DRUG BASICS

What is a Drug

What is a drug:
Any chemical compound that may be used on or administered to humans to help diagnose, treat, cure, mitigate, or prevent disease or other abnormal conditions

Regulatory definition of drug
An article or substance that is recognized by the US Pharmacopoeia, National Formulary, or official Homeopathic Pharmacopoeia, or supplement to any of the above intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or animals intended to affect the structure or any function of the body of man or animals Substance abuse Any medication

Radioactive Drug: Any substance defined as a drug in 201(b)(1) of the Federal Food, Drug and Cosmetic Act that exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons [21 CFR 310.3(n)]. Included are any nonradioactive reagent kit or nuclide generator that is intended to be used in the preparation of a radioactive drug and “radioactive biological products,” as defined in 21 CFR 600.3(ee). Drugs such as carbon-containing compounds or potassium-containing salts containing trace quantities of naturally occurring radionuclides are not considered radioactive drugs.

Radiopharmaceuticals: Radioactive drugs that are labeled or tagged with a radioisotope. These materials are largely physiological or subpharmacological in action, and, in many cases, function much like materials found in the body. The principal risk associated with these materials is the consequent radiation exposure to the body or to specific organ systems when they are introduced into the body.
Investigational New Drug or Device: A drug or device permitted by FDA to be tested in humans, but not yet determined to be safe and effective for a particular use in the general population, and not yet licensed for marketing.
Drug product:
Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3 (b)).

Drug substance:
Drug substance means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3 (b)).

What is a Prodrug :
A prodrug is as such a pharmacologically inactive drug but when administered it get converted in vivo in to a pharmacologically active molecule. Prodrugs are intentionally designed to overcome degradation in gut and first pass metabolism , and make a drug available for action for longer time and also to increase its bioavailability, some naturally occurring drugs too are prodrugs which get converted in to pharmacologically active form.
Example of prodrugs :
Lisdexamfetamine it is a prodrug L-Lysin is coupled with dextroamphetamine molecule form Lisdexamfetamine it get metabolized in to an active form dextroamphetamine .

What is an orphan drug:
An orphan drugs is a drugs which are developed specifically for treating a rare diseases , a rare medical condition or disease symptoms such diseases are also termed as orphan disease.
Usually a disease that affects about one individual out 200000 peoples.

Development of orphan drugs are always encouraged as there is very less market requirement for such drugs and developmental costs too are high , hence some relaxation in fees and clinical trials is given by governments of USA and along with exclusive marketing rights to pharma manufacturer taking initiatives for developing orphan drugs, many European countries too encourage pharmaceutical companies for developing orphan drugs by giving similar facilities topharma manufacturer.

What is a Investigational New Drug (IND):
A drug is said to be Investigational New Drug when a pharma manufacturer want to develop it for treating a disease or an indication , to undertake research and development such drug , the drug should be get approval from US FDA , for which pharma manufacturer is required to submit investigational new drug (ind), after getting an approval for such drug it can be then transported and used in a clinical trials normally it is tested first in phase 1 of drug
What is Placebo ?
Placebo is a substance which do not contain any active ingredient, or any drug, rather it is designed to just look alike the actual drug dosage form, it is formulated by using sugar, or other inert pharmaceutical addaitives, it is widely used in research as control to find out the effect of an actual drug with respect to the treatment with placebo, some times placebo produce equal effect when used to treat a disease or a condition, which is merely because of the psychological effects and feeling of being treated with drug and doctor. Similarly a treatment and medical procedures are designed just to mimic the actual therapy are also called as placebo, some patients are given treatments which are not actually real ones but they just mimic the actual treatments are called as simulated medical intervention.

Process of approval of a drug for marking in USA:
Drugs which has some hope for beneficial effects in treating any disease, conditions or symptoms are first tested in animals . As animal trials do not necessarily demonstrate complete physiological, pharmacological, or toxicological effects of a new drug under study.
Drugs are approved for marketing only after evaluation of their effectiveness , efficacy and safety in human beings. These evaluations are usually done through clinical trials, and after thorough evaluation of out come of clinical trial, if it is found that a drug is effective and safe and properly labeled [21 CFR 312 and 21 CFR 314] for use in conditions indicated , then only a drug is approved for marketing in USA. The Food and Drug Administration (FDA) is responsible for monitoring the testing of new drugs in humans, and all clinical trial are regulated by US FDA.

What is a Brand Name Drug :
When drug molecule is completely researched and developed in to a drug product for a particular disease or its symptom or for a indication or when he applies new technology to an existing molecule so as to enhance the efficacy safety or new route of administration , such drug products then are investigated for their safety and efficacy , and after approval clinical studies , a manufacturer generally applies for a patent for the drugs developed by them so as to enjoy the monopoly of getting his product’s sale for which he invented the drug for a particular disease.

Why there are some drugs said to be unapproved and are there available in market.

Many of these unapproved drugs are older products introduced well before formation of FFDCA in 1938 these drug products were approved on the basis of 1906 Pure Food and Drug Act, that required a drug for getting an approval only to comply with some standards of strength and purity and not for safety.

Also earlier in 1960’s drugs were given approval based on only aspects of safety and efficacy , but safety study likeclinical trials for safety were not under control by FDA, until the heroic rejection of drug containing thalidomide in 1960 by madam kelsey an US FDA employee then. Her decision actually saved millions of American children’s from disabilities,which forced US legislation to pass an act to provide an additional authority to FDA to make it mandatory for a drug to be proved that it is a safe by conducting clinical trials which are completely assessed by US FDA to get an approval for marketing a drug in USA.

What is a Grand Fathered Drug , Which are the Grand Father Drug Clauses:

Under the 1938 grandfather clause a drug product that was on the market prior to passage of the 1938 Act and which contained in its labeling the same representations concerning the conditions of use as it did prior to passage of that Act was not considered a new drug and therefore was exempt from the requirement of having an approved new drug application.

Under the 1962 grandfather clause, the Act exempts a drug from the effectiveness requirements if its composition and labeling has not changed since 1962 and if, on the day before the 1962 Amendments became effective, it was (a) used or sold commercially in the United States, (b) not a new drug as defined by the Act at that time, and (c) not covered by an effective application.

The two grandfather clauses in the Act have been construed very narrowly. There are very few drugs on the market that are actually entitled to grandfather status because the drugs currently on the market likely differ from the previous versions in some respect, such as formulation, dosage or strength, dosage form, route of administration, indications, or intended patient population. If a firm claims that its product is grandfathered, it is that firms burden to prove that assertion.

There are three types of unapproved drugs
A.DESI Drugs
DESI means Drug Efficacy Study Implementation
Refers to a drug that is a subject of 1938-1962 NDAs (safety only) and drug which is identical, related, and similar to such drugs.
DESI drugs are not “grandfathered” or generally recognized as safe and effective (GRAS/E)

B.Prescription “Wrap-Up”
Refers to drugs that are on the market based on a claim of being a pre-’38 or pre-’62 product or identical, related, or similar to such a product

C.Post ’62 Drugs
Drugs initially marketed after 1962

What is a generic drug

Pharmaceutical or Drug is considered as a generic drug , where it is not protected by patent protection .It is possible that a generic drug have a patent on the formulation but not on the active ingredient, in such case formulation can not be taken by any one but the active ingredient can be formulated so as to form a suitable dosage form.
A generic Drug or Pharmaceutical should contain the same active ingredients as that of the original or parent formulation.
According to the U.S. Food and Drug Administration (FDA),Generic Pharmaceuticals or generc drug equivalent to or acceptable within an bioequivalent range with respect to pharmacokinetic and pharmacodynamic properties of the to the branded pharmaceutical product. Hence, Generic Pharmaceuticals or generic drugs are considered by US FDA as drugs identical in dose, strength, route of administration, safety, efficacy, and intended use.

US FDA establishes required standards for a generic drug giving a range of acceptable values and range of variations that a generic drug is required to be bioequivalent to a brand name drug .

Generic drugs is likely to differ from original brand name drug with respect to inactive ingredients or excipients, its configuration, release mechanisms, packaging shape , scoring.

In the US, drug patents grant twenty years of protection.

More about Generic Drugs

A generic drug is equivalent to it’s brand name counterpart, but is usually much less expensive. A generic drug must have the same active ingredients, route of administration, dosage form, strength, and indications as the original brand product. Generic drugs are approved by the U.S. Food and Drug Administration, and are deemed to be as safe and effective as the brand name product.

Generics cannot be sold until after the drug patent expires on the original brand name product. For example, generic fluoxetine could not be sold until the patent had expired on the brand name equivalent Prozac. A drug manufacturer applies for a patent to protect their drug from being copied and sold by another company and losing profits.

Patents typically expire 20 years from the date of filing. During this period of patent protection, only the original manufacturer can research, develop and sell the brand name drug. When the patent expires, other manufacturers can submit an abbreviated new drug application (ANDA) to the FDA for approval to market the generic version.

Generic drugs have lower research costs and increased market competition and those substantial savings are passed on to the patient. However, generic drugs still must meet strict FDA requirements with respect to quality, performance, labeling, manufacturing, and bioequivalence. By law, generic drugs must have the same active ingredients as the brand name product, and they can be expected to have the same effect when used in place of a brand name drug.

What is US FDA’S Orange Book , Pharmaceutical Equivalents,Pharmaceutical Alternatives,Therapeutic Equivalents.,Bioavailability. Reference Listed Drug (RLD) ,Bioequivalent Drug Products ,statistical methodology for analyzing these bioequivalence

This article is featuring detailed information about US FDA’S Orange BookUS FDA’S list of pharmaceutical products with all relevant details about them . If you are a pharmacy student or a pharmacist, or if you are working in pharmaceutical regulatory affairs and want to register your products for sale in USA , then you need to submit ANDA on perticular drug or pharmaceutical product , this article will help you to learn and understand various requirements in ANDA and about various things about getting approval of a pharmaceutical or a drug for sale in USA

What is US Food and Drug Administration’s Orange Book and related terms which we often use in association with ANDA preparation and submission like Pharmaceutical Equivalents,Pharmaceutical Alternatives,Therapeutic Equivalents.,Bioavailability. Reference Listed Drug (RLD) ,Bioequivalent Drug Products ,statistical methodology for analyzing these bioequivalence
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Orange Book
(Please read as US FDA where ever it is mentioned as “agency” and “FDA” )

Center for Drug Evaluation and Research Approved pharmaceutical or Drug Products with Therapeutic Equivalence Evaluations
The publication, Approved Drug Products with Therapeutic Equivalence Evaluations (the List, commonly known as the Orange Book), identifies drug products approved on the basis of safety and effectiveness by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the Act).Pharmaceuticals or Drugs on the market approved only on the basis of safety (covered by the ongoing Drug Efficacy Study Implementation [DESI] review [e.g., Donnatal® Tablets and Librax® Capsules] or pre-1938 drugs [e.g., Phenobarbital Tablets]) are not included in this publication. The main criterion for the inclusion of any product is that the product is the subject of an application with an effective approval that has not been withdrawn for safety or efficacy reasons. Inclusion of products on the List is independent of any current regulatory action through administrative or judicial means against a drug product. In addition, the List contains therapeutic equivalence evaluations for approved multisource prescription drug products. These evaluations have been prepared to serve as public information and advice to state health agencies, prescribers, and pharmacists to promote public education in the area of drug product selection and to foster containment of health care costs. Therapeutic equivalence evaluations in this publication are not official FDA actions affecting the legal status of products under the Act.

Content and Exclusion

The List is composed of four parts: (1) approved prescription drug products with therapeutic equivalence evaluations; (2) approved over-the-counter (OTC) drug products or pharmaceuticals for those drugs that may not be marketed without NDAs or ANDAs because they are not covered under existing OTC monographs; (3) drug products or pharmaceuticals with approval under Section 505 of the Act administered by the Center for Biologics Evaluation and Research; and (4) a cumulative list of approved products that have never been marketed, are for exportation, are for military use, have been discontinued from marketing, or have had their approvals withdrawn for other than safety or efficacy reasons subsequent to being discontinued from marketing. [Note: Newly approved products are added to parts 1, 2, or 3 of the List, depending on the dispensing requirements (prescription or OTC) or approval authority, unless the Orange Book staff is otherwise notified before publication.

Therapeutic Equivalence-Related Terms

Pharmaceutical Equivalents.

Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration (e.g., chlordiazepoxide hydrochloride, 5mg capsules). Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity), but they may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration time, and, within certain limits, labeling.

Pharmaceutical Alternatives.

Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or are different dosage forms or strengths (e.g., tetracycline hydrochloride, 250mg capsules vs. tetracycline phosphate complex, 250mg capsules; quinidine sulfate, 200mg tablets vs. quinidine sulfate, 200mg capsules). Data are generally not available for FDA to make the determination of tablet to capsule bioequivalence. Different dosage forms and strengths within a product line by a single manufacturer are thus pharmaceutical alternatives, as are extended-release products when compared with immediate-release or standard-release formulations of the same active ingredient.

Therapeutic Equivalents.

Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.
FDA classifies as therapeutically equivalent those products that meet the following general criteria:
(1) they are approved as safe and effective; (2) they are pharmaceutical equivalents in that they (a) contain identical amounts of the same active drug ingredient in the same dosage form and route of administration, and (b) meet compendial or other applicable standards of strength, quality, purity, and identity; (3) they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b) if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard; (4) they are adequately labeled; (5) they are manufactured in compliance with Current Good Manufacturing Practice regulations (cgmp ). The concept of therapeutic equivalence, as used to develop the List, applies only to drug products containing the same active ingredient(s) and does not encompass a comparison of different therapeutic agents used for the same condition (e.g., ibuprofen vs. naproxen for the treatment of pain). Any pharmaceutical or drug product in the List repackaged and/or distributed by other than the application holder is considered to be therapeutically equivalent to the application holder’s drug product even if the application holder’s drug product is single source or coded as non-equivalent (e.g., BN). Also, distributors or repackagers of an application holder’s drug product are considered to have the same code as the application holder. Therapeutic equivalence determinations are not made for unapproved, off-label indications.

FDA considers pharmaceutical or drug products to be therapeutically equivalent if they meet the criteria outlined above, even though they may differ in certain other characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration date/time and minor aspects of labeling (e.g., the presence of specific pharmacokinetic information) and storage conditions. When such differences are important in the care of a particular patient, it may be appropriate for the prescribing physician to require that a particular brand be dispensed as a medical necessity. With this limitation, however, FDA believes that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product.

Bioavailability.
This term means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For pharmaceuticals or drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.

Bioequivalent Drug Products.
This term describes pharmaceutical equivalent or alternative products that display comparable bioavailability when studied under similar experimental conditions. Section 505 (j)(7)(B) of the Act describes one set of conditions under which a test and reference listed drug shall be considered bioequivalent, the rate and extent of absorption of the test drug do not show a significant difference from the rate and extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses; or the extent of absorption of the test pharmaceuticals or drug does not show a significant difference from the extent of absorption of the reference drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses and the difference from the reference drug in the rate of absorption of the drug is intentional, is reflected in its proposed labeling, is not essential to the attainment of effective body drug concentrations on chronic use, and is considered medically insignificant for the drug. Where these above methods are not applicable (e.g., for drug products that are not intended to be absorbed into the bloodstream), other in vivo or in vitro test methods to demonstrate bioequivalence may be appropriate.

Bioequivalence may sometimes be demonstrated using an in vitro bioequivalence standard, especially when such an in vitro test has been correlated with human in vivo bioavailability data. In other situations, bioequivalence may sometimes be demonstrated through comparative clinical trials or pharmacodynamic studies. Statistical Criteria for Bioequivalence Under the Drug Price Competition and Patent Term Restoration Act of 1984, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the drug product is bioequivalent to the pioneer (innovator) drug product. A major premise underlying the 1984 law is that bioequivalent drug products are therapeutically equivalent and, therefore, interchangeable. Bioavailability refers to the rate and extent to which the active ingredient or therapeutic ingredient is absorbed from a drug product and becomes available at the site of drug action (Federal Food, Drug and Cosmetic Act, section 505(j)(8)). Bioequivalence refers to equivalent release of the same drug substance from two or more drug products or formulations. This leads to an equivalent rate and extent of absorption from these formulations. Underlying the concept of bioequivalence is the thesis that, if a drug product contains a drug substance that is chemically identical and is delivered to the site of action at the same rate and extent as another drug product, then it is equivalent and can be substituted for that drug product. Methods used to define bioequivalence can be found in 21 CFR 320.24, and include (1) pharmacokinetic (PK) studies, (2) pharmacodynamic (PD) studies, (3) comparative clinical trials, and (4) in-vitro studies. The choice of study used is based on the site of action of the drug and the ability of the study design to compare drug delivered to that site by the two products.

The standard bioequivalence (PK) study is conducted using a two-treatment crossover study design in a limited number of volunteers, usually 24 to 36 adults. Alternately, a four-period, replicate design crossover study may also be used. Single doses of the test and reference drug products are administered and blood or plasma levels of the drug are measured over time. Pharmacokinetic parameters characterizing rate and extent of drug absorption are evaluated statistically. The PK parameters of interest are the resulting area under the plasma concentration-time curve (AUC), calculated to the last measured concentration (AUC(0-t)) and extrapolated to infinity (AUC(0-inf)), for extent of absorption; and the maximum or peak drug concentrations (Cmax), for rate of absorption. Crossover studies may not be practical in drugs with a long half-life in the body, and a parallel study design may be used instead. Alternate study methods, such as in-vitro studies or equivalence studies with clinical or pharmacodynamic endpoints, are used for drug products where plasma concentrations are not useful to determine delivery of the drug substance to the site of activity (such as inhalers, nasal sprays and topical products applied to the skin).

The statistical methodology for analyzing these bioequivalence studies is called the two one-sided test procedure. Two situations are tested with this statistical methodology. The first of the two one-sided tests determines whether a generic product (test), when substituted for a brand-name product (reference) is significantly less bioavailable. The second of the two one-sided tests determines whether a brand-name product when substituted for a generic product is significantly less bioavailable. Based on the opinions of FDA medical experts, a difference of greater than 20% for each of the above tests was determined to be significant, and therefore, undesirable for all drug products. Numerically, this is expressed as a limit of test-product average/reference-product average of 80% for the first statistical test and a limit of reference-product average/test-product average of 80% for the second statistical test. By convention, all data is expressed as a ratio of the average response (AUC and Cmax) for test/reference, so the limit expressed in the second statistical test is 125% (reciprocal of 80%).

For statistical reasons, all data is log-transformed prior to conducting statistical testing. In practice, these statistical tests are carried out using an analysis of variance procedure (ANOVA) and calculating a 90% confidence interval for each pharmacokinetic parameter (Cmax and AUC). The confidence interval for both pharmacokinetic parameters, AUC and Cmax, must be entirely within the 80% to 125% boundaries cited above. Because the mean of the study data lies in the center of the 90% confidence interval, the mean of the data is usually close to 100% (a test/reference ratio of 1). Different statistical criteria are sometimes used when bioequivalence is demonstrated through comparative clinical trials pharmacodynamic studies, or comparative in-vitro methodology.

The bioequivalence methodology and criteria described above simultaneously control for both, differences in the average response between test and reference, as well as the precision with which the average response in the population is estimated. This precision depends on the within-subject (normal volunteer or patient) variability in the pharmacokinetic parameters (AUC and Cmax) of the two products and on the number of subjects in the study. The width of the 90% confidence interval is a reflection in part of the within-subject variability of the test and reference products in the bioequivalence study. A test product with no differences in the average response when compared to the reference might still fail to pass the bioequivalence criteria if the variability of one or both products is high and the bioequivalence study has insufficient statistical power (i.e., insufficient number of subjects). Likewise, a test product with low variability may pass the bioequivalence criteria, when there are somewhat larger differences in the average response.
This system of assessing bioequivalence of generic products assures that these substitutable products do not deviate substantially in in-vivo performance from the reference product. The Office of Generic Drugs has conducted two surveys to quantify the differences between generic and brand name products. The first survey included 224 bioequivalence studies submitted in approved applications during 1985 and 1986. The observed average differences between reference and generic products for AUC was 3.5% (JAMA, Sept. 4, 1987, Vol. 258, No. 9). The second survey included 127 bioequivalence studies submitted to the agency in 273 ANDAs approved in 1997. The three measures reviewed include AUC(0-t), AUC(0-inf), and Cmax. The observed average differences between the reference and generic products were + 3.47% (SD 2.84) for AUC(0-t), + 3.25% (SD 2.97) for AUC(0-inf), and + 4.29% (SD 3.72) for Cmax (JAMA, Dec. 1, 1999, Vol. 282, No. 21).
The primary concern from the regulatory point of view is the protection of the patient against approval of products that are not bioequivalent. The current practice of carrying out two one-sided tests at the 0.05 level of significance ensures that there is no more than a 5% chance that a generic product that is not truly equivalent to the reference will be approved.

Reference Listed Drug (RLD)

A reference listed drug (21 CFR 314.94(a)(3)) means the listed drug identified by FDA as the drug product upon which an applicant relies in seeking approval of its ANDA. FDA has identified in the Prescription Drug Product and OTC Drug Product Lists those reference listed drugs to which the in vivo bioequivalence (reference standard) and, in some instances, the in vitro bioequivalence of the applicant’s product is compared. By designating a single reference listed drug as the standard to which all generic versions must be shown to be bioequivalent, FDA hopes to avoid possible significant variations among generic drugs and their brand name counterpart. Such variations could result if generic drugs were compared to different reference listed drugs. However, in some instances when listed drugs are approved for a single drug product, a product not designated as the reference listed drug and not shown to be bioequivalent to the reference listed drug may be shielded from generic competition. A firm wishing to market a generic version of a listed drug that is not designated as the reference listed drug may petition the Agency through the Citizen Petition procedure (see 21 CFR 10.25(a) and CFR 10.30). When the Citizen Petition is approved, the second listed drug will be designated as an additional reference listed drug and the petitioner may submit an Abbreviated New Drug Application citing the designated reference listed drug. Therapeutic Equivalence Evaluations Codes Products meeting necessary bioequivalence requirements explains the AB, AB1, AB2, AB3 coding system for multisource drug products listed under the same heading with two reference listed drugs.
In addition, there are two situations in which two listed drugs that have been shown to be bioequivalent to each other may both be designated as reference listed drugs. The first situation occurs when the in vivo determination of bioequivalence is self-evident and a waiver of the in vitro methodology. The reference listed drug is identified by the symbol “+” in the Prescription and Over-the-Counter (OTC) Drug Product Lists. These identified reference listed drugs represent the best judgment of the Division of Bioequivalence at this time. The Prescription and OTC Drug Product , pharmaceuticals Lists identify reference drugs for oral dosage forms, injectables, ophthalmics, otics, and topical products. It is recommended that a firm planning to conduct an in vivo waiver of bioequivalence will be requested, contact the Division of Bioequivalence, Office of Generic Drugs, to confirm the appropriate reference listed drug are not affected by the drug registration and listing requirements of Section 510 of the Act.

DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

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