Originally published May 1996
FDA has worked out the kinks in its process for reviewing electronic submissions, opening the door for industry to submit in electronic form every type of medical device application from investigational device exemptions (IDE) to premarket approvals (PMA).
The holy grail of electronic submissions is faster review times, and it appears that the technology implemented by FDA has brought the agency to the verge of achieving that objective. "Clearly, for the last few submittals--from the reviewer's perspective and certainly from the administrative perspective--the review process has speeded up," says Neil Goldstein, deputy associate director of the Office of Systems and Management at FDA's Center for Devices and Radiological Health and one of the agency's prime movers in the electronic submissions process.
One company has already used electronic submissions extensively. Cardiac Pacemakers, Inc. (CPI; St. Paul, MN), which is part of the cardiac rhythm management group at Guidant (Indianapolis), has sent 12 electronic applications to FDA--two IDEs, nine PMA supplements, and an original PMA. Karen Peterson, manager of regulatory affairs for CPI, has capitalized on the process to build an electronic library of submissions that has helped the company to standardize its submission process. Peterson says feedback from FDA indicates that electronic submissions allow the reviewers to search for specific information in the applications. That ability can be enormously helpful, Peterson says. "Our submissions are huge," she explains. "One of our supplements alone was 2208 pages."
The first electronic applications were submitted on floppy disk, but the size of the documents has made CD-ROM the preferred method. Receiving submissions in this form means a reduction in the amount of paper that must be handled and a consequent improvement in document flow and document tracking. "Instead of having to get a half dozen copies to reviewers in different buildings, we put the electronic submission up on a server and reviewers can download it whenever they are ready," Goldstein says. Reviewers working with electronic documents can cut and paste materials electronically to create a review log that includes their comments. With paper-based submissions that process had to be done by hand.
As yet there are no written guidances on how to prepare electronic submissions, and reviewers have been trained selectively in the technology and methods involved. For those reasons, Goldstein says, "we would like sponsors to give us as much notice as they can before submitting an electronic application, just to be sure that we understand each other. We also need to identify reviewers, to make sure they have the necessary software and hardware, and more importantly, if they haven't done an electronic submission before, to be certain they have the right training." A workshop planned for summer might smooth the process. As it is now conceived, representatives of industry and FDA would use the workshop to examine and record the tenets of electronic submissions.
The pilot project that developed the current methodology for electronic submissions began in June 1994 with two PMA supplements sent in by CPI and another group within Guidant, Advanced Cardiovascular Systems (Santa Clara, CA), which focuses on vascular intervention technology. Hard lessons in software incompatibility and communications were learned in the early stages of these submissions.
The companies and FDA initially decided to use WordPerfect as a common software package, but it was soon apparent that the software was not up to the task. Reviewers found inconsistencies between the on-screen text and the paper copy submitted along with the electronic version, particularly differences in pagination. There were printing problems caused by different fonts. And graphics, created using such common software as AutoCad and Illustrator, could not be seen on-screen.
There were several other problems that seemed to accompany the medium itself. Reviewers wanted to make the equivalent of marginal notes on-screen, but couldn't. Even reading the document was a problem, because only a quarter of the text appearing on a printed page appeared on the computer screen at one time.
Communications were also flawed. FDA and the companies had agreed to use an off-the-shelf electronic mail and fax service. E-mail, it was later learned, was unworkable because WordPerfect files could not be sent using the software chosen--and the agency rejected the idea of sending non-ASCII files because of the potential for transmitting computer viruses.
Solutions to each of these problems, however, were found in the second phase of the pilot program. Software was acquired that allowed the electronic document to be viewed as it appeared on paper, independent of the word processing and graphics packages that were being used. The software used for document translation and display was Adobe Exchange and Adobe Acrobat.
Various documents can be distilled into portable document format using Adobe Acrobat, and the new document can be read with Adobe Exchange on any system--IBM-compatible PC, Macintosh, or even a UNIX-based platform. Janice Kates, regulatory affairs associate at Hybritech (San Diego), successfully used these software packages to create and read an electronic submission regarding an in vitro diagnostic product now being reviewed at FDA. Acrobat also provided the means for Kates and her colleagues to input intelligent navigational tools. "We can install links indicated by highlighted pieces of text," she says. "By clicking on them, the reviewer is taken to another place in the document. So we are able to help reviewers navigate around the document."
Another convenience of the software is the ability to insert electronic post-it notes containing dialogue at specific points in the document. Hybritech uses these notes to help the reviewer find related information or understand why information appears in certain places. Reviewers can also place their own post-it notes in the text, notes that bear reviewer names and comments. The notes can then be collated into a separate document with each one indicating the time and date created, who created it, and specific comments. Ultimately, video might be embedded at various points in the text. "I can see down the road where a manufacturer might have a hard time describing a process in narrative but might easily be able to demonstrate it on an embedded video," Goldstein says.
The E-mail problem of sending messages between reviewers and company staff was solved by using the Internet. Initially, messages sent over the Internet were encrypted to ensure security. Hybritech eliminated the need for encryption by simply agreeing with FDA not to send sensitive information by that route.
In the future, videoconferencing may be integrated into the process. Potentially, FDA reviewers could discuss an electronic submission among themselves, interactively pointing to text on the screen while voice and visual communications are simultaneously transmitted. That capability might be extended to include the companies submitting the applications, raising the potential of interactively making changes in the document, says Goldstein.
But even without videoconferencing, the agency is satisfied that a feasible methodology has been identified for electronic submission and review of medical device applications, Goldstein says. The pioneers of this effort agree. Both CPI and Hybritech plan to continue submitting applications electronically to FDA. Peterson, whose department handles CPI submissions to the agency, has set a goal of electronically submitting at least 75% of the company's 1996 applications. She and her colleagues are well ahead of schedule. All of the submissions so far this year have been electronic, "so we are definitely heading down that path," she says.--Greg Freiherr