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Founded in 1989, Isis Pharmaceuticals is a genomics drug discovery and development company whose 500 employees focus exclusively on the untapped therapeutic target RNA. The company is the world leader in the discovery and development of antisense drugs, which work at the genetic level to interrupt the process by which disease-causing proteins are produced. Vitravene®, a drug that treats CMV-induced retinitis in AIDS patients, became the world's first antisense drug to be approved for marketing in the United States in 1998 and received European regulatory approval in 1999.

Isis continues to exploit this rapid and efficient novel approach to drug discovery by developing therapeutics utilizing new formulations to treat a wide variety of diseases. As evidenced by its expanding pipeline and rights to nearly 1,200 issued or licensed patents, Isis has made significant progress in understanding antisense technology, its applications, and how to use it to create exciting new drugs.

The Challenge
As the company prepared to submit its first New Drug Application (NDA) to the FDA, executives gave considerable thought to the best method of filing. The company knew a paper-based method for producing an NDA would be highly complex, requiring the use of high-speed photocopiers and manual pagination of every page in the 388-volume submission. Then, of course, the entire document would need to be reviewed for accuracy. Furthermore, if the submission required even a single change, it would necessitate manually searching through tens of thousands of pages.

The Solution
Liquent's CoreDossier® electronic publishing solution enabled the company's NDA to be easier to review, prompting quicker approvals. Using CoreDossier, Isis filed the world's first simultaneous U.S. NDA and European Marketing Authorization Application (MAA) for Vitravene. Isis is also the first U.S. pharmaceutical company to submit a PDF virtual publication to EMEA.

The Results

• Increased overall efficiencies in submission publishing lifecycle that dramatically decreasedtime to submission.
• Technology infrastructure that promoted the sharing and reviewing of information internally.
• Ability to reuse and repurpose information for global submissions.
• Supported multiple document formats to create consistent, compliant documents easilyand efficiently.
• First NDA deadline successfully met despite final document being received just 24 hours prior to printing and 96 hours prior to submission of NDA.

As a typical small company with constraints on resources, Isis realized that leveraging technology properly would gain them the competitive edge it needed. So when developing its initial product - Vitravene – Isis implemented Liquent's CoreDossier electronic publishing software solution to streamline internal review and approval processes of its submissions to various regulatory agencies. Today, Isis uses CoreDossier to produce all of its regulatory submissions, including investigational New Drug Applications (INDs), IND amendments, IND annual reports, clinical study reports, investigator brochures, protocols, and protocol amendments.

CoreDossier is a flexible solution for assembling and publishing regulatory submissions and other complex documentation. It enables the user to gather information from disparate sources in over 100 different file formats and assemble a dynamic document, complete with tables of contents and hyperlinks to cross-referenced information. The specialized submission publishing software eliminates the hassles of manually reviewing, revising, and republishing the entire document when changes -- no matter how small -- are required.

Using CoreDossier to submit the company's first NDA electronically paid off. Isis eliminated the labor-intensive work traditionally associated with creating and publishing massive, paper-based regulatory submissions. The company electronically produced a 388-volume NDA for Vitravene that included quality-control reviews and the republishing and reprinting of the document in the last week before shipping the submission. Five months later, the FDA approved Vitravene.

"CoreDossier pulls together all the various information and source documents from different departments and make it one cohesive, usable document," said Tess Hildesheim, Manager, Regulatory Affairs Operations at Isis. "Once we have a single document, the whole company can look at it electronically to review it and make any additions, revisions, or notations. This saves us a great deal of time and manpower."

Isis is also using CoreDossier for any regulatory submissions and updates for its current drugs, which require the collaboration of information from researchers across the enterprise. "Pretty much everything we touch for the FDA goes through CoreDossier," says Maria Feldman, Manager of Regulatory Affairs at Isis. "It is a vital part of getting our products to market."

But the functionality of CoreDossier goes beyond the U.S. regulatory agencies. CoreDossier is used for the filings Isis makes in Canada and for clinical trial exemptions with European regulatory agencies. One of the business challenges of filing applications and submissions in various countries includes the short time constraints for preparing each regulatory dossier. In response, Isis has devised a system that divides up each report or application into different sections. Isis is then able to mix and match sections from different reports, allowing the company to use a variety of different formats for various regulatory boards in many countries.

"Depending on which regulatory agency we need to address, there are certain sections we can harmonize and some we cannot," said Feldman. "The format may be different, but the content is the same. Either way, CoreDossier makes it easier even when we need to put the submission together piece by piece. It speeds the process and saves us a tremendous amount of labor."

By sharing everything electronically, regulatory professionals at Isis can access the information they need instantly and simultaneously from the desktop, which, in turn, supports regulatory agencies worldwide. Just as electronic submissions bring faster review, they also enable companies to respond more quickly to questions from the reviewing agency. These savings in review time can translate into revenue for drug makers by helping them get products on the shelf faster. And ultimately, reduced cycle times mean patients receive potentially beneficial new therapies more quickly