Bioavailability and Bioequivalence Studies – A Comprehensive Overview

Bioavailability (BE) refers to the rate and extent to which drugs become bioavailable at their site of action, making it a key consideration when seeking ANDA approval to market generic versions of innovator products.

As part of our proposed rule, we sought to deepen FDA’s understanding of BE by requiring ANDA applicants to provide data from all BE studies conducted on final drug product formulation.

In Vitro

In vitro experiments are experiments performed outside of living organisms, typically using test tubes or Petri dishes as locations for research. They have increasingly replaced studies conducted using whole animals; when applied to food-related studies, in vitro tests can measure antibiotic sensitivity of bacteria as well as chemical residues on fruits and vegetables.

As there is no precise way of assigning numerical values to in vitro study results, it is necessary to conduct an individual assessment for each in vitro study. This assessment should include consideration of its predicted effects; its validity in identifying substances responsible for particular adverse reactions and its quality as an individual study; its consistency; its findings may also need to be taken into account; information that meets all these criteria should merit low levels of concern regarding its risk to public health (see Chapter 7); anything outside this criterion must be approached with caution.

In Vivo

In-vivo experiments refer to tests carried out within living organisms, most often animal testing or clinical trials in human participants. These steps are considered crucial components of any drug development process, with 30% of drugs that pass preclinical studies showing adverse reactions when tested in vivo (Tagle, 2019). Furthermore, such experiments are frequently employed as means to understand disease pathologie. 

Professor Harry Smith used in-vivo experiments to demonstrate that extracts of culture fluid from animals infected with Bacillus anthracis were lethal to other animals while sterile filtrates of this same bacteria grown in vitro were not. This discovery proved pivotal to the creation of anthrax vaccines and antibiotics, taking its name from Latin proverb “in vivo veritas”, meaning “there is truth within living things”. Today, antibacterial drugs developed from this discovery are used globally.

In vivo research can involve animal tests and clinical trials as well as cell culture experiments, tissue culture techniques, cell isolation techniques, and various other forms of biomedical research. Results obtained through in vivo experimentation tend to be more accurate because researchers gain a comprehensive picture of how new compounds or products impact either one cell type in particular or all parts of their subject body as a whole.

Due to their unique experimental design requirements and topical themes, it is crucial that researchers know how to optimize In Vivo research. Somshuvra Bhattacharya of JAX Technical Information Scientist will discuss critical factors affecting reproducibility of your in-vivo assays during this webinar.

Mispronounced as “in the living,” in vivo is commonly misunderstood as meaning something outside the body such as in vitro, which refers to processes taking place outside such as petri dishes and test tubes. It’s important to keep in mind that both terms apply when discussing medical procedures involving tissues outside their natural environments – in vivo refers to what occurs within our own bodies while vitro refers to procedures performed outside them – which have different meanings altogether.

BA is the measurement of how quickly and completely a drug enters the body and becomes available at its site of action. FDA requires in vivo tests to measure or establish BA for most drug products and to support 505(j) applications, but for accuracy and sensitivity in measuring BA/BE in-vivo dissolution rate tests or comparably designed comparative clinical trials are often the best ways of doing so.

Food Effect

For drug products intended for oral ingestion, the rate and extent of drug absorption must be accurately quantified. Pharmacokinetics (PK) provides an analytical method for this, measuring both pharmacodynamics (how a drug affects its body) and pharmacokinetics (how fast/how much drug enters bloodstream). Drug absorption is affected by both physiological and experimental factors that influence how quickly/how much drug enters systemic circulation.

Since the late 1990s, approaches for determining BE have become standardized as a result of discussions and consensus reached at various national and international meetings, conferences and workshops. Numerous research programs are now underway in order to enhance these approaches further and enable production of high quality generic drugs at reduced costs.

BE studies analyze the pharmacokinetics of drug products under fed conditions to measure bioavailability. Their results can help verify equivalence between generic versions and their reference products, or at the very least provide some way of validating generic equivalents with their reference versions.

APIs typically show a linear correlation between in vitro dissolution and human food effects (FE). This corresponds to the theory that food effects in vivo are driven primarily by dissolution/precipitation behavior between fed and fasted states; other mechanisms (blood flow, gastric motility/residence time differences, competition for cytochrome-mediated metabolism pathways and food components’ influx/eflux may impact risk; but most APIs tested have not demonstrated such impacts.

FDA’s BE/FE guidance currently suggests the use of an average criterion for replicate BE studies and single endpoint criterion for nonreplicate studies, while sponsors are allowed to select either for certain class D drugs with wide therapeutic windows and high within-subject variability when it comes to recruitment of study subjects – thus decreasing costs and testing burden. Public comments to draft guidance have generally supported keeping individual BE criterion as part of these drug studies.

Food Intake

BA/BE studies (also referred to as bioavailability and bioequivalence studies or BA/BE) measure how much of a drug is absorbed after administration to human subjects in various forms, such as oral solution, capsule, tablet or injection, over time. They are an indispensable research method in developing generic pharmaceuticals as lower cost alternatives to innovator drugs.

Sponsors should utilize log-adjustment of BE measures consistently and clearly outline whether a natural or common logarithmic transformation should be selected in their clinical study protocol and statistical analysis plan. They should refrain from testing normality of BE measurements after log-transformation unless absolutely necessary and, should they do, should provide justification for this decision.

Frontage Laboratories conducts bioequivalence/bioavailability (BA/BE) studies and provides medical writing and regulatory support in China. As one of the premier CROs providing bioequivalence/bioavailability studies for this market, we have assisted over 70 applications to the Chinese FDA seeking equivalence recognition. Our services include design, monitoring, data processing/reporting/analysis as well as statistical analyses by our experienced staff who can assist your product meet these requirements regardless of brand name versus generic drugs.

Spinos

Spinos, a pioneering force in (Ba Be Studies) Bioavailability (BA) and Bioequivalence (BE) studies, revolutionizes drug development. BA, the measure of drug absorption and availability at the site of action, takes center stage in Spinos’ commitment to excellence. I

n vivo experiments, conducted within living organisms, showcase Spinos’ dedication to precision and reliability. Researchers, led by experts like Somshuvra Bhattacharya, optimize in vivo assays, ensuring reproducibility.

The Food Effect, a critical aspect for orally ingested drugs, undergoes meticulous analysis. Spinos’ contribution extends globally, offering comprehensive BA/BE studies, aligning with FDA standards. As a leader in CROs, Frontage Laboratories, a partner of Spinos, provides unparalleled support for bioequivalence studies, facilitating regulatory success in the dynamic pharmaceutical landscape.