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ANDA- Abbreviated New Drug Application

BY,

N.NARESH KUMAR

M-PHARMACY

(PHARMACOLOGY)

G.P.R.C.P

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Definition of a Generic Drug

“A drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use”.

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Basic Generic Drug Requirements

Same active ingredient(s) Same route of administration Same dosage form Same strength Same conditions of use Inactive ingredients already approved in a similar

NDA

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

Definition of a ANDA

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Advent of Generic drug competition:

Generic drugs always been available in US market.

DESI: Drug Efficacy Study Implementation.

When the DESI program was in progress, the agency estimated that there were between 5-13 products without NDA’s that were identical and similar to each of the 13,000 products that held NDA’s under the 1938 Act.

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These products contain same active ingredients in the same amount and dosage form, often though they claim some unique characteristics i.e., a different salt or ester, a different amount, a different dosage form or an extra added ingredients.

As part of the DESI project the FDA thought to introduce uniformity and control over these products.

First, the agency said that a copy had to be identical, unless the proponent got FDA permission to vary from the innovator.

Advent of Generic drug competition: - contd

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Second, the manufacturer had to obtain an ANDA showing that the product was identical.

In essence, it was an application that contain all the CMC of a full NDA, but omitted any preclinical or clinical data.

A number of generic firms opposed even these requirements and significant litigation followed.

Advent of Generic drug competition: - contd

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Evolution of ANDA:

Physicians were reporting that CHF patients who had been treated carefully with a specific dose of Digoxin, went out of control upon getting prescriptions refilled.

Investigations revealed that Digoxin, a pre 1938 drug that never subject to an NDA, varied from manufacturer to manufacturer not in quantity of actual drug per tablet, but in the amount of drug released from the tablet into the body.

The consequences could be life threatening.

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The agency responded with an order that each manufacturer submit an ANDA that included bioavailability studies showing the rate and extent of absorption into the body.

Thus, was born an idea of bioequivalence: that competing products not only be pharmaceutically identical but also show no significant difference in the rate and extent of absorption in controlled bioavailability studies.

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The ANDA process and bioequivalence permitted the agency for the first time to declare individual generic products to be therapeutically equivalent to approved brand drug.

The FDA began making such declarations in 1975, 1976 and 1979, the agency began to publish them in orange book.

The generics doesn’t have a great competitive threat because state pharmacy laws did not permit the substitution of a generic drug for the innovator drug.

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In 1979 the federal trade commission revealed a model state drug product selection law, which guided state legislatures how to amend pharmacy laws to permit druggists to substitute equivalent generics for innovators without the permission of the prescribing physicians.

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Abbreviated New Drug Application (ANDA): Generics

An 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.

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(ANDA): Generics - contd

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

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(ANDA): Generics - contd

Generic applicants must scientifically demonstrate that their product is bioequivalent.

One way to demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36hrs healthy, volunteers.

This gives the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug.

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Why is it called “ABBREVIATED”?

The term abbreviated is used in generic drug applications because, these applications does not require including preclinical and clinical data to establish safety and efficacy.

Scientific demonstration of the bioequivalence is important and must.

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Necessary items for ANDA:

i. The composition of drug, stating the name and amount of each ingredient, whether active or not, contained in a stated quantity of the drug in the form in which it is to be distributed.

ii. Identify the place where the drug will be manufactured, processed, packaged, and labeled and the name of the supplier of the active ingredient.

iii. Identify any person other than the applicant who performs a part of those operations.

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iv. Include certifications from the applicant and the methods used in process, and the facilities and controls used for, the manufacture, processing, packing, and holding of the drug are in conformity with current good manufacturing practice.

v. Assure that the drug dosage form and components will comply with the specifications and tests described in an official compendium.

vi. If the drug differ from the compendium drug, that the specifications and tests applied to the drug and its components are adequate to assure their identity, strength, quality and purity.

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vii. Outline the methods used in, and the facilities, and controls used for, the manufacture, processing, and packaging of the drug.

vii. If the drug requires only an ANDA also specifies that there must be included adequate data to assure the biologic availability of the drug, and the preparations claiming sustained action, such data should show that the drug is available at a rate of release that will be safe and effective.

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Goals of ANDA:

To reduce the price of the drug.

To reduce the time development.

Increase the bioavailability of the drug in comparison to references list drug.

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Waxman-Hatch Act:

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.

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Waxman-Hatch Act – contd

At the same time, it provides a mechanism to grant drug companies up to 5 years additional patent protection for new drugs to compensate for some of the years of patent life lost as a result of the time consuming testing required by the FDA.

Under this provision, patent office, working in collaboration with FDA, can grant up to 5 years additional time of patent protection to certain new pharmaceutical entities depending on the length of time for which these entities were required to go through the regulatory review process.

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The FDA, which will not grant any additional time for delays caused by the neglect or mistakes of the pharmaceutical company.

Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.

Waxman-Hatch Act – contd

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Conditions which must be fulfilled in order to ask for an extension are:

1. The patent must not have expired at the time of filing the request for extension.

2. The patent must never have been extended.

3. The product must have been subjected to examination by the FDA.

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4. The request for extension must have been filed within 60 days of the granting of the NDA.

5. The request for extension must have been filed, at the latest during the last three months of the life of the patent.

6. A fee of $750 must be paid.

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Patent Certification condition for ANDA: Brand drug applicants are to provide the FDA with the

identity and expiration date of any patent that claims the drug for which FDA approval is required.

ANDA’s must certify that:

i. No Such patents have been identified by the original brand drug applicant.

ii. The identified patents have expired.

iii. The date the patents will expire.

iv. The patents are invalid or will not be infringed by the marking, use or sale of the generic drug.

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If the first (i) and second (ii) certifications are made, approval can be immediate.

If the third (iii) certification is made approval is delayed until the patents expire.

If the applicant makes the fourth (iv) certification, the generic applicant must apply the original brand drug applicant a detailed statement supporting the assertion non-infringement or invalidity.

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ANDA

(Reviewed by CDER)

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Center for Drug Evaluation and Research – (CDER)

The center reviews applications for new and generic pharmaceuticals, manages US cGMP regulations for pharmaceutical manufacturing, determines which medications require a medical prescription, monitors advertising of approved medications, and collects and analyzes safety data about pharmaceuticals that are already on the market.

CDER reviews New drug Applications to ensure that the drugs are safe and effective. It is one of the Centers at the FDA. Its primary objective is to ensure that all prescription and over-the-counter(OTC) medications are safe and effective when used as directed.

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(NDA) Requirements (ANDA) Requirements 1. Labeling 1. Labeling2. Pharm/Tox 2. Pharm/Tox3. Chemistry 3. Chemistry4. Manufacturing 4. Manufacturing5. Controls 5. Controls6. Microbiology 6. Microbiology7. Inspection 7. Inspection8. Testing 8. Testing9. Animal Studies10. Clinical Studies 9. Bioequivalence11. Bioavailability

NDA vs. ANDA Review Process

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How is Generic Drug Quality Assured?

First 8 steps of review process identical to NDA process

Bioequivalence requirements for ANDA’s same as NDA’s

FDA has experience with the product Product is known to be safe Scientific literature published Post-approval product surveys

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Labeling:

“Same” information as brand name labeling

May delete portions of labeling protected by patent or exclusivity (i.e., an indication, strength)

May differ in excipients and product description (i.e., colors, shapes)

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Pharm / Tox :

All inactive ingredients must be approved in either the reference listed drug or similar NDA in same or higher levels. (FDA publishes the ingredient and highest approved levels.)

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Chemistry, Manufacturing and Controls (CMC):

Components and composition Manufacturing and Controls Batch formulation and records Description of facilities Specifications and testing Packaging Stability

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Microbiology:Includes for anti infective drug products.requires the following technical information and data:- A complete description of the biochemical basis of the

drug action on microbial physiology The drugs antimicrobial spectrum Describe any known mechanism of resistance to the drug

and provide information/data of any known epidemiologic studies demonstrating prevalence to resistance factor

Clinical microbiology laboratory methods Assure the sterility of the product through the

manufacturing process – especially important with injectable drug products.

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Inspections/Testing: Assure manufacturing facilities are in compliance with

current good manufacturing practices (cGMPs) Assure bioequivalence sites are in compliance with

current good clinical practices (cGCPs) Conducted primarily by Field/Office of Regulatory

Affairs with support from Center (Office of Compliance) and assigned geographically

Labs are in the Office of Regulatory Affairs and the Center

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Bioequivalence:

A generic drug is considered to be bioequivalent to the brand name drug if:

The rate and extent of absorption do not show a significant difference from listed drug, or

The extent of absorption does not show a significant difference and any difference in rate is intentional or not medically significant.

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Bioequivalence – contd:

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Original Abbreviated New Drug Application(ANDA) Approvals: July 2010 Drug Name

andFDA Appl. # ActiveIngredients

Marketing Status

Company ApprovalDate

TRIAMCINOLONE ACETONIDE(ANDA # 040771)TRIAMCINOLONE ACETONIDE

Prescription LYNE 07/01/2010

RANITIDINE HYDROCHLORIDE(ANDA # 078890)

RANITIDINE HYDROCHLORIDE

Prescription VINTAGE PHARMS

07/01/2010

TACROLIMUS(ANDA # 090402)

TACROLIMUS Prescription WATSON LABS 07/01/2010

DOXYCYCLINE(ANDA # 090855)

DOXYCYCLINE Prescription MYLAN 07/01/2010

ADAPADENE(ANDA # 091314)

ADAPALENE Prescription GLENMARK GENERICS

07/01/2010

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Conclusion: NDA ANDA

Applicable for new drug Applicable for generic drugTake longer time ( 12-15 years)

Compare to NDA less time taken(1-2 years)

More expenditure of money Comparatively lessCost of drugs are more Cost of drugs are lessNonclinical studies and clinical investigations are essential

Nonclinical studies and clinical investigations are nonessential except bioavailability and bioequivalence

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References: http://www.fda.gov/cder/guidance/index.htm. Modern pharmaceutics 4th edition by Banker and Rhodes. Burgers Medicinal Chemistry and drug discovery – Vol-II. A Text Book of Pharmaceutical medicine 5th Edition by

John p.Griffin and John O’Grady. Comprehensive Medicinal chemistry by Hansch,

Sammer, Taylor. The Theory and Practice of Industrial Pharmacy by Leon

Lachman.

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