This article discusses in detail following subjects .
What is US Food and Drug Administration’s Orange Book and related terms which we offten 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of any product is that the product is the subject of an application with an effective approval that has not been withdrawn for safety or efficacy reasons.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.
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