GxP Lifeline Feature Article

Optimizing Your eCTD Submission: How to Achieve an Efficient and Timely Review

Ginny Ventura of the FDA?s Review Technology Staff shares the top 12 mistakes in eCTD submissions she sees nearly every day

If you’re having problems submitting your eCTDs, you are not alone.  Ginny Ventura, Regulatory Information Specialist in the Center for Drug Evaluation and Research frequently sees submissions with common errors.  In a presentation to DIA, she outlined the top 12 issues for eCTD success:

12. SPL must be in an “SPL” folder

11. Use elements and leaf titles correctly

  • Elements
    • Not necessary to use every element in the eCTD Specification
    • Use only the elements you need
    • Placeholder documents are not necessary, and can divert reviewers’ time and attention
  • Leaf titles
    • Should be informative and succinct
    • Should not include the eCTD numbering
    • Should immediately reveal to the reviewer what’s inside

10. Be sure to reference all files in the XML backbone(s).

Unreferenced files result from missing or mislocated directory references in xlink:href, “extra” files and from failing to repeat a complete directory structure on each media component in a set.  Unreferenced files can’t be located by reviewers.

9. Include Module 1 in all eCTD submissions.

Every eCTD submission requires Module 1, which identifies the following important information:

  • Company name
  • Drug name
  • Submission type
  • Submission Date
  • Application Number
  • Sequence Number

8. Make sure all application numbers are six digits

  • No alpha characters
  • No “-” “,” or other punctuation
  • No spaces
  • Six Numbers – pad left “0” if 5 digits are given
  • The application number is key – it ties all submissions together as an application

7.  Make sure all sequence numbers are four digits

  • Sequence-number values must be 4 digits
    • No Alpha Characters
    • No “-” “,” or other punctuation
    • No spaces
  • Sequence number is key and relates all submission components together
  • Sequence numbers need not be received/submitted in “sequence”

6. Do not use node extensions

    • Node extensions are unwanted
      • ICH and FDA do not recommend node extensions
      • At best they are ignored; at worst they defeat the standard headings
    • Node extensions are unnecessary
      • Leaf title can be used to differentiate between documents at the same level

5. Verify that all MD5 Checksums are correct

    • MD5 Checksum values should be
      • Lower case
      • Coded as a leaf attribute in either us-regional.xml or index.xml
    • Except
      • The MD5 Checksum value is provided in a one-line text file – index-md5.txt in the 0000 (sequence number directory).

4. All documents should conform to eCTD granularity

    • Avoid “combining” documents at a higher parent leaf level (allowed by Module 3)
      • It’s tempting – there’s a small initial savings in combining documents
      • There is a large cost in life cycle complexity
      • “Legacy” study reports make for life cycle issues down the road

3. All XML must use Standard Components

    • UTIL Folder
      • Three standard DTDs
        • There are three standard style sheets in the UTIL folder
        • Custom components create issues in FDA processes and defeat standards efforts
      • Avoid GIFs, custom CSS, custom DTDs, and custom elements with standard DTDs

2. Be sure all PDF hyperlinks and bookmarks are correct

    • Validate all hyperlinks and bookmarks
    • Broken hyperlinks and bookmarks diminish reviewer confidence in the submission
    • Test before you submit

1. Include TOCs in all PDF documents

    • For each document:
      • If a paper document needs a TOC, a PDF documents needs a hyperlinked TOC
      • No change from eNDA – both bookmarks and hyperlinks
      • Cross-document links still work in an eCTD

“I think sponsors are catching up to the idea of eCTD’s,” Ventura says.  “Some sponsors who don’t have in-house solutions are using consulting firms to file their forms, which can be helpful.  There’s always new software coming out, too.  In the near future, FDA will also make available something called XForms which will allow sponsors to easily create eCTDs on the fly.  The envisioned submission types to be covered by this project are SPL submissions to a paper NDA/BLA, electronic dataset submissions to a paper IND/NDA/BLA, and single investigator INDs.  Companies are also using the FDA Electronic Submissions Gateway, which is great because it gets submission into the hands of reviewers more quickly.”

Ventura frequently receives questions about signatures and printed copies required with eCTDs.  “Let me make this clear,” she says.  “No paper is needed!  If you follow the directions re signatures on the Gateway website, you’ll see that it asks only for digital/electronic or flattened signatures.  Those instructions apply to eCTDs also.  Paper letters and forms should be sent electronically. ”

The new eCTD process is a big improvement, she adds.  “I understand the position sponsors and small companies are in and I know this change can be challenging,” she says.  “But the reviewers love the eCTD format.  It’s absolutely a more efficient way to work.  Getting the data sets in this way will improve the process enormously because reviewers won’t have to hunt down what they need, consuming lots of time.  All the necessary information is at a reviewer’s fingertips.”

The FDA hasn’t yet published its validation checks document, Ventura says, but this document should be available shortly.  “The validation checks document spells out exactly what our software validates,” she says.  “If you file over the Gateway, the plan is that you’ll get a report back right away that tells you whether you’ve achieved a high, medium or low validation grade.  This will save time for you in the validation process.”

She also stresses that it’s important for sponsors and applicants to be aware of the June 2007 Guidance for Industry entitled “Providing Regulatory Submissions in Electronic Format — Receipt Date (http://www.fda.gov/cder/guidance/7627dft.htm). 

“This draft guidance clarifies how CDER will help sponsors rectify technical issues that might exist in your incoming submission,” she says.  “The sponsor won’t receive a Refuse To File because of a strictly technical problem.  This is significant because you’ll have an opportunity to correct the problem and re-submit without a penalty.  You could lose a few days while you correct your problem, but you won’t have to deal with an RTF.”

To ensure the success of your first eCTD, Ventura advises taking advantage of FDA’s offer to help.  For general questions, ask your project manager within FDA or email the CDER ESUB group directly at  esub@fda.hhs.gov for specific technical concerns.

More information will also be available at the 21st Annual DIA Conference for Electronic Document Management, slated for February 5-8 in Philadelphia.  “CDER will be on hand for a half-day workshop on preparing eCTDs for beginners,” Ventura says.  “The workshop will provide all the basics needed to get started on your first eCTD. “


Read more about eCTD submissions:

Product Data Sheet:

MasterControl Submissions Gateway

Product Data Sheet:

MasterControl Submissions Locker




Click here to view all available resources.

If you are a current MasterControl customer click here to download documents directly through our Customer Center.

 

FDA Links

  • eCTD Backbone File Specification for Module 1
    Full Article

  • eCTD Backbone File Specification for Modules 2 through 5
    Full Article

  • Final Guidance for Industry: Providing Regulatory Submissions in Electronic Format--Human Pharmaceutical Applications and Related Submissions Using the eCTD Specifications.
    Full Article

  • Visit CDER's eCTD Page
    Full Article

  • Submit Electronically via the Gateway
    Full Article

Additional Links

  • ?Creating eCTD Applications? Journal of Generic Medicines (2006) 3, 140?146
    Full Article