The Electronic Solution to the FDA Submission

October 1, 2003

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-10-01-2003,

The expense of developing electronic submissions is manageable, even in a small company, and the benefits are great for both FDA and industry.

The Electronic Solution to the FDA Submission

Electronic submissions to the FDA are gradually being implemented by the biotechnology community. Even small companies are able to use off-the-shelf, available software to convert operations to an electronic format. A modest computer set up and a box of CD-ROMs can replace the mountains of paper once required to prove the safety and efficacy of a new product. Starting at the front end with the Investigational New Drug application (NDA), through the clinical trial process with electronic data capture, to the biologics license application (BLA), biotechnology companies can ultimately convert all systems to an electronic format.

Table 1. Components of the Rituxan (rituximab) and the Zevalin (ibritumomab tiuxetan) Electronic BLAs Submitted to FDA

Filing an e-BLA

IDEC Pharmaceuticals Corporation, a growing San Diego, CA, biotechnology company with two approved oncology products, is one company pursuing the electronic route. The company filed its first BLA in 1997 for the monoclonal antibody Rituxan, the first monoclonal antibody for the treatment of non-Hodgkin's lymphoma.

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At that time, the United States Food and Drug Administration (FDA) had published a draft guidance manual for Computer-Assisted Product License Applications (CAPLAs); however, final standards and requirements were still under development.

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The BLA was a new entity and no guidelines had been published specifically for its electronic submission in 1997. Therefore, IDEC worked with the Center for Biologics Evaluation and Research (CBER) to design a user-friendly e-BLA, while simultaneously laying the groundwork for future standards. Because all parties were new to the process in 1997, and 21 CFR 11 had not been implemented, IDEC was required to provide the FDA with a paper version as a backup to the electronic version of the Rituxan application. Preclinical data and case report forms were provided in hard copy only. Table 1 displays the components and cost of creating the first BLA for Rituxan and second one for Zevalin.

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While FDA/CBER had received electronic applications prior to IDEC's BLA, submission standards that would ensure consistency had not been implemented. Applications were submitted using several different types of media. Orienting reviewers was challenging as formats varied between submissions, thus preventing reviewers from applying knowledge learned from prior applications to subsequent ones. Because of the inconsistencies, archiving applications was difficult.

IDEC's 1997 Rituxan submission was part of a new era. This electronic BLA was affordable and the process could easily be replicated by other companies. Several factors made replication possible.

  • In-house employees were used to create the final product, avoiding the need for costly outside consultants.

  • The electronic BLA (e-BLA) featured a new design and was the first CBER submission to fully integrate all application sections and supply them on CD-ROM. Subsequently, safety updates were also submitted in this format.

  • The Table of Contents, for the first time, acted as a roadmap to hyperlinked data, much like linked text found commonly on Internet Web sites. A series of bookmarks functioned as an index that enabled reviewers to jump to sections of choice and navigate between documents. Because these sections were linked but independent, individual reviewers could focus on their areas of expertise but easily access other sections at will.

  • A footnote capability enabled reviewers to add electronic memos directly on the document.

  • A "cut and paste" function allowed CBER reviewers to copy text and tables from the application, edit them, and subsequently place them directly into their reviews.

  • It was the first CBER BLA to be submitted with text entirely in PDF format on a CD-ROM. This type of presentation later became CBER's standard for all electronic and paper submissions.4-6

The second e-submission

Based on the success of the first e-BLA submission, IDEC geared up for a second electronic filing three years later. This second product, 90Y Zevalin for the treatment of non-Hodgkin's lymphoma, ultimately became the first radioimmunotherapy approved by the FDA.

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By then, the FDA had established specific guidances for the process based on its overall submission experience. A paper back-up was no longer required. Therefore, the entire application was submitted electronically. More extensive hyperlinking was included to create a user-friendly, comprehensive package. The entire BLA fit on 7 CD-ROMs, with 23 additional CD-ROMs required for subject CT scans and gamma camera images.

Benefits of e-submission

The benefits of converting to electronic submissions have been enormous. Simply stated by Michael Fauntleroy, Director of Electronic Submissions at CBER, "Electronic submissions provide a huge advantage to reviewers. They are able to get to the hard-hitting discussion points quickly. They are able to access databases quickly. Data are presented in context rather than in a disjointed fashion. Reviewers have the option of moving throughout the documents rapidly." All of these points ultimately benefit the pharmaceutical company as review time is decreased.

Importantly, reviewers have rapid access to the submission once the CDs arrive at the FDA. When an e-BLA is sent to CBER, it is first delivered to the document control center (DCC). Within two days of receipt, the electronic submission is loaded onto the server known as the Electronic Document Room (EDR) and a notice is sent to reviewers indicating that the submission is available for review. Then reviewers can download any pertinent sections of the submission onto their computers or onto a network space for review. If reviewers are traveling or want to review the application from home, they can copy the required documents onto their laptop or a CD-ROM, or they can access the submission remotely through a high-speed, secure connection. With electronic submissions, no paper routing and no paper delays occur. The documents are available to the reviewers 24 hours a day, seven days a week.

The accessibility of electronic submissions contrasts sharply with the traditional process at the FDA, where paper documents are physically stored in the DCC. When hard copies are stored in the DCC, reviewers must submit their document retrieval requests after the initial regulatory review and wait for the paper copy of the submission to arrive at their offices. Typically, this takes a couple of days, depending on the reviewer's location. If reviewers don't want to be subject to DCC turnaround time, they obtain the volumes that they are responsible for reviewing and keep them in their office. This leads to additional storage problems.

Electronic submissions simplify the review process for those at the FDA. They also facilitate communication between the agency and the biotechnology or pharmaceutical company. "What I found most useful," commented Antonio Grillo-Lopez, MD, chief medical officer and senior vice president of Medical and Regulatory Affairs, during the approval process, "was sitting in front of the screen and knowing that we at IDEC were looking at the same data as the reviewer in Bethesda when we discussed issues over the phone."

The team that designed the e-BLA estimated that some former submissions had cost sponsors as much as $500,000 to $1.5 million for an FDA filing. In the past, companies even provided each of their FDA reviewers with a software-loaded computer and the detailed training required to use a customized system.5 All the equipment and resulting documentation required long-term storage space at government expense. In comparison, IDEC prepared the Rituxan electronic submission in less than three months using the equivalent of four full-time individuals. IDEC prepared the more comprehensive Zevalin submission in just under one year, also with four full-time employees. These employees, hired initially to create the e-BLA, remain an asset to the company by furthering the goal of converting all phases of IDEC drug development to an electronic format. Of note, those who orchestrated the project were recruited for their regulatory background, not for their technological expertise. According to Daniel Kim, manager of the electronic submissions program, the project required familiarity with a few software tools—it didn't demand a technological wizard.

Completing the e-puzzle

The e-BLA represents the first piece of the puzzle. Several more pieces must be added to complete the picture. The company is taking steps toward

that goal through its participation in two pilot programs sponsored by CBER. One allows for electronic submission of INDs, the other, known as Electronic Secure Messaging (ESM), provides for secure e-mailing of documents and electronic signatures. Both of these programs have recently moved beyond the pilot stage and become standard practice. Both programs offer unique benefits. Submission of electronic INDs could impact the pharmaceutical industry positively, as the ratio of submitted INDs to finalized BLAs or New Drug Applications (NDAs) is high. Thus, a growing percentage of FDA review time could ultimately be spent with electronic documents. With ESM, IDEC is able to email IND amendments to the FDA as formal submissions. Documents that once required several days to reach reviewers can now be on their desktops in 15 minutes (see Table 2).

Table 2. Comparison of Information Transfer Time

Aside from FDA interactions, IDEC is looking for additional ways to eliminate hand-written documents, such as case report forms (CRFs), that are scanned for submissions. Along these lines, electronic data capture (EDC) will be tested in an upcoming trial. With EDC, data are entered directly at the clinical site, thus eliminating the paper CRF. The potential rewards to the company are considerable. EDC could facilitate data collection during the trial and simplify preparation of both the clinical study report and BLA after the study is concluded.

Not all BLAs or NDAs are created equal. In particular, applications for cancer drugs are based on fewer subjects and shorter follow-up periods than those for treatments outside the oncology field. The BLA for Rituxan was relatively simple; the second for Zevalin was more complex. Overall, both applications were small compared with those for other diseases. The challenge of creating electronic applications is certainly greater for pharmaceutical companies testing more conventional treatments. However, the rewards are worth the effort.

As noted, CBER has initiated these pilot programs to further their goals of completing the electronic puzzle. Industry participation in pilot programs is one way to advance the mission. CBER is actively setting standards so all of industry can function on the same page. "When the electronic submission program was first initiated," Fauntleroy said, "we took whatever industry wanted to bring us. This was a totally untenable situation." Providing standards helps both the pharmaceutical industry and the FDA—it makes the FDA's job of reviewing submissions easier and provides a starting point for companies that are new to the game.

In conclusion, developing electronic submissions need not be a daunting, overwhelming task. The expense is manageable, even in a small company. And the benefits are great for both FDA and industry. But ultimately, the greatest beneficiaries will be the patients as electronic submissions improve the efficiency and thoroughness of the drug review process, allowing needed products to reach the public rapidly.

References

1. Antonio J. Grillo-López, "Monoclonal Antibody Therapy for B-cell Lymphoma," International Journal of Hematology, 76 (5) 385-93 (2002).

2. Food and Drug Administration, Draft Guidance Manual for CAPLAs (FDA, Rockville, MD, 1996).

3. Antonio J. Grillo-López, "Rituximab: An Insider's Historical Perspective," Seminars in Oncology, 27 (6 Supplement 12) 9-16 (2000).

4. U.S. Department of Health and Human Services, Guidance for Industry: Providing Regulatory Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic Format—Biologic Marketing Applications. (DHHS, Rockville, MD, Novemeber 1999).

5. Mary A. Buesing and Edward McSweegan, "Submitting Biologic Applications to the Center for Biologics Evaluation and Research Electronically," Drug Information Journal, 33 1-15 (1999).

6. Alice Wei and David Shen, "Supporting the Smaller Enterprise: IDEC Experience," Drug Information Association Workshop 1998.

7. Antonio Grillo-López, "Zevalin: The First Radioimmunotherapy Approved for the Treatment of Lymphoma," Anticancer Therapy, 2 (5) 485-93 (2002).

Alice Wei is vice president of Regulatory Affairs and Quality, Favrille, Inc., 10865 Altman Row, Ste. 150, San Diego, CA 92121, (858) 450-5945, fax (858) 450-5948, www.favrille.com. David Shen, PhD, is senior director, Biostatistics, Favrille, Inc. Daniel Kim* is manager, Regulatory Affairs, IDEC Pharmaceuticals Corporation, 3030 Callan Rd., San Diego, CA 92121, (858) 431-8977, fax (858) 431-8889, email: dkim@idecpharm.com. Antonio J. Grillo-López, MD, is chairman, Neoplastic and Autoimmune Diseases Research Institute, P.O. Box 3797, Rancho Santa Fé, CA 92067.

*To whom correspondence should be addressed.

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