Therapeutic Equivalence Ratings: AB, AP, AT Codes Explained
Therapeutic equivalence (TE) ratings are FDA's evaluation codes published in the Orange Book that indicate whether approved generic drugs are therapeutically equivalent to their reference listed drugs (RLDs). A-rated products (AB, AP, AT, AN, AO) are considered therapeutically equivalent and eligible for automatic generic substitution at pharmacies. B-rated products (BC, BD, BE, BN, BP, BR, BS, BT, BX) are not considered therapeutically equivalent, and substitution requires prescriber authorization. The AB rating is the most common designation, indicating that bioequivalence has been demonstrated through in vivo or in vitro studies meeting FDA's 80-125% confidence interval criteria.
Key Takeaways
Key Takeaways
- A-rated products (AB, AP, AT, AN, AO) are considered therapeutically equivalent and eligible for automatic pharmacy substitution in most states; B-rated products are not
- Therapeutic equivalence requires both pharmaceutical equivalence (same active ingredient, dosage form, strength, route) and bioequivalence (same rate and extent of absorption)
- AB-rated products with numerical subscripts (AB1, AB2, AB3) are equivalent to the RLD but may not be equivalent to each other
- Approximately 90% of generic prescriptions dispensed in the US involve A-rated products
- Therapeutic equivalence ratings are the mechanism FDA uses to communicate whether approved multisource drug products may be substituted for one another with the expectation of producing the same clinical effect and safety profile in patients. Published in the Orange Book (Approved Drug Products with Therapeutic Equivalence Evaluations), these ratings directly govern pharmacy substitution practices, hospital formulary decisions, insurance coverage, and generic drug market access.
- Understanding the TE rating system is essential for regulatory professionals submitting ANDAs, pharmacists making substitution decisions, and formulary committees evaluating generic products.
- In this guide, you'll learn:
- The legal and scientific basis for therapeutic equivalence evaluations
- Every TE evaluation code and what it means
- The difference between pharmaceutical equivalence and bioequivalence
- How AB rating subcategories (AB1, AB2, AB3) work
- How TE ratings affect generic substitution and formulary decisions
- When A-rated generics may still have clinically relevant differences
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What Is Therapeutic Equivalence?
Therapeutic equivalence, as defined by FDA, means that drug products (1) are pharmaceutical equivalents (same active ingredient, dosage form, route of administration, and strength), (2) are bioequivalent (deliver the same rate and extent of drug absorption), and (3) are adequately labeled, manufactured in compliance with cGMP, and meet applicable standards of identity, strength, quality, and purity. Products meeting all three criteria are rated as therapeutically equivalent (A-rated) and expected to produce the same clinical effect and safety profile when administered to patients under the same conditions.
Two Requirements for Therapeutic Equivalence
FDA evaluates therapeutic equivalence based on two sequential criteria:
1. Pharmaceutical Equivalence
Drug products are pharmaceutical equivalents if they contain:
- The same active ingredient(s)
- The same dosage form and route of administration
- The same strength or concentration
- Meet compendial or other applicable standards of identity, strength, quality, purity, and potency
Pharmaceutical equivalence is a necessary but not sufficient condition for therapeutic equivalence. Two products may be pharmaceutical equivalents without being bioequivalent.
2. Bioequivalence
Drug products are bioequivalent if they meet one of the following criteria under 21 CFR 320.1:
- The rate and extent of absorption of the active ingredient do not show a significant difference from the reference product when administered at the same molar dose under similar conditions
- The criteria specified by FDA for the specific drug product (in vivo pharmacokinetic, pharmacodynamic, clinical endpoint, or in vitro studies)
The combined requirement:
Therapeutic Equivalence = Pharmaceutical Equivalence + Bioequivalence
FDA's Orange Book lists therapeutic equivalence evaluations for over 12,000 multi-source prescription drug products, with approximately 90% rated as A (therapeutically equivalent).
Complete TE Code Reference
The TE coding system uses a two-character code. The first character (A or B) indicates whether the product is therapeutically equivalent. The second character provides additional classification detail.
A-Rated Codes (Therapeutically Equivalent)
| Code | Category | Description | Typical Products |
|---|---|---|---|
| AA | No bioequivalence problems | Products in conventional dosage forms not presenting known or suspected BE problems | Simple solutions, certain powders |
| AB | Bioequivalence demonstrated | Products meeting actual or potential BE problems have been resolved with adequate in vivo/in vitro evidence | Most solid oral dosage forms, many liquids |
| AN | Aerosol products | Solution-based aerosol products that meet BE requirements | Metered-dose inhalers (solution-based) |
| AO | Injectable oil solutions | Injectable products formulated in an oil vehicle | Oil-based injectable solutions |
| AP | Injectable aqueous solutions | Injectable products in aqueous solution | IV solutions, aqueous injectable solutions |
| AT | Topical products | Topical products that have demonstrated BE | Creams, ointments, gels, lotions |
B-Rated Codes (Not Therapeutically Equivalent)
| Code | Category | Description | Typical Products |
|---|---|---|---|
| B* | Under review | Tentative code; FDA has not yet determined TE | Products pending evaluation |
| BC | Extended-release | Extended-release dosage forms with different release mechanisms that have not demonstrated BE | ER tablets/capsules, transdermal patches |
| BD | Documented BE problems | Active ingredient and dosage form same but known BE issues exist | Products with documented bioavailability concerns |
| BE | Enteric-coated products | Delayed-release (enteric-coated) products that have not demonstrated BE | Enteric-coated tablets |
| BN | Aerosol products | Aerosol products not considered equivalent | Inhalers with different delivery mechanisms |
| BP | Not pharmaceutical equivalent | Active ingredient is same but products differ in dosage form or other characteristics | Products with different salt forms in some cases |
| BR | Suppositories/enemas | Suppository and enema forms without adequate BE evidence | Rectal and vaginal suppositories |
| BS | Known BE problems | Drug products with known bioequivalence problems that have not been resolved | Narrow therapeutic index drugs in some cases |
| BT | Topical products | Topical products without adequate BE evidence | Certain creams, ointments without demonstrated BE |
| BX | Insufficient data | Insufficient data to determine therapeutic equivalence | Products with incomplete evaluation |
AB Ratings: The Most Important TE Code
The AB rating is by far the most common and commercially important TE designation. It applies to drug products that had actual or potential bioequivalence problems that have been resolved through adequate evidence.
What AB Rating Means
An AB-rated generic drug has:
- Demonstrated pharmaceutical equivalence to the RLD (same active ingredient, dosage form, route, strength)
- Demonstrated bioequivalence to the RLD through appropriate studies
- Met FDA's statistical acceptance criteria (90% confidence interval of geometric mean ratio within 80.00-125.00% for log-transformed AUC and Cmax)
- Been manufactured under cGMP with adequate quality controls
AB Rating Subcategories
When multiple generics are approved for the same RLD but are not necessarily bioequivalent to each other, FDA assigns numerical subscripts to create substitution groups.
| Scenario | TE Assignment | Substitution Rule |
|---|---|---|
| Generic A is AB to RLD | AB | Can substitute for RLD |
| Generic B is AB to RLD | AB | Can substitute for RLD |
| Generic A and B are BE to each other | Both AB (same subscript) | Can substitute for each other |
| Generic A and B are NOT demonstrated BE to each other | AB1 and AB2 (different subscripts) | Should not be substituted for each other |
Example:
- Brand X (RLD): Reference product
- Generic A: AB1 rated (bioequivalent to Brand X)
- Generic B: AB2 rated (bioequivalent to Brand X, but not demonstrated BE to Generic A)
- Generic C: AB1 rated (bioequivalent to Brand X and to Generic A)
In this example:
- Generic A can substitute for Brand X (AB1 to reference)
- Generic B can substitute for Brand X (AB2 to reference)
- Generic C can substitute for Brand X and for Generic A (same AB1 group)
- Generic A should NOT substitute for Generic B (different subscript groups)
AB subscript numbers are critical for pharmacy operations and formulary management. When evaluating generic alternatives, always check whether the products share the same subscript number. Products with different subscript numbers may produce different clinical outcomes despite both being individually equivalent to the RLD. This phenomenon is known as the "transitivity" limitation of bioequivalence.
How FDA Determines TE Ratings
The Evaluation Process
FDA's therapeutic equivalence evaluations follow a structured assessment:
Step 1: Pharmaceutical Equivalence Assessment
- Confirm same active ingredient (including salt form in most cases)
- Confirm same dosage form classification
- Confirm same route of administration
- Confirm same strength or concentration
- Verify compliance with applicable USP/NF standards
Step 2: Bioequivalence Assessment
- Review submitted BE study data
- Verify study design meets FDA requirements
- Confirm bioanalytical method was validated per FDA guidance
- Evaluate statistical analysis (90% CI for AUC and Cmax)
- Assess whether additional studies are needed (e.g., fed state, multiple strengths)
Step 3: TE Rating Assignment
- If both criteria met: A rating assigned (specific code based on dosage form)
- If pharmaceutical equivalence met but BE not demonstrated: B rating assigned
- If pharmaceutical equivalence not met: Product is not a pharmaceutical equivalent and does not receive a TE evaluation
When TE Ratings Change
TE ratings are not permanent. FDA may change a TE rating based on:
| Trigger | Direction | Example |
|---|---|---|
| New BE data submitted | B to A | Previously B-rated product submits adequate BE data |
| Post-market problems identified | A to B | Safety signals suggest clinical inequivalence |
| New scientific understanding | A to B or B to A | Updated evaluation criteria change assessment |
| Product reformulation | Reassessment | Changed formulation requires new TE evaluation |
TE Ratings and Generic Substitution Laws
Therapeutic equivalence ratings directly govern generic substitution at the pharmacy level. However, substitution laws are state-specific.
General Substitution Framework
| Substitution Type | Description | Typical State Requirement |
|---|---|---|
| Mandatory substitution | Pharmacist must substitute A-rated generic unless prescriber prohibits | Some states (e.g., Florida, Massachusetts) |
| Permissive substitution | Pharmacist may substitute A-rated generic at their discretion | Most states |
| Substitution prohibited | Pharmacist cannot substitute without prescriber authorization | Only for B-rated products in most states |
| DAW (Dispense as Written) | Prescriber blocks substitution | Universally recognized |
State-Level Variations
| State Approach | Impact on TE Ratings |
|---|---|
| Positive formulary states | Only products on state-approved formulary may be substituted (even if AB-rated) |
| Negative formulary states | Products on state exclusion list may not be substituted (even if AB-rated) |
| Orange Book-based states | Substitution permitted for any A-rated product in the Orange Book |
Narrow Therapeutic Index (NTI) Drug Considerations
Some states have specific substitution restrictions for narrow therapeutic index drugs, even when A-rated:
- Certain states require prescriber notification before substituting NTI drugs
- Some states restrict NTI drug substitution to the same manufacturer
- FDA has proposed tighter bioequivalence criteria for NTI drugs (90% CI within 90-111.11%)
Examples of NTI drugs with substitution considerations: warfarin, levothyroxine, phenytoin, carbamazepine, cyclosporine, tacrolimus, theophylline, digoxin.
According to the Association for Accessible Medicines, generic drugs account for approximately 90% of prescriptions dispensed in the United States, with the vast majority involving AB-rated products eligible for automatic substitution.
TE Ratings and Formulary Decisions
Hospital Formulary Committees
Hospital Pharmacy and Therapeutics (P&T) committees use TE ratings as a primary criterion for generic product selection:
| Committee Consideration | Role of TE Rating |
|---|---|
| Product selection | A-rated (preferably AB) products preferred for formulary inclusion |
| Therapeutic interchange | TE ratings guide which products can be interchanged within a therapeutic class |
| Cost management | A-rated generics selected for cost savings vs. brand products |
| Formulary restriction | B-rated products may require prior authorization or non-formulary status |
Insurance and PBM Formularies
Pharmacy benefit managers (PBMs) and insurance companies use TE ratings to determine:
| Decision | TE Rating Impact |
|---|---|
| Tier placement | A-rated generics typically placed on lowest copay tier |
| Step therapy | A-rated generics may be required as first-line before brand |
| Prior authorization | Brand may require PA if A-rated generic is available |
| MAC (Maximum Allowable Cost) pricing | A-rated generics included in MAC pricing lists |
Clinical Significance of TE Ratings
When A-Rated Generics Perform Identically
For the vast majority of drug products, A-rated generics are clinically interchangeable with their RLDs. FDA's bioequivalence standard (80-125% CI for AUC and Cmax) is designed to ensure that differences in drug exposure between generic and brand are within a range that does not produce clinically meaningful differences.
Supporting evidence:
- Meta-analyses of BE studies show average differences in AUC between generics and brands of approximately 3-4% (Davit et al., 2009, published in Annals of Pharmacotherapy)
- FDA review of cardiovascular generics found no evidence of clinically significant differences between AB-rated generics and RLDs
Known Limitations and Considerations
Despite the robustness of the TE rating system, regulatory professionals should be aware of certain limitations:
| Limitation | Description |
|---|---|
| Transitivity | Two generics individually equivalent to the RLD may not be equivalent to each other |
| Population differences | BE studies in healthy volunteers may not predict performance in all patient populations |
| Excipient sensitivity | Patients may react to different inactive ingredients in generic products |
| NTI drugs | Small exposure differences may matter more for drugs with narrow therapeutic windows |
| Complex dosage forms | Modified-release and locally acting products may have BE challenges not fully captured by PK criteria |
Post-Market Surveillance
FDA monitors generic drug performance through several mechanisms:
- MedWatch adverse event reporting: Reports of therapeutic failure or adverse events after generic substitution
- Sentinel Initiative: Active surveillance of generic drug outcomes using electronic health records
- FDA-requested studies: Post-market BE studies if concerns arise
- Product quality reporting: Complaints about generic drug quality submitted to FDA
TE Ratings for Special Product Categories
Modified-Release Products
Extended-release, delayed-release, and other modified-release dosage forms present unique TE challenges:
| Dosage Form | Common TE Issues | Typical Rating |
|---|---|---|
| Extended-release tablets/capsules | Different release mechanisms may affect drug delivery | AB if BE demonstrated; BC if not |
| Enteric-coated tablets | Release timing may differ | AB if BE demonstrated; BE if not |
| Transdermal patches | Adhesion, delivery rate differences | AB if BE demonstrated; BC if not |
| Depot injections | Release kinetics may differ | AB if BE demonstrated; BD if not |
Topical Products
Topical drug products have historically been challenging for TE evaluation:
- Solution-based topicals: Generally rated AA or AB if formulation is equivalent
- Semi-solid topicals (creams, ointments, gels): Rated AT if BE has been demonstrated through adequate studies
- Topical BE methods: May include clinical endpoint BE studies, PK studies with dermal microdialysis, or in vitro permeation testing per FDA guidance
Injectable Products
| Injectable Type | Common TE Code | Basis |
|---|---|---|
| Aqueous solutions | AP | Formulation equivalence |
| Oil solutions | AO | Formulation equivalence in same vehicle |
| Suspensions | AB | BE demonstrated |
| Liposomal products | AB or BX | Complex BE assessment required |
| Emulsions | AB or BX | Complex BE assessment required |
How to Look Up TE Ratings
Online Orange Book Database
- Go to FDA's Orange Book search page (fda.gov)
- Search by active ingredient or proprietary name
- TE codes appear in the "TE Code" column of search results
- Click on the product for additional details (patents, exclusivity)
Downloadable Data Files
FDA provides downloadable Orange Book data files in text format:
- Product data file: All approved products with TE codes
- Patent data file: All listed patents
- Exclusivity data file: All active exclusivities
These files can be imported into databases or spreadsheets for systematic analysis.
Third-Party Databases
Several commercial databases provide enhanced Orange Book data:
- Clinical Pharmacology (Elsevier)
- Facts & Comparisons
- Micromedex
- First Databank
These typically provide additional clinical context, substitution recommendations, and state-specific substitution law information beyond what the Orange Book alone provides.
References
Yes. Products rated AA have no known or suspected bioequivalence problems and may be rated without an in vivo BE study. Additionally, products qualifying for BCS-based biowaivers under 21 CFR 320.22 may receive an AB rating based on in vitro dissolution data alone. For details on study design, see our bioequivalence study requirements guide. Injectable aqueous solutions (AP) and injectable oil solutions (AO) may receive A ratings based on formulation equivalence without in vivo studies.