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:
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.
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:
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”.
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).
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 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.
Announcement: See GlobalSubmit’s web site for a brand new presentations page linking to recent agency presentations!
GlobalSubmit recently attended two informative DIA conferences:
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 FDA initiatives
Gary Gensinger provided updates in both San Diego and Vienna. Some of the more significant metrics included:
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.
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:
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.
She continued by providing descriptions of additional problems and their correction strategies:
And wrapped up with some sound advice if you run into problems:
Next time… Health Canada news.
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.
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 firstname.lastname@example.org ). EMEA expressly forbids them.
The new spec explicitly supports them as shown in the following requirements:
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.
New NMV requirements regarding lifecycle are likely to be applauded by sponsors:
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.
New mechanisms for grouping files at levels below sections are called for:
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.”
For those worried about the impact of the switch on their current eCTDs, some compatibility requirements should provide some reassurance:
The RPS (Regulated Product Submissions) Working Group met last week in Atlanta. The main discussion points were around ICH requirements, multi product submission, facility submissions, linking to other applications, multi regulator submission and how should the project be managed going forward.
All current ICH requirements were reviewed. Most of the requirements are already met. Some more requirements need to be addressed.
I expect both Europe and Japan, in regards to human pharmaceutics, to submit new requirements in the next 3-6 months either through ICH or directly. I would not expect these requirements to be ground breaking.
Device attendance was lower than I hoped; but they were present. To gather more support within the device community, the device folks would like to have a joint project with ISO TC 210 Quality management and corresponding general aspects for medical devices. This is different TC that the human pharmaceutics folks are accustomed to work with, namely, ISO TC 215 Health Informatics.
There was a small change to the management process; that is, less phone calls.
The next milestone for the project is the January DSTU ballot. I would expect the FDA to test the draft standard, and depending on the test results, implement.
The RPS (Regulated Product Submissions) Working Group is preparing for a September 23 working group meeting in Atlanta. Topics include:
Just a reminder that all sorts of good stuff is on the HL7 RPS Wiki!
This year’s DIA annual meeting was more of a checkpoint rather than revealing startling new information – at least in the eSubmissions area. However, a lot of interesting information was exchanged. Today, I’ll focus on the FDA’s presentations. I’ll follow up later with information from other authorities and industry.
Gary Gensinger provided his usual update on eSubmissions at the FDA:
· In the CDER town hall meeting, Gary noted that FDA is looking at drafting legislation to require eCTD – however, this is a lengthy process and no target date is being released at this point.
· As of shortly before the meeting, FDA had received a total of 6015 applications consisting of 72154 sequences. FDA expects to receive in excess of 4500 eCTD sequences in July of 2009.
· There are some interesting trends by application type:
o 52% of NDAs received are now fully electronic.
o ANDAs have grown by 70% since November 2008 – a huge uptick. If you’re in the generics industry and still submitting on paper, you are behind the curve.
o While only 12% of INDs are submitted electronically (up by 1% since last year), 28% of IND Amendments are submitted electronically – a result of maintaining an ever larger number of INDs submitted electronically to date. (By the way, I had an FDA reviewer who stopped by my booth mention that he cringes when presented with a paper IND these days…)
o An impressive 83% of Efficacy supplements are electronic, up by 12%
o CMC supplements are holding flat at 47% electronic
· FDA is working on an agency level receipt date guidance (the current document applies only to currently only CBER/CDER)
· Gary reminded sponsors that briefing packages must still be submitted in paper even if they are also submitted as an eCTD sequence.
Mark Gray gave an overview of RPS, and stated that RPS will be in production use at FDA by September 2011. Mark and Gary mentioned that ICH will not be making any significant updates to the eCTD spec – there will be no DTD changes as ICH and the regulators look towards moving to RPS as “eCTD Next Major Version”.
I was not able to attend the HL7 Working Group meeting in Japan last week, but I did give an RPS education session remotely.
The agenda including the background of RPS, the foundation of the standard, document lifecycle, release two of the standard and a comparison of RPS to eCTD.
In the background section we discussed the goal, scope, how the project was initiated and the project’s acomplishments.
In the foundation section we discussed how submission are tied together for regulatory activities (e.g. approvals) and how multiple regulatory activates are tied together (e.g. for one product).
In the document lifecycle section we discussed how document are handled with in RPS and how to assign keyword (e.g. study title, manufactures) to documents.
We then discussed the status of release 2 of RPS and went in to some detail about two-way communication, approvals, country specific documents and product information.
We ended the session with a comparison of RPS to eCTD and briefly discussed how one can convert an eCTD to RPS.
I have posted this presentation to my RPS educational page (http://www.globalsubmit.com/XPortal/Presentations/PresentationsLogin.aspx). Every few weeks I add new educational material about RPS.
The codes needed to implement Regulated Product Submission (RPS) are here and can be found at the following location:
Unlike eCTD, where XML element names define your table of contents, coded terminology determines table of contents in a RPS submission.
The codes provided are only the table of contents sections for ICH’s Common Technical Document (CTD) and the US FDA’s regional table of contents.
US FDA’s food submissions content is pending. Codes for other countries or other product types within the United States have not developed for their respective table of contents.
The CTD codes provided are not perfect and are not complete.
Most of the attributes (e.g. manufacturer, study id; a.k.a. keywords in RPS speak) of the CTD, section1.11.4, Description: Multiple Module Information Amendment in the US FDA’s regional section and the study heading, mainly defined by ICH’s E3 specification are missing.
The FDA and NCI are working to update the code list.
The following are the list of study heading that where codes need to be created
This is not really new news, but ICH has posted the short presentation ”Update on the eCTD“ from the November meeting on their website. This presentation was given by Joe Cipollina.
The key elements of the presentation include:
The ICH M2 Group focus will be to:
So it’s official, folks – RPS is coming!
It’s time to get educated. In a previous post, I mentioned the RPS wiki and list server.
Also, keep your eyes on my company’s web site www.globalsubmit.com. My colleague Jason Rock, who serves on the leadership steering team that is developing RPS, will be presenting a series of RPS educational sessions at the request of the FDA. You will be able to register for these sessions on our website shortly.
An RPS2 Working Group meeting was held in Vancouver the week of September 15.
The working group discussed a number of business scenarios including: