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Archive for the ‘Guidance’ Category
21 CFR Part 11 and Electronic Publishing: the Elephant in the Room?
posted by Kathie Clark @ 8:16 PM
Friday, July 23, 2010
In my document management career, my company provided specialized EDMS solutions for Pharma (for submissions, SOPs, trial master files, etc.). It was a given that these systems needed to be Part 11 compliant, and I authored our position paper on how Part 11 compliance was achieved and demonstrated in our product. If our product had ever been viewed as being noncompliant, no one would buy it – end of story.
For whatever reason, few sponsors seemed to apply that same requirement to their publishing vendors. Back in the days of paper submissions, this didn’t seem too unreasonable. After all, the FDA says in Guidance for Industry: Part 11, Electronic Records; Electronic Signatures — Scope and Application”:
“Under the narrow interpretation of the scope of part 11, with respect to records required to be maintained under predicate rules or submitted to FDA, when persons choose to use records in electronic format in place of paper format, part 11 would apply. On the other hand, when persons use computers to generate paper printouts of electronic records, and those paper records meet all the requirements of the applicable predicate rules and persons rely on the paper records to perform their regulated activities, FDA would generally not consider persons to be “using electronic records in lieu of paper records…”
But eCTDs don’t meet these criteria. By definition, when you submit an eCTD you are asking the government to accept “in electronic format in place of paper”- and as part of the conditions of acceptance, they state that “Electronic documents that bypass the controls for electronic files described in 21 CFR 11 are not considered official documents for review.” (see Guidance for Industry: Providing Regulatory Submissions in Electronic Format — General Considerations.”)
Despite this, I don’t hear a lot of talk about Part 11 and publishing tools. Vendors don’t post much on their websites about Part 11 compliance (and what they have often applies more to document management). Googling Part 11 and electronic publishing doesn’t return anything useful.
So where does that leave sponsors in terms of the need for compliance? Granted that in these days of McNeil plant closures, tainted heparin, accusations of suppressed safety data, and etc., it seems unlikely that the FDA’s risk-based approach to inspections and audits will result in scrutiny of sponsors’ publishing systems. But sponsors certainly don’t intend to entirely flout requirements or fail to follow good practices. It would be interesting to define what the essential elements of compliance and good practices are.
Some areas are straightforward. Most people would agree that their publishing tools should have limited access and operational controls to prevent errors. But other areas aren’t so clear. To add to the ambiguity, in the Scope and Application document, the FDA announced its decision to exercise “enforcement discretion”, specifically lack of intention to take enforcement action to enforce compliance with the validation, audit trail, record retention, and record copying requirements of Part 11.
Audit trail almost always remains one of the most complicated issues for electronic systems – so given the “enforcement discretion” what needs to be audit trailed in a publishing system?
As a reminder, Part 11 applies to “Records that are required to be maintained under predicate rule requirements and that are maintained in electronic format in place of paper format.” In the document management world, almost everyone interprets this as meaning that draft documents do not require an audit trail, as you aren’t required to create or retain them at all in most cases. When you are publishing, everything is a draft, right up until you lock things down and send them through the gateway. When you are working on a sequence, if you add a specification, then remove it, is an audit trail needed? If so, is it because Part 11 requires it, or because the sponsor wants an “electronic watchdog” reporting on who made changes to the submission prior to finalization?
Many other Part 11 requirements should be important to the sponsor regardless of whether they are subject to inspection. I would want my electronic publishing system to be installed in accordance with an IQ protocol and validated with an OQ and PQ protocol regardless of whether they FDA requires this or not, because incorrect installation or operation could have a profound impact on my submission quality or timeliness.
I would be interested in hearing from my readers on this subject. Do you disagree with the assessment that Part 11 applies to publishing software? What do you consider the necessary elements for Part 11 compliance for your publishing tool? Is Part 11 the “elephant in the room” that no one will acknowledge related to publishing software, or addressed by following basic good practices?
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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:
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Accepts and encourages electronic-only (paperless) submissions since 1 July 2008
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Accepts National and MRP/DCP procedures
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Accepts e-CTD or EU-NeeS
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Exploring a possible shift from EU-NeeS to eCTD
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Enforces “Once e-CTD, always e-CTD” - once first submission as eCTD, all regulatory activities accepted
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Attempting to shift paper to electronic : all regulatory activities except IA/IB variations (volumetry factor)
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EU-NeeS : IA & IB variations never accepted
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Receives about 1/3 eCTD and about 2/3 EU-NeeS, of which roughly one half are nonconforming at the time of first submission
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.
Announcement: See GlobalSubmit’s web site for a brand new presentations page linking to recent agency presentations!
GlobalSubmit recently attended two informative DIA conferences:
- The 8th Annual Electronic Submissions Conference “eCTD: The Adventure Continues” in San Diego
- The 10th Conference on European Electronic Document Management in beautiful Vienna, Austria
During these conferences, industry received updates from a number of regulators, including the FDA, Health Canada, the European Medicines Agency, the MEB, AGES PharmMed, and SwissMedic. In my next series of blog postings, I’ll be passing on interesting news from the regulators. Since there’s quite a bit of material, I’ll cover it in three postings: US, Canada, and Europe.
The FDA’s presentations focused on three major areas:
- Status and metrics for various initiatives
- Data standards
- Study Tagging Files
Status and metrics for FDA initiatives
Gary Gensinger provided updates in both San Diego and Vienna. Some of the more significant metrics included:
- The percentage of IND Originals in electronic and standardized format remained relatively stable, the number of amendments in electronic and standardized formats have nearly doubled.
- The percentage of new NDAs/Supplements submitted electronically has remained relatively stable, the number submitted in eCTD format rose between 28% to 51%
- Of original NDAs submitted in FY 09 94 out of 131 (72%) were in eCTD format)
- If mixed submissions (paper & electronic) are included, the percentages around new NDAs/Supplements with electronic components approach 90+%
- The total number of eCTD sequences submitted to date is over 98,000, with almost 5000 eCTD sequences received every month in recent months
- SPL submissions have also increased dramatically, and are approaching 2000 per month
- CDER gateway submissions also approach 5000 / month
Gary spoke about the importance of the emerging RPS standard. He emphasized that RPS is critical to FDA’s meeting their PDUFA IV commitments – as well as supporting their goal of to conducting all their business electronically. Gary referenced a Draft Standard for Trial Use (DSTU) date of January 2010, and a target acceptance date for RPS Submissions for drugs and biologics of the 4th quarter of 2011.
Gary also provided an update on the DARRTS initiative. DARRTS is “A flexible, integrated, fully electronic workflow tracking and information management system to receive, log, track, assign, process, and manage official submissions with internal and external stakeholders. The system maintains the official submission records and will manage and track all communications and documentation concerning submission.” Release 3 of DARRTS was implemented successfully in July 2009, resulting in the retirement of 17 legacy systems. Phase 4 (CDER and CBER BLAs) is being planned.
Data Standards
Lilliam Rosario described a major FDA challenge: The FDA receives massive amounts of clinical research data in extremely disparate formats, using a variety of proprietary standards. This makes it extremely difficult, if not impossible, to do cross-study and application reviews.
FDA has been working towards a standardized approach to capture, receive, and analyze study data. Standardization of study data is vital to integrate pre-marketing study data and post-marketing safety data to improve public health and patient safety. Central to this vision is the creation of an enterprise data infrastructure within FDA to improve the management of all structured scientific data (Janus).
Data standards to support this vision are needed in three broad categories: Exchange standards, analysis standards, and terminology standards. FDA is moving towards XML exchange standards based on the HL7 Reference Information Model to submit study data to the FDA. FDA is also currently working on a proposed rule that would require the electronic submission of study data to the FDA. Study data content for creation of SDTM views will be sent to FDA as an XML files modeled using the HL7 RIM.
Study Tagging Files
Virginia Ventura of the Office of Business Process Support spoke on “Study Tagging Files: Their Vital Role In Submissions To The FDA.”
Virginia described some of the most common problems she sees with STFs:
- Not using STFs
- Using STFs for only some of the study documents, and not all
- Modifying the study title results in additional study structures (even if the study ID remains the same)
- Using the same study tag for all documents or tagging a document with an incorrect tag
She clarified that an STF is needed any time you are including documents in Modules 4 or 5, except 5.2 Tabular Listings, and 4.3 or 5.4 Literature references.
A case study provided by Virginia should give sponsors pause.
- An original NDA (0000) was submitted in May ’09, and the Sponsor used no STFs. The eCTD was unreviewable, and the review clock was stopped.
- The sponsor submitted corrections in June, but the sponsor’s correction did not resolve the problem – the eCTD was still not reviewable. The sponsor then submitted a third sequence as “original” in late August.
- The sponsor lost 2 ½ months due to this issue.
- The issue required numerous communications between the FDA PM, ESUB and the sponsor.
She continued by providing descriptions of additional problems and their correction strategies:
- Study under wrong heading element
- Created wrong indication under 5.3.5.1
- Multiple study structures for one study
- Referenced documents in the wrong STF
And wrapped up with some sound advice if you run into problems:
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Contact ESUB@fda.hhs.gov
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Please follow ESUB’s technical advice for fixing
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If unable to follow ESUB’s advice on your own, get professional help
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Do not attempt multiple fixes that are unproven –this can make a bad situation worse
Next time… Health Canada news.
Analysis: New, final Health Canada eCTD Guidance for Industry
posted by Kathie Clark @ 7:47 PM
Monday, November 9, 2009
Health Canada has posted a final version of Guidance for Industry: Preparation of Drug Submissions in Electronic Common Technical Document (eCTD) Format on their web site. This version, dated November 4, 2009, replaces the draft version dated January 25, 2006.
On the whole, the changes are more evolutionary than revolutionary. Throughout the document, the previous terminology of “Annual update forms summarizing the Notices of Change” has been updated to refer to “Forms summarizing the Changes to Marketed Human New Drug Products”. Some of the more significant changes are described below.
Guidance on placement of leaf elements
In the section “3.3.1 Module 1: Administrative Information and Prescribing Information”, considerably more detail is provided for the organization and content of Module 1. New items in this section include:
· Granularity and placement of Appendix I, Life Cycle Management Table
· Construction of summary responses and placement in Module 1, along corresponding original requests
· Placement of the Product Monograph (PM) certification form
· Handling of notes to reviewers
In the section “3.3.2 Modules 2 to 5”, additional information includes placement of PSURs requested during the pre-market review process by TPD and BGTD as well as placement of Case Report Forms.
Changes to Recommended Module 1 File Naming Conventions
Module 1 recommended file naming conventions have changes.
Choice of file naming convention is up to the sponsor… Health Canada suggests that file names begin with the sequence number, followed by “ca,” followed by the module and, if applicable, the section number, and then a phrase describing the contents of the file. All components of the file name can be divided by hyphens.
For more details and examples, see “3.2.6 Leaf File Naming Convention”.
More Help with eCTD Operations
Section 4.3 and its subsections have been enhanced to provide additional guidance on and examples for operation attributes. Some useful advice includes:
· In general, how the operation attributes “append” and “replace” should be used is related to how the content of a document is managed. The operation attribute “replace” should be used when the additional information and the previously submitted information are provided as a consolidated document. The operation attribute “append” should be used when the additional information submitted is used to build upon previously submitted information, without resubmitting it.
· Health Canada does not recommend using the operation attribute to modify a document twice in the same sequence.
· The “append” operation attribute should not be used to link files that are split because they would otherwise exceed the 100 megabyte limit. Instead, proper file management using an adequate level of granularity will ensure that no file exceeds the limit.
· Notes to Reviewers, the Lifecycle Management Table, and Q&A Leaf Elements should always be new (along with letters of attestation).
· Detailed guidance on how to handle the PM leaf element and forms summarizing the Changes to Marketed Human New Drug Product is provided.
· Figures are provided to illustrate life cycle management scenarios for the Product Monograph (PM) and Certified Product Information Document (CPID).
Bookmarking Guidance
Section 4.4, Bookmarks in PDF Files, provides guidance for the first time on bookmarking. This guidance differs in some places from that provided by FDA.
· Documents of ten pages or more should be bookmarked. (FDA says three pages or more.)
· Too many levels of bookmarks are inefficient; in most instances, three levels of bookmarks should be sufficient. (FDA says four levels.)
· Health Canada recognizes that bookmarks are generated automatically from document headings, but nevertheless recommends they be kept concise. (This is a point I have often thought about but never seen discussed – if you are following good authoring practices most bookmarking should be automatic.)
Clarifications
Some other noteworthy clarifications include:
· Periodic Safety Update Reports (PSURs) requested during the pre-market review process by Therapeutic Products Directorate (TPD) and Biologics and Genetic Therapies Directorate (BGTD may be filed in eCTD format. PSURs submitted to the Marketed Health Products Directorate (MHPD) may not be filed in eCTD format.
· SNDS and SANDS are not longer limited to being filed when the original NDS or ANDS was in eCTD format. Apparently, Health Canada will now allow a sponsor to switch to eCTD format for any major submission (like the FDA and EMEA).
· Lot release documentation and Yearly Biologic Product Reports (YBPRs) may not be filed in eCTD format.
· When a sponsor initially files in the paper-based CTD format and subsequently moves to the eCTD format, the sponsor is not expected to refile the previously approved paper-based submissions in electronic format.
· Leaf titles should not include a file format (e.g., “Pristine Product Monograph.MS Word” should not include the .MS Word portion)
· Annotated PMs should only be submitted in PDF and Non-annotated and Pristine PMs should only be submitted in word-processed format.
· PDF versions of documents should be generated from electronic source documents and not from scanned material, except where the source electronic files are not available or where a signature is required.
· Sponsors should only label discs. CD or DVD cases do not need to be labelled since Health Canada will place its own label on the front covers of the cases. Requested label information is slightly updated.
· For all drug submission types (NDS, SNDS, ANDS, SANDS, and NC) when they are first filed, the related-sequence-number sub-element should be empty. (Formerly, guidance said it should not be used.)
· All mention of digital or electronic signatures has been dropped.
Additional Background Material
A significant amount of additional background material has been added, including:
· A figure illustrating an eCTD Structure showing multiple sequences
· An Example Life Cycle Management Table
· A series of tables illustrating valid and invalid scenarios for Life Cycle Management Scenarios for Operation Attributes
Note: The Guidance document is a 59 page document with no bookmarks or hyperlinks. I have thoroughly bookmarked and hyperlinked my copy. If you work for a sponsor organization, send me an email (kathleen.clark@globalsubmit.com) from your company email account and I’ll send you a copy. No CROs, consultants or vendors please – I’m not quite that nice J.
Free educational webinar “eCTD Regulations and Status Worldwide”
posted by Kathie Clark @ 10:25 PM
Tuesday, October 27, 2009
***This just in: our first session is completely full, and we have added a second session on December 8th, 11 am EST (a time more friendly to our European colleagues):
http://www.eventbrite.com/event/474671756
_______________________________________________________________
Don’t have time to keep up-to-date on eCTD regulations and guidance around the world? Wondering when eCTD will become mandatory, (or even accepted), in a given market? Join GlobalSubmit and Cato Research on Thursday, November 5th at 2:00 PM EST for a free educational webinar titled, eCTD Regulations and Status Worldwide.
I’ll be the main presenter, and I’ll review the status of eCTD in the US, Europe, Canada, Japan, Australia and Switzerland. I will also provide you with a convenient list of references and contacts.
At the end of the session’s Q&A, a CATO representative will give a brief overview of the latest happenings in the CRO realm and answer any questions you may have.
Date: November 5, 2009
Time: 2:00 PM EST
Please note: this event is designed for sponsors, and is open only to users registering with a valid email address from a pharmaceutical domain (no gmail, yahoo, etc. accounts).
To Register: Click here or paste this URL into your browser: http://www.eventbrite.com/event/471856335
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.
New EMEA M1 Spec (V1.4) in August; Other Agency News
posted by Kathie Clark @ 9:36 PM
Thursday, July 16, 2009
EMEA has announced that they will be releasing a new M1 eCTD specification in early August. EMEA will be releasing version 1.4, including a new DTD, implementation guide, transition guide, and validation guide. According to Claire Holmes of EMEA, this new version will accommodate recent updates to guidance on variations.
The new version will be recommended from January 2010, and mandatory from February 2010.
Gary Gensinger of the FDA has also confirmed that a new US module 1 specification is in the works, with no target date announced yet.
As I reported earlier in the week, SwissMedic has released their draft eCTD M1 specification and validation criteria. Stephan Jaermann of SwissMedic has stated that additional documentation – Guidance for Industry and Q&A – will follow soon. The SwissMedic pilot program will continue through October, with implementation to follow. Initially, only MAAs will be accepted, with Variations accepted in a future phase. SwissMedic will still accept paper submissions for the foreseeable future, but all electronic submissions must be in eCTD format (no NeeS).
Addendum: SwissMedic has as of July 17 published Guidance for Industry on Providing Regulatory Information in eCTD Format and Questions and Answers of Swissmedic eCTD Implementation.
SwissMedic issues M1 Guidance/Validation Criteria: EMEA NeeS for Vet Meds
posted by Kathie Clark @ 2:23 AM
Tuesday, July 14, 2009
SwissMedic has issued a package of eCTD related specifications
· Swiss M1 Specification for eCTD
· Swiss eCTD Validation Criteria
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.
SwissMedic has added new information to its website on their plan for accepting eCTDs. Some key points:
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Swissmedic intends to accept authorisation applications in the eCTD format, i.e. in electronic form and with no paper documentation. In doing so, Swissmedic aligns itself with the EMEA road map for implementing eSubmissions in the EU Member States (Centralised procedure). Electronic submissions are to be accepted in eCTD format only as of 2010. The implementation of applications is to be accepted in eCTD Format only as of 2010.
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In order to conform to the tight schedule of the introduction of eCTD by January 2010, Swissmedic needs to restrict the range of technical options, specifications and guidelines accordingly. Possible extensions to the project (such as electronic signatures, an online portal or long-term archiving) will be developed later.
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Swissmedic is looking for companies that are willing to submit an electronic version in eCTD format (Modules 1-5), in addition to a paper submission, during the period from 1 June to 31 August 2009. See the announcement for details.
Guidance Documents are not yet available, but will be produced on the following plan:
Information on the eSubmissions business process
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A Questions and Answer Document to handle the issues that arise most frequently (publication in July 2009)
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Guidance for Industry on Providing Regulatory Information in eCTD Format (publication October 2009)
Information on specifications for the eCTD format for eSubmissions
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The Swiss Module 1 specifications for eCTD (publication October 2009)
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Swiss eCTD Validation Criteria (Publication October 2009)
Implementing eSubmissions within the SIMES project includes the following milestones:
Milestone 1: as of March 2009: publication of project information on the Swissmedic website
Milestone 2: July 2009: first version of the eCTD specifications and Swissmedic practical guidelines ready for feedback and review.
Milestone 3: October 2009: revised eCTD specifications and practical guidelines are released.
Milestone 4: January 2010: going live. Submissions in eCTD format authorised for certain types of applications.
Milestone 5: March 2010: follow-up evaluation and adjustments.
You can also find contacts for additional information on the website.
A significant new guidance document, Guidance for Industry on Providing Regulatory Information in Electronic Format: eCTD electronic Submissions, has been posted on the EMEA eSubmissions website.
This document has been prepared by the eCTD Guidance Topic Group of the TIGes. It is largely based on Guidance for Industry on Providing Regulatory Information in Electronic Format: Non-eCTD electronic Submissions (NeeS) Version 1.4, and also reproduces a significant amount of information from “QUESTIONS AND ANSWERS RELATING TO PRACTICAL AND TECHNICAL ASPECTS OF THE IMPLEMENTATION”, hereafter referred to as “Q&A”. However, it also provides a fair amount of new guidance and that’s what I’ll be focusing on in this post.
It’s important to note that this is not a final document – it’s a “Draft for Testing”. The Topic Group anticipates comments from NCAs and applicants which will enable future versions to reflect practical experience of users. In this way the document will evolve to become an essential work of reference in this area. They did not describe a specific mechanism for obtaining these comments. National Competent Authorities have been strongly recommended to adopt this guidance as the basis for their dealings with applicants.
The document includes a shout-out to RPS, for those of you wondering if Europe will really move in that direction. “International standards development through ICH, ISO and HL7 will eventually lead to the eCTD becoming part of a wider group of regulated product submissions, covering medical devices, veterinary products and food additives as well as medicinal products.”
Unfortunately, it is not bookmarked (I took a few minutes to create my own bookmarked copy as I anticipate using it a lot.) There are a also number of references to NTA that I find puzzling. For example, the applicant is referred to Volume 2B for the following “subfolders should be used to organise the files for each module in a submission: m1, m2, m3, m4, and m5 following the principles set out for the CTD in Notice to Applicants, Volume 2B” – but 2B never mentions folders. Volume 2A Chapter 7 is a reference for file formats, but again that is not discussed in the current Volume 2A. Possibly a re-issue of these documents is in the works?
New Guidance
Cover Letter. The cover letter guidance does not repeat the information that was in “Q&A”. Instead it states “The cover letter should, at least for MRP and DCP applications, include as a minimum, the information specified in the CMDh Guidance document” and also mentions that there is a template that can be used. The NeeS guidance document included a link to a cover letter template, but this link (which was on http://www.hma.eu/) is now broken. If anyone knows the location of the cover letter template (for NeeS or eCTD) please post a response on the blog! The guidance also states that the cover letter should mention if the product information is being provided as PIM data. Finally, good naming practices for forms and cover letters are discussed.
Sequence Numbers: clarification was provided that if possible the initial sequence number should be 0000, even if the first sequence is not an initial MA application (if there is a good reason for deviating, it should be explained in the cover letter). Sequences numbers should normally follow the order of submission but EMEA and most NCAs are able to accept and view sequences submitted out of numerical order. A Sequence Tracking Table should always be included as an annex to the cover letter in every submission within MRP/DCP. A similar tracking table is recommended for national applications.
Placement of word documents. EMEA has already said that these files should not be added as leaf elements within the eCTD structure, but never before stated where the physical files should be placed. In this guidance, they state “They should be provided in a separate folder called, e.g.“<sequence>-working documents” on the CD/DVD containing the eCTD.
Explicit forbidding of cross-application references. Although I believe EMEA has stated this in presentations before, they explicitly state “Currently it is outside the scope of current eCTD specifications to allow cross references to documents, sections or modules in other eCTD dossiers.”
Additional Guidance on Product Names. Some guidance is included in the M1 V1.3 specification. Additional details include:
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ATC If unknown at the time of submission, the entry can say ‘to be confirmed’.
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Invented-name The trade name/invented name for the medicinal product covered by the application. If the eCTD covers multiple strengths or dosage forms, this entry does not need to describe the complete name, a simple entry, for example, ‘Wonderdrug’ will suffice.
Use of Response Documents section. This section is worth quoting verbatim, as it gives new guidance on use of node extensions, folder structure, etc.
To help in the management of responses over the lifecycle of the eCTD, the responses relating to a particular regulatory activity should be grouped under a node-extension in the eu-regional.xml file. The title of the node-extension should identify the regulatory activity (e.g. Responses to Questions for the Initial Application, Responses to Questions for Type II Variation 028, etc.). It is recommended that you provide a full copy of the list of questions received from the agencies as the first leaf in this section.
It is recommended that the responses be split up into separate files for each major section of the submission (e.g. Quality, Non-clinical and Clinical). You should use the leaf title to identify the particular set of responses (e.g. Response to Major Objections - Quality). If responses to more than one question are submitted in a single file then you should use bookmarks within the PDF file to clearly identify each response. It is possible to submit the response to each question in a separate file but if you choose to do so then you must use node-extensions and leaf titles to group and identify the responses under the top level node-extension.
All of the files for the response documents should be placed in the folder m1/eu/responses/CC, where CC is the appropriate country identifier code for use in MRP/DCP.
Use of the additional data section. Previously stated guidance is repeated – that is, this is not used in the Centralised procedure – but a comment mentions that this section can be used for all procedures when an old version of a DTD is being used during an agreed transition period, to support inclusion of a newly defined section of Notice to Applicants.
Organization of the dossier. Annex 3 discusses advantages and disadvantages of eCTD application structures, including one combined eCTD for multiple strengths and dosage forms, or one eCTD application per strength or dosage form.
Organization of Module 3. An entire annex addresses best practices in the structure of Module 3. This annex discusses
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Recommendations around the choices of attribute names (drug product, substance, manufacturer, dosage form, etc.)
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Approaches for handling manufacturers (separate for each manufacturer, single section for all, or a possible hybrid)
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Approaches for handling strengths (separate for each strength, single section for all, or a possible hybrid)
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Excipient issues, including handling of compendia excipients (a single file that addresses CTD topics 3.2.P.4.1 to 3.2.P.4.4 for all excipients can be provided), naming conventions, etc.
Modular Nonclinical Study Reports. The guidance sates that granular reports created for the US can be submitted without re-organization in Europe.
Organization of Clinical Studies. For the first time, a recommendation is given to use node extensions for all reports, even those containing only one document. If case report forms and individual patient data listings are submitted, they should be placed in the same order as the clinical study reports appearing in m535 and should be indexed by study. Note that bookmarks will not be required as there will be no further internal structure. Study synopses can be provided either as copies in 2.7.6 or as hyperlinks to synopses in Module 5.
Withdrawal of an application. Instructions are given for withdrawal of an entire product or a specific dosage form or strength.
Guidance on Text Searchable Documents. For the first time, this guidance is given for eCTD in Europe. It is identical to the guidance given for NeeS.