Therapeutic Equivalence in the Orange Book

An AB rating means FDA considers the product therapeutically equivalent to other products under the same Orange Book heading that carry the same AB code. FDA "believes" such products "can be substituted with the full expectation that the substituted product can be expected to have the same clinical effect and safety profile" under the labelled conditions. The rating covers only products under that heading. If there is a number after it (AB1, AB2), the product is equivalent only to products with that exact code.

Approach: I searched the FDA Orange Book approved drug products listings for real AB-coded entries. Those listings hold the codes but not their meaning, so the definitions come from FDA's Orange Book Preface (Sections 1.6 and 1.7).

What the code means (Preface, Section 1.7)

• "A" codes are for products "that FDA considers to be therapeutically equivalent to other pharmaceutically equivalent products." That covers products with no bioequivalence problem and products whose problem has been resolved with adequate evidence.
• "AB, AB1, AB2, AB3..." are "Products meeting necessary bioequivalence requirements." Multisource products under the same heading "generally will be coded AB if data and information are submitted demonstrating bioequivalence."
• AB differs from the other A codes because it rests on bioequivalence data that was submitted. The other A codes work like this:
  • AA: the active ingredients are not regarded as having actual or potential bioequivalence problems.
  • AN: aerosolization solutions and powders.
  • AO: injectable oil solutions.
  • AP: injectable aqueous solutions.
  • AT: topical products with a waiver or in vitro bioequivalence.

The substitution boundary

• "Drugs coded as AB under a heading are considered therapeutically equivalent only to other drugs coded as AB under that heading."
• A number is added to make AB1, AB2 and so on. FDA generally does this "only in situations when more than one RLD of the same strength has been designated under the same heading." Drugs with a three-character code "are considered therapeutically equivalent only to other drugs coded with the same three-character code." FDA's own example is the two different nifedipine extended-release reference products, Adalat CC and Procardia XL.

A live example from the Orange Book Topiramate extended-release oral capsules have two reference listed drugs under the same heading, and they carry different codes:

• Trokendi XR (Supernus), NDA 201635: AB1 at 50 mg, 100 mg and 200 mg; RLD = Yes ^[1][2][3]
• Qudexy XR (Upsher Smith), NDA 205122: AB2 at 50 mg, 100 mg, 150 mg and 200 mg; RLD = Yes ^[4][5][6][7]

So a generic rated AB1 is a therapeutic-equivalence substitute for Trokendi XR, not for Qudexy XR. A generic rated AB2 is a substitute for Qudexy XR only. That holds even though both products have the same ingredient, dosage form and route.

Who decides on substitution (Preface, Section 1.6)

• The Preface notes that "virtually every state has adopted laws and/or regulations that encourage the substitution of drug products." Whether a pharmacist may or must substitute is set by state law, not by the AB code.
• FDA's evaluation "in no way relieves practitioners of their professional responsibilities."
• As covered in the earlier answer, the ratings "are not official FDA actions affecting the legal status of products," and the Orange Book does not mandate what is dispensed or substituted.

I can list every AB-rated product, or its numbered AB variants, for a specific ingredient or reference product.

Pharmaceutical equivalence compares the two products themselves: same active ingredient, amount, dosage form, route and quality standard. Bioequivalence compares how they perform in the body: whether the active ingredient becomes available at the site of action at the same rate and to the same extent. Products need both to be therapeutic equivalents ^[8].

Approach: I used the current eCFR text of 21 CFR Part 314: the definitions in § 314.3(b) and the ANDA bioequivalence requirement in § 314.94(a)(7).

Side-by-side (21 CFR 314.3(b)) ^[8]

	Pharmaceutical equivalence	Bioequivalence
What it measures	Whether the two products are the same	Whether the body gets the active ingredient at the same rate and to the same extent
Active ingredient	"Identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety"	Covers "pharmaceutical equivalents or pharmaceutical alternatives," so the salt, ester, amount or dosage form may differ
Dosage form and route	"Identical dosage forms and route(s) of administration"	Not required to be identical; the products are compared "at the same molar dose under similar conditions"
Inactive ingredients	"Do not necessarily contain the same inactive ingredients"	Not addressed; what counts is the result
Standard	Meet "the identical compendial or other applicable standard of identity, strength, quality, and purity," including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates	"The absence of a significant difference in the rate and extent" of availability at the site of drug action "in an appropriately designed study"
How it is shown	Through formulation and quality specifications	Through a study (in vivo or in vitro)

Details in the definitions that matter in practice ^[8]

• Modified-release products and prefilled syringes: pharmaceutical equivalence is met if the products "deliver identical amounts of the active drug ingredient over the identical dosing period." This applies where a reservoir, overage or variable residual volume means the amounts in the products differ.
• Intentional rate differences: for some extended-release forms, products "may be considered bioequivalent" if there is no significant difference in extent alone. This applies only if the rate difference is intentional and reflected in the proposed labelling, "is not essential to the attainment of effective body drug concentrations on chronic use," and "is considered medically insignificant for the drug."
• Products not meant to be absorbed: bioequivalence "may be assessed by scientifically valid measurements intended to reflect the rate and extent" of availability at the site of action, rather than blood levels.
• Bioavailability vs bioequivalence: bioavailability is a property of one product: "the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of drug action." Bioequivalence compares that property between two products.

How they combine

• Therapeutic equivalents are "approved drug products that are pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the same clinical effect and safety profile" under the labelled conditions ^[8].
• Pharmaceutical equivalence without bioequivalence is not therapeutic equivalence. Two tablets with the same strength and quality standard can still release the drug differently, for example because of different inactive ingredients.
• Bioequivalence without pharmaceutical equivalence is possible. The definition expressly covers pharmaceutical alternatives (for example a different salt or dosage form). Such products are still not therapeutic equivalents, because that status requires pharmaceutical equivalence first ^[8].

What an ANDA must show

• Under 21 CFR 314.94(a)(7)(i), an ANDA must include "information that shows that the drug product is bioequivalent to the reference listed drug." A "complete study report must be submitted" for the pivotal bioequivalence study ^[9].
• For other bioequivalence studies on the "same drug product formulation," the applicant "must submit either a complete or summary report." FDA "may require" the complete report if it sees possible bioequivalence concerns ^[9].
• For each study, the ANDA must also describe "the analytical and statistical methods used" ^[9].

I can also pull the other ANDA "sameness" requirements in § 314.94 (active ingredient, route, dosage form, strength, labelling) if you need them.