FDA: eCTD Popularity On the Rise, But More To Be Done

More companies are beginning to accept the electronic common technical document (eCTD), and it is showing good signs of progress, but it "still has a long way to go," an FDA official said.

While eCTD usage is increasing, it still accounts for only about 10 percent of esubmissions, Gary Geinsinger, director of review technology for the FDA's Center for Drug Evaluation and Research, said. He urged attendees of the Drug Information Association meeting in Philadelphia Feb. 8 to move toward eCTD now, instead of waiting for new specifications or technologies. "The tools are here," he said, adding that the agency is exploring whether to mandate esubmissions. "It is not imminent -- it won't happen in June," he said, "but the time to start moving forward on eCTDs is now."

Among its advantages over traditional esubmissions, eCTD boasts a higher level of "granularity," which means individual documents can be controlled easier. "You can reach back into the FDA to change the attributes" in one document in a particular area with eCTD, Geinsinger said. And you can then easily and quickly notify your reviewer electronically of your change, speeding the review process, he added.

Resistance to Change

Industry is not the only one to show reluctance in committing to eCTD. Even some of FDA's own reviewers have had cold feet accepting eCTD, Geinsinger said. Many have said this is because the FDA's guidance and specifications are not clear. "We're the first to admit" those need revision and input, he said. He advised industry to notify the FDA anytime they saw something in guidance or other documents that is unclear or could be improved. "We revise these," he pointed out. "If you see things that don't make sense, contact us."

As confusing as they may be, however, understanding and following the specifications is essential for eCTD submissions, Geinsinger said. For firms just getting familiar with eCTD, he advised exploring traditional esubmissions with a PDF table of contents, versus the extensible markup language (XML) backbone used for eCTD's table of contents. "Those 'hybrid' systems are a good place to start," he said.

FDA's Top 10 eCTD Suggestions

Several hundred eCTD submissions later, FDA regulatory information specialist Virginia Ventura recently pulled together the top 10 problems agency reviewers have encountered when going through eCTDs. She also noted that it was not usually a single issue that triggered an esubmission failure, but a combination. Her top 10 suggestions, in order of importance and frequency, are:

Include a table of contents in all PDF documents, preferably at the beginning of the document if possible; Be sure all PDF hyperlinks and bookmarks are current. Broken links "diminish reviewer confidence in the submission," she warned; All XML must use standard components. "Avoid cascading or cute little GIFs," she said. Those are a good way to get your submission "kicked out" by the FDA's electronic document review (EDR) team; All documents submitted should conform to eCTD granularity. Avoid "combining" documents at the higher parent levels, she warned. Some sponsors try to avoid the granularity in the early stages because it is more expensive to produce, but you'll pay more at the back-end if you get this wrong at the outset, she said; Verify that all Module 5 checksums are correct. Keep them in lower case; Do not use node extensions. At best, they are ignored by reviewers and, at worst, they can slow things down by knocking out the standard headings. Make sure all sequence numbers are four digits. They should not have spaces or alphabetic characters. Make sure all application numbers are six digits. "This is key -- it ties all submissions together as an application," Ventura stressed. Include "module 1" in all eCTD submissions. Module 1 includes basic information such as company and drug name, submission type and date, and the application and sequence numbers. Be sure to reference all files in XML backbone. "Unreferenced files may not be located by reviewers" and that will also slow the process down, she said. -- Michael Causey