Abbreviated New Drug Application (ANDA)

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An Abbreviated New Drug Application (ANDA) contains data which when submitted to FDA’s Center for Drug Evaluation and Research, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public.

A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. All approved products, both innovator and generic, are listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).

Generic drug applications are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy, volunteers. This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug. The generic version must deliver the same amount of active ingredients into a patient’s bloodstream in the same amount of time as the innovator drug.

Using bioequivalence as the basis for approving generic copies of drug products was established by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Waxman-Hatch Act. This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA’s approval process. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation. For more information on generic drug bioequivalency requirements, please see the chapter entitled “FDA Ensures Equivalence of Generic Drugs” in “From Test Tube to Patient: Improving Health Through Human Drugs.”

The Office of Generic Drugs home page provides additional information to generic drug developers, focusing on how CDER determines the safety and bioequivalence of generic drug products prior to approval for marketing. Generic drug application reviewers focus on bioequivalence data, chemistry and microbiology data, requests for plant inspection, and drug labeling information.

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An Abbreviated New Drug Application (ANDA) is an application for a U.S. generic drugapproval for an existing licensed medication or approved drug.

The ANDA is submitted to FDA‘s Center for Drug Evaluation and Research, Office of Generic Drugs, which provides for the review and ultimate approval of a generic drug product. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public. Electronic submissions of ANDAs have grown by 70% since November 2008.^[1] The Section IV challenge has been credited with suppressing new drug innovation.^[2]

A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use. All approved products, both innovator and generic, are listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).

Generic drug applications are termed “abbreviated” because they are generally not required to include preclinical (animal and in vitro) and clinical (human) trial data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy volunteers. This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug. The generic version must deliver the same amount of active ingredients into a patient’s bloodstream in the same amount of time as the innovator drug. The bioequivalence of a drug can be demonstrated by comparing drugs dissolution or transdermal drug absorption in case of topically active drug, in case of systemically active drug blood concentration of that drugs is compared with innovator drugs

Using bioequivalence as the basis for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act. This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA’s approval process. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.

Kathie Clark (June 30, 2009). “DIA Update: News from the FDA”. The eCTD summit.
http://www.sciencemag.org/cgi/content/full/326/5951/370

A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use.

I. Important facts about generics and generic drug applications (ANDA)-

Generic drug applications are termed “abbreviated” because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.

Generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug).

Bioequivalence is generally determined by measuring the time taken for generic drug to reach the bloodstream in 24 to 36 healthy, volunteers. This gives the rate of absorption, or bioavailability, of the generic drug, which can be compared to that of the innovator drug.

The generic version must deliver the same amount of active ingredients into a patient’s bloodstream in the same amount of time as the innovator drug.

The basis for approving generic copies of drug products was established by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the “Hatch -Waxman Act”.

II. Facility and Drug Registration for filing an ANDA-

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.

III.Format and content of ANDA-

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

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. Forms and cover letter-

FDA form 356h

Cover letter

Form FDA 3674

2. Comprehensive table of contents

The next document in Module 1 should be the comprehensive table of contents for the entire submission. Each ANDA submission is required to have a comprehensive table of contents or index for the entire submission (as per 21 CFR 314.94)

3. Administrative documents

a. Administrative documents

Appropriate administrative documents should be provided with the submission. Examples of administrative documents are listed below. 21 CFR 314.94 consists of details on the administrative documents needed for ANDA.
Field copy certification
Debarment certification
Financial Certification
Patent information on any patent that claims the drug, if applicable
Patent certifications
Letters of authorization for reference to other applications or drug master files (if applicable)
US Agent Letter of Authorization
Proprietary name request (if applicable )
Basis of ANDA submission
Comparison between Generic Drug and RLD-505(j)(2)(A)
Request for waiver
Draft labeling
Listed drug labeling
Labeling requirements
Financial disclosure information
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. Labeling comparison

For the ANDA, the comparison of labeling should be provided that is described in 21 CFR 314.94(a)(8).

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

For an ANDA submission Module 4 is not necessary.

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.

For information in module 5 specific to an ANDA, refer –ANDA filing checklist.

V. Number of Copies of ANDA– The regulations requires archival, review, and field copies of ANDAs

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 314.94 for an individual submission include:

Quality (Module 3),

Clinical (Module 5) – Bioequivalence 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 ANDA.

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 ANDA Copies