The drug designated for production has to be manufactured in compliance with Current Good Manufacturing Practices (cGMP) following USFDA requirements, EU Directive or International Conference on Harmonization (ICH) Guidelines or Regulatory Authority of respective country. Regulatory authorities bear the responsibility to conduct inspections on pharmaceutical manufacturing plants to ensure they follows cGMP guidelines so that the drug manufactured is safe and effective. A quality system has to be set up such that the drug is manufactured in accordance with approved procedures. A drug is not permitted for sale until the marketing application for the new drug has been reviewed and approved by regulatory authorities. Extensive dossiers are provided to the authorities to demonstrate the safety, potency, efficacy and purity of the drug. After the drug has been approved and marketed, there is continuous monitoring of the safety and performance of the drug to ensure that it is prescribed correctly and adverse events (side effects) are investigated. The United States Food and Drugs Administration (FDA) has one of the most comprehensive and transparent regulatory systems in the world. In US Common Technical Document (CTD) format and most recently its electronic version-the electronic Common Technical Document (eCTD) format is used for submission of dossiers. Inclusion of a paragraph IV certification permits the Applicant to file its ANDA 4 years after the approval of a new chemical entity that is 1 year before the actual expiry of the 5 years exclusivity. In case patent exists that claims the drug, drug product, or method of use, the applicant is requested to file a patent certification with regards to the patent status. The different types of patent certifications are discussed. This project work elucidates US FDA’s previous interpretations of the statute regarding 180 days exclusivity and latest amendments in the current guidance. Information considered helpful in the compilation of different CTD modules 1, 2, 3, and 5 is discussed. Electronic submission in eCTD format is outlined.

Reference Id: PHARMATUTOR-ART-2534

PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 5, Issue 11

Received On: 20/06/2017; Accepted On: 10/07/2017; Published On: 01/11/2017

How to cite this article: Thakur M, Setia A, Neetu; An Approval to manufacture and sale the copy of innovator product in the US Market; PharmaTutor; 2017; 5(11); 9-16

Drug discovery occurs when a new compound is developed that addresses a specific disease target. After scientists identify a potentially viable drug candidate in the early drug discovery process, that compound proceeds to laboratory testing against specific targets to determine its effects. Most compounds are eliminated as they proceed from the discovery to the human development phase. When a chemical is found to impact a specific target, human testing is conducted through clinical trials to show the safety and efficacy of the chemical so that it may be approved by the FDA as a drug. The emphasis is that drugs should be safe, pure, effective and of consistent quality to ensure that they are fit to be used for their intended functions1. A drug is not permitted to sale until the marketing application for the new drug has been reviewed and approved by regulatory authorities. This process is performed within legislative framework which defines the requirements necessary for application to the concerned regulatory authority, details on the assessments procedure and the ground for approval or rejection of the application, and also the circumstances where a marketing authorization already granted may be withdrawn, suspended or revoked2. The authorities in The United States, The European Union and Japan asks for the common Technical Documents format and more recently, its electronic version the Electronic Common Technical Document.The current framework for generics in the United States is governed by the Drug Price Competition and Patent Term Restoration Act of 1984, more commonly known as Hatch-Waxman Act, and the Medicare Prescription Drug Improvement and Modernization Act (MMA) 3. The Hatch-Waxman created the section 505(j) of FD&C Act which was codified under title 21 of the CFR in section 314. Section 505(j) provides the statutory basis allowing pharmaceuticals companies to file Abbreviated New Drugs Application (ANDAs) instead of providing a full new drug application comprising the whole range of preclinical and clinical studies.
At the same time Hatch-Waxman allows brand name companies to apply for up to five additional years of patent protection for new medicines to compensate for time lost while their products were going through FDA’s approval process4.

Provisions of the Hatch-Waxman Act that protect products of innovator companies comprise:
A) Market Exclusivity upto 5 years
B) Patent Term Restoration
Benefits of the Hatch-Waxman Act for the generic manufacturer:
A) Implementation of Abbreviated New Drugs Application.
B) Establishment of Bioequivalence as the basis for approving generic drugs.
C) Providing manufacturer of generics with an exemption for pre expiry development and testing including the use of brand name drug to perform studies required for the approval process.
D) 180 days generic exclusivity.

With the publication of the Generic Drugs Final Rule and Initiative in June 20035, FDA revised its interpretation of the Hatch-Waxman Act by improving the implementation regulations with regards to generic drugs. The final rule facilitates the market entry of generic medicines by allowing a maximum of one 30-month stay per ANDA instead of previously possible multiple and overlapping 30 month stays. It clarifies the type of patents that must and must not be submitted to FDA for listing in Orange Book, revising the information required to be submitted on patents and consolidating all patent information on declaration forms to make those submissions are more informative and precise.


The Medicare Prescription Drug Improvement & Modernization Act which changed provisions of the FD&C Act that were originally added by the Hatch-Waxman Act.
Regarding Generics MMA provides for:
A) Single 30 month stay on a statutory basis.
B) First Commercial Marketing to trigger the 180 days exclusivity.
C) Forfeiture Mechanism to avoid scenarios where multiple first filers block one another to market.
D) Modification to be included in a single drug application on a statutory basis.

The Legal basis for the filling of an ANDA is laid down in section 505(j) of the FD&C Act, which was implemented by Hatch-Waxman Act. Regulatory action required for the submission of an ANDA by the applicant is provided in the corresponding section of CFR, that is subpart c or section 314.62 to 314.99. The content and format of and abbreviated applications described in section 314.94 of the CFR. An ANDA is usually submitted for a drug product that is the same as a drug product previously approved (Reference Listed Drug) by the FDA.
Application submission is generally substantiated by the following particulars
A) Reference to the name of the Listed Drug,including gits dosage for m and strength
B) Astatementasto whether the Listed Drug is entitled to aperio do f marketing exclusivity
C) However,asstipulatedin§314.92anAbbreviatedNewDrugApplicationmay only be submitted for drug products that are thesameasthe(Reference)Listed Drug.As further detailed in § 314.92(a)(1) theterm"same as"means, the drug product and Listed Drug6:
(i)     Shall contain the identical activeingredients
(ii)   Shall beidentical in strength, dosageform, androute of administration
(iii) Shall haveidentical conditions of use

New drug exclusivity is implemented by provision sunder section 505(j)(5)(F) of the Act codifiedin21CFR314.108. This section of the Act provides for specific time periods, known as new drug product exclusivity or market exclusivity, during which an ANDA can not be submitted or the effective date of approval for an ANDA must be delayed.Aspersection505(c)(3)(E) and 505(j) (5) (F) of the Act a 5-year period of exclusivity is granted for new chemical entities (NCE) not previously approved by FDA.

The selections of the Act expressly state that no ANDA may be submitted during the exclusivity period an d that such applications may be submitted after 4 years only if they contain a certification of patent in validity or non- infringement. Under the same sections it islaid down that certain drugs or changes to drugs  such as a  change  in dosage  form or strength, new  indications or routes of administrationcanreceive 3 years periodof exclusivity. However, approval of three-year exclusivity requires new clinical investigations (other than bioavailability studies).

PATENT PROTECTION The patent confers"theright to exclude others from making, using, offering for sale,or selling the in vention through out the United States or importing the in vention in to the United States” Patent applications are filed with the USPTO,  which is part of the US Department of Commerce. Hence, the role of the USPTO is only  to grant patents  or  to  register trademarks  but  not  to protect  theinventions. Generally, the period of validity of a new patentis 20 years from the date offiling of the patent application7. Patents may only been forced vialawsu its. If a patent is in fringed, the patentee may  sue forrelief in the appropriate federalcourt. The patentee may ask the  court for a restriction  to prevent the continuation of in fringement and may also ask the court for an award of damages because of the in fringement. In such an in fr in gement suit, the defend an tmayra is e the question of the validity of the patent, which is then decided by the court. Patent Term Restoration (PTR) enacted by the Hatch-Waxman Act in1984 compen sates patent holders for marketing time lost while developing theproduct and awaiting FDA approval by extending the patent term up to five years.



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