Ba Be Studies

Bioavailability and Bioequivalence Studies in Clinical Research

Studies evaluating bioavailability (BA) and bioequivalence (BE) are an integral component of drug development and regulatory approval, and you’re here to learn the various approaches, designs, and basic regulatory considerations involved with conducting such analyses.

BA BE studies are used to compare the rate and extent of drug absorption between test products and reference products. Raptim offers experienced scientists as well as an GLP-compliant facility capable of conducting BE/BA studies.

Regulatory Requirements

BA/BE studies (also known as bioavailability or bioequivalence tests) are tests designed to measure how quickly and to what degree a drug reaches its site of action within the body, for both new and generic medications. They’re necessary to ensure patients receive correct dosage without suffering toxic side effects; though costly, such assessments must take place for safety and efficacy purposes.

Commenters suggested that the primary goal of the rule should be to increase FDA’s knowledge and understanding of bioequivalence (BE), without placing regulatory requirements on ANDA applicants. Unfortunately, however, the final rule did not address this goal directly – instead requiring applicants to submit all BE studies conducted on one product formulation that fail to demonstrate bioequivalence with its RLD reference listed drug (RLD).

This requirement aims to ensure that FDA can make an evidence-based determination regarding bioequivalence. While an ANDA applicant may perform multiple bioequivalence (BE) studies on their final formulation, and achieve more than one passing result, they often fail to submit these additional BE studies for FDA review, so FDA remains unaware of them until reviewers assess an applicant’s explanations for failed results and conduct their own independent scientific analysis of submitted study reports.

These analyses will consider factors like statistical power of studies, minor variations between formulations used, whether product was administered consistent with RLD labeling requirements and any other relevant design issues. A reviewer will assess overall quality and validity of conclusions drawn from studies.

The final rule also allows small entities submitting BE studies for the first time as part of an ANDA submission to FDA to report only summary results rather than full reports when doing so for cost savings purposes. Furthermore, using binomial distribution one can estimate an expected number of additional BE studies that each small entity will need to submit; estimated costs for 69 small entities would total $6,768 (2 x $3,384).

Design of a Trial

BE clinical trials typically employ a randomised cross-over design with wash out periods to ensure drug concentrations fall below their lower limit of quantification prior to each new treatment period. Washout periods must span at least five elimination half lives.

Pharmaceutical Kinetic (PK) studies typically follow FDA guidance when it comes to trial design. Sponsors should clearly communicate the chosen method in their BE clinical study protocol and statistical analysis plan, and use logarithmic adjustment across a series of BE clinical trials in order to maintain consistent effect size across trials. It is not advised to perform tests for normality following log-transformation as this could result in unnecessary stringency of statistical tests that increases risk of rejecting study hypothesis.

Frontage Laboratories is an experienced veterinary contract research organization (CRO), specialising in BA/BE and PK studies conducted under GLP and VICH-GCP guidelines. Our expert team offers in vivo and ex vivo testing to support pharmaceutical product development for animal healthcare.

Raptim offers help in designing Glucose Clamp experiments to measure the blood-glucose-lowering effects of an insulin or oral antidiabetic drug, usually by administering an intermittent infusion of glucose to patients to keep blood-glucose concentrations within predefined target levels.

Sample Size

There is no definitive method of selecting the appropriate sample size for BA/BE clinical trials, although larger samples tend to increase development costs while small ones may fail to fulfill their purpose. A useful starting point would be using one of several available formulae published for assessing average BE and population BE; these calculations use simulations of two-period replicated crossover designs with wash out periods every five elimination half lives as models for sample selection.

Bioavailability (BA) refers to the speed and degree to which a drug reaches and becomes accessible at its site of action. It plays an integral part of drug pharmacokinetics – which studies how drug compounds enter and exit the body – including absorption, distribution, metabolism and excretion processes.

Researchers use high-performance liquid chromatography, or HPLC, to measure how much drug has reached its intended site in the body. A variety of factors can impact this test such as its type and concentration as well as degradation products or interactions with other substances in the body.

For accurate measurements of BE, it must be administered under fasting conditions. According to FDA’s SUPAC-MR guidance, all modified release solid oral dosage forms that change their components, composition or manufacturing process should undergo an investigation on both fed and fasted conditions in order to properly measure BE.

SUPAC-MR guidance recommends that BE measurements be log-transformed prior to statistical analysis, with common or natural logarithms remaining consistent throughout a study. Sponsors and applicants are strongly discouraged from using normality of error distribution as an excuse for conducting statistical analyses on original rather than log-tranformed data sets.

SUPAC-MR guidance encourages conducting two or three period controlled clinical trials with balanced designs across sequences to test individual BEs. The results from this trial provide the primary basis for estimating whether they meet regulatory acceptance standards; this approach may prove especially valuable when testing long-acting drugs that cannot easily be evaluated through two period, placebo-controlled parallel group trials.

Statistical Analysis

Statistical analysis is an essential research tool used by scholars and scientists alike. It allows them to identify patterns and trends within data, make predictions, and determine causal relationships among variables. There are multiple forms of statistical analysis, such as descriptive and inferential statistics. Businesses and organizations rely heavily on statistics when making informed decisions.

BABE studies should be performed before marketing modified-release oral drug products to ensure that their PK profile matches up with that seen in primary clinical trial material. Furthermore, FDA recommends performing BE/BA trials under both fasting and fed conditions for any orally administered drug formulation.

Results of BE/BA trials typically consist of mean values and standard deviations (SD). An analysis may include information regarding maximum concentration attained by participants. Washout periods must also be included between treatment periods to allow elimination half-lives to reach zero; this is especially essential when working with highly variable experimental drugs where intrasubject variability exceeds 30 percent; for these cases a replicate cross-over design trial may be utilized to meet European Medicines Agency (EMA) requirements.