Lin Chapter 9: Bioequivalence
What is category A? What is category B?
Category A lists products that do not pose bioavailability problems These products are bioequivalent and may be substituted with other products listed in Category A Category B lists products that do pose serious bioavailability problems These products are not bioequivalent and can not be substituted
What are the three factors that are known to affect drug absorption and therefore systemic availability of a drug after administration of the drug dose?
From a pharmaceutical standpoint, there are three inherent factors that are known to affect drug absorption and therefore systemic availability of a drug after administration of the drug dose. These are: . (a) formulation technique used in the development of the dosage form, (b) method and equipment used in the manufacture of dosage form, and (c) materials used in the formulation of dosage form even though these materials are .considered inert. These include the particle size and crystal form or polymorphic form of the drug substance, diluents and excipients used in the dosage form including binders, disintegrating agents, fillers, lubricants, coating materials, solvents, suspending agents, and dyes. Lubricants and coating materials are foremost among the materials that are suspect in the bioavailability problems.
How many people are used for bioequivalence studies? What are the subjects similar in?
A panel of 24 or more subjects is used for the study Usually healthy subjects are selected for the study Subjects should be of similar age and weight All subjects are evaluated by a physician to assure that they are suitable for participation in the study
What is a generic drug?
According to the FDA, a generic drug is the same as a brand name drug in dosage, safety, strength, how it is taken, quality, performance, and intended use. Before approving a generic drug product, the FDA requires many rigorous tests and procedures to assure that the generic drug can be substituted for the brand name drug. The FDA bases evaluations of substitutability, or "therapeutic equivalence," of generic drugs on scientific evaluations. By law, a generic drug product must contain the identical amounts of the same active ingredient(s) as the brand name product. Drug products evaluated as "therapeutically equivalent" can be expected to have equal effect and no difference when substituted for the brand name product.
What is the definiton for therapeutic equivalents
According to the FDA, 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. The concept of therapeutic equivalence used by the FDA applies only to those products that contain the same active ingredients, e.g., tetracycline hydrochloride tablets manufactured by different manufacturers, or different strengths of tetracycline hydrochloride tablets made by the same manufacturer. The concept of therapeutic equivalence does not include a comparison of different therapeutic agents used for the same condition, Le., different chemical compounds used for a therapeutic effect e.g., aspirin versus acetaminophen, or aspirin versus ibuprofen, or ibuprofen versus acetaminophen for pain relief, or propoxyphene hydrochloride versus pentazocine hydrochloride for treatment of pain. They are pharmaceutical equivalents in that (i) they contain identical amounts of the same active drug ingredient in the same dosage form, and (ii) meet compendial or other applicable standards of identity, strength, purity,· and quality. The FDA generally considers 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 and size' of the dosage form, scoring and/or embossing configuration on the product, packaging of the finished product, expiration time of the product, certain minor aspects of labeling on the finished product (e.g., presence of specific pharmacokinetic data and/or information). In addition, therapeutic equivalent products may not necessarily contain the same formulation excipients (e.g., fillers or diluents, disintegrating agents, binders, lubricants, etc.), including colors, flavors, preservatives, etc.
What test has been used to discriminate between supposedly identical articles?
According to the USP, whenever a medically significant difference in bioavailability has been found among supposedly identical articles, a dissolution test has discriminated among these articles. The USP considers dissolution test discriminating and satisfactory, because, according to studies conducted by the USP, dissolution requirements can exclude definitively any unacceptable article. Therefore, the USP feels that there is no need for compendial requirements for in vivo bioavailability.
Can pharmaceutical alternatives also be bioequivalents?
Although the defInition specifIes comparison of pharmaceutical equivalents, it is obvious that pharmaceutical alternatives are also included in defInition, because the comparison being made here is between therapeutic drug ingredient (drug moeity) and not between identical chemical compound. Therefore, bioequivalence refers to "the absence of signifIcant difference in the rate and extent to which the active ingredient or active moiety in, pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study"
What is category AB? What type of products can these substituted with?
Category AB lists those products whose bioavailability problems have been resolved The resolution of the problem is shown by an in vitro : in vivo correlation Products listed in Category AB may only be substituted with products listed in Category AB
What are pharmaceutical alternatives?
Different dosage forms and strengths within a product line by a single maI1ufactUrer are thus phannaceutical alternatives, as are extended-release products when compared with immediaterelease or standard-release formulations of the same active ingredient (e.g., phenytoin 100 mg immediate-release oral capsules versus phenytoin 100 mg extended-release oral capsules). Since, by definition, products are considered pharmaceutical alternatives as long as they contain the same therapeutic moiety, not necessarily the same drug entity, a variety of dosage forms of the given drug product may fall in this category. Examples of pharmaceutical alternatives include such prcx;lucts as similar strengths of the antibiotic tetracycline hydrochloride capsules versus tetracycline phosphate complex capsules, and similar strengths of quinidine sulfate tablets versus quinidine sulfate capsules.
What is another term used for pharmaceutical equivalents and why?
Pharmaceutical equivalents have sometimes been referred to as chemical equivalents, because the only requirement of pharmaceutically equivalent products is that they must contain the same chemical entity (drug) in the same strength. Since pharmaceutical equivalents are not required to contain identical amounts of same formulation excipients, it is conceivable that differing amounts and/or tyPes of inert ingredient used in the manufacture of pharmaceutically equivalent products may not necessarily provide similar availability of active ingredient for systemic effect.
What may pharmaceutical equivalents be different in?
Pharmaceutically equivalent drug products may differ in characteristics such as shape, release mechanism, labeling (to some extent), scoring, and excipients (e.g., colors, flavors, and preservatives) .
What are the requirements for generic drugs?
Some of these requirements are (i) contain the same active ingredient(s) as the innovator drug, while the inert ingredients may vary, (ii) be identical in strength, dosage form, and route of administration, (iii) have the same indications and precautions for use, (iv) meet the same batch-ta-batch requirements for identity, strength, purity, and quality, (v) have the same labeling instructions, (vi) be bioequivalent, and (vii) be manufactured under the same strict standards of FDA's Good Manufacturing Practice regulations as required for the innovator products.
What is the 75/2 5 rule?
The 75/25 Rule was a predecessor to the 80/20 Rule The 75/25 Rule signified a 75% probability of detecting a 25% difference between the products being evaluated At that time, if the products exhibited similar bioavailability under the 75/25 Rule, then the products were declared bioequivalent
What is the 80/20 rule?
The 80/20 Rule signifies 80% probability of detecting a 20% difference between the products being evaluated If the products exhibit similar bioavailability under the 80/20 Rule, they are declared bioequivalent The FDA publishes a list of products that it feels are Therapeutic Equivalents This list is published as a book, and is updated periodically The FDA calls this publication the list, but it is popularly referred to as the ORANGE BOOK (because of the orange-colored cover when the book was first published
What are the 2 categories the FDA uses for therapeutic equivalence evaluations?
The FDA classifies all products into 2 categories, Category A and Category B Each category identifies the products using a 2 letter system The first letter is either A or B, signifying the category in which the product is placed The second letter usually identifies the dosage form of the product
When are drugs considered to be pharmaceutical alternatives?
The FDA considers drug products to be 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, 250 mg capsules versus tetracycline phosphate complex, 250 mg capsules; quinidine sulfate, 200 mg tablets versus quinidine sulfate, 200 mg capsules).
What are biological equivalents?
The FDA considers those pharmaceutical equivalent products as Biological equivalents (or Bioequivalents) that display similar rate of absorption and similar extent of absorption of therapeutic moiety when studied under similar experimental conditions. Biological equivalents or bioequivalents are pharmaceutical equivalents that exhibit comparable bioavailability when studied under similar experimental conditions
when are drug products considered to be pharmaceutically equivalent?
The Food and Drug Administration (FDA) considers drug products to be pharmaceutical equivalents if they meet these three criteria: (i) they contain the same active ingredients, (II) they are of the same dosage from and route of administration, and (III) they are identical in strength or concentration. ex:Thus, all brands of diazepam 5 mg oral ~blets manufactured by various manufacturers are pharmaceutically equivalent as long as each brand of tablets contains 5 mg of diazepam, regardless of the type and amount of inert ingredient or ingredients used in the formulation of the tablet dosage form. For example, one manufacturer may use lactose as the diluent, another manufacturer may use dicalcium phosphate as the diluent, and another manufacturer may use starch as the diluent in the production of their tablet dosage forms. Similarly, different manufacturers may use different amounts and different types of other excipients (for example, binder, disintegrant, lubricant, etc.) in the fabrication of their tablet dosage forms.
What is used to compare between the test and reference product?
The comparison between test (T) and reference (R) product - difference: T-R - ratio: T/R - log ratio: log T/R or ln T/R
How are results for bioequivalence studies analyzed?
The data generated are analyzed by an impartial researcher or agency (to avoid bias) The average plasma-drug concentration vs time for each product is plotted on a graph paper Cmax, Tmax, and AUC for both products is determined These parameters for each product are compared to determine bioequivalence The results of the study are evaluated using suitable statistical methods
What type of study is the bioequivalence study? What subject receives what product? What is a wash out period?
The subjects are divided into 2 groups All subjects receive both products, but one product at a time Blood samples are collected at predetermined times and concentration of drug in each sample is determined A wash-out period is used for each subject between treatments This is done to assure that the first product is virtually eliminated from the body before the second product is administered Neither the researcher nor the subject knows which product is given to which subject (hence the term "double blind")
WHat are drugs are Candidates for Bioeqivalence Studies
Thus, candidates for the potential of reduced bioavailability are those drugs which exhibit the following characteristics: a. All drugs which have a low solubiiity at the site of admiriistration or absorption « 0.3% solubility). b. All drug products from which the active ingredient is too slowly or incompletely released. c. All drugs with a narrow therapeutic index.
Out of all the types of bioequivalence terms (pharmaceutical equivalents, pharmaceutical alterantives, bioquivalents and therapeutic equivalents) which type can substitutions in?
products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same clinical effect as the originally prescribed product.
What does bioequivalence mean?
this term indicates biological equivalence The term bioequivalence indicates biological equivalence. Bioequivalence has also been referred to as comparative bioavailability. The concept of bioequivalence started to gain increasing attention during the last forty years or so, after it became evident that some marketed products containing the same amount of drug marketed in the same dosage. form exhibited marked differences between their . therapeutic responses.