Bioequivalence Explained: How Generics Are Approved

Bioequivalence is the test that decides whether a generic medicine can stand in for the product it copies. It compares how much of the active ingredient reaches the bloodstream, and how fast.

Generic medicines are approved on that comparison rather than on fresh trials in patients. The rules governing the comparison are set by regulators, and they differ in detail between countries.

What is bioequivalence?

Bioequivalence is a comparison between two formulations of the same active ingredient. India’s New Drugs and Clinical Trials Rules, 2019^[1] define a bioequivalence study as one establishing the absence of a statistically significant difference in the rate and extent of absorption. That comparison is made against a reference formulation with the same active ingredient.

The World Health Organization^[2] frames it as two products being bioequivalent when their bioavailabilities are similar to such a degree that the same effects can be expected from both. It treats Cmax and tmax as the measures of rate, and the area under the curve as the measure of extent.

The US FDA^[3] states the same idea more plainly. A generic drug is bioequivalent when it delivers the same amount of active ingredient at the same rate and to the same extent as the brand-name drug.

What is a generic medicine?

A generic medicine is a copy of a brand-name medicine that has already been approved. The FDA’s summary of generic drug facts^[4] states that a generic must have the same active ingredient, strength, dosage form and route of administration as the brand-name drug.

It must also be made under the same strict standards, carry the same label with certain exceptions, and be bioequivalent to the brand-name medicine. The FDA states that approved generics work in the same way and provide the same clinical benefit and risks as their brand-name counterparts.

Those statements describe the United States regulatory standard. An India-specific regulatory source is needed before making the same claim about a particular Indian product.

What does a bioequivalence study measure?

A bioequivalence study measures the active ingredient in the blood over time. WHO names the measures that matter and the range the result has to fall inside.

Measure	What it shows
Cmax	The highest concentration the active ingredient reaches. WHO treats this as one of the two measures of the rate of absorption.
tmax	The time at which that highest concentration is reached. It is the second measure of rate.
Area under the curve	The total exposure over time, which WHO treats as the measure of the extent of absorption.
90% confidence interval	The statistical result. WHO states the interval for the geometric mean ratio should normally fall within 80 to 125% for log-transformed data.

The underlying quantity is bioavailability. The New Drugs and Clinical Trials Rules define a bioavailability study as one assessing the rate and extent to which a drug is absorbed from a formulation. The definition covers the drug becoming available in the systemic circulation, or at the site of action.

Those acceptance limits are the WHO figures, and an Indian regulatory source setting the same numbers was not available for this article. WHO states that the primary concern in a bioequivalence assessment is to limit the risk of a false declaration of equivalence.

How is a bioequivalence study run?

The study compares a test product against a comparator. WHO defines the comparator product as the one the generic is intended to be interchangeable with in clinical practice, and normally that is the innovator product.

WHO states that bioequivalence studies should generally be performed with healthy volunteers rather than with patients. The FDA’s description of an abbreviated new drug application^[5] says much the same, measuring how long the generic takes to reach the bloodstream in healthy volunteers.

WHO lists four ways of assessing equivalence:

Comparative pharmacokinetic studies in humans
Comparative pharmacodynamic studies in humans
Comparative clinical trials
Comparative in vitro tests

In a pharmacokinetic study the active ingredient or its metabolites are measured over time in a biological fluid such as blood, plasma, serum or urine.

Who approves bioequivalence studies in India?

CDSCO oversees them. The CDSCO BA/BE Division^[6] is responsible for regulatory oversight, for the evaluation of bioavailability and bioequivalence studies, and for the approval of BA/BE study centres in India.

Stage	What happens
Protocol review	The CDSCO BA/BE Division evaluates the study protocol before the study begins.
Ethics Committee review	Under the New Drugs and Clinical Trials Rules, an Ethics Committee reviews the protocol, and every member signs a declaration that there is no conflict of interest.
Registration	The same rules state that a bioavailability or bioequivalence study requires registration from the authorities specified in rules 8 and 17.
Approval or NOC	The Division grants approval or a no objection certificate, including for studies conducted only for export.

The Division also assesses therapeutic equivalence and interchangeability between the test product and the reference or innovator product.

Why do generic medicines cost less?

Generic makers do not repeat the original trials. The FDA states that generic applicants do not have to repeat the animal and clinical studies required for the brand-name medicine.

Competition then does the rest. The FDA states that a single competitor can cut the price by about 30%, and that around five competitors bring the reduction to nearly 85%.

Those figures describe the United States market. Indian prices are set under a different system, which that source does not describe.

Also Read: How reliable are generic medicines? Why do generic medicines cost less?

When is a bioequivalence study not needed?

Not every generic needs a study in people. WHO describes a biowaiver as an approval granted on evidence of equivalence rather than through in vivo equivalence testing.

Comparative in vitro tests sit among the four methods WHO lists for assessing equivalence. Whether that route is open for a particular product is a regulatory decision, and not something that can be read off a pack.

The limits of a bioequivalence result

A bioequivalence result is about absorption, not about everything on the pack. The FDA states that generics may contain different inactive ingredients, and that in rare cases those can affect absorption or how well someone tolerates the product.

WHO frames bioequivalence as a comparison between a multisource product and its comparator. That single comparison is what the approval rests on.

Any switch between products should be discussed with a doctor or pharmacist.

How to compare generic and branded medicines on Medkart

Medkart groups products by composition, so that everything sharing an active ingredient and strength appears in one place, with the manufacturer shown for each. Composition pages cover molecules such as:

Medkart states that the medicines it sells are sourced from WHO-GMP certified manufacturers. Medkart’s medicine comparison tool places products side by side, and the medicines index lists what is in stock. The details a reader can compare include:

Active ingredient
Strength
Dosage form
Manufacturer
Pack size
Current price

Any change from a prescribed product should be discussed with a doctor or pharmacist first.

Key takeaways

Bioequivalence compares the rate and extent to which an active ingredient is absorbed from two formulations.
India’s New Drugs and Clinical Trials Rules, 2019 define a bioequivalence study as establishing the absence of a statistically significant difference in that absorption.
The comparison is made against a reference formulation, which is normally the innovator product.
Cmax and tmax describe the rate of absorption, and the area under the curve describes the extent.
WHO states the 90% confidence interval should normally fall within 80 to 125% for log-transformed data.
The CDSCO BA/BE Division oversees these studies in India and approves the study centres.
Generic medicines cost less partly because the original animal and clinical studies are not repeated.
A bioequivalence result covers absorption, and inactive ingredients can still differ between products.

FAQs: Common Questions About Bioequivalence

Q. Who takes part in a bioequivalence study?

Healthy volunteers, rather than patients. WHO states that bioequivalence studies should generally be performed with healthy volunteers. Where a product is intended for use in both sexes, it says the sponsor should include both males and females. Clear inclusion and exclusion criteria have to be set out in the study protocol.

Q. Why is the comparator usually the innovator product?

Because that is the product whose evidence already exists. WHO states the comparator will normally be the innovator product, for which efficacy, safety and quality have been established. The generic is measured against that established product rather than against an unproven one.

Q. Does a bioequivalence study prove that a generic is safe?

It stands in for that evidence rather than generating it fresh. WHO describes a bioequivalence study as a surrogate for clinical evidence of the safety and efficacy of the multisource product. The underlying safety and efficacy evidence belongs to the comparator product it was measured against.

Q. What is an abbreviated new drug application?

It is the application route for a generic in the United States. The FDA states that an abbreviated new drug application contains the data submitted for the review and potential approval of a generic drug product. It is called abbreviated because applicants are generally not required to include animal and human data establishing safety and effectiveness.

Q. Are two generics of the same medicine compared with each other?

Not as part of the route described in the guidance. WHO frames a bioequivalence study as a comparison between a multisource product and a comparator product, which is normally the innovator. The sources used for this article do not describe a head-to-head comparison between two generic products. A doctor or pharmacist is the right person to ask about moving between them.

Q. Does a generic have to look like the brand?

No. The FDA states that generic medicines may differ from the brand in minor cosmetic ways such as colour. It adds that these differences do not affect how the medicine works. A change in the look of a pack is therefore not by itself a reason to doubt it, and a pharmacist can confirm what has changed.

References

Medical disclaimer: This article gives general information only. It does not replace advice from a doctor or pharmacist. No medicine should be started, stopped or changed without advice from the prescriber or a qualified pharmacist.

Bioequivalence: How Generic Medicines Are Tested and Approved in India