Therapeutic equivalence: FDA finalizes guidance on TE evaluations
The US Food and Drug Administration (FDA) on Monday finalized guidance on its approach to making therapeutic equivalence (TE) evaluations and assigning therapeutic equivalence (TE) codes for abbreviated new drug applications (ANDAs). These codes are listed in the agency’s Orange Book and denote a drug’s bioequivalence to a reference-listed drug (RLD).
The guidance is little changed from the draft guidance of the same title issued in July 2022. (RELATED: FDA offers new guidance on therapeutic equivalence evaluations, Regulatory Focus 20 July 2022)
FDA's regulations state that for products to be considered therapeutically equivalent (TE) to a reference-listed drug, they must have the same clinical effect and safety profile when administered to patients. These TE evaluations are designed to provide public information and guidance to state health agencies, prescribers, and pharmacists to assist in drug product selection.
FDA states that the guidance primarily applies to ANDAs submitted under Section 505(j) of the Federal Food, Drug, and Cosmetic (FD&C) Act. Sponsors of these products must show that the proposed generic product is the same as the RLD with respect to the active ingredient, conditions of use, route of administration, dosage form, strength, and labeling and that the drug is bioequivalent to the RLD.
The agency also notes in the guidance that it does not routinely conduct TE evaluations for products submitted via the hybrid 505(b)(2) application pathway. The guidance states that “although the 505(b)(2) application may rely, in part, on a finding of safety and/or effectiveness for another listed drug, the requirements for approval of these applications do not necessarily encompass the considerations relevant to evaluating whether the products are therapeutically equivalent to the listed drug they rely upon.”
However, a new process has been introduced for applicants of certain hybrid 505(b)(2) applications to request TE codes. The guidance now states that “in certain circumstances, a 505(b)(2) application holder may use the process described in section 505(j)(7)(A)(v)(I) to request that FDA make a therapeutic equivalence evaluation for a prescription drug in a 505(b)(2) application where the sole difference from a listed drug relied upon in the application is a difference in inactive ingredients not permitted under 21 CFR 314.94(a)(9)(iii)-(iv).”
FDA states in the guidance that it does not conduct TE evaluations for new drug applications (NDAs) submitted under Section 505(c) of the FD&C Act.
It notes that “in most cases, a stand-alone NDA drug product would not be pharmaceutically equivalent—and thus not therapeutically equivalent—to another approved stand-alone NDA drug product. Drug products approved in stand-alone NDAs are generally designated as RLDs upon which prospective generic drug applicants can rely in developing their ANDA drug products.”
The guidance indicates that drug products are assigned an "A" as the first letter of their TE code if the FDA considers them therapeutically equivalent to other pharmaceutically equivalent products, and these are grouped together in the Orange Book. The agency assigns products an AB code if bioequivalence problems have been found.
Products beginning with the letter B are not considered therapeutically equivalent to other pharmaceutically equivalent products at the time of evaluation because actual or potential bioequivalence concerns have not been adequately resolved.
FDA may revise a TE evaluation if it identifies documented bioequivalence issues or “significant potential” for such issues for one or more applications under regulatory review.
The guidance also contains 14 frequently asked questions (FAQ) that address issues such as when TE codes for ANDAs are listed in the Orange Book; whether there are any instances in which an approved ANDA drug product would not have a TE code; an example of a 505(b)(2) application for which a request for an A rating may be granted; and if a drug product is repackaged and distributed by either the applicant or a party other than the applicant, if it will be given its own TE code.
