Expediting the FDA Approval Process

Computers have made paper files virtually obsolete, so why do manufacturers still submit volumes of clinical product data to the FDA? Here's how one contact lens company paved the way for quicker approvals using electronic submission.

Contact lenses and solutions have come a long way in the 25 years that they've been regulated by the Food & Drug Administration (FDA). Submission procedures, however, have evolved less dramatically over the same time period. Last year, CIBA Vision, in cooperation with the FDA, became the first contact lens company to try to secure daily wear marketing clearance for two new contact lenses using electronic submission, which is submission of clinical documentation using a single compact disc in place of hundreds of sheets of paper.

"To get started, CIBA Vision structured its first electronic submission using pharmaceutical industry standards," explains Alicia Plesnarski, CIBA Vision senior regulatory associate, referencing the FDA draft guidance document titled "Submitting Application Archival Copies in Electronic Format."

The document, issued in 1996, describes electronic submission standards for drug, biologic and medical device applications. It details the types of programs that are acceptable (Microsoft Word, Adobe Acrobat PDF files, etc.) and describes the structure that the electronic document should take.

With permission from the FDA and confirmation of software compatibility, CIBA Vision created its first electronic submission to mirror a conventional paper submission for approval of its Dailies one-day disposable contact lens. The company submitted the CD-ROM version to the FDA approximately one month after the paper submission. Both the electronic and the conventional paper documents were available to the FDA staffers during the review process.

After Dailies gained approval, FDA staffers and CIBA Vision personnel met to evaluate all facets of the electronic submission. FDA staffers were given the opportunity to critique the new technology and make suggestions for improvement. As could be expected, some were hesitant about changing work patterns, while many others were enthusiastic about the possibilities of this new medium.

Maximizing Efficiency

Paper submissions are incredibly large and bulky. A typical daily wear paper submission may total 1,000 pages spread through five or more volumes. Manufacturers typically send three copies to the FDA, which holds one as an original. It then circulates the other two copies of the submission sequentially to each pertinent section in the review process (toxicology, microbiology, clinical, etc.).

Electronic submission eliminates problems associated with a sequential process. The FDA receives the CD-ROM submission and simply loads the data onto its local area network (LAN) for simultaneous access by participating reviewers. Simply having the complete document at every reviewer's disposal was an enormous change and improvement.

The feature of electronic submission that's most useful to the reviewers is the use of hyperlinks which connect various pieces of information. For example, a large part of the FDA submission document concerns labeling of the new device, and all labeling claims must be supported with data in the submission. With a paper submission, this would mean tracking down the appropriate research report.

With an electronic submission, hyperlinks similar to those used in Internet sites connect the reviewer directly to the supporting documents, facilitating verification of information and claims. Ann Perry, CIBA Vision senior regulatory associate, explains that "Reviewers can simply point and click to navigate through the information easily, so that it's much quicker and more user-friendly."

Phase II

Using the feedback from CIBA Vision's meeting with the FDA, the company prepared another submission using an electronic document for a second product -- a new high Dk soft contact lens. For the first time, an electronic submission document was used to gain marketing clearance for a new contact lens material, lotrafilcon A.

At the conclusion of the clinical trial for the new high Dk soft contact lens, the company created the CD-ROM and delivered it to the FDA supported by hardcopy back-up. Although no one at the FDA or CIBA Vision is willing to chalk it up solely to electronic submission, the product secured daily wear marketing clearance in less time than the statutory review period, with clearance granted in just over two months.

The Making of an Electronic Submission

"It is important to understand that electronic submissions are simply an innovative approach to the standard medical device submission process," explains Scott Robirds, OD, CIBA Vision head of Americas Product Registration. "Doctors are still seeing real patients wearing lenses to prove safety and effectiveness. The only difference is the way the documents are organized and presented."

The requirements for approval of lenses and solutions have not changed (see sidebar on page 38). With electronic submission, however, the scientific information, such as toxicology and clinical reports, is organized differently.

CIBA Vision Regulatory Affairs personnel are responsible for pulling together the various items they need to file for approval and create the PMA (pre-market approval) or the 510(k) (pre-market notification) document in the required format. They establish hyperlinks between various reports within the submission for cross-referencing. An electronic format also allows critical information to be highlighted. Once the document is complete, they burn it onto a read-only compact disc.

"The same information can be used to create international registration documents," explains Suzan Hargreaves, the head of International Product Registration at CIBA Vision. "The difference between a regulatory document in the United States and elsewhere is not so much in the type of information required but in the order or format in which it is presented. Using our electronic submission database, it is much easier for CIBA Vision's international divisions to create their own documents using the same information rather than duplicating the same tests in each jurisdiction. This results in significant savings of both money and time. Using electronic submission, it is possible to simultaneously establish or file registration documents for new products in many countries."

Bottom Line Benefit

Electronic submission is not just another technological toy. The bottom line payoff for patients and practitioners is that new products can move through the regulatory process and into the market in a much more streamlined fashion. While it's too early to state conclusively that electronic submission has a major impact on cycle time, indications are that it may reduce the FDA's processing time, allowing manufacturers to be more responsive to market needs. Electronic submission may also simplify modifications and extensions to product lines, and may reduce cycle time for international registrations.

The Next Generation of Submissions

The current electronic submission documents being developed at CIBA Vision are only a hint of what the future may bring. Already under consideration is multimedia submission. For example, next-generation electronic submissions might include short videos showing lens movement or photographs documenting corneal health, which greatly augment the value of the submission. Instead of relying on an investigator's description, a multimedia submission would enable a reviewer at the FDA to virtually examine a study subject. Key investigators could also videotape their impressions about the new product for inclusion; in essence, they could testify before the FDA's Ophthalmic Devices Advisory Committee.

Also being developed is fully automated data reporting. This means furnishing a clinical investigator with a computer and equipment to capture data chairside and instantly relay it to CIBA Vision headquarters. Missing or questionable data would be immediately apparent, making the submission process much more efficient. "We would like to be completely electronic," says John McNally, O.D., CIBA Vision head of Global Regulatory and Clinical Affairs. "We are working toward being able to download data directly from doctors and lab scientists, analyze it appropriately, and then assemble regulatory documents with no actual paper steps in the process. This effort started with our group in Europe, but has really taken off with these first FDA submissions."

Ophthalmic device electronic submissions will play a pivotal role in bringing contact lenses, solutions and the regulation of these products into the next millennium. By developing it in close contact with the FDA Ophthalmics Division, CIBA Vision has demonstrated that the relationship between industry and regulators can be a positive one which advances the field to everyone's benefit. CLS