[A]pproved drug products that FDA has determined are pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

The purported purpose of the Guidance and the standards set forth therein is to provide states, formularies, pharmacies, and the like in situations where there are multiple sources of the same drug (e.g., branded and generic).  The asserted policy goal of the Guidance is to give the public easier access to more inexpensive drugs.  However, the Guidance emphasizes that economics is to be a beneficial consequence and not the determinant of TE, by stating that "[t]herapeutic equivalence evaluations are a scientific judgment based upon evidence" (as opposed to "social and economic policies").  Interestingly, in the context of this Guidance the word should means "suggested or recommended, but not required," which is certainly a departure from how words of command are interpreted.

The Guidance sets forth three types of equivalence:  pharmaceutical, bioequivalence, and the state of having the "same clinical effect and safety profile" for conditions of use set forth on the drug label.  TE is limited to drugs having multiple sources because there needs to be a comparator (such as a drug approved under an NDA).  The Guidance also set as a goal that drugs deemed to have TE can be substituted "with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified in the labeling."

The Guidance then sets forth the standards for each of the equivalency requirements.  Pharmaceutical equivalence, defined at 21 C.F.R. § 314.3(b), has four criteria:

• in identical dosage form and route(s) of administration;

• contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified-release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period;

• do not necessarily contain the same inactive ingredients; and

• 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 requirements for bioequivalence, defined as:

[T]he absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

As set forth in FDA Regulations at 21 C.F.R. § 314.94(a)(7) and 21 C.F.R. part 320, supplemented by further Guidances, the Guidance makes a distinction for drugs not intended to be absorbed into bloodstream, wherein bioequivalence is determined at the site of action.

For the requirement of having the "same clinical effect and safety profile" the Guidance states that labeling is a critical criteria:  "pharmaceutically equivalent products with differences in labeling may not be considered therapeutically equivalent to one another."  This determination is (particularly) product-specific.

Regarding coverage and applicability, the Guidance asserts that only certain drug products evaluated for TE.  FDA does not evaluate TE for NDA-approved drugs because they are not pharmaceutically equivalent (and thus not TE) to any other drug.  With regard to drugs filed under § 505(b)(1) and approved under 505(c), the FDA will not accept filing for a drug that is a duplicate of one eligible under § 505(j) (ANDA), wherein while duplicate is defined as a "drug product that has the same active ingredient(s), dosage form, strength, route of administration, and conditions of use as a listed drug," it doesn't mean "identical in all aspects."  TE for drugs approved under § 505(b)(2) can be obtained by Citizen's Petition.  Drugs approved under an ANDA (§ 505(j) approval pathway) satisfy the TE requirements "generally" so there's no need for an applicant to request a TE determination by the agency.  "Petitioned" ANDAs on the other hand differ from the reference product in some way ("dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient)") and approval can be obtained on petition under § 505(j)(2)(C).

The Orange Book reflects these TE determinations using a multi-letter coding system.  The Guidance sets forth the following specific code types:

• first letter A codes, which indicate FDA considers the drug to be TE to "other pharmaceutically equivalent products";

• first letter B codes, which indicate whether there were any bioequivalence problems upon filing and how they have been resolved.

• three-letter codes for instances e.g. where there are "more than one RLD of the same strength has been designated under the same product heading (i.e., same active ingredient(s), dosage form, route(s) of administration, and strength)."

These codes can be revised by the FDA as deemed warranted by evidence.

The Guidance also contains a set of FAQs in the Guidance, including an assertion that so-called "skinny label" ANDAs can be eligible for TE determinations and that differences in inactive ingredients generally don't negatively affect TE determinations for ANDA products, among other questions.

As with all draft Guidances, this one contains prominently set out in a black-lined box the qualification that that:

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.