XML a frequent problem with eCTD submissions; speaker says refuse-to-files are painful.(Electronic clinical trials)(electronic c

Drug and device sponsors should use caution as they prepare their eCTD submissions for NDAs particularly with XML documents-because failure to follow FDA's strict procedures could yield a refuse-to-file (RTF) decision on NDAs, which with one biotech firm caused it to spiral downward.

Addressing a Nov. 20 Expertbriefing on FDA's new requirements for eCTD submissions, Antoinette Azevedo, president-CEO of e-SubmissionSolutions.com, based in San Diego, said the agency's Jan. 1 deadline requiring the use of the eCTD format for electronic submissions is just around the corner, and many things can go wrong in such an application in the areas of PDFs, the table of contents and poor XML coding.

She said FDA can issue an RTF if the submission is "illegible, uninterpretable ... including having incompatible formats or inadequate organization."

Azevedo detailed a case study of a small biotech firm that had major problems that cost it millions.

The company submitted the NDA to the agency in the eCTD format. It used an eCTD toolkit, an electronic document managing system and the company hired consultants to assist with PDF preparation and eCTD publishing and quality control.

This firm partnered with a large pharmaceutical company that would assist with international sales and marketing post-approval. Two hundred salespeople were hired in anticipation of approval, she said.

FDA issued a refuse-to-file because of "inadequacy of individual PDF files," and poor "navigability of content of submission," Azevedo noted. The company's market capitalization dropped 50% overnight.

In early 2006, the biotech company prepared a resubmission, she said, explaining: "The company reworked source files, CTD folders and file structure, and rebuilt the XML backbone. FDA accepted the resubmission for review under the user fee timeline.

In May 2006, the agency issued an "approvable" letter under user fee requirements, noting the drug could be approved in the future if certain conditions could be met. Those conditions would be determined in a future FDA meeting.

The next month, the large pharmaceutical company withdrew from the partnership, and the biotech company laid off its sales force, as well as 100 additional employees.

The firm met with the agency the next month, and learned it had to conduct additional studies and analysis. The company then announced it intended to resubmit the NDA in the second quarter of 2007.

Most of these delays could have been avoided if more care had been taken in preparing the eCTD, noted Azevedo.

She had the following tips for success with eCTDs:

1. SPL must be in an SPL folder

2. Use elements and leaf titles correctly

3. Always reference all files in the XML

4. Include Module 1 in all eCTD submissions

5. Make sure all application numbers are six digits

6. Make sure all sequence numbers are four digits

7. Do not use node extensions

8. Verify that all MD5 checksums are correct

9. All documents should conform to eCTD granularity

10. All XML must use standard components

11. Be sure all PDF hyperlinks and bookmarks are correct

12. Include a table of contents in all PDF documents

One of the most common problems Azevedo said she sees with eCTDs is with the XML. Sponsors often hand-code the XML improperly, and sometimes the eCTD publishing vendor misinterprets the XML document type definition. Another problem is that "the eCTD publishing vendor is not providing enough guidance and control of user actions," she said.

Another challenge, she continued, is document authoring. "The creation of PDFs is highly dependent on the use of the word processor." This includes styles, templates and cross references.

Azevedo said this problem extends to collecting documents and data from study sites. "Case report forms (CRFs) are costly in terms of time and expense to convert to a compliant electronic format." Also, consistency of organization of documents is a problem. There are changes in study protocol, different CROs involved in different study phases, electronic data capture, and different locations of queries and data correction time forms.

Other questions about documents and data from study sites include:

* Can all the data be delivered in electronically-reviewable format?

* Can I convert from proprietary formats into SAS XPT compliant formats?

* Will the agency review my electronic datasets?

Regarding electronic document management systems (EDMS) versus shared file systems, Azevedo said she has seen the following questions arise:

* How do I know I have the final, approved document?

* What if the final, approved document changes?

* What is the effective version for a submission sequence?

* Do I have the time/budget/resources to implement EDMS?

* Will the EDMS meet the needs of my entire enterprise?

* Will the EDMS integrate with my e-Submission publishing process and tools?

* How do I assure the EDMS is Part 11 compliant?

She said some of the most common problems in the U.S., EU and Japan to date are with PDF files. "They are lacking in navigation aids, such as bookmarks, hyperlinks and document tables of contents.

Problems also are cropping up with absolute paths on hyperlinks, security, file format, incorrect granularity and referencing proprietary style sheets."

Some of the conclusions Azevedo has reached from these experience are:

* A system is needed to produce the XML backbone for an eCTD submission

* Source documents and data need to be submission-ready and compliant with requirements

* Sponsors need intimate knowledge of the XML output of their commercial off-the-shelf system

* Sponsors must understand how agencies use the components of an eCTD for review

Regarding electronic document sources, she stressed: "Avoid scanning unless there is no other choice."

PDFs should be created from intelligent sources, such as Microsoft Word, Excel and PowerPoint, other word processors and spreadsheets, or ASCII text.

Regarding tables of contents, she advised:

* Use hyperlinks designated by blue text or rectangles with thin lines (blue text for PDFs from an intelligent source; thin rectangles only an option for scanned documents)

* Table of contents must be hyperlinked with invisible rectangles and blue text preferred

* eCTD publishing systems can automate some of this A CD recording of Azevedo's Expertbriefing, plus her slides, is available for purchase for only $325 to subscribers. Please email us at service@ExpertBriefings.com or call (703) 779-8777.

PDFs should be searchable and should to able to be copy and pasted to edit in other documents.

By Joseph Pickett, Managing Editor

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