Bioequivalence and the Orange Book

A third character to the TE code is sometimes added

- Assigned when multiple sources of the drug are available but these sources are not considered therapeutically equivalent to each other - Two or more reference listed drugs that are not bioequivalent to each other - Example: Procardia XL and Adalat CC • Both nifedipine but not therapeutic equivalent to each other • Adalat CC is AB1 • Procardia XL is AB2

In 1980, the FDA published the Approved Drug Products with Therapeutic Equivalence Evaluations

- Better known as the Orange Book - Lists if generic versions of medications are therapeutic equivalents to the reference listed drug

FDA considers drug products to be pharmaceutical alternatives if the drug products contain the same active drug but have....

- Different salt forms • Example: tetracycline phosphate vs. tetracycline HCl - Different dosage strength • Example: 10 mg vs 20 mg - Different type of dosage form • Example: IR tablet vs ER tablet • Example: omeprazole capsule vs omeprazole tablet

BD

Documented bioequivalence problems

Bioequivalent products

have comparable bioavailability • The rate and extent of absorption of the test drug is not significantly different from the reference drug

BX

insufficient data to determine bioequivalence

Bioequivalence testing can be waived and in vitro dissolution testing substituted for drugs contained in dosage forms with the following properties:

- High solubility - High permeability - Rapid dissolution - Similar dissolution profile to brand product - Wide therapeutic window - Excipients used in dosage form used previously in FDA approved IR solid dosage forms

FDA considers drug products to be pharmaceutical equivalents if they meet these three criteria:

- Same active ingredient(s) - Same strength or concentration - Same dosage form and route of administration

Statistical Evaluation of Bioequivalence

- The 90% confidence intervals for both Cmax and AUC for the test product must be within 80-125% of the reference product • Often expressed as a percentage but not always • 80-125% = 0.8-1.25 - 80-125% is used instead of 80-120% because the data is log transformed

Summary of B codes: Drug products that FDA at this time, considers NOT to be therapeutically equivalent to other pharmaceutically equivalent products, i.e

- drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence. Often the problem is with specific dosage forms rather than with the active ingredients. These are designated BC, BD, BE, BN, BP, BR, BS, BT, BX, or B*.

Pharmaceutically equivalent drug products may differ in characteristics such as

- shape - release mechanism - scoring - excipients (including colors, flavors, preservatives) - packaging - expiration time - labeling (to some extent)

Steps in Determining Therapeutic Equivalency

1) Determine if you have pharmaceutical equivalents - Same active ingredient(s) - Same strength or concentration - Same dosage form and route of administration 2) If the products are pharmaceutically equivalent, look at the TE code provided in the Orange Book to determine if the products are bioequivalent. 3) If the products are pharmaceutical equivalents and have the same TE code, they are therapeutically equivalent.

What are the 3 parameters that are used to quantify rate and extent of drug absorption?

1. Peak Concentration (Cmax) 2. Time to peak (Tmax) 3. Area Under the Curve (AUC)

Summary of A codes: Drug products that FDA considers to be therapeutically equivalent to other pharmaceutically equivalent products, i.e., drug products for which:

1. there are no known or suspected bioequivalence problems. These are designated AA, AN, AO, AP, or AT, depending on the dosage form; or 2. actual or potential bioequivalence problems have been resolved with adequate in vivo and/or in vitro evidence supporting bioequivalence. These are designated AB.

TE codes

2- or 3- character code

TE: First letter of Code

A codes: Considered therapeutically equivalent to another pharmaceutically equivalent drug B codes: Considered not therapeutically equivalent

TE: Second letter of Code A-rated Drugs

AA: Dosage forms not suspected to have bioequivalence problems • These are often solution dosage forms AN, AO, AP, or AT: Gives information about specific routes AB: Shown to have no bioequivalence problems through in vivo or in vitro evidence •these are the drugs that have had bioequivalence studies or in vitro biowaivers completed

Responsible for knowing TE codes:

AB, AA, AB1/AB2/AB3, BD, BP, BX

TE: Second letter of Code B-rated Drugs

B-rated drugs: drug products for which actual or potential bioequivalence problems have not been resolved by adequate evidence of bioequivalence. - the second letter of the TE code gives more information about the bioequivalence problem or dosage form

Which BCS class drugs are eligible for a waiver of in vivo bioequivalence testing?

BCS Class I Drugs

Absolute Bioavailability

Comparison of AUC of other routes with AUC by IV administration reveals whether any drug is lost during absorption

Relative Bioavailability

Comparison of AUCs of three different formulations of a drug via the same route of administration

Sometimes the RLD is no longer on the market. This makes it so the generic manufacturer cannot compare their formulation to the RLD. In these cases what does the FDA do?

FDA assigns a reference standard (RS) to which all generics are compared. -this reference standard is generally a generic that has been an the market for a long period of time.

Therapeutic Equivalence (TE)

FDA considers drug products to be therapeutic equivalents if the products are both pharmaceutically equivalent and bioequivalent

Bioequivalence Testing

In vivo pharmacokinetic studies most commonly used to determine bioequivalence • Assesses the relative bioavailability of the test formulation to that of the reference formulation • Conducted in randomized crossover design in healthy volunteers - Plasma levels of the drug are measured over time - Healthy volunteers are randomized to take one dose of a reference formulation and then one dose of test formulation with washout periods in between - Usually single dose, sometimes multiple dose studies

AB

Meet necessary bioequivalence standards

AA

No issues with bioequivalence

Mylan and Sandoz both manufacture metoprolol tablets. Based upon the information available in the below table, are these two tablets considered pharmaceutical equivalents? Why or why not? Are they considered pharmaceutical alternatives? Why or why not?

No, these two products are not considered pharmaceutical equivalents. Instead, they are considered pharmaceuitcal alternatives. They both contain metoprolol but it's in a different salt form. Additionally, they are different types of dosage forms (tablet vs ER tablet)

Bioavailability can be highly variable and can be influenced by:

Physiochemical properties of drug substance - Salt form - Crystalline or amorphous form - Particle size Pharmaceutical excipients Dosage Form characteristics - Disintegration rate - Dissolution time Physiologic factors and patient characteristics - Gastric emptying time - Intestinal transit time - Gastric contents (food, liquids, other drugs) - GI pH - Drug metabolism and transport

TE: Second letter of Code

Provides additional information about the dosage form or actual/potential bioequivalence problem

When is generic substitution NOT appropriate?

Remember that pharmaceutically equivalent drug products may differ in characteristics such as • shape • release mechanism* • labeling (to some extent) • scoring • excipients (including colors, flavors, preservatives) Generic substitution is not appropriate if one of the above is an important consideration

Pharmaceutical equivalent:

Same active ingredient(s), strength/concentration, dosage form, and route

Bioavailability (F)

The fraction of the dose of intact drug that reaches systemic circulation A measure of the extent of absorption of a drug

True or False, 10mg drug in brand name does NOT mean an equal response if 10 mg of the same drug is given in a different formulation.

True

True or False, Generic drug manufacturers are not required to complete preclinical and clinical studies to demonstrate safety and effectiveness of a generic product.

True

True or False, different excipients and different manufacturing processes can result in two dosage forms with the same amount of drug to behave very different clinically

True

True or False, every generic product is compared to a reference formulation.

True

True or False, large amount of evidence suggests a correlation between in vitro data and in vivo exposure

True

True or False, the bioavailability of most generic drugs differs from brand name by <4%

True

True or False, authorized generics are generics that are IDENTICAL to the brand.

True Made by the brand company or subsidiary but repackaged for sale under the generic name - Used to compete with generic companies These generic products will look the same as the brand

Equal amount does NOT equal response. True or False?

True having an equal amount of drug in a dosage form does not guarantee you will have an equivalent response

True or False, Therapeutically equivalent drug products can be substituted or interchanged

True will produce the same clinical effect and safety profile

Definition of Bioequivalence

Two drug products (test vs. reference) do not differ significantly in their rate and extent of absorption Will be "bioequivalent" to each other

The following table reports bioequivalence data from a generic manufacturer. Based upon the results in the table below, which one of the following statements is TRUE regarding this study? a) The generic product is statistically bioequivalent to the reference product. b) The generic product is statistically bioinequivalent (i.e. not bioequivalent) to the brand name formulation. c) The data is inconclusive. The drug is not statistically bioequivalent to the brand nor is it statistically bioinequivalent to the brand.

a) The generic product is statistically bioequivalent to the reference product. This data indicates the test formulation and reference formulation are bioequivalent. The 90% confidence intervals for both Cmax and AUC are within the boundaries of 0.8 and 1.25

A table of information from the Orange Book is displayed. Based on this information, can these two products be considered as therapeutic equivalents and substituted for each other? Why or why not? a. No, they are not pharmaceutical equivalents. b. Yes, they are both AB rated. c. Yes, they are pharmaceutical equivalents. d. No, they are not reference listed drugs.

a. No, they are not pharmaceutical equivalents. They are not pharmaceutical equivalents because they are not the same type of dosage form (remember that IR is different from ER which is different from chewable, ect)

BP

active ingredient (s) with potential bioequivalence concerns

The following table reports bioequivalence data from a generic manufacturer. Based upon the results in the table below, which one of the following statements is TRUE regarding this study? a) The generic product is statistically bioequivalent to the reference product. b) The generic product is statistically bioinequivalent (i.e. not bioequivalent) to the brand name formulation. c) The data is inconclusive. The drug is not statistically bioequivalent to the brand nor is it statistically bioinequivalent to the brand.

b) The generic product is statistically bioinequivalent (i.e. not bioequivalent) to the brand name formulation. This data indicates the test formulation and reference formulation are bioINequivalent. The 90% confidence intervals for Cmax and AUC are entirely outside the boundaries of 0.8 and 1.25

Which of the following most appropriately describes the rating of AB? a. The product has no issues with bioequivalence. b. Meets necessary bioequivalence standards. c. The product has documented bioequivalence problems. d. The product has potential bioequivalence problems.

b. Meets necessary bioequivalence standards.

A table of information from the Orange Book is displayed. Based on this information, which of the following products would be appropriate to dispense if a physician permits substitution for Fortamet 1 gram? a. Metformin hydrochloride by Lupin LTD (A091664) b. Metformin hydrochloride by Mylan Pharms Inc (A200690) c. Glumetza by Santarus Inc (N021748) d. Metformin hydrochloride by Alkem (A091184)

b. Metformin hydrochloride by Mylan Pharms Inc (A200690) The product by Mylan is a pharmaceutical equivalent to Fortamet (same active ingredient, same dosage form, same route, same strength) and is also bioequivalent as denoted by the TE of AB2 which matches the TE code of Fortamet

RLD=

brand name product that was the first approved for that particular drug/dosage form reference listed drug (RLD)

The following table reports bioequivalence data from a generic manufacturer. Based upon the results in the table below, which one of the following statements is TRUE regarding this study? a) The generic product is statistically bioequivalent to the reference product. b) The generic product is statistically bioinequivalent (i.e. not bioequivalent) to the brand name formulation. c) The data is inconclusive. The drug is not statistically bioequivalent to the brand nor is it statistically bioinequivalent to the brand.

c) The data is inconclusive. The drug is not statistically bioequivalent to the brand nor is it statistically bioinequivalent to the brand. This data indicates the test formulation and reference formulation are bioequivalent. The 90% confidence intervals for both Cmax and AUC extend outside the boundaries of 0.8 and 1.25

Which of the following is FALSE? a. Tmax is the time to maximum concentration. b. Cmax is the maximum concentration obtained following a dose of a drug. c. Area under the plasma-concentration time curve (AUC) is a measure of the rate of absorption. d. Tmax is a measure of the rate of absorption.

c. Area under the plasma-concentration time curve (AUC) is a measure of the rate of absorption.

Absolute Bioavailability

compares oral (extravascular) dose with IV

Relative Bioavailability

compares two oral (extravascular) doses with each other

Bioequivalence testing contd.

• Plasma samples analyzed for drug concentrations • Calculation of AUC, Cmax • Data is log transformed • Ratios of each parameter are calculated: