Bioequivalence and Bioavailability Study Design and Requirement

Bioequivalence Study Design | Bioequivalence Guidelines | EMA Bioequivalence Guideline | Bioequivalence Study

As indicated by the various regulatory agencies like FDA and EMA, an approved generic drug product can be used as a substitute for the brand-name drug.

Bioavailability (BA)

Bioavailability refers to the relative amount of drug from an administered dosage from which enters the systemic circulation and the rate at which the drug appears in the systemic circulation.

Bioequivalence (BE)

Two drug products are called bioequivalent if the 90% CI of the ratio of geometric means of the primary PK responses is within the bioequivalence limits of 80% and 125%. 

 

Two products are called bioequivalent if their extent and rate of absorption are not statistically significantly different when administered at the same molar dose.

The plasma concentration time curve is usually used to assess the rate and extent of drug absorption in bioequivalence studies. 

Pilot Study

A pilot study in a small number of subjects can be carried out before proceeding with a full-scale BA or BE study.

Standard Study Design for a Bioequivalence Study

If two formulations (for example Brand and Generic product) are compared, a randomised, two-period, two-sequence single dose crossover design is recommended.

Number of Subjects

The number of subjects in a bioequivalence studies should not be less than 12.

Subjects Age

Subjects should be 18 years of age or older and preferably have a Body Mass Index (BMI) between 18.5 and 30 kg/m².

Strength to be Investigated for Bioequivalence

The bioequivalence study should (in general) be conducted at the highest strength of the test product.

With Food or Without Food

If the Pack Insert of Reference Medicinal Product recommends drug to be on an empty stomach or irrespective of food intake, the bioequivalence study should be conducted under fasting conditions. 

If the Pack Insert of the reference medicinal product recommends drug to be taken only in fed state, the bioequivalence study should be conducted under fed conditions.

Parameters to be Analysed and Acceptance Limits

The parameters to be analysed in studies to determine bioequivalence after a single dose are:

·         AUC(0-t)

·         AUC(0-72h)

·         Cmax

90% confidence interval for the ratio of the test and reference products = 80.00- 125.00%.

For all above parameters the 90% CI for the ratio of the test and reference products should be contained within the acceptance interval of 80.00- 125.00%.

Bioequivalence requirements for different types of product:

Oral Immediate Release Products

Bioequivalence studies should be performed for all immediate release products intended for systemic action unless the applicant can establish that in vitro data are sufficient to ensure Bioequivalence.

Modified Release Dosage Form

For extended-release and delayed-release drug products:

·         A single dose, non replicate, fasting study required comparing the highest strength of the test and reference drug product.

·         A food-effect study comparing the highest strength of the test and reference product.

Fixed Dose Combination Product

Combination of product should be assessed as individual active substance either separately or as an existing combination to assess the bioavailability and bioequivalence.

Parenteral Products  

A bioequivalence study is not required for products administered as an intravenous solution containing the active ingredient in the same concentration as the approved product.

Locally Applied Products

A bioequivalence study is not required for nasal, ocular, dermal, rectal, vaginal, etc products for local use administration.  

Gases

A bioequivalence study is not required for a gaseous product for inhalation.

Narrow Therapeutic Index Drugs (NTIDs)  

Products having narrow therapeutic index, the acceptance interval for AUC should be 90.00-111.11%.

Other Pharmacokinetic Parameters

AUC(0-t): Area under the plasma concentration curve from time 0 to t

AUC(0-∞): Area under the plasma concentration curve from time 0 to infinite

AUC(0-τ)): AUC during a dosage interval at steady state

AUC(0-72h): Area under the plasma concentration curve from time 0 to 72h

Cmax: Maximum plasma concentration

Cmax,ss: Maximum plasma concentration at steady state

Rmax: Maximal rate of urinary excretion

tmax: Time until Cmax is reached

tmax,ss: Time until Cmax,ss is reached

t1/2: Plasma concentration half-life

λz: Terminal rate constant