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FDA Computational Science Center and Data Standards

posted by Kathie Clark @ 2:07 AM
Saturday, February 20, 2010

This week’s blog posting is from Laura Wright, who attended the 23rd Annual DIA EDM conference in National Harbor, MD, February 16 through 19.  In Laura’s role as Account Manager at GlobalSubmit, she talks to many people in regulatory, clinical and IT roles in the biopharmaceutical industry.  Hearing some of their interests and concerns led Laura to attend a session entitled “Regulatory Update: Future Directions”.  Here, she offers her impressions. 

Data standards – whew!!  Nothing quite as exciting as data standards.  Have you ever seen a group of people arguing about SDTM (Study Data Tabulation Model)?  It can get pretty heated.  If you think that is a joke, then you haven’t seen it.

I am not interested in joining that debate today.  I just got back from DIA’s Annual US EDM conference and I would rather share some insights from the new Computational Science Center and the Office of Planning and Analysis at CDER.  Turns out that some people at the FDA see the lack of truly standardized data streaming into their servers as a real problem and they are proposing real solutions.  Chuck Cooper and Marni Hall spoke at a regulatory session on Thursday that highlighted new directions at CDER and CBER.  The data problem was summed up for the audience and it sounded something like this:

The reviewers are spending too much of their review time trying to manipulate incoming data so that they are able to analyze it.  And they are spending more time manipulating than analyzing.  Because of different data standards, the overall quality, consistency and transparency of the review suffers.  And your NDA approval takes longer.  Certainly not a new issue, but a problem nonetheless.

In many cases the data is consistent within the sponsor organization.  SDTM has been around for more than 6 years and most sponsors really do want to make the reviewer’s life as easy as possible.  But what does “standardized” mean to a therapeutic area that doesn’t have universal data sets available to them?  What about all of the well-meaning statisticians who are submitting “SDTM-like” data?  The FDA is accepting 5,000 eCTD submissions a month.  If everyone is doing their own thing, that is a LOT of data to manipulate before actually reviewing it.

Not only is your drug approval taking longer (I know that you are still stuck on that) but the agency’s ability to retrieve important information about trials that have been conducted in the past is completely arrested.  Picturing those handcuffs?  They can’t retrieve legacy study information today to easily compare it to new data.  There are no audit trails showing how the reviewer came up with the analysis they used last year or five years ago.  That means more time is spent on finding answers that the reviewers should be able to have access to in order to help them make sense of the data in front of them today.  This cycle seemed kind of hopeless.

Until Chuck and Marni told us about what their offices are doing to support reviewers.  Between converting the legacy trial data from prior submitted Phase II studies to diving into that age-old debate to create new specs surrounding data standardization, the new Computational Science Center will be a busy place.  You can help, too – your input is very valuable, whether you are a physician, statistician, a regulatory ops manager or a software vendor.  There are forums and specialized conferences for you to weigh in. After all, who doesn’t want transparency, consistency and quality? 

eCTD 2010 Conference and Talking to the Speakers

posted by Kathie Clark @ 8:34 PM
Friday, February 12, 2010

I have often noticed that people attending conferences would like a chance to talk to the speakers that they have found to be interesting.  Of course, you can ask questions at the end of the session, but often what you would really like to do is to pick someone’s brain – talk to them about your ideas and challenges.  That’s why you often see the speakers mobbed during the cocktail hour!

eCTD 2010, being held March 10th in my hometown of beautiful Philadelphia, PA, has implemented a practical strategy for extending this benefit to their conference attendees.  The conference will feature three Interactive Break-Out Discussion Groups:

  • Is Your Organization Moving toward Collaborative Authoring and Content Management? Hosted by Don Palmer, Associate Director, Regulatory Systems, Regulatory Affairs, MedImmune 
  • In Search of Submission Efficiencies:  Is Your Organization Using Tools/Processes To Handle The Growing Workload of eCTDs?  Hosted by S. Albert Edwards, Director, Regulatory Affairs Operations-US, Takeda
  • Preparing for Future FDA, EU and ROW Initiatives for eCTD: What is ahead and what does it mean to you? Hosted by Meredith Sewell, Associate Director, Global Regulatory Affairs Publishing, Allergan, Inc.

During these breakouts, you’ll be able to have a more extended discussion with the speakers.  These folks are great speakers and industry experts – I can personally vouch for that! I’ll be at eCTD 2010 and urge you to consider attending as well.  If you’ll be there, think about asking your colleagues what questions they wish they could ask Don, Meredith and Albert.  It will make for interesting conversation.

After the conference, I’ll be posting highlights on The eCTD Summit.

European Agency Roundup

posted by Kathie Clark @ 10:00 AM
Wednesday, February 3, 2010

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:

  • Accepts and encourages electronic-only (paperless) submissions since 1 July 2008
  • Accepts National and MRP/DCP procedures 
  • Accepts e-CTD or EU-NeeS
  •  Exploring a possible shift from EU-NeeS to eCTD
  •  Enforces “Once e-CTD, always e-CTD” - once first submission as eCTD, all regulatory activities accepted
  •  Attempting to shift paper  to electronic : all regulatory activities except IA/IB variations (volumetry factor)
  • EU-NeeS : IA & IB variations never accepted
  • 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.

IND in eCTD Format: Considerations

posted by Kathie Clark @ 10:23 PM
Monday, January 25, 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.

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.

Updates from the Regulators – EMEA

posted by Kathie Clark @ 12:49 AM
Wednesday, January 13, 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:

  • Electronic-only submissions are accepted
  • The eCTD is accepted as a ‘common currency’ for product marketing authorization applications - EMEA expects to receive marketing authorization applications & variations in eCTD format
  • The use of the eCTD is supported on the “agency side” by appropriate SOPs for receipt, validation, storage etc.
  • The use of the eCTD is supported on the “agency side” by appropriate business processes
  • 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:

  • Q2 2009: Detailed planning of migration and Proof of Concept
  • Q1 2010: Migration commences
  • Q3 2010: Planned end of pilot phase comes (no longer need permission to submit)
  • 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.

Update from the Regulators: Health Canada

posted by Kathie Clark @ 8:42 PM
Tuesday, January 5, 2010

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.

Updates from the Regulators: FDA

posted by Kathie Clark @ 1:36 AM
Tuesday, December 15, 2009

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:

  • Contact ESUB@fda.hhs.gov 
  • Please follow ESUB’s technical advice for fixing
  • If unable to follow ESUB’s advice on your own, get professional help
  • Do not attempt multiple fixes that are unproven –this can make a bad situation worse

Next time… Health Canada news.

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:

  • 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
  • Case Study: Global Submission Management from Concept to Realization
  • Taking eCTDs off the Critical Path to Drug Development
  • Working with an eCTD Vendor: Best Practices and Lessons Learned
  • 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.”]
  • Achieving Efficiency through Rounding Out Submission Standards: Format, Data, and Content Standards
  • 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.
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