24 February 2009 in London, included several interesting presentations about eCTD and NeeS.
Claire Holmes of EMEA presented on eCTD/Non eCTD electronic Submission (Nees): impact on the centralised procedure. Ms. Holmes explained the background of the recent announcement about mandatory eCTD: based on legal advice from EMEA, instruction was given that although eSubmissions cannot be mandated for the Centralised Procedure due to lack of legislative basis, it is possible to mandate the format of the eSubmission if received. Thus, the recent milestone of requiring all eSubmissions to be eCTDs by 1 January 2010. After that date, non-eCTD format electronic submissions will be rejected. Paper-only submissions will continue to be accepted, but will lead to handling and review issues as EMEA processes are being engineered for eSubmissions.
The number of eCTDs received has been increasing exponentially at EMEA (988 eCTD sequences since 1 July 2008). Around one-third of eSubmissions in recent months have been eCTDs. Although the majority of eCTDs are still new applications, an increasing number of converted “baselines” has been seen in the last six months.
There’s lots more in the presentation, especially concerning NeeS, but I’ll wrap up for today by repeating Ms. Holme’s Key Messages for Industry:
Sounds like EMEA stayed busy through the holiday season as they posted four new or updated guidance documents at the end of December. Most significantly, EMEA implementation of electronic-only submissions and mandatory eCTD submissions in the centralised procedure: Statement of Intent tells us:
“From 1 January 2010, the EMEA will mandate the use of the eCTD format for all electronic-only submissions for all applications (new and existing) and all submission types. Rapporteurs and CHMP members will not receive paper copies or other electronic formats.”
As with the rest of the EMEA’s statements and guidelines pertaining to eCTD, this only applies to the Centralised Procedure.
A “matching” statement of intent for non-eCTD electronic submissions tells of the retirement of NeeS. It also announces the introduction of a set of specific guidelines on submission structure, format and presentation, which non-eCTD submissions should adhere to for the centralised procedure from 1 February 2009 until such time as the eCTD format is mandatory. These guidelines are found in EMEA implementation of electronic-only submissions eCTD submission: Practical guidelines relating to Non-eCTD submissions.
Finally, the highly useful document EMEA Implementation of Electronic Submissions and eCTD Submissions Statement of Intent Q&A Relating to Practical and Technical Aspects has been re-issued. Changes are minor and include asking for virus checking information in the cover letter instead of a reviewer guide, and acknowledging a discrepancy between the eCTD file naming
convention and the PDF file naming requirements for EPAR (product information) documents (you are advised to use eCTD file naming conventions for the time being).
My collegue discussed this announcement with EMEA representatives this week, and they have indicated that although they are not in a legal position to require electronic submissions, they strongly recommend against paper submissions.
(P.S. After an internal struggle, I suppressed the urge to label this post “It’s Been NeeS”.)
As the EU authorities continue their progress towards welcoming eSubmissions, information continues to surface on their web sites and elsewhere.
The Swedish National Authority (MPA) has updated their web site with new eSubmission information – see Electronic submissions to the MPA. The MPA maintains a dedicated email address (eSubmissions@mpa.se) for general questions on electronic submissions. They also provide guidance on media, cover letters, handling of MS Word documents, etc. Some of the information is only in Swedish (which BabelFish unfortunately won’t translate!).
If you visit the web site of the Spanish agency La Agencia Española de Medicamentos y Productos Sanitarios, look for a Welcome link in the top toolbar to access some content in English. Click the Electronic Submission link and look for the link to Instructions for electronic submission eCTD/NEES Pilot Phase. The agency has instructions for generating electronic submissions, to take effect in January 2009. The agency requuires sponsors to register new authorizations and variations in the AEMPS Regulatory Tool: RAEFAR, and to use the Belgian tool eCTDchecker on NEES submissions. A more detailed guide is available in Spanish: Guide AEMPS v1.11 .
Finally, an interesting presentation on Electronic Submissions in Hungary, by Dr. Gergely Zajzon of National Institute of Pharmacy is available. Since 2006, the National Institute of Pharmacy (OGYI) in Hungary has been accepting full electronic eCTD applications, without any printed sections of the dossier. Dr. Zajzon’s presentation discusses status, progress, challenges, requirements for eCTD and NEES in Hungary, and the agency’s ongoing program to digitize paper submissions.