Regulatory One: New Drug Application (NDA)

What is a New Drug Application (NDA)?

The NDA is the vehicle through which drug sponsors (pharma companies) formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA.

In simple terms “It is an application filed with USFDA to get approval for marketing a new pharmaceutical for sale in the U.S.”

Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization.

I. Goals of NDA-

The goals of the NDA are to provide enough information to permit FDA reviewer to reach the following key decisions:

Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the drug outweigh the risks.

Whether the drug's proposed labeling (package insert) is appropriate, and what it should contain.

Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.

II. Chemical type and review classification codes for NDA-

Chemical type classification

*Number*	*Meaning*
1	New molecular entity (NME)
2	New active ingredient (new salt, new noncovalent derivative, new ester)
3	New dosage form
4	New combination
5	New formulation or new manufacturer
6	New indication [no longer used]
7	Drug already marketed without an approved NDA
8	OTC (over-the-counter) switch
9	New indication submitted as distinct NDA, consolidated with original NDA after approval
10	New indication submitted as distinct NDA - not consolidated

Review Classification

*Letter*	*Meaning*
P	Priority review drug: A drug that appears to represent an advance over available therapy
S	Standard review drug: A drug that appears to have therapeutic qualities similar to those of an already marketed drug
O	Orphan drug - a product that treats a rare disease affecting fewer than 200,000 Americans

III. Facility and Drug Registration for filing an NDA-

Within 5 days of filing the NDA-

The facility should be registered with FDA using form FDA 2656(Registration of Drug Establishment/Labeler Code Assignment form).

The product(s)/Drugs to be listed with FDA using form FDA 2657 (Drug listing form) .

Note : From June 1, 2009 FDA is accepting only electronic submissions of forms FDA 2656 and 2657.

IV. Format and content of NDA-

The FDA recommends ICH’s CTD for filing the NDA.

Documents in each Module-

*Module*	*Information*
1	Administrative and prescribing information (region specific)
2	Summaries and overview
3	Information on product quality
4	Nonclinical study reports
5	Clinical study reports

Module 1- Administrative and prescribing information

Documents should be organized in the order listed below. Generally, all of the documents in Module 1 can be provided in a single volume. Environmental assessments should be submitted separately.

1. FDA form 356h

The first document in Module 1 should be FDA form 356h.

2. Comprehensive table of contents

The next document in Module 1 should be the comprehensive table of contents for the entire submission. Each NDA submission is required to have a comprehensive table of contents or index for the entire submission (as per 21 CFR 314.50)

3. Administrative documents

a. Administrative documents

Appropriate administrative documents should be provided with the submission. Examples of administrative documents are listed below. 21 CFR 314.50 consists of details on the administrative documents needed for NDA.

· Patent information on any patent that claims the drug, if applicable

· Patent certifications

· Debarment certification

· Field copy certification

· User fee cover sheet

· Financial disclosure information

· Letters of authorization for reference to other applications or drug master files (if applicable)

· Waiver requests

· Environmental assessment or request for categorical exclusion

· Statements of claimed exclusivity and associated certifications

*Environmental assessment should be provided as a separate volume.

b.Prescribing information

All copies of the labels and all labeling for the product should be included. Examples are provided below-

Container and package labels
Package inserts
Draft labeling
Patient leaflets
Information sheets
Medication Guides

c. Annotated labeling text

A copy of the proposed labeling text with annotations directing reviewers to the information in the summaries and other modules that support each statement in the labeling should be provided.

Module 2 – Common Technical Document Summaries

Module 2 should include the summary documents. The documents for this module should be provided in the order as described below.

1. Overall CTD table of contents

For the first document in this module, a comprehensive table of Contents should be provided listing all of the documents provided in the submission for modules 2 through 5.

2. Introduction to the summary documents

Introduction to the summary should be provided as described in the guidance document M4: Organization of the CTD as a one page document.

3. Overviews and summaries

Module 2 should contain the following additional documents as described in the appropriate guidance documents (M4Q: The CTD -Quality, M4S:The CTD - Safety, M4E: The CTD – Efficacy):

·Quality overall summary (2.3, Module 2, section 3)

· Non clinical overview (2.4)

· Clinical overview (2.5)

· Nonclinical summary (2.6)

· Clinical summary (2.7)

The nonclinical summary and the clinical summary should be provided in separate volumes for ease of use by reviewers.

Module 3 - Quality

Module 3 should include information on the drug and product that should be provided in the order described below.

1. Module 3 table of contents

The first document in this module should be a table of contents listing all of the documents provided for module 3. See the guidance document M4Q: The CTD Quality for the headings and order to be used in the table of contents, including numbering of section headings.

2. Body of data

Each individual subsection related to the drug and product should be provided as an individual document either bound separately or divided by tab identifiers, depending on the size of the subsection. The documents should be presented in the order in which they are listed in the table of contents.

3. Literature References

Each literature reference should be provided as an individual document, separated from the others by tab identifiers.

Module 4 - Nonclinical Study Reports

Module 4 should contain the nonclinical study reports and related information. The documents should provide for this module in the order described below-

1. Module 4 table of contents

The first document in this module should be a table of contents listing all of the documents provided for module 4. See the guidance to industry M4S: The CTD – Safety for the headings and order to be used in the table of contents, including numbering of section headings.

2. Study reports and related information

Each study report and each related document should be provided as an individual document, separated from the other documents by binders or tab identifiers. These documents should be presented in the order in which they are listed in the table of contents.

3. Literature References

Each literature reference should be provided as an individual document, separated from the others by tab dividers.

Module 5 - Clinical Study Reports

Module 5 should contain clinical study reports and related information. The documents for this module should be provided in the order described below.

1. Module 5 table of contents

The first document in this module should be a table of contents listing all of the documents provided in Module 5. See the guidance to industry M4E: The CTD – Efficacy for the headings and order to be used in the table of contents, including numbering of section headings.

2. Study reports and related information

Each study report and each related document should be provided , such as tabular listings of all clinical studies, as an individual document separated from the other documents by binders or tab dividers. Tab identifiers be provided for each appendix in a study report. These documents should be presented in the order in which they are listed in the table of contents.

3. Literature References

Each literature reference should be provided as an individual document separated from the others by tab identifiers.

V. Number of Copies of NDA- The regulations requires archival, review, and field copies of NDAs

1.Archival Copy- The archival copy is a complete copy of the application. It serves as the official archive of the application and may be used during the review of the application.

2. Review copy- It includes 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 21 CFR 314.50 for an individual submission include:

· 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

· Clinical (Module 5) – clinical microbiology documents.

Copy of Modules 1 and 2 should be provided in each review copy. Each review copy should be labeled and bound separately.

3. Field copy-The field copy should be a separately bound copy of the Quality section (Module 3) for the NDA.

VI. Paper size, font size, pagination, binder colors and mailing address-

Paper size-Standard U.S. letter size paper (8.5 x 11 inches) should be used for all submissions.

Font size-Narrative text be submitted in Times New Roman 12 point font. Font sizes 9 to10 points are considered acceptable in tables.

Pagination-Page numbering should be at the document level and not at the volume or module level. (The entire submission should never be numbered consecutively by page.) In general, all documents should have page numbers. Since the page numbering is at the document level, there should only be one set of page numbers for each document.

Binder Colors for NDA Review Copies

Review copy for:	Binder color
Quality	Red
Nonclinical	Yellow
Clinical- pharmacokinetics and bioavailability	Orange
Clinical – microbiology	White
Clinical - safety and efficacy	clinical Tan
Clinical - safety and efficacy	statistical Green