FDA offers new guidance on therapeutic equivalence evaluations

Regulatory NewsRegulatory News | 20 July 2022 |  By 

In draft guidance issued on Wednesday, the US Food and Drug Administration (FDA) explains its approach to therapeutic equivalence (TE) evaluations and the assignment of therapeutic equivalence codes, which are listed in the agency’s Orange Book and provide information about whether drugs are bioequivalent and can be substituted for one another.
“Therapeutic equivalence evaluation 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,” FDA writes.
To be considered therapeutically equivalent to another drug, a product must be pharmaceutically equivalent, bioequivalent and have the same clinical effect and safety profile.
FDA explains that two- or three-character TE codes are assigned to multi-source drug products “to allow users to determine quickly whether the Agency has evaluated a particular approved drug product as therapeutically equivalent to another approved pharmaceutically equivalent drug product.”

TE Codes beginning with the letter “A” are considered therapeutically equivalent, either because “there are no known or suspected bioequivalence problems,” or because “actual or potential bioequivalence problems have been resolved with adequate evidence.” Products that fall under the latter category are coded “AB”; for other therapeutically equivalent drugs, the second letter signifies the product’s dosage form. In some cases, a three-character code is given when there are multiple reference listed drugs listed under the same product heading in the Orange Book.
What products are evaluated for therapeutic equivalence?
FDA notes that it “only evaluates certain drug products approved under section 505 of the [Food, Drug, and Cosmetic Act] FD&C Act for therapeutic equivalence, such as generic drugs submitted under an abbreviated new drug application (ANDA) and some drugs submitted under a 505(b)(2) application.
“FDA generally does not conduct therapeutic equivalence evaluations upon approval of drug products in stand-alone NDAs. In most cases, a stand-alone [new drug application] NDA drug product would not be pharmaceutically equivalent—and thus not therapeutically equivalent—to another approved stand-alone NDA drug product,” FDA explains. For 505(b)(2) applications, FDA says the applicant would need to submit a citizen petition to request a therapeutic equivalence evaluation. The agency notes that some differences between a 505(b)(2) product and another listed drug “may preclude a finding that the products are therapeutically equivalent,” including differences in the active ingredient, dosage form, strength, route of administration, formulation or when there is a new indication.
For generic drugs, FDA explains that for most approved generics, the product is considered therapeutically equivalent to the reference listed drug as the requirements for ANDA approval overlap with the data the agency would need to determine therapeutic equivalence. However, the agency states that ANDAs subject to a suitability petition, or petitioned ANDAs, are not considered therapeutically equivalent to the RLD as they are not pharmaceutically equivalent.
When will FDA revise a therapeutic equivalence rating?
FDA says it may revise a TE evaluation when it receives or becomes aware of new information in certain circumstances.
Potential revisions include revising a TE code if the agency decides that another code is more accurate, removing a code from a product that has moved to the Discontinued Drug Product List section of the Orange Book and removing the TE code from a drug that becomes a single-source product.
FDA notes that it may switch a product’s TE code from an A-rating to a B-rating if it learns of any information that “raises questions about the data and information that the Agency relied on in approving that drug product,” such as facility issues where a drug product was tested.
The guidance also contains a frequently asked questions (FAQ) that contains 14 questions touching on issues such as when an approved ANDA or NDA would not have a TE code, when a 505(b)(2) application may be granted an A-rating, how inactive ingredients affect a therapeutic equivalence evaluation, and how therapeutic equivalence is evaluated for drug-device combination products.
Guidance, Federal Register notice


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