USFDA Guidance: Evaluation of Therapeutic Equivalence

Therapeutic equivalence is an important consideration when evaluating multisource prescription drug products and their potential substitution. The U.S. Food and Drug Administration (FDA) uses therapeutic equivalence evaluations to determine whether certain approved drug products can be expected to have the same clinical effect and safety profile when used under the conditions specified in their labeling.

The FDA has issued the Guidance for Industry: Evaluation of Therapeutic Equivalence, which explains the principles used to evaluate therapeutic equivalence and assign therapeutic equivalence (TE) codes. These evaluations are included in the Approved Drug Products With Therapeutic Equivalence Evaluations, commonly known as the Orange Book.

Understanding Therapeutic Equivalence

FDA considers drug products therapeutically equivalent when they are pharmaceutical equivalents, have demonstrated bioequivalence, and can be expected to have the same clinical effect and safety profile when administered under the conditions specified in the labeling.

The evaluation generally applies to applicable multisource prescription drug products approved under section 505 of the Federal Food, Drug, and Cosmetic Act.

Therapeutic equivalence evaluations provide information that can support drug product selection and substitution decisions by healthcare professionals and others.

Key Elements of Therapeutic Equivalence

The assessment of therapeutic equivalence is based on three important elements:

• Pharmaceutical equivalence

• Bioequivalence

• The same expected clinical effect and safety profile

Products must meet the applicable requirements for identity, strength, quality, and purity. FDA also considers relevant labeling and other product characteristics when making therapeutic equivalence evaluations.

Pharmaceutical Equivalence

Pharmaceutical equivalents are drug products that contain the same active drug ingredient or ingredients, have the same dosage form and route of administration, and contain the same amount of the active ingredient.

They must meet applicable standards for identity, strength, quality, and purity, including relevant requirements for potency, content uniformity, disintegration, and dissolution.

Pharmaceutical equivalents do not necessarily have to contain identical inactive ingredients. They may also differ in characteristics such as shape, scoring, release mechanisms, packaging, expiration date, and certain labeling information.

Bioequivalence

Bioequivalence is another key component of therapeutic equivalence.

In general, bioequivalence means there is no significant difference in the rate and extent to which the active ingredient or active moiety becomes available at the site of drug action when pharmaceutical equivalents are administered at the same molar dose under similar conditions in an appropriately designed study.

For products that are not intended to be absorbed into the bloodstream, other scientifically appropriate measurements may be used to evaluate bioequivalence.

FDA evaluates bioequivalence using the applicable regulatory and scientific approaches for the specific drug product.

Same Clinical Effect and Safety Profile

Therapeutically equivalent products are expected to have the same clinical effect and safety profile when administered according to their labeling.

FDA considers labeling as part of the therapeutic equivalence evaluation. Certain permitted labeling differences may be acceptable, while other differences may affect therapeutic equivalence.

The assessment can also depend on the characteristics of the product. For certain drug-device combination products, differences in the device or user interface may require additional consideration.

Therapeutic Equivalence Evaluations

FDA evaluates therapeutic equivalence for certain drug products approved under section 505 of the FD&C Act.

These products can include those approved through ANDAs and certain products approved through NDAs or 505(b)(2) applications.

An approved ANDA generally meets the requirements needed to establish therapeutic equivalence to its reference listed drug. However, products approved through other pathways may have differences that prevent them from being considered therapeutically equivalent.

ANDAs and Therapeutic Equivalence

An ANDA generally applies to a generic drug product that is a duplicate of a previously approved Reference Listed Drug (RLD).

The proposed generic generally needs to have the same active ingredient or ingredients, conditions of use, route of administration, dosage form, strength, and applicable labeling as the RLD, subject to permitted differences.

It must also demonstrate bioequivalence.

Because these requirements generally support therapeutic equivalence, an approved ANDA is generally considered therapeutically equivalent to its RLD.

Petitioned ANDAs

A petitioned ANDA may involve certain differences from the RLD, such as a difference in dosage form, route of administration, strength, or one active ingredient in a combination product.

Because the approved product may not be pharmaceutically equivalent to its RLD, a petitioned ANDA is generally not considered therapeutically equivalent to that RLD.

If another ANDA is subsequently approved for the same permitted change, FDA may evaluate the applicable products for therapeutic equivalence.

Understanding TE Codes

FDA uses multiletter therapeutic equivalence codes in the Orange Book.

Products beginning with the letter A are considered therapeutically equivalent to other pharmaceutically equivalent products.

An AB code indicates that an actual or potential bioequivalence issue has been adequately resolved with appropriate evidence.

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.

The second letter provides additional information about the type of product or the basis for the evaluation.

Changes to Therapeutic Equivalence Evaluations

FDA may revise a therapeutic equivalence evaluation when new information or data indicate that a change is appropriate.

A TE code may be changed when new information raises questions about the evidence supporting the original evaluation or when FDA becomes aware of a documented or potential bioequivalence problem.

FDA may also remove a TE code when a product is moved to the Discontinued Drug Product List or becomes a single-source product.

Therapeutic Equivalence and the Orange Book

The Orange Book contains FDA's therapeutic equivalence evaluations for applicable multisource prescription drug products.

TE codes provide a way to understand whether FDA has evaluated a drug product as therapeutically equivalent to another pharmaceutically equivalent product and provide additional information about the evaluation.

Therapeutic equivalence evaluations are based on FDA's scientific assessment. They do not determine which products must be prescribed, dispensed, purchased, or substituted. Drug substitution may also be affected by applicable state requirements.

Considerations for Healthcare Professionals

Products evaluated as therapeutically equivalent can generally be expected to have the same clinical effect and safety profile when used according to their labeling.

However, therapeutically equivalent products may still differ in characteristics such as color, shape, flavor, scoring, excipients, packaging, storage conditions, and expiration date.

These differences may be relevant to individual patients and should be considered when prescribing or dispensing products.

505(b)(2) Products

Products approved through a 505(b)(2) application may contain differences from the listed drug that prevent therapeutic equivalence.

However, a 505(b)(2) product can receive an appropriate TE code when FDA determines that it meets the applicable requirements for therapeutic equivalence.

A 505(b)(2) product may, for example, contain certain differences in inactive ingredients while still meeting the requirements for pharmaceutical equivalence, bioequivalence, and the same expected clinical effect and safety profile.

A Structured Approach to Therapeutic Equivalence

The FDA's Evaluation of Therapeutic Equivalence guidance provides a framework for understanding how therapeutic equivalence is assessed and how TE codes are assigned.

The assessment focuses primarily on pharmaceutical equivalence, bioequivalence, and the expectation of the same clinical effect and safety profile. The guidance also explains therapeutic equivalence evaluations for different types of applications, the use of A and B codes, and circumstances in which evaluations may be revised.

Understanding these principles can help applicants and healthcare professionals interpret FDA therapeutic equivalence evaluations and use the information provided in the Orange Book.

References

U.S. Food and Drug Administration (FDA): Evaluation of Therapeutic Equivalence, Guidance for Industry.