The Approved Drug Products with Therapeutic Equivalence Evaluations publication (the List, commonly known as the Orange Book) identifies drugs that have been approved by the Food and Drug Administration (FDA) under the Federal Food, Drug, and Cosmetic Act (the Act) on the basis of safety and efficacy. In order to contain drug costs, almost every country has enacted laws and/or regulations that encourage drug switching. The agency also acknowledged that providing a uniform list based on common criteria would be preferable to evaluating drugs based on different definitions and criteria in different state laws.
Consequently, on May 31, 1978, the Commissioner of the Food and Drug Administration sent a letter to officials in each state stating FDA's intent to provide a list of all prescription drugs approved by FDA for safety and efficacy, along with therapeutic equivalence. It included only currently marketed prescription drugs approved by the FDA through new drug applications (NDAs) and abbreviated new drug applications (ANDAs) under the provisions of § 505 of the Act. A complete discussion of the background and basis of the FDA's therapeutic equivalence assessment policy was published in the Federal Register on
The 1984 amendments require the FDA, among other things, to publicly release a list of approved drugs with monthly supplements. The publication Approved Drug Products with Therapeutic Equivalence Evaluations and its monthly cumulative supplements meet this requirement.
Content and Exclusion
Therapeutic Equivalence-Related Terms
Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety but are different salts, esters or complexes of this moiety, or are different dosage forms or strengths (e.g. tetracycline hydrochloride, 250 mg capsules vs. tetracycline phosphate complex, 250 mg sulfate capsules, 250 mg tablets, 250 mg sulfate-250 mg tablets, ... quinidine sulfate, 200 mg capsules). Drug products are only considered therapeutically equivalent if they are pharmaceutical equivalent and if they can be expected to have the same clinical efficacy and safety profile when administered to patients under the conditions indicated in the labeling. The 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.
The concept of therapeutic equivalence as used to prepare the List applies only to drugs that contain the same active ingredient(s) and does not include comparisons of different therapeutic agents used for the same condition (eg, propoxyphene hydrochloride versus pentazocine hydrochloride for the treatment of pain). Distributors or repackagers of the applicant's medicine are also considered to have the same code as the applicant. With this limitation, however, the FDA believes that products classified as therapeutically equivalent may be substituted with the full expectation that the substitute product will produce the same clinical effect and safety profile as the prescribed product.
For drugs that are not intended to be absorbed into the bloodstream, bioavailability can be estimated by Where the above methods are not applicable (eg for drugs not intended to be absorbed into the bloodstream), other in vivo or in vitro test methods may be appropriate to demonstrate bioequivalence.
Statistical Criteria for Bioequivalence
Alternative study methods, such as in-vitro studies or studies equivalent to clinical or pharmacodynamic endpoints, are used for medicinal products where plasma concentrations are not useful to determine the distribution of the drug substance at the site of activity (such as inhalers, nasal sprays and topical products applied to the skin). The first of two one-sided tests determines whether a generic (test) product, when substituted for a brand-name (reference) product, is significantly less bioavailable. The second of the two one-sided tests determines whether a branded product when substituted for a generic product is significantly less bioavailable.
Conventionally, all data are expressed as a ratio of the mean response (AUC and Cmax) of test/reference, so the limit expressed in the second statistical test is 125% (reciprocal of 80%). Because the mean of the survey data lies in the middle of the 90% confidence interval, the mean of the data is usually close to 100% (a test/reference ratio of 1). 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 variability within the test subject and reference products in the bioequivalence study. The main concern from a regulatory point of view is patient protection against the approval of products that are not bioequivalent.
General Policies and Legal Status
The current practice of performing two one-tailed tests at a significance level of 0.05 ensures that there is no more than a 5% chance that a generic product that is not truly equivalent to the reference product will be approved. To the extent that the list identifies drug products approved under section 505 of the Act, it sets forth information that the Agency must publish and to which the public is entitled under the Freedom of Information Act. Delisting a drug does not necessarily mean that the drug either violates section 505 of the Act, or that such product is not safe or effective, or that such product is not therapeutically equivalent to other drugs.
Rather, the exclusion is based on the fact that the FDA has not evaluated the drug's safety, effectiveness, and quality.
Practitioner/User Responsibilities
Therapeutic Equivalence Evaluations Codes
Description of Special Situations
Gaviscon®'s activity in treating reflux acid is made possible by the physico-chemical properties of its inactive ingredients, sodium bicarbonate and alginic acid. A full non-disclosure agreement is required to support the drug's effectiveness if several inactive ingredients need to be substituted. Levothyroxine Sodium Tablets (Mylan ANDA 76187) have been determined to be therapeutically equivalent to corresponding strengths of Unithroid Tablets (Jerome Stevens NDA 021210).
Levothyroxine Sodium Tablets (Mylan ANDA 076187) and Levothyroxine Sodium Tablets (Genpharm ANDA 76752) have been determined to be therapeutically equivalent to the respective strengths of Levoxyl Tablets (King Pharms NDA 021301). Levothyroxine Sodium tablets (Mylan ANDA 76187) have been determined to be therapeutically equivalent to corresponding strengths of Levothroid tablets (Lloyd NDA 021116). If a drug product has received this exclusivity, the FDA will delay approval of a 505(b)(2) application or abbreviated new drug application (ANDA) under section 505(j) of the Act until the exclusivity expires.
However, the NDA holder may waive its exclusivity with respect to any or all of the 505(b)(2) and ANDAs. An NDA for which the holder has waived its exclusivity with respect to all 505(b)(2) and ANDA applications will be marked with a W in the Patents and Exclusivity section of the Orange Book and will be listed in that section.
Therapeutic Equivalence Code Change for a Drug Entity
Change of the Therapeutic Equivalence Evaluation for a Single Product
Discontinued Section
Changes to the Orange Book
Applicant holders are requested to notify the FDA Orange Book Staff (OBS) of any changes or corrections. Notification to Orange Book staff of the inclusion of a newly approved product on the Discontinued Drug List instead of Part 1, 2 or 3 of the List (as described in Section 1.1) must be sent by the end of the month in which the product is approved to ensure that the product is not included in the “active” parts of the next published update of the Orange Book.
Availability of the Edition
