Nixon estimates that the analysis stage of development has been reduced by 5% to 10%, thanks to the Optix system alone. "But the best savings," he says, "is that material isn't misplaced or left out." Before the company got the Optix and 4D databases, the case-report forms had to be photocopied and distributed to several people for review, including data-entry operators and clinical research scientists. If any of them needed to review a form from a different study, it meant a long cruise through rows of file cabinets. Now the information from the forms is entered once and then reviewed in Optix via the company's LAN, which is made up of Windows NT running on a Compaq server. A field monitor on-site at one of the clinical studies follows a similar protocol: if, say, she wants to review a patient's temperature from the previous week's assessment, she just dials into the LAN, opens the Optix database, and searches for the appropriate form.
Nixon's greatest worry is that data will be entered incorrectly. Even the slightest inconsistencies in clinical findings can raise an eyebrow or two at the FDA. To avoid mistakes, he has designed an elaborate error-control system, complete with stringent checks and balances (see sidebar, below). In the best of all possible worlds, he says, on-site personnel would enter the information remotely (perhaps using pen-based laptops), dial up the LAN, and input the information directly into the company's 4D database. To date, however, Isis's only foray into electronic data collection involves its central laboratory services, which send the company a disk containing blood values from the clinical trials; Nixon then imports the data electronically into the 4D database. But with the popularization of the Internet, he says, that may soon change. "It used to be too expensive and difficult to set up proprietary remote data-entry systems," Nixon says. "But expanding our use of the Internet would be relatively inexpensive, and everyone would be familiar with how to use the system. We should be able to shave weeks off the average time it takes to complete a clinical trial."
Mark Lotz leans forward in his chair in one of Isis's nondescript conference rooms and waves his arm toward the hall. It used to be, he explains, that when he needed a statistic from a clinical trial he'd have to scrounge around in a dusty closet stuffed with the hundreds of three-ring binders that contain a single drug's NDA. Now, however, with the development of Isis 2922's completely electronic version, he'll be able to hold all that information, literally, in the palm of his hand. And finding the most obscure number will require little more than a swift electronic search. "Having this on disk will change the way I work," Lotz says.
Filing an NDA isn't exactly like applying for a new credit card. Lotz and his staff of four will use FrameMaker, a desktop-publishing application from Adobe, to assiduously compile every cell culture, every animal test, every case-report form, every chart, and every graph into one cohesive, cogent electronic document that meets the government's strict guidelines. "At just 40,000 pages, our NDA is really small," says Lotz. "But I still must read every page of it."
For years the FDA has required that pharmaceutical companies submit at least three copies of the NDA in binders that were no more than 3 inches thick. Dr. Carl Peck, who served as the executive director of the FDA's Center for Drug Evaluation and Research (CDER) from 1987 to 1993, recalls workers unloading countless binders from semitrailers and then lugging them into the agency's headquarters in Rockville, Md. Even by the late 1980s, the FDA had done little to automate the NDA review process. "I was astounded at the lack of computers at the agency when I first arrived," says Peck, who also claims that most medical reviewers had little computer expertise and knew only how to do minor tasks on the agency's out-of-date Wang word processors.
The FDA officially started accepting computer-assisted NDAs (CANDAs)--paper applications supported by some background material in an electronic format--in the mid-1980s, but until recently few small companies had bothered submitting them. The CANDA was a fairly expensive proposition because the drug companies typically had to loan computers to the FDA. "A company our size couldn't afford to tie up its computers at the FDA," says Lotz. It wasn't unheard of for medical reviewers to have four or five computers from different drug companies packed into their cramped offices. "I think the record was six," says Robert Bell, director of the CDER's Office of Management from 1987 to 1995. But there was more than just a space problem; the reviewers had no clue how to run the various systems, which meant that despite the background data on disk or on a loaned computer's hard drive, they continued to rely almost exclusively on the paper applications. "We weren't just stacking up paper," says Bell, "we were stacking up computers."
Things are very different today. The FDA upgraded its computer system three years ago and currently has networked PCs running Windows on almost every reviewer's desk. And according to both Peck and Bell, the new breed of medical reviewer is much more technically savvy. The agency now encourages drug companies to present the electronic portions of their NDAs in the Portable Document Format (PDF), a popular computer-file format invented by Adobe that converts printed documents into computer files without losing the original documents' design qualities. The advantages of PDFs are that almost anyone can create a document in the formats and it can contain hyperlinks like those on the Web.
