Bioequivalence
Encyclopedia
Bioequivalence is a term in pharmacokinetics
used to assess the expected in vivo
biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.
Birkett (2003) defined bioequivalence by stating that, "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities
(rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards."
The United States
Food and Drug Administration
(FDA) has defined bioequivalence as, "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."
In addition to data from bioequivalence studies, other data may need to be submitted to meet regulatory requirements for bioequivalence. Such evidence may include:
, the Therapeutics Goods Administration (TGA) considers preparations to be bioequivalent if the 90% confidence interval
s (90% CI) of the rate ratios, between the two preparations, of Cmax and AUC lie in the range 0.80-1.25. Tmax should also be similar between the products.
There are tighter requirements for drugs with a narrow therapeutic index
and/or saturable metabolism – thus no generic products exist on the Australian market for digoxin
or phenytoin
for instance.
two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. This is considered demonstrated if the 90 % confidence interval
s (90 % CI) of the ratios for AUC0-t and Cmax between the two preparations lie in the range 80.00 – 125.00 %.
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
used to assess the expected in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
biological equivalence of two proprietary preparations of a drug. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same.
Birkett (2003) defined bioequivalence by stating that, "two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
(rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards."
The United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) has defined bioequivalence as, "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."
Bioequivalence
In determining bioequivalence, for example, between two products such as a commercially-available Brand product and a potential to-be-marketed Generic product, pharmacokinetic studies are conducted whereby each of the preparations are administered in a cross-over study to volunteer subjects, generally healthy individuals but occasionally in patients. Serum/plasma samples are obtained at regular intervals and assayed for parent drug (or occasionally metabolite) concentration. Occasionally, blood concentration levels are neither feasible or possible to compare the two products (e.g. inhaled corticosteroids), then pharmacodynamic endpoints rather than pharmacokinetic endpoints (see below) are used for comparison. For a pharmacokinetic comparison, the plasma concentration data are used to assess key pharmacokinetic parameters such as area under the curve (AUC), peak concentration (Cmax), time to peak concentration (Tmax), and absorption lag time (tlag). Testing should be conducted at several different doses, especially when the drug displays non-linear pharmacokinetics.In addition to data from bioequivalence studies, other data may need to be submitted to meet regulatory requirements for bioequivalence. Such evidence may include:
- analytical method validation
- in vitro-in vivo correlation studies
Australia
In AustraliaAustralia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
, the Therapeutics Goods Administration (TGA) considers preparations to be bioequivalent if the 90% confidence interval
Confidence interval
In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...
s (90% CI) of the rate ratios, between the two preparations, of Cmax and AUC lie in the range 0.80-1.25. Tmax should also be similar between the products.
There are tighter requirements for drugs with a narrow therapeutic index
Therapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
and/or saturable metabolism – thus no generic products exist on the Australian market for digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
or phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
for instance.
Europe
According to regulations applicable in the European Economic AreaEuropean Economic Area
The European Economic Area was established on 1 January 1994 following an agreement between the member states of the European Free Trade Association and the European Community, later the European Union . Specifically, it allows Iceland, Liechtenstein and Norway to participate in the EU's Internal...
two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and if their bioavailabilities after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, will be essentially the same. This is considered demonstrated if the 90 % confidence interval
Confidence interval
In statistics, a confidence interval is a particular kind of interval estimate of a population parameter and is used to indicate the reliability of an estimate. It is an observed interval , in principle different from sample to sample, that frequently includes the parameter of interest, if the...
s (90 % CI) of the ratios for AUC0-t and Cmax between the two preparations lie in the range 80.00 – 125.00 %.
United States
The FDA considers two products bioequivalent if the 90% CI of the relative mean Cmax, AUC(0-t) and AUC(0-∞) of the test (e.g. generic formulation) to reference (e.g. innovator brand formulation) should be within 80.00% to 125.00% in the fasting state. Although there are a few exceptions, generally a bioequivalent comparison of Test to Reference formulations also requires administration after an appropriate meal at a specified time before taking the drug, a so-called "fed" or "food-effect" study. A food-effect study requires the same statistical evaluation as the fasting study, described above.Further reading
- Hussain AS, et al. The Biopharmaceutics Classification System: Highlights of the FDA's Draft Guidance Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration.
- Mills D (2005). Regulatory Agencies Do Not Require Clinical Trials To Be Expensive International Biopharmaceutical Association: IBPA Publications.
- FDA CDER Office of Generic Drugs – further U.S. information on bioequivalence testing and generic drugs