FDA Final Guidance Shows How Orange Book Therapeutic Equivalence Codes Work

The FDA has finalized its guidance on how it decides whether drug products are therapeutically equivalent and how it assigns the codes that record those decisions, RAPS reported on Aug. 24. A Federal Register notice scheduled for publication that day announces the final guidance, "Evaluation of Therapeutic Equivalence," which finalizes a July 2022 draft. RAPS said the final version is little changed from the draft.

The codes it describes appear in the Orange Book, FDA's list of approved drug products with therapeutic equivalence evaluations. States draw on them when deciding which generics can be substituted for a brand-name drug.

What the codes mean

The Orange Book preface says approved products are therapeutic equivalents if they are pharmaceutical equivalents for which bioequivalence has been demonstrated, and "they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling." Pharmaceutical equivalents contain identical amounts of the identical active ingredient in the identical dosage form and route of administration.

The first letter of a TE code sorts products into two groups. An "A" code marks products FDA considers therapeutically equivalent to other pharmaceutically equivalent products; the preface describes them as having no known or suspected bioequivalence problems, or problems that have been resolved with adequate evidence. The most familiar is AB, used generally when data demonstrating bioequivalence have been submitted. A "B" code marks products FDA, at this time, does not consider therapeutically equivalent, often because of bioequivalence concerns with a specific dosage form.

The preface notes why the system exists: virtually every state has laws or regulations encouraging drug product substitution, and FDA compiled the evaluations to serve those programs. It also says the Orange Book "does not mandate the drug products that are purchased, prescribed, dispensed, or substituted for one another." According to the Federal Register notice, the evaluations serve as public information and advice to state health agencies, prescribers and pharmacists on drug product selection.

Which pathway gets a code

TE codes are tied to the generic drug pathway. FDA's ANDA page says generic applications are called "abbreviated" because they are generally not required to include preclinical and clinical data to establish safety and effectiveness; instead, applicants must show their product performs in the same manner as the innovator drug, including by demonstrating bioequivalence. According to RAPS, the guidance says it primarily applies to these abbreviated new drug applications, or ANDAs.

The 505(b)(2) pathway is different. It is a new drug application that relies at least partly on studies the applicant did not conduct, and is often used for changed versions of approved drugs, such as a new dosage form or strength. RAPS reported that FDA does not routinely conduct TE evaluations for 505(b)(2) products, but the final guidance describes a process through which certain 505(b)(2) holders can request one when the only difference from the listed drug is in inactive ingredients. FDA also does not conduct TE evaluations for stand-alone NDAs, which generally serve as the reference drugs that generics copy.

A companion draft on choosing a pathway

The guidance arrived days after FDA updated a related document. RAPS reported on Aug. 18 that FDA issued revised draft guidance on determining whether to submit an ANDA or a 505(b)(2) application, replacing a 2019 version and adding information on duplicates and eligibility for the ANDA route. As RAPS described it, a product that duplicates a previously approved drug belongs on the ANDA pathway.

For generic drugs that do receive an A rating, FDA's generic drug facts page says approved generics must be the same as the brand-name drug in active ingredient, strength, dosage form and route of administration, with the same label apart from certain exceptions.