eCTD on Twitter
- One day course - AN OVERVIEW OF THE eCTD - London 19 Mar 2010
http://bit.ly/7LzKKW2010/02/08 08:31 - BTW, it's not true that FDA's viewing tool (GlobalSubmit) can't handle node extensions -just that FDA doesn't want them w/out prior approval2010/02/04 12:59
- The eCTD Upgrade: Cross-Application Linking
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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 “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).
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.
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Today’s blog features a guest posting by Dr. Shannon Strom, Senior Regulatory Specialist at Cato Research.
Acceptance of electronic submissions by small to mid-size early-stage pharmaceutical companies has been characterized by a slow, but steady, conversion to the eCTD standard, and nowhere is that fact more evident than in the rate of IND conversions to eCTD format. According to the FDA, 52% of original marketing applications and 83% of efficacy supplements are received in eCTD format, but only 12% of original IND submissions are in eCTD format. However, the FDA’s numbers also offer positive signs for the future. While the percentage of original INDs submitted in eCTD format remained stable from FY 2008 to FY 2009, the number of IND amendments in eCTD format nearly doubled, indicating that companies are beginning to understand the benefits of electronic submissions.
Small to mid-size pharma companies most frequently cite infrastructure requirements as the reason to delay conversion to electronic submissions. For a small or early?stage organization with limited budgets and internal resources, the expense of purchasing electronic submission software, including the implementation and validation effort, can be overwhelming enough to wait until the FDA or other global regulatory authorities require electronic-only submissions. After the software is purchased, installed, and validated, a company must also make another investment in hiring a regulatory submission specialist with experience in electronic submissions or providing training to existing regulatory affairs resources to actually create and review the electronic submissions. Additional infrastructure considerations may include implementation of an electronic document management system, on-going validation requirements for software updates, implementation of standardized document templates, and training of medical authors to write for electronic submissions. It’s no wonder why electronic submissions can be so easily delayed by corporate management until strong convincing data justifies the investment.
But this “wait-and-see” type attitude ignores the very real benefits of electronic submissions for small firms. The FDA has stated repeatedly that the eCTD is their preferred format for both INDs and marketing applications, and that the review process is significantly facilitated by the automatic processing of sequences through the Electronic Submission Gateway. Large pharma companies have, for the most part, already made the transition to, or are actively engaged in, the transition process to electronic submissions. A product portfolio that already contains an electronic regulatory submission can be more attractive to a large pharma company than a paper-based regulatory dossier because the time and effort to convert the submission to electronic format is saved. Therefore, it’s within a smaller company’s best interest to develop electronic dossiers as soon as possible.
Software providers have developed very cost- and time-effective solutions to minimize the impact of electronic submissions on existing corporate infrastructure and business goals. The best solution for some companies may be to outsource some, if not all, of the components of the electronic submission process. One of the more innovative solutions in the last few years has been to utilize Software as a Service. In this business model, the submission software is “rented” as a hosted solution from the software vendor to minimize the internal infrastructure requirements and the validation effort and to maximize the time spent on creation of electronic submissions.
In summary, the transition to electronic submissions for IND-phase submissions can be difficult, but represents a real economic and time-effective choice for innovative early-stage companies.
Cato Research is a full-service CRO with international resources dedicated to helping pharmaceutical and biotechnology companies efficiently and expeditiously navigate the regulatory approval process in order to bring new drugs, biologics, and medical devices to the people who need them. One of Cato’s specialties is outsourced regulatory publishing, and they bring considerable expertise and experience to creating and maintaining NDAs, BLAs and INDs in the eCTD format. For more information about Cato’s services, contact Christine Warrington at 919-368-5995. Also check back for a URL to Cato’s new blog, which will be launched shortly.
Regulated Product Submission (RPS) Clear First Hurdle
posted by Jason Rock @ 1:06 AM
Wednesday, January 20, 2010
Our posting this time is from Jason Rock, GlobalSubmit CTO and Chair of the HL7 RPS Specification Development Group.
The Draft Standard for Trial Use (DSTU) ballot of the Regulated Product Submission Release 2 standard barely passed ballot on Monday January 11th. The ballot passed by two votes with a result of 53 affirmative and 33 negative.
Even though the ballot passed, the process is not over. Every comment must be evaluated. This process can take months. Most projects try to resolve comments to the satisfaction of the commenter, but this is not a requirement.
One of my responsibilities as Chair of the HL7 Specification Development Group is to manage the ballot process. In that role, I have already compiled all of the comments. There are over 180 comments in total. Each comment has a proposed resolution. Nearly 150 of the comments were accepted or accepted with minor alteration. It is the last 30 comments that will be most difficult to resolve. I believe that the comment evaluation should run smoothly though, and not hold up the process.
Of the 150 comments that were accepted, some were related to words that addressed two-way communication which is not supported at this time. These words were originally added for release one, but will now be removed. The vast majority of comments were updates to text, either in relation to correcting typos or offering suggestions to help make the text more clear.
I expect that the ballot will be altered with the text changes, but that the model will not change. I also expect the FDA to start testing at the beginning of the third quarter, 2010.
Attending the DIA EU EDM Conference in December gave me a great opportunity to catch up on eCTD-related status and activities at various European agencies. We heard from a number of presenters representing EMEA (now just European Medicines Agency), the MEB, SwissMedic, and AGES PharmMed. Since the updates are fairly lengthy, today I’ll cover EMEA, and will address the other agencies in a future posting.
Tim Buxton gave the update from the EMEA. He clarified what eCTD implementation means to this agency:
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Electronic-only submissions are accepted
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The eCTD is accepted as a ‘common currency’ for product marketing authorization applications - EMEA expects to receive marketing authorization applications & variations in eCTD format
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The use of the eCTD is supported on the “agency side” by appropriate SOPs for receipt, validation, storage etc.
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The use of the eCTD is supported on the “agency side” by appropriate business processes
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The technical infrastructure is in place to support the foregoing
EMEA now receives over 500 eCTD sequences a month. In November, they also received 149 NeeS sequences. (A further update can be found in the recently published Update on the implementation of the EU Telematics strategy, which states that since July 1st 2008, over 2,500 eCTD submissions have been received by EMEA, and 406 centrally-authorised products are managed in eCTD format, representing more than two thirds of the total number of centrally-authorised products).
electronic Application Form (eAF)
Although this was an important initiative for the EMEA, adoption has not been good in the past because no tool was provided to create this XML document. The upcoming release of the eMF will include a Data Exchange Standard, receiving tool (initially EMEA only), authoring tool, and validation tool. Prototypes of the receiving tool and authoring tool under evaluation. Support for variations is still under development.
PIM
Likewise, for PIM, EMEA is delivering a Data Exchange Standard, PIM Review System, PIM Light Authoring Tool, and PIM Data Validation Engine. A statement of intent and migration details are still in pilot. The timetable for PIM (from the Statement of Intent) is:
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Q2 2009: Detailed planning of migration and Proof of Concept
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Q1 2010: Migration commences
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Q3 2010: Planned end of pilot phase comes (no longer need permission to submit)
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Q4 2011 (end): migration exercise complete
There has been a change of approach for migration to PIM - EMEA had planned to migrate sponsor’s data but sponsors want to do it themselves with “hand holding”.
eSubmission Gateway
The eSubmission Gateway is in production for ICSRs and has been tested for MAAs. Tim characterized the go-live of the gateway as “around the corner” (but said he was glad that he declined to commit to a date at the DIA annual back in June).
Digital Signatures
A limited pilot was being conducted for digital signatures, but is on hold right now due to other priorities. It won’t be completed in 2010, but may be implementatd in 2011. SAFE is a not the only valid form of eSig. Rules in some countries specify some types of electronic signatures. The EC has just released a call for ideas on how to harmonize eSignatures requirements across Europe. To quote Tim - “The storm for eSig is just around the corner – ignore at your own peril.”
Other Initiatives
Other current initiatives include identification of medicinal products, and ICSRs (update of E2B standard for better ID of medicinal products causing problems).
Upcoming initiatives include eCTD Next Major Version (Regulated Product Submissions) – by the way EMEA has just added a web page for this topic, including links to last year’s meeting minutes.
New Q&A/Change Request Tracking Table
In other EMEA news, a new version (V1.21) of the EU Telematics EU eCTD Change Request/Q&A Tracking Table has been posted. This is an update following discussion of open CRs by the TIGes subgroup, and general review of status and presentation of all CRs. All closed/withdrawn/rejected/duplicated CRs have been moved to new worksheets; all CRs implemented in EU M1 v1.4 were moved to the appropriate ‘Implemented in EU M1 v1.4′ worksheet. Most importantly, all CRs for a potential EU M1 v1.4.1 (spec update only) have been identified and marked.
Well,it’s back to business after the holiday break… and as promised, here’s my update on what’s happening at Health Canada.
At the recent DIA eSubmissions conference, Health Canada’s Vianney Caron presented an update on eCTD at Health Canada.
The E-Review Program
The purpose of Health Canada’s E-Review program is to support branch business processes throughout the health product life cycle across product lines using an integrated secure electronic environment that facilitates the exchange of information and conforms to international standards.
Health Canada has made a lot of progress in E-Review recently. Important milestones achieved include:
- Implementation of an electronic document management system (RDIMS) for Drug Master Files
- Establishment of business process for receipt, validation, processing & storage of eCTDs, supported by SOPs
- Initiation of a pilot providing remote users (e.g. teleworkers and external reviewers) access to electronic submissions via Citrix Web Office
- Recent update of guidance documents (see my previous post Analysis: New, final Health Canada eCTD Guidance for Industry)
Regulatory Activities in eCTD Format
Metrics were provided on eCTDs received:
Cumulative through September of 2009:
- Total number of Dossiers: 205 (Pharmaceutical 182, Biologic 23)
- Total number of Regulatory Activities: 457 (Pharmaceutical 322, Biologic 126, Pharmacovigilance 9)
- Total number of Sequences: 2318
Totals for 2009 (as of September), received from 53 sponsors:
- Total number of Dossiers: 53 (59 in 2008)
- Total number of Regulatory Activities: 145 (151 in 2008)
- Total number of Sequences: 841 (748 in 2008)
Health Canada is not seeing a significant rise in applications and sequences received, such as has been experienced by the FDA and EMEA – perhaps because they still require at least part of the dossier in paper. As of 2009, 8.7% of regulatory activities are received in eCTD format.
eCTD Validation
Sponsors are improving the quality of their submissions to Health Canada. In 2009, 4.5% of sequences failed validation. This is down considerably from previous years: 8.3% failed in 2008 and 11% failed in 2007.
Top 10 errors and warnings encountered during validation include:
1. Inactive bookmarks -no link destination
2. Inactive hyperlinks -no link destination
3. External links -pointing to the folder or destination that does not exist in the folder structure on the CD/DVD. The folder or destination would only exist in the sponsor’s repository.
4. Incorrect naming of the 3011 form; correct name is hc-sc-3011-en.pdf
5. Unreferenced files in the index.xml or ca.regional.xml
6. Life cycle management of the document: invalid file reference or no previous ID found
7. Subfolders created in ca regional folder
8. Missing top level folder
9. Missing attestation letter; content as per eCTD Guidance, letter needs to be dated and signed
10. Printed content of MD-5 Checksum does not match the one in the index-md5.txt file
Preliminary Experience with eCTD
Health Canada reports that they have buy-in from all stakeholders, but no legal basis to make eCTD mandatory. They continue to experience logistical and process issues. Reviewers perceive that paper & electronic in parallel is difficult and the process is excessively manual. Validation is perceived as an extra step. Other review issues including understanding lifecycle management in the eCTD and dealing with scanned documents and resolution of graphics.
Some upcoming milestones include the retirement of hybrid submissions as of January 2010 (this month). A date is yet to be announced for accepting fully electronic submissions.
Assessment of Hybrid Pilot
Health Canada surveyed reviewers participating in their hybrid pilot with some interesting results:
- 41% say they are almost ready for submissions filed in the hybrid filing format, and 59% say they are totally ready
- Using the electronic hybrid filing format, 44% of reviewers believed that their review/screening time remained the same and 39% believed that their review/screening time decreased. 50% believe that this format will save time in the future.
- Reviewers recommended the following next steps: 47% wanted to continue the hybrid filing format, 24% wanted electronic only, and 29% wanted electronic only with Print on Demand
- When asked if they would be comfortable with e-Only (no paper), 53 % would be very comfortable, 29% would be somewhat comfortable, and 18% would not very comfortable)
Next Steps at Health Canada
Health Canada defined their next steps as:
- Opening the scope to more electronic submissions
- Revising the DTD and guidance for the Canadian Module 1
- Implementing two-way secure electronic communication (secure channel, secure email and gateway)
- Improving their tracking system and integrating it with a workflow system
- Strengthening international collaborations
Health Canada closed by saying that they strongly recommend electronic submissions in eCTD format, and support the development of common standards. They will be expanding the existing infrastructure to support as many application types across product line as possible. Questions can be sent to them at ereview@hc-sc.gc.ca.
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.
Upcoming Conference: eCTD 2010: Achieving Efficiency and Compliance in Electronic Submissions
posted by Kathie Clark @ 2:26 PM
Saturday, December 5, 2009
We’ve had several good eCTD-related conferences lately. I’ll be providing some updates on them in my next blog entry, but first I wanted to mention an upcoming conference that sounds really good. This is the Cambridge Healthtech Institute conference: eCTD 2010: Achieving Efficiency and Compliance in Electronic Submissions. This conference will be held March 10, 2010 at the Crowne Plaza Philadelphia Downtown in Philadelphia (which is almost across the street from our GlobalSubmit office).
I’m looking forward to attending this conference as I know many of the speakers and their presentations are excellent. Some of the presentations on the agenda include:
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How to Prepare Your Product Dossier for Global Simultaneous eCTD/CTD Submissions – A Look at Tools, Tips and Taking the Mystery Out of Submission Planning and Publishing
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Case Study: Global Submission Management from Concept to Realization
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Taking eCTDs off the Critical Path to Drug Development
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Working with an eCTD Vendor: Best Practices and Lessons Learned
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Electronic Signatures and Regulatory Processes, What the Agencies are Saying [This should be interesting – Tim Buxton of EMEA made a remark yesterday at EU DIA EDM in Vienna that “the storm for eSig is around the corner – ignore it at your own peril.”]
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Achieving Efficiency through Rounding Out Submission Standards: Format, Data, and Content Standards
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Current Challenges and Implications of eCTD Implementation
There are also panel discussions and ask the experts sessions.
For those of you involved in clinical trials, CHI is holding a co-located Electronic Data in Clinical Trials on March 8-9.
When I spoke to Jim Prudhomme of CHI concerning registration, he alerted me to the early discount for those who register by December 11 via the conference web site or by calling 781-972-5400.
Analysis: New ICH M2 Requirements into eCTD NMV (=RPS)
posted by Kathie Clark @ 3:08 AM
Wednesday, November 18, 2009
The ICH M2 ESTRI Main Page has been updated with the following announcement:
“ICH M2 has initiated the development of the Next Major Version of the eCTD (eCTD NMV) to improve robustness, flexibility and long term stability of the message. In accordance with the decision by the ICH Steering Committee that technical specifications should no longer be developed solely within ICH, but should be created in collaboration with Standards Development Organisations (SDOs), the eCTD NMV will be developed jointly with the HL7 RPS project. M2 has developed this list of requirements as input into the HL7 RPS Project.”
I took a look at the requirements (which have been posted before in various drafts). They stretch to nine pages, and range from some that are uncontroversial and obvious to some that signal a significant change in direction. In this posting, I point out some of the more interesting requirements.
Regulatory Activities
The new spec really supports the concept of organizing sequences into regulatory activities. A regulatory activity is a collection of sequences that lead to a decision by the regulatory agency (such as an MAA, Variation, NDS, SNDS, Original NDA, Supplement, etc.) which can be mapped to individual ICH-regional regulatory processes. This concept does not exist in ICH eCTD, although the regional authorities have added it using the concept of “related sequence.” The NMV spec includes a number of formal requirements to support the Regulatory Activity concept.
Cross Application References
Current eCTD does not support cross application references, but neither does it prohibit their use. The only authority to my knowledge who actively supports them is the FDA (who will send you a document providing directions if you email them at esub@fda.hhs.gov ). EMEA expressly forbids them.
The new spec explicitly supports them as shown in the following requirements:
- Files should only need to be submitted once to a Health Authority and can be included by reference in multiple regulatory submissions to support multiple regulatory actions even across applications
- The message should support the reuse of electronic files from a previously submitted instance across applications.
Future of Study Tagging Files (STFs)
When I first read the requirement
When the same documentation is provided, it should be submitted in the same way across HAs. For example, when a study report is submitted in US it is submitted using the STF which is not acceptable in other HAs. This minimizes reuse capabilities and adds to Industry costs to prepare globally harmonized dossiers.
I wasn’t sure if ICH was suggesting that the STF concept should go away altogether. I asked my colleague Jason Rock, who represents the FDA at ICH M2. Jason explained that the goal was to do away with the STF as a separate XML file. STF information would be contained in the main backbone, and could be ignored by authorities who don’t want it. This was also confirmed in a later requirement reading “STF construct should be integrated into the message standard.”
Maintenance of Metadata:
Many sponsors have experienced problems with their eCTD due to the inability of the standard to accommodate corrections or changes in metadata (such as manufacturer). eCTD NMV requirements include the requirement for the message to support the addition, updating and deletion of metadata to a previously submitted instances, e.g., related sequences, submission type, operation attribute, manufacturer name, etc.
Lifecycle
New NMV requirements regarding lifecycle are likely to be applauded by sponsors:
- Replacement of multiple leafs with single leaf and vice versa should be supported in eCTD.
- The operation attribute value “append” be removed from the list of allowed values (leaving only new, replace and delete)
- Allow a replace or delete leaf to modify more than one leaf in a previous sequence or sequences
- Allow a single leaf to be “modified” by more than one leaf in later sequences (supports changes in granularity)
Physical File Rules
The days of relying on a standard folder structure for XML-based eSubmissions are coming to an end as all parties move to acknowledge that they should be using the backbone/TOC and not the file system. The NMV spec includes a requirement that “The physical file structure. (file/folder structure) should be minimal”.
File names would also be able to include underscores, which will come as a relief to anyone who has struggled with if or how to eliminate underscores from SAS file names.
Logical Groupings
New mechanisms for grouping files at levels below sections are called for:
- Provide ability to group a collection (or set) of files that together represent a document or reviewable grouping (e.g, all files related to a study report, all files related to a labeling document, all files related to a manufacturer or manufacturing component (e.g., container closure))
- Provide ability to treat a grouping of files as a single entity and to be treated as if it were a single file (complete with all descriptive attributes e.g., title) for all life cycle operations and relationship management and reuse needs
Scope
An important architectural concept for eCTD NMV/RPS is the separation of the messaging mechanism from the TOC. The TOC is no longer built into the specification, but supplied by the regional authorities. This is encapsulated in the requirement “Allow the capacity to modify the ICH CTD organizational structure (ToC) without modifying or changing the eCTD message structure.”
Compatibility
For those worried about the impact of the switch on their current eCTDs, some compatibility requirements should provide some reassurance:
- It should be possible for an applicant to build on an eCTD lifecycle started using the eCTD 3.2.x specification and continued using the eCTD NMV specification.
- No applicant should be required to resubmit data in the eCTD NMV specification if it has previously been submitted using the eCTD 3.2.x specification.
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
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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