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Writing and submitting electronic 505(b)(2) INDs

Any use of a drug product not previously authorized for marketing in the United States first requires submission of an Investigational New Drug Application (IND) to the FDA. To date, the FDA accepts IND submissions in the ‘old format‘ and in the Common Technical Document (CTD) format. The CTD is maintained by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and is designed to be used by regulatory agencies across the 3 regions, namely Europe (European Medicines Agency, EMEA), Japan (the Ministry of Health, Labour and Welfare) and the United States (FDA). As drug development becomes more complex and tightly regulated, the CTD is becoming the choice IND format for registration of human pharmaceuticals by many applicants. In our experience, one practical advantage of preparing INDs in the CTD format is that it allows the starting point for building into an eventual NDA. Therefore, the CTD format in particularly appropriate for those applicants using the 505(b)(2) pathway, where large amounts of pre-existing information need to be incorporated and the time from IND to NDA submission may be short.

INDs in the CTD format can be submitted to the FDA in paper or electronically (eCTD). The content organization of both paper CTD and eCTD are identical, with the only obvious difference that paper is not involved in the eCTD. Also, if filing an IND in eCTD format, all the future applications must be submitted electronically. This basic characteristic of the eCTD format can be a major advantage. For example, because the IND application can range from hundreds to several thousands of pages, the eCTD format significantly reduces time and resources used to compile a paper application. Very useful features of the eCTD include hypertext links and bookmarks, which allow easier navigation through a large IND document.

When writing an IND in eCTD format, you must first familiarize yourself with its organization.  A great place to start is by consulting the guidances issued by the ICH, particularly “M4: Organization of the CTD. For those familiar with the ‘old format’, the FDA provides the Comprehensive Table of Contents Headings and Hierarchy indicating where sections of the CFR Citation (‘old format’) should go in the CTD document. Basically, the CTD/eCTD is organized in 5 modules: Module 1 (Administrative Information and Prescribing Information), Module 2 (Common Technical Document Summaries), Module 3 (Quality), Module 4 (Nonclinical Study Reports), and Module 5 (Clinical Study Reports). Module 1 is specific to each of the 3 ICH regions (Japan, Europe, and the United States). Module 2 should include a general introduction to the pharmaceutical (normally not exceeding one page), nonclinical overview and summaries, and clinical overview and summaries.

As with any other IND submission, the information provided in the eCTD should be unambiguous and transparent. This should help a reviewer to become quickly oriented to the application contents and should facilitate the review of basic pharmaceutical data.