By Ann Neuer

July 28, 2008 | It’s been six months since the Center for Drug Evaluation and Research (CDER) division of FDA started requiring all electronic submissions to use the electronic common technical document (eCTD) format, and all is not well. Although CDER made the January 1 deadline known to the clinical trials world well in advance, the industry is just waking up to the new reality and is struggling to comply with the recent mandate.

Virginia Ventura, regulatory information specialist at CDER’s Office of Business Process Support, says that sponsors are adapting to the eCTD requirement as evidenced by the near four-fold increase in the number of eCTD submissions from 2007 to 2008, but the poor quality of many of the submissions is a major concern. “As of June 30, we have received 3,169 applications comprised of 31,386 submissions, as compared to 846 applications comprised of 10,560 submissions one year earlier. But the quality of those submissions is not what we would have expected,” Ventura says. She says that submissions sometimes lack the basics of the eCTD such as a comprehensive table of contents and navigation links to individual files.

Ventura points to several reasons for the sub-par submissions: inadequate electronic tools, not following the eCTD guidance, misunderstanding the guidance or vagueness of the guidance. But also, Ventura believes that some companies are trying to move too quickly and are ill prepared to make quality submissions. “Companies seem to be rushing to put something together. I would urge them to slow down and consult with somebody who knows what they’re doing,” she suggests.

Many sponsors are, in fact, taking this route – turning to consultants or providers of electronic submissions software and services to help them improve submission quality either by outsourcing this activity or by bringing expertise in-house. Companies such as Image Solutions Inc. (ISI) are reaping the benefits of this trend as sponsors work with them in various capacities to prepare for an eCTD world.

Michelle Perez, manager of regulatory consulting for ISI, says that a key reason why some sponsors are struggling with eCTD submissions is that they lack the business process and infrastructure. “The change in process that is required to put together an eCTD is challenging. Not only are changes necessary at operations level, change is also needed for the authoring piece to conform to the eCTD format,” Perez explains. Changes in process are required whether technology is brought in-house or if the sponsor decides to outsource this function. “All of this change means a lot of planning and for the most part, planning isn’t adequately done,” says Perez.

To manage the broad scale lack of preparedness for eCTD submissions, sponsors who would like to submit electronically but are unable to conform to the eCTD format have the option of filing an eCTD waiver. The granting of the waiver allows the filer to use another electronic format, such as a pdf file, but FDA is working toward a goal of all electronic submissions using the eCTD format. Waivers can be filed for new drug applications (NDAs), amended NDAs, and biologic license applications (BLAs). They are not accepted for investigational new drug (IND) applications except under certain circumstances, such as a mixed paper/electronic INDs or if datasets are sent electronically.

Since the inception of the waiver program, CDER has granted the overwhelming majority of waiver requests, but according to Ventura, there have been some denials, “mostly because they are incomplete,” Ventura says. Also, CDER is not granting waivers for IND applications, since they were never officially accepted in electronic format.

Sponsors will be wrestling with eCTD preparation as more regulatory agencies start requiring this format. According to Perez of ISI, agencies worldwide are at dramatically different places in terms of accepting or requiring eCTD submissions, but they are moving in that direction. “Some, such as Argentina, don’t have the technical infrastructure in place, but others, such as Canada, European Medicines Agency (EMEA), and Australia are farther along,” she explains.

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