Updates from the Regulators: FDA

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.

Article written by

I am GlobalSubmit’s director of professional services. My area of expertise is electronic document management and regulatory submissions, specifically eCTD. I have 12 years of biopharmaceutical industry experience in the US, Europe, Israel and Japan, concentrating on content management for Regulatory Affairs & Submissions, Clinical Development, and Manufacturing, and in submission assembly and publishing. I have worked with over 50 pharmaceutical clients. Previously, I was the practice lead for the Subject Matter Experts/Business Analysts group at First Consulting Group (FCG), now part of CSC. I supervised a group of 12 SMEs/BAs. I was instrumental in the development of the FirstDoc® suite. I developed the project delivery methodology for FirstDoc® R&D, including training materials, project plans, workshop methodology and materials, and requirements and design specifications. I managed the design and development of FirstDoc® GMP and FirstDoc® Legal. Please feel free to contact me at kathleen.clark@globalsubmit.com if you are interested in talking about eCTD products or consulting services, or if you have ideas for the blog.

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