FDA Draft Guidance on Evaluation of Therapeutic Equivalence

On July 21, 2022, the FDA issued draft guidance titled “Evaluation of Therapeutic Equivalence.” In this guidance, the FDA explains therapeutic equivalence evaluations, including the assignment of therapeutic equivalence codes (“TE” codes). The FDA’s therapeutic equivalence evaluations are listed for certain drug products approved under section 505 of the FD&C Act in the Orange Book and serve as public information and advice to state health agencies, prescribers, and pharmacists.

The first part of the guidance explains the criteria the FDA uses to assess whether a drug product can be deemed therapeutically equivalent to a previously approved drug product. The guidance explains that for a prescription drug product to be considered “therapeutically equivalent” to another product, the drug product must be:

(1) pharmaceutically equivalent,

(2) bioequivalent, and

(3) have the same clinical effect and safety profile for the conditions of use specified in the labeling.

Pharmaceutical equivalence is shown when two products share: (i) identical dosage form and route(s) of administration, (ii) identical amounts of the identical active drug ingredient to be delivered over an identical dosing period, and (iii) meet identical standards for identity, strength, quality, and purity, including potency. In short, the active drug ingredient in the two products are pharmaceutically (i.e. chemically) indistinguishable, though they may have different inactive ingredients.

Bioequivalence relates to the availability of the drug to the body. A drug product is deemed bioequivalent to another when there is no “significant difference in the rate and extent to which the active ingredient or active moiety . . . becomes available at the site of the drug action when administered at the same molar dose under similar conditions in an appropriately designed study.” The FDA has issued regulations and other guidance concerning how to demonstrate bioequivalence.

Finally, to determine if a product has the same clinical effects and safety profile for a given use identified in the labeling, the FDA looks carefully at what is specified in the labeling. This inquiry is a product-specific determination and may result in two pharmaceutically equivalent products not being considered therapeutically equivalent if there are labeling differences.

The second part of the draft guidance explains that the FDA only evaluates certain drug products approved under section 505 of the FD&C Act for therapeutic equivalence, such as generic drugs submitted under an ANDA and some drugs submitted under a 505(b)(2) application. The FDA explains that generally, except for a drug product approved in a petitioned ANDA, when the FDA approves a drug product under an ANDA, it is therapeutically equivalent to its Reference Listed Drug, or RLD.

The third part of the FDA draft guidance discusses the multi-letter TE coding system used in the Orange Book. The TE code quickly signals to the reader whether a given drug is therapeutically equivalent to another product and the dosage form. For example, the FDA will assign an “A” as the first letter of a drug product’s TE code if the FDA considers the drug product to be therapeutically equivalent to other pharmaceutically equivalent products, whereas a “B” coded drug product indicates that there are actual or potential bioequivalence problems (i.e., the FDA considered such products not therapeutically equivalent to other pharmaceutically equivalent products). In the case of “A” codes, the second letter in the TE code identifies either (1) that actual or potential bioequivalence problems have been resolved, or (2) if there are no known or suspected bioequivalence problems, the dosage form. In the case of “B” codes, the second letter provides further general information regarding why the product is not considered to be therapeutically equivalent. In some instances, a number is added to certain TE codes making a three-lettered code.

The final part of the draft guidance provides a “nonexclusive list” of examples of when the FDA may revise its therapeutic equivalence evaluation. The FDA also includes answers to fourteen frequently asked questions touching on related 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 alter a TE evaluation, and how to contest a TE evaluation.

Readers are encouraged to read the draft guidance, also available on the FDA’s website. Comments and suggestions regarding this draft guidance should be submitted within sixty days.