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Archive for January, 2010
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.
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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.