INTRODUCTION:

Generic drug is a pharmaceutical drug that has the same chemical substance as the drug that was originally developed, patented and innovated. Generic drugs are allowed for sale after the expiry of the patent of the original drugs. Because the active chemical substance is the same, the medical profile of generics is believed to be equivalent in performance.^[1][2] The generic drug has the same active pharmaceutical ingredient (API) as the original, but it may differ in characteristics such as manufacturing process, formulation, excipeints, colour, taste, and packaging.^[2][3]

HISTORY:

Generic drugs are nothing new. Back in the 1920s, the company that made Bayer aspirin fought vigorously to keep generic versions off the shelves. The company lost in court, and consumers suddenly had an array of choices in generic aspirin.[5] Today, generic drugs are both widely available and carefully regulated. Those days effectively ended in 1962 when the Food and Drug Administration dramatically revamped the Federal Food, Drug, and Cosmetic Act, originally passed in 1938.[5] The new regulations applied to both brand name and generic drugs, a fact that slowed the release of new generics to a trickle.[6] Any new generic drug had to go through the same investigational trials as any other drug, even if its active ingredients were identical to an already established brand name drug. Companies also had to wait for the brand name patent to expire before they could even do the testing require to produce a generic. Most companies didn't bother.[6] By 1983, only 35 percent of the top-selling drugs with expired patents had a generic competitor, according to the Congressional Budget Office.[6]

REGULATION:

Most nations require generic drug manufacturers to prove that their formulations are bio equivalent to their brand-name counterparts.^{[8][9][10][11][1}^2][¹^3]

Bio equivalence does not mean generic drugs must be exactly the same as the brand-name product ("pharmaceutical equivalent"). Chemical differences may exist; a different salt or ester may be used, for instance. Different inactive ingredients means that the generic may look different to the originator brand.^[14] However, the therapeutic effect of the drug must be the same ("pharmaceutical alternative") Most small molecule drugs are accepted as bio equivalent if their pharmacokinetic parameters of area under the curve (AUC) and maximum concentration (C_max) are within a 90% confidence interval of 80–125%; most approved generics are well within this limit.^[15] For more complex products—such as inhalers, patch delivery systems, liposomal preparations, or bio similar drugs—demonstrating Pharmacodynamics or clinical equivalence is more challenging.^[16]

ACQUINTANCE:

A series of scandals around the approval of generic drugs in the late 1980s shook public confidence in generic drugs; there were several instances in which companies obtained bio equivalence data fraudulently, by using the branded drug in their tests instead of their own product, and a congressional investigation found corruption at the FDA, where employees were accepting bribes to approve some generic companies' applications and delaying or denying others.^[17][18][19]

Some generic drugs are viewed with suspicion by doctors. For example, warfarin (Coumadin) has a narrow therapeutic window and requires frequent blood tests to make sure patients do not have a sub therapeutic or a toxic level. A study performed in Ontario showed that replacing Coumadin with generic warfarin was safe,^[20] but many physicians are not comfortable with their patients taking branded generic equivalents.^[21] In some countries (for example, Australia) where a drug is prescribed under more than one brand name, doctors may choose not to allow pharmacists to substitute a brand different from the one prescribed unless the consumer requests it.^[22]

CHALLENGES FACED BY GENERIC DRUGS:

In 2007, North Carolina Public Radio's The People's Pharmacy began reporting on consumers' complaints that generic versions of bupropion (Wellbutrin) were yielding unexpected effects.^[22] Subsequently, Impax Laboratories's 300 mg extended-release tablets, marketed by Teva Pharmaceutical Industries, were withdrawn from the US market after the FDA determined in 2012 that they were not bio equivalent.^[23][24]

Two women, each claiming to have suffered severe medical complications from a generic version of metoclopramide, lost their Supreme Court appeal on June 23, 2011. In a 5-4 ruling in PLIVA, Inc. v. Mensing,^[25][26] in which the court held that generic companies cannot be held liable for information, or the lack of information, on the originator's label.^[27][28][29]

APPROVAL:

Unlike the approval process for new chemical entities, that for generic drugs allows use of the ANDA, which does not require the submission of clinical data regarding safety and efficacy since this information was already provided for the pioneer product.[5] Since the original active ingredient was already proven safe and effective, the manufacturer must now prove bio equivalence for the pharmaceutically equivalent generic drug product.[5]

In order to receive approval for marketing, a generic drug must meet the same batch requirements for identity, strength, purity, and quality and be therapeutically equivalent to the branded product.[5]. Additionally, the drug must be manufactured according to the same Good Manufacturing Practice regulations required by the FDA.4 For the generic drug to be therapeutically equivalent, two clinical characteristics must apply: It must be pharmaceutically equivalent as well as bio equivalent. Pharmaceutical equivalence means that the active ingredient(s), dose form, route of administration, and strength are the same for both the branded product and the generic product. Bio equivalence is when both products have comparable bioavailability when studied under similar conditions.[6]

While pharmaceutical equivalence is relatively easy to comprehend, the concept of bio equivalence is more difficult to grasp. Bio equivalence is determined by evaluation of the AUC and the maximum concentration of drug (Cmax). A generic product is considered to be bio equivalent to the pioneer product if the 90% confidence interval (CI) of the mean AUC and the relative mean Cmax is 80% to 125%. This criterion is the same standard used for testing the bio equivalence of branded products with reformulation or manufacturing changes. Bio equivalence is determined by conducting crossover studies of at least 12 patients in which half of the patients receive the generic drug first and then the pioneer drug, with a washout period in between. The remaining patients receive the pioneer drug first, followed by a washout period and then the generic drug.[6] The Cmax, time to reach Cmax, and AUC are determined by taking multiple blood samples from individual patients. Based on the 90% CI, if drug levels vary by more than 10%, failure to reach FDA criteria disqualifies a drug for a bio equivalence rating. According to data for bio equivalence testing performed on 224 drugs after 1962, the mean variation in bioavailability between branded and generic drug products was approximately 3.5%.11[6]

Despite determinations of statistical bio equivalence, some health care providers still have concerns about interchangeability between narrow-therapeutic-index (NTI) branded and generic drugs. Currently, however, no data suggest that the bio equivalence criteria for NTI drugs should be more rigorous. Opponents of generic substitution have raised questions about changes in efficacy and toxicity in drugs such as anti epileptics and have voiced concerns about receiving consistent product with routine refills. In addition, it has been difficult to determine bio equivalence in products with timed-release properties.[6]

A common misconception in the evaluation of generic substitution relates to therapeutic equivalence. While a generic drug may be AB-rated to a branded drug, there is no testing to determine whether generic products are bio equivalent to each other, although it is expected that their efficacy would not differ significantly. [6]

GENERICS AS DRUGS AVAILABLE TO ALL: [29]

Generics, common man best friend. This can be well stated by the below example:

Branded Drug

Generic Drug

Allegra (180mg, 30 Tablets).

Its Price : $17.99.

Fexofenadine (180mg 30 Tablets)

Its price $11.99

Tylenol (Extra Strength,

100 Tablets). -$9.49

Acetaminophen (Extra Strength,

100 Tablets)-$2.39

Brand Name Drug	Generic Equivalent	Medical use
Abilify	Aripiprazole	Psychosis, Depression
Adderall	Dextroamphetamine and Levoamphetamine	ADHD treatment
Advil	Ibuprofen	Painkiller, fever reducer
Advair Diskus, Seretide	Fluticasone + Salmeterol	Asthma
Agiolax	Sphagula husk + Senna	Gastrointestinal disorders
Allegra	fexofenadine	Seasonal allergies
Amoxil	amoxicillin	Antibiotic used to treat infection
Atripla	Emtricitabine/tenofovir/efavirenz	HIV infection
Avastin	Bevacizumab	Colorectal cancer
Copaxone	Glatiramer	Multiple sclerosis
Crestor	Rosuvastatin	Cholesterol
Cymbalta	Duloxetine	Depression, Anxiety disorders
Enbrel	Etanercept	Rheumatoid arthritis
Epogen	Erythropoietin	Anemia
Humira	Adalimumab	Rheumatoid arthritis
Januvia	sitagliptin	Diabetes
Lantus	Insulin analog (Insulin glargine)	Type 2 and type 1 diabetes
Lipitor	methylphenidate	Cholesterol
Lyrica	Pregabalin	Neuropathic pain
Motrin	Ibuprofen	Painkiller, fever reducer
Neosporin	neomycin	Infection
Neulasta	Filgrastim	Neutropenia
Nurofen	Ibuprofen	Painkiller, fever reducer
Oxy Contin	Oxycodone	Pain
Prevacid	Lansoprazole	Acid reflux, GERD
Prozac	fluoxetine	Depression, OCD
Provigil	Modafinil	Narcolepsy, obstructive sleep apnea
Remicade	Infliximab	Crohn's disease, Rheumatoid arthritis
Ritalin	methylphenidate	ADHD, postural orthostatic tachycardia syndrome and narcolepsy
Rituxan, MabThera	Rituximab	Non-Hodgkin’s lymphoma, Rheumatoid arthritis
Spiriva	Tiotropium	Chronic obstructive pulmonary disease
Tamiflu	Oseltamivir	Flu
Truvada	Tenofovir + Emtricitabine	HIV infection
Tylenol	Acetaminophen	Pain reliever, Fever reducer
Vicodin	Acetaminophen + hydrocodone	Moderate to severe pain relief
Vyvanse	ADHD treatment
Xanax	Alprazolam	Anxiety, Panic disroders

These polymers used for modified release. Modified release systems³⁰ are designed to reduce the frequency of dosing by modifying the rate of drug absorption has been available from many years. This type of release dosage³¹ forms is far better than the conventional release dosage forms. Mucoadhesive³² are synthetic or natural polymers that will interact with the mucus layer which is present in the body at buccal cavity, and gastric mucosal layers. Antibiotics³³can be used for preparation of tablets.

The specific approach to their use is dependent on the individuals affected and stage of the disease. Researchers³⁴ are developing customized picoparticles the size of molecules that can deliver drugs directly to diseased cells in your body.

Antibiotics³⁵ are also used to treat this disease. Oral modified³⁶ drug delivery systems can be classified in to two broad groups Single Unit dosage forms and multiple unit dosage forms.

The advances³⁷ and progress made by pharmaceutical industry have greatly contributed in terms of treatment of disease, thereby enhancing the quality of life. Mucilage and Gums are hydrophilic polysaccharides³⁸. Smoking is bad for your health³⁹.

A drug is any substance (other than food that provides nutritional support) that, when inhaled, injected, smoked, consumed, absorbed via a patch on the skin, or dissolved under the tongue causes a temporary physiological (and often psychological) change in the body⁴⁰.

Venous thrombus may be a grume (thrombus) that forms inside a vein⁴¹. Too much iron can result in damage to the heart, liver, and endocrine system, which includes glands that produce hormones that regulate processes throughout the body⁴².

CONCLUSION:

Today, the generic drug industry is driven by many stakeholders. Consumers demanding low-cost alternatives to expensive brand-name products are at the forefront. Federal and state programs, which were some of the original supporters of generic drug development, also lead the way in encouraging healthy competition and ensuring the safety and efficacy of generic drug products. Additionally, the professional services of medicine and pharmacy, despite having a somewhat conflicting relationship in the past, now jointly advocate the development of low-cost alternatives to serve the needs of their patients and have identified some common ground regarding pharma co therapeutic decision-making and substitution. Regardless of who is involved and in spite of the controversies surrounding economics, professional interests, and drug development, the generic drug industry is and will continue to be an invaluable player in the health care field.

REFERENCES:

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5. Food and Drug Administration. Consumer Education: What You Should Know About Buying and Using Generic Drugs. July 2009.

6. journals.sagepub.com/doi/pdf/10.1177/0972063417747747 by A Dixit – 2018.

7. Who Technical Report Series No. 937: Annex 7 (pdf) WHO Expert Committee on Specifications for Pharmaceutical Preparations, Fortieth Report (WHO Technical Report Series No. 937): Annex 7 - Multi source (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability, May 2006. Accessed 2008-06-15.

8. Food and Drug Administration, Department of Health and Human Services: Code of Federal Regulations 320 Title 21, Volume 5, Revised as of April 1, 2008 CFR 320 21/5, Revised as of April 1, 2008. Accessed 2008-06-15.

9. Health Canada, Drugs and Health Products, Bioavailability and Bioequivalence Health Canada, Guidance Documents. Accessed 2008-06-15.

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15. Warren, JB (2013). "Generics, chemisimilars and biosimilars: is clinical testing fit for purpose?” Br J Clin Pharmacol. 75 (1): 7–14. doi:10.1111/j.1365-2125.2012.04323.x. PMC 3555041,PMID 22574725.

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21. "Generic medicines training kit: safe and appropriate use of generic medicines". Pharmaceutical Society of Australia Competency Standards for Pharmacists in Australia 2003. National Prescribing Service Limited (NPS). 2003-07-09. Archived from the original on 2009-10-20. Retrieved 2010-01-24."Prescribers may disallow brand switching by ticking the relevant box on the PBS prescription form".

22. "Drug Tests: Wellbutrin vs. Generic Bupropion". 2012-12-06. Retrieved 20.

23. Healy, Melissa (2012-10-05). "Generic antidepressant pulled from U.S. shelves after FDA finding". Los Angeles Times. Retrieved 2013-04-20.

24. FDA Update: Budeprion XL 300 mg Not Therapeutically Equivalent to Wellbutrin XL 300 mg". U.S. Food and Drug Administration. 2012-10-03. Retrieved 2013-04-20.

25. "PLIVA, Inc. v. Mensing - SCOTUSblog". Retrieved 23 May 2017.

26. Supreme Court of the United States 564 PLIVA, Inc. v. Mensing U. S. (2011).

27. Adam Liptak for the New York Times. June 23, 2011 Drug Makers Win Two Supreme Court Decisions.

28. Steven Casey for Law360. October 24, 2012 Generic Pharmaceutical Liability: Challenges and Changes.

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39. M.Venkataswamy¹*, Neha Thahaseen¹, MD Kareemuddin¹, JP Priyanka¹, Jaggareddy Gari Manasa Reddy¹“Formulation and Evaluation of sustained release matrix tablets using drug Cytisine isolated from Fava Beans to quit Smoking” Research Journal of Pharmaceutical Dosage Forms and Technology, A and V publications, 10(3): July- September, 2018.

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Received on 30.09.2018 Modified on 18.11.2018

Res. J. Pharma. Dosage Forms and Tech. 2019; 11(2): 121-125.

DOI: 10.5958/0975-4377.2019.00019.3