INTRODUCTION• The generic drug is a safe, effective and economical substitute of a brand name drug product• The act which surrounds the generic drug approval process of the USFDA is the “Hatch Waxman Act of 1984” which we also identify by the “Drug price control and Patent Term Restoration Act of 1984” which led to a plethora of generic drugs entering into the market• Early before the passage of the act the pharmaceutical market was ruled by the brand name drug manufacturers which we also call as the Innovators• The generic drug manufacturers seldom used to compete with them and invest their funds for the already existing brands in the market
• There was a lack of competition and the innovator enjoyed his elite monopoly period within which no other brand of the drug can enter into the market• This exclusivity period also allowed the innovator to quote highest prices of the drugs• To stop these practices and to make a user friendly drug market, the US congress passed the Hatch Waxman Act in 1984 which was regarded as one of the most successful segments of the US legislation at that time• The act was passed taking into consideration the interests of both the innovator and the brand name drug manufacturer
• An Abbreviated New Drug Application (ANDA) contains data submitted to FDAs Center for Drug Evaluation and Research, Office of Generic Drugs, for review and ultimate approval of a generic drug product.• Once ANDA is approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the public.• 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).• This will 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 patients bloodstream in the same time as the innovator drug.
• Use of bioequivalence as the base for approving generic drug products was established by the "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the HATCH-WAXMAN ACT.• It is because of this Act that there is the availability of less costly generic drugs into the market without conducting costly and duplicative clinical trials.• At the same time, the brand-name companies (innovators) can apply for up to five additional years longer patent protection for the new medicines that they developed to make up the time lost while their products were going through FDAs approval process.
BIRTH OF GENERICS: THE HATCH WAXMAN ACT OF 1984• The act which gave rise to the generic drug industry was passed as amendments of the Federal Food, Drug, and Cosmetic Act (FFD & C).• The main objectives of the act were to:1. Offset the drug approval delay:• Early before the passage of this act, the innovators used to encounter a delay in approval of their New Drug Applications (NDA) for brand name product which eventually affected their brand entry in the market and financial losses.
2.Bring healthy competition and to avoid price rise:• Early before its passage there was no scope of the generics to enter the market until the patent term of the innovator has expired as no provisions of challenging the validity of the innovator patent was there.• Also there were not many benefits expected by the generic in investing capital to relaunch another version of already existing brand of the drug after its patent expiry.• This product monopoly kept competition away and the drug prices high as per the innovators will.3. Make life easier for the generic:• Generic manufacturers used to face a lot of difficulties in doing all the pre-clinical and clinical studies as done by the brand name manufacturers to get their generic approved
• The act was passed keeping one eye on the interests of both the brand name and the generic drug manufacturers providing almost equal benefits to both.• The benefits received by the brand name manufacturers are:1. Regulatory delays in brand approval were deciphered.2. The market exclusivity and the „effective patent life‟ (the time left when the drug comes into the market after drug development and FDA approval) was extended from 8.5 years (1980) to 13 years (late 1980s) and now it‟s nearly 16-17 years.
• The benefits received by the generic manufacturers are:1. The generic could challenge the validity of the patent issued to the innovator2. The act provided with the stipulation to file an Abbreviated New Drug Application (ANDA) and to leave out the expensive pre-clinical and clinical trials as done by the innovator and provided with the provision of relying on the safety and efficacy data of the innovator drug and to perform a much cheaper substitutable study called „bioequivalence‟ to establish equivalence with the innovator.3. As per the act, once approved the generic gets an exclusivity period of six months to rule the market along with the innovator during which no other generic can be given approval.
• The FDA publishes the information on every approved drug product in the “Approved Drug Products with Therapeutic Equivalence Evaluations” which we also know by the name of “Orange Book”.• It lists the NDA‟s and ANDA‟s along with the expiry dates of patents and generic exclusivities. It is a ready reference of brand name drug products for the generic companies who usually use this information to identify the reference for developing their generic versions.• The Orange book also contains certain therapeutic equivalence codes.• An A- prefixing product is considered to be substitutable and B- prefixing is a safe and effective product for use but is regarded inequivalent and non- substitutable with the brand name drug product.
Content and format of an abbreviated application1. Application form2. Table of contents3. Basis for abbreviated new drug application submission4. Conditions of use5. Active ingredients6. Route of administration, dosage form and strength7. Bioequivalence8. Labeling9. Chemistry, manufacturing and controls10. Samples11. Patent certification
1. Application form.• The applicant shall submit a completed and signed application form.2. Table of contents.• The archival copy of the abbreviated new drug application is required to contain a table of contents that shows the volume number and page number of the contents of the submission.3. Basis for abbreviated new drug application submission.• The name of the reference listed drug, including its dosage form and strength.• For an abbreviated new drug application, a reference to FDA- assigned docket number for the petition and a copy of FDAs correspondence approving the petition.
4. Conditions of use.• A statement that the conditions of use prescribed, recommended, or suggested in the labeling proposed for the drug product have been previously approved for the reference listed drug.• A reference to the applicants annotated proposed labeling and to the currently approved labeling for the reference listed drug provided.
5. Active ingredients.• Statement that the active ingredients of the proposed drug product are the same as those of the reference listed drug, or if one of the active ingredients differs from one of the active ingredients of the reference listed drug,• Information to show that the other active ingredients of the drug product are the same as the other active ingredients of the reference listed drug,• Information to show that the different active ingredient is an active ingredient of another listed drug and such other information about the different active ingredient that FDA may require.
6. Route of administration, dosage form, and strength.• A statement that the route of administration, dosage form, and strength of the proposed drug product are the same as those of the reference listed drug.• If the route of administration, dosage form, or strength of the drug product differs from the reference listed drug and the abbreviated application is submitted such information about the different route of administration, dosage form, or strength that FDA may require.
7. Bioequivalence .a) Information that shows that the drug product is bioequivalent to the reference listed drug upon which the applicant relies.• A complete study report must be submitted for the bioequivalence study upon which the applicant relies for approval.• The applicant must submit either a complete or summary report. If a summary report of a bioequivalence study is submitted and FDA determines that there may be bioequivalence issues or concerns with the product, FDA may require that the applicant submit a complete report of the bioequivalence study to FDA.b) If the abbreviated new drug application is submitted the results of any bioavailability of bioequivalence testing required by the agency.• any other information required by the agency to show that the active ingredients of the proposed drug product are of the same pharmacological or therapeutic class as those in the reference listed drug and that the proposed drug product can be expected to have the same therapeutic effect as the reference listed drug.• If the proposed drug product contains a different active ingredient than the reference listed drug, FDA will consider the proposed drug product to have the same therapeutic effect as the reference listed drug if the applicant provides information demonstrating that.
8. Labelinga) Listed drug labeling. A copy of the currently approved labeling for the listed drug referred to in the abbreviated new drug application, if the abbreviated new drug application relies on a reference listed drug.b) Copies of proposed labeling. Copies of the label and all labeling for the drug product.c) Statement on proposed labeling. A statement that the applicants proposed labeling including, if applicable, any Medication Guide required is the same as the labeling of the reference listed drug.d) Comparison of approved and proposed labeling. The applicants proposed labeling and labeling approved for the reference listed drug may include differences in expiration date, formulation, bioavailability, or pharmacokinetics, labeling revisions made to comply with current FDA labeling guidelines or other guidance, or omission of an indication or other aspect of labeling protected by patent or accorded exclusivity.
9. Chemistry, manufacturing, and controls.a) The information required shall contain the proposed or actual master production record, including a description of the equipment, to be used for the manufacture of a commercial lot of the drug product.b) Inactive ingredients. an applicant shall identify and characterize the inactive ingredients in the proposed drug product and provide information demonstrating that such inactive ingredients do not affect the safety or efficacy of the proposed drug product.c) Inactive ingredient changes permitted in drug products intended for parenteral use. Generally, a drug product intended for parenteral use shall contain the same inactive ingredients and in the same concentration as the reference listed drug identified by the applicantd) Inactive ingredient changes permitted in drug products intended for ophthalmic or otic use. . Generally, a drug product intended for ophthalmic or otic use shall contain the same inactive ingredients and in the same concentration as the reference listed drug identified by the applicant .
e)Inactive ingredient changes permitted in drug products intended for topical use. Generally, a drug product intended for topical use, solutions for aerosolization or nebulization, and nasal solutions shall contain the same inactive ingredients as the reference listed drug identified by the applicant.10. Samples. Samples need not be submitted until requested by FDA.
11. Patent certification• While filing an ANDA, the generic manufacturer is required to file one of the following four possible certifications on the subject of the reference brand name patent listed in the Orange Book.1. Para I certification: There is no patent for the drug listed in the orange book2. Para II certification: Patent is listed but has expired3. Para III certification: Patent is listed, is valid but the generic wants approval to market the drug once the pertinent patent expires
Para IV certification: The generic manufacturer either challenges the validity of the brand name listed patent asserting it to be invalid or fake, or it affirms not to cross the fringe of the brand name patent claims.• Para IV certification is the most critical of all and gives rise to almost all the anti-competitive practices associated with the Hatch Waxman amendments of the FFD and C act.
Manufacturing and control requirement of ANDARequirements for Drug substances sources: 1.copy of potential supplier‟s most recent establishment inspection report describing FDA‟s findings. This document should be reviewed by the applicant to check acceptability of that manufacturer by FDA. 2.In addition, the supplier should have a DMF available at FDA for reference purposes .This will describes the facilities, personnel, equipment, and manufacturing & controls procedure used at the site (s) where the bulk drug substance is made.
ANDA Expiration dates1.The FDA will tentatively approve a two year expiration date for a product if satisfactory data reflecting at least three months storage under accelerated conditions is submitted.2.The sponsor is also expected to provide a commitment to continue to monitor the stability of the product periodically report the results to FDA, and to remove from market any batches failing to meet specifications prior to product‟s labeled expiration period.3.Final approval for the expiration date is obtained when acceptable shelf life data for two years on more than one production lot is made available to FDA.