As mentioned in the section "X3.2.1X. Format and content of a Marketing Authorization Application Dossier – Regulatory Requirements" most of the dossier requirements are
identical for the three ICH regions. As mentioned before the content from Module 2 – 5 is quite similar for all three ICH regions.
Nevertheless, each region has some special requirements, which are only applicable for one region.
The FDA in USA under federal law regulates the NDA and the biologics license application (BLA) process. The FDA Center for Drug Evaluation and Research (CDER) is responsible for the review of the NDAs and for parts of the BLAs.F18
CDER is responsible for the regulatory review and supervision of drug applications andX18X:
• MAbs for in-vivo use
• Cytokines, growth factors, enzymes, immunomodulators; and thrombolytics
• Proteins intended for therapeutic use that are extracted from animals or microorganisms, including recombinant versions of these products (except clotting factors)
• Other non-vaccine therapeutic immunotherapies
The BLA review process is handled by two different divisions of FDA, the Center for Biologics Evaluation and Research (CBER) and the CDER. The CBER is responsible for the regulatory review and supervision of:X18
• Viral-vectored gene insertions (i.e., “gene therapy”)
• Products composed of human or animal cells or from physical parts of those cells
• Allergen patch tests
• Allergenics
• Antitoxins, antivenins, and venoms
• In vitro diagnostics
• Vaccines, including therapeutic vaccines
• Toxoids and toxins intended for immunization
• Blood, blood components and related products
NDAs and BLAs can be submitted either as paper submission or electronically to the CDER or CBER.
The NDA contains all data collected during the development of a new drug whereas a BLA contains all data assembled during the development of a biological product. The NDA and
BLA contain also all data from preclinical and clinical studies, which were already submitted through the Investigational New Drug (IND) process. The content of an NDA and BLA may differ based on the nature or class of the drug or the biological product.X18
Three copies of the application are requested for NDAs and Abbreviated New Drug Application(s) (ANDA(s)) which differ in their intended purpose and therefore in content:X19X
• An archival copy
• A review copy
• A field copy
For BLAs it is requested only to submit archival and review copies, so no field copy is requested.
The archival copy includes the entire submission and is the “official” complete copy of the application whereas review and field copy request only parts of the complete submission.
The archival copy acts as the official archive of the application and may be used during the review of the application.F19
The archival copy includes the following information:
• A cover letter to:
• confirm any agreements made between the FDA and the applicant
• identification one or more people the FDA may contact
• any other important information about the application
• Application Form FDA 356h serves as a cover sheet for the submission. It contains the applicant, the drug product, and indicates the applicant’s intention to comply with applicable laws and regulations.
• All INDs, drug master files (DMFs) and other applications referenced in the application should be identified in the form.
19 Federal Register Vol. 68, No. 72, April 15, 2003 – Draft Guidance - Guidance for Industry-submitting MAs according to the ICH CTD format http://edocket.access.gpo.gov/2003/pdf/03-8802.pdf 18248 - Federal Register / Vol. 68, No. 72 / Tuesday, April 15, 2003 / Notices
• The FDA recommends using the following format:
o The submission content should be organized and labeled as described in Form FDA 356h (4/06)F20F. This form gives a comprehensive list of each section requested in the NDA, ANDA or BLA.
The review and field copies require only a portion of the application.
• Review copies are precise duplicates of the technical sections of the archival copy. They include the information needed by each review discipline for its evaluation. These copies facilitate the concurrent review of the application by the different review disciplines.
Review copies that may be necessary according to Title 21, Code of Federal Regulations (CFR) part 314.50F21F for an individual submission includes:
• Quality (Module 3),
• Nonclinical (Module 4),
• Clinical (Module 5) - safety and efficacy documents for clinical reviewer,
• Clinical (Module 5) - safety and efficacy documents for the statistical reviewer,
• Clinical (Module 5) - clinical pharmacology and pharmacokinetics documents (or bioequivalence documents for ANDAs), and
• Clinical (Module 5) – clinical microbiology documents.
A copy of Modules 1 and 2 should be included in each review copy including a ToC for the section, cover letter, a copy of the application form, any letter of reference or authorization, index to the entire application and the application summary. Each review copy should be labeled and bound separately.
The applicant should contact the office with the responsibility for the review of its product to determine how many copies of each module or sections of modules should be submitted.X19
20 Form FDA-356h “Application to market a new drug, biologic or an antibiotic drug for human use” (Title 21, Code of Federal Regulations parts 314 and 610) http://www.fda.gov/opacom/morechoices/fdaforms/internal/FDA-356h.pdf
21Code of Federal Regulations, Title 21 – Foods and Drugs, Volume 5, Revised as of April 1, 2008 (CITE: 21 CFR 314.50) http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.50
Chapter 1 – Food and drugs administration department of health and human services Subchapter D – drugs for human use
Part 314 – Applications for FDA approval to market a new drug
Subpart B – Applications; Section 314.50 – Content and format of an application
The field copy which is used by FDA inspectors during pre-approval manufacturing inspections is a copy of the Quality section (Module 3) plus form FDA 356h and the NDA summary. The field copy is only requested for the NDA and ANDA (not for BLAs). This separately bound copy should be sent directly to the appropriate field office.X19
The “Guidance for Industry-submitting MAs according to the ICH CTD format”X19X describes the US typical documents and their content. The content of the CTD sections is not in the scope of this guidance document.
Besides the usual CTD sections, which are requested for all ICH regions the additional documents, are requested for an NDA or BLA in USAX19X which are listed in appendix 4 (“XAPPENDIX 4X: Table of contents for an NDA in USA “).