CTD and e-CTD Defined

Information Overload The goal of pharma companies' regulatory operations is to minimize time to marketing approval while ensuring compliance. The typical pharma company regulatory department processes thousands of documents a month, all part of applications for new drug marketing approval. It must also keep approvals current in dozens, even hundreds, of regions. Every change in a regulation, manufacturing process, or product indication must trigger an update to the original application to maintain compliance. And the volume of marketing applications that needs to be processed and maintained-with the same set of regulatory resources-is rapidly growing, thanks to drug discovery technology advances, licensing agreements, and productive corporate partnerships.

Organizational compliance is achieved only when every employee in a company can access the most current marketing application, for every product, in every region. In fact, that is more than a compliance issue: The ability to share intellectual assets globally can be a critical competitive advantage. Yet, despite the billions of dollars invested in content management products, few life sciences companies report that kind of access to product information.

Unfortunately, the average company reuses only 10 percent of content in global submissions. Marketing in multiple regions generates multiple sets of overlapping authored content and production of disparate regional marketing applications. Paper, rather than electronic, processes and documents still dominate, further restricting reuse and tracking. Decentralized regulatory units have the most difficulty sharing information globally because of differing strategies, time lines, or other barriers to communication.

To reduce operating costs, many companies have begun to centralize those operations. But that approach often fails to achieve faster submissions, because it centralizes results in fewer individuals with a broader knowledge base. The remaining staff must be familiar with the requirements of several regions rather than specializing in one. It is difficult to achieve regulatory operational savings by centralizing jobs if each region still requires different submission structures, compliance requirements, and content.

ROI Estimates of Electronic Submissions

Yet, because the CTD still has all the limitations of paper submissions, its potential for reuse and for companies' compliance is still limited. So although global companies view the CTD as important-especially considering that it is an impending requirement for 2003-they also view it as a steppingstone to the e-CTD.

Speed Limits Electronic submissions accelerate time to market, reduce costs, and facilitate review. Much of the time savings is realized by beginning submissions' preparation and publication well before all the content is finalized, promoting faster turn-around of last-minute documents. Some of that benefit is also achievable with more cumbersome paper submission formats-as long as preparers use an electronic compilation process. Companies can realize other cost savings by eliminating the printing, copying, distribution, and storage of massive amounts of paper.

With lengths of up to one million pages, pharma regulatory submissions are among the largest publications in the world. Regulatory agencies also benefit during the review cycle because they are more able to search content, find related or referenced information, and perform direct analysis on raw data. (See "ROI Estimates of Electronic Submissions," page 70.)

One practical limitation of current electronic submission formats is their region-specific nature. The DAMOS in Germany and electronic new drug application (e-NDA) in the United States, for example, are both electronic drug marketing applications but with completely different technical formats, content organization, and viewing tools. In the case of the electronic investigational new drug application (e-IND), electronic biologics license application (e-BLA), and e-NDA, different technical structures are required for different regulatory filing types within one region. Even where specifications requiring sponsors to do so do not exist, an application is often reformatted multiple times for different regional authorities in order to accommodate companies' subjective views of what approach best facilitates the review process.

Executives at Isis Pharmaceuticals, the first US pharma company to submit a PDF "virtual publication" to the European Medicines Evaluation Agency (EMEA) agrees that one of the greatest business challenges of filing applications and submissions in various countries is the short time constraint for preparing each regulatory dossier for the different regions. So the company devised a system to divide each report or application into different sections. It then mixes and matches sections from different reports, allowing Isis to use a variety of different formats for an international group of regulatory boards. The company admits that the ability to harmonize certain sections depends on the regulatory agency being addressed. Nevertheless, although the format may differ, the content remains fundamentally the same. Either way, electronic publishing speeds the process and saves labor.

Another practical limitation is that electronic formats tend to be associated with large, original submissions only, and not with the subsequent maintenance forms, which are often on paper, thereby losing some of the initial electronic benefits. Companies are unable to track changes in applications over time. So, although manufacturers may easily retrieve the originally approved manufacturing process, they may not know whether subsequent amendments have been made to it on paper.