What is the difference between bioavailability study and bio equivalence study

Whereas, for the bioequivalence study of a generic drug product, the reference product should be the innovator drug product or reference listed drug. BE study is to measure and compare formulation performance between two or more drug products.

But in the case of BE studies of a new formulation of an innovator drug product the reference product should be the already approved drug product. For regulatory approval of a generic drug product test product, T must be bioequivalent to the Reference listed drug product R usually the brand or innovator drug product that is designated by the applicable regulatory authority.

Bioavailability is an indirect or surrogate measure of the rate and extent to which the drug substance or active moiety is absorbed from a drug product and becomes available at its target sites of action. Bioavailability is measured by using three main pharmacokinetic variables:.

On the other hand, Bioequivalence BE is a surrogate measure of in vivo drug product performance and dissolution profile comparisons as a measure of in vitro drug product performance. BE has been established via bioavailability testing. Bioequivalence is measured based on the relative bioavailability of the innovator drug product versus the generic drug product.

It is important to note that bioequivalence studies are also performed for innovator drug product in some situations such as: between early and late clinical trial formulations; between formulations used in clinical trials and stability studies, if different; or between clinical trial formulations and to-be-marketed drug products, if different; or between equivalence of product strengths; between marketed innovator product and a new formulation of marketed innovator product change in one or more excipients.

Bioavailability studies are expletory. Whereas, bioequivalence studies are a confirmatory or statutory term that requires ANDA applicants to demonstrate, among other things, that the proposed generic product is bioequivalent to its reference listed drug.

Bioavailability is not been assessed via bioequivalence testing. Bioavailability is assessed using three main pharmacokinetic variables. Example of bioequivalence: two medicines are bioequivalent if there is no clinically significant difference in their bioavailability.

Based on the bioequivalence studies under fasting and fed conditions, Idiazole, Rabeprazolnatrium, and Rodesa 20 mg tablet are bioequivalent with Pariet 20 mg. Here, Idiazole, Rabeprazolnatrium, and Rodesa 20 mg tablet are the generic drug product. BA provides useful information to establish dosage regimens and to support drug labeling, such as distribution and elimination characteristics of the drug.

To measure and compare formulation performance between two or more drug products. To determine the therapeutic equivalence between the pharmaceutical equivalence generic drug product and a corresponding reference listed drug. The number of subjects involved in a study is determined by the following considerations: The level of significant should be 0.

The error variance associated with the primary characteristics to be studied as estimated from a pilot experiment, from previous studies. The studies should be performed on healthy adult volunteers with the aim to minimize variability between the study drugs.

Subjects may be males or females; however, the choice of gender should be consistent with usage and safety criteria of the drug. To minimize intra and intersubject variation, the study design should be standardized as much as possible and acceptable. Generally, a single dose study should be conducted after an overnight fast at least 10 hours and subsequent fasting of 4 hours after administration dosing.

For multiple dose studies, 2 hours of fasting before and after the dose are acceptable. Estimation of C max and T max for the modified release products or drug is given with food in such case fed state studies also been carried out in addition to the normal fasting state bioavailability studies [ 22 ].

During fed state studies, the consumption of a high fat breakfast of — KCals is required before dosing. A single standard diet should be followed taking into consideration of all the Indian subcontinent people.

The high fat breakfast must be consumed approximately 15 minutes before dosing in fed state condition. Study conditions such as study environment, diet, fluid intake, post dosing postures, exercise, sampling schedules, etc. These conditions are stated in the protocol, and at the end of the study, these should be complied, to assure that all variability factors involved in the study to minimize the products to be tested. Least 48 hours before commencement, the study subjects abstain from smoking, drinking alcohol, xanthine containing foods, coffee, tea and beverages, and fruit juices.

Steady state study is considered in the following conditions: The drug has a long terminal elimination half-life. For drugs, which are toxic or have adverse effects that are ethically should not be administered to patients but they are a necessary part of therapy cytotoxics. For modified release products or sustained release products which assess the fluctuation in plasma drug concentration at steady state.

For combination products where the ratio of plasma concentration of the individual drugs is important. Ideally, the biological samples collected as per the sampling procedure have to be analyzed immediately after the study but most of the times the samples are stored for several days before subjected to analysis.

During storage, the drug may undergo a chemical degradation, adsorption on the walls of the container, etc. The analytical method used for the estimation of the active ingredient responsible for the therapeutic efficacy must be selective and sensitive.

In the analysis of blood and urine, the major problem is to extract quantitatively and then separate the intact drug from its major metabolites or even to separate a mixture of two or more drugs from their metabolite.

Pharmacokinetic methods are used for the assessment of bioavailability of drug products that exists as a linear relation between the drug level in the biological fluid and therapeutic response. Therefore, these methods are also known indirect methods. Because therapeutically active drug can be accurately measured in biological fluids, plasma and urine data give the most objective information on bioavailability [ 23 ].

Plasma data are most widely used and accepted method for the assessment of bioavailability of the drug product. The basic assumption in this method is that drug products that are bioequivalent product super imposable plasma level time curve. The parameters T max and C max are the measures of the rate of absorption of the drug, while the parameters AUC is a measure of the extent of absorption.

Urinary excretion method is based on the general observation that the rate of urinary excretion of a drug is directly proportional to the concentration of the drug in the blood. Therefore, the bioavailability can be calculated as the ratio of the total amount of the unchanged drug recovered in urine following the administration of test and standard formulations.

Urinary metabolite excretion data are not used for the estimation of bioavailability since the drug can undergo metabolism at different sites including the gut and liver, and the rates of metabolism may vary because of various reasons.

The relative bioavailability should lie within an acceptance range of 0. In case of an especially narrow therapeutic range, the acceptance range may need to be tighter. In rare cases such as highly variable drugs, a wider acceptance range may be acceptable if it has right clinical justification. C max ratio is the measure of relative bioavailability that may be more variable than the AUC ratio, and a wider acceptance range may be acceptable.

The range used in the protocol should be justified taking into account safety and efficacy consideration. Tmax is a measure of release or action or signs for a relation to adverse effects.

The two pharmacodynamic methods used for the estimation of bioavailability are based on the measurement of acute pharmacological effect and clinical response. In order to estimate the bioavailability of a drug product accurately by measurement of acute pharmacological effect, the following criteria should meet. These are an easily measurable response such as heart rate, ECG, blood pressure, pupil diameter, etc. Due to biological and experimental variations, some differences always exist, and it is necessary to ascertain whether these differences are simply chance occurrences or are due to actual differences in treatment administered to the subjects.

Statistical methods are used to evaluate the pharmacokinetic data in order to identify the different sources of variation and if possible to measure the contribution of each identified variable and isolate the specific observation of primary interest. The analysis of variance ANOVA , a statistical procedure that used for a crossover design is widely used method in bioavilability testing [ 24 ]. The pharmacokinetic parameters derived from blood drug concentration and time from bioavailability studies are subjected to ANOVA.

Bioavailability studies are designed in two ways, and these are design 1 and design 2. Design 1 is parallel design in which the subjects divide into two treatment groups and assign one treatment to each group. Design 2 is crossover design in which each subject has one block and applies both the treatments to each subject with washout period in between them. In a parallel design, variability due to the treatment is considered, and in the crossover design, variability due to treatment, subject, and period are considered to minimize variability.

The error mean sum of square for design 1 MSE1 will be greater than the error mean sum of square for design 2 MSE2 if the degrees of freedom for SSE are the same in the both designs then error variability is greater in the parallel group design compared to the crossover design Tables 3 and 4. The treatment mean sum of squares is larger than the error mean sum of squares if difference is achieved between the treatments.

Then the chances of getting treatment mean sum of squares being bigger than the error mean sum of squares are more in design 2 compared to design 1. Therefore, chances of showing a statistically significant difference are higher in design 2 compared to design 1. This is equivalent to saying that design 2 is more competent than design 1.

They may be different or nearly equal but not identical in most of the cases. If the trial is run under tightly controlled conditions and the number of subjects is large enough, no matter how small the difference between the formulations and it will be detected as significant.

The difference may give rise to following anomalies due to a large difference between two formulations, sample size not large enough Table 5. Evaluation of bioavailability and bioequivalence studies will be based upon the measurement of concentrations of the active drug substances in the plasma with respective of time. In some situations, the measurements of an active or inactive metabolite may be necessary.

These situations include where the concentrations of the drugs may be too low to accurately measure in the biological matrix, limitations of the analytical method, unstable drugs, and drugs with a very short half-life. Racemates should be measured by an achiral assay method. Measurement of individual enantiomers in bioequivalence studies is required where they exhibit different primary efficacy, safety activity, pharmacodynamic and pharmacokinetic characteristics with the minor enantiomer.

Bioavailability and bioequivalence testing are carried out for two formulations such as new and commercially marketed brand drug [ 25 ]. These studies are conducted by experimental designs such as parallel and cross over design in healthy volunteer subjects but occasionally in patients. After administration of formulation under standard study conditions, plasma samples are withdrawn at regular time intervals and assayed for parent drug or occasionally metabolite concentration in plasma or urine.

In some cases, concentration of drug in the blood is neither feasible nor possible to compare. Plasma concentration data are used to determine the pharmacokinetic parameters such as AUC, C max , T max , and absorption lag time T lag. Bioavailability studies should be conducted at different doses, especially when the drug follows nonlinear pharmacokinetics. In addition to a data from bioequivalence studies, other data may need to be submitted for evidence to meet regulatory requirements for bioequivalence includes analytical method validation and in vitro - in vivo correlation studies.

In bioavailability studies, closer limits are considered for drug that have a narrow therapeutic index, serious dose-related toxicity, steep dose, effect curve, and nonlinear pharmacokinetics within the therapeutic dose range. A wider acceptance range may be admissible if it is based on sound clinical justification.

In case of suprabioavailability, a reformulation of the drug product is required and again bioequivalence study has to be carried out. Application of new formulation is required to support the clinical trial data especially for dosage recommendations. Such formulations are usually not being accepted as therapeutically equivalent to the existing reference drug.

There are closer limits for drugs with a narrow therapeutic index and saturable metabolism. Thus, no generic drug formulations exist in for digoxin or phenytoin for instance in the Australian market.

European Economic Area considers two formulations to be bioequivalent if they have pharmaceutically equivalency and their bioavailabilities are similar after administration in the same molar dose with respect to both efficacy and safety.

Sometimes, fed state bioequivalent comparison studies were carried out for test to reference formulations where required to administer the formulations after an appropriate meal at a specified time before taking the drug to know the food effect.

Food effect study requires the same statistical evaluation as the fasting study as described above. Most bioavailability studies, whether for a new or generic product, are carried out for the common theme. These studies are conducted to identify the quantitative nature of a specific product comparison. Drug development is an expensive process with a high failure rate. Reformulated or generic drugs can be manufactured and marketed through bioequivalence study design, without the need to demonstrate therapeutic equivalence in clinical trials, given they are benchmarked against an approved product.

Bioequivalence and bioavailability studies are essential in early Pilot Bioequivalence and late Pivotal Bioequivalence clinical development of drug candidates. Generally, BE studies are performed if there is a change in dose formulation, salt forms, or manufacturing process. For filing abbreviated new drug application ANDA , an applicant generally must demonstrate that their drug candidate is reasonably bioequivalent to the reference listed drug RLD.

To this end, FDA regulations require an applicant to use the most accurate, sensitive, and reproducible approach available among those outlined in the FDA guidance on bioequivalence 21CFR As per these guidelines, the descending order of determining bioequivalence BE includes pharmacokinetic, pharmacodynamic, clinical, and then in vitro studies. Here, the establishment of BE based on pharmacokinetics relies on endpoints such as Cmax and AUC for a direct comparison between the two products.

Applicants may conduct a pilot study before full BE study to validate the analytical methodology, optimize sample collection time intervals, and flesh out protocol details.

Contact Us. Request Quote Contact Us. Why choose us for your Bioequivalence and Bioavailability Studies? Bioequivalence and Bioavailability: Measuring and Comparing Systematic Drug Circulation Bioavailability of drugs is the concentration of the drug compound that reaches the systemic circulation or the site of action. What Our Sponsors Have to Say?

VP, PK. Executive Director, Drug Research. Head, Bioanalytical Development. Head, PK. Director, PK. VP, Development Operations. Ready to Take the First Step? Bioequivalence Studies: Evaluating Drug Safety and Efficacy A bioequivalence study is usually carried out for generic drug product. Pharmacokinetic Evaluation. The pharmacokinetic method for assessing the bioavailability of drugs is an indirect method which traces the path of medication from absorption in the body until its excretion.

Pharmacodynamic Evaluation. Importance of Bioavailability and Bioequivalence in Drug Development Generic drugs contribute to modern healthcare by accomplishing effective, safe, and low- cost alternatives to currently available modern medicines…. Read More at our Learning Center. Bioequivalence and Bioavailability Studies by NorthEast BioLab Drug Discovery At the time of drug discovery, various compounds of the drugs are assessed for bioavailability. Preclinical Study NorthEast BioLab strictly follows mandated regulations for preclinical bioavailability and bioequivalence studies, leading to secure execution and valuable data collection.

Clinical Study Once a drug candidate moves to the clinical phase, a suitable formulation with optimum bioavailability is developed. Registered and Inspected by Various Regulatory Agencies.

Proficient Bioequivalence and Bioavailability Studies to Advance your Generic or Novel Formulation Bioequivalence establishes generic drugs as interchangeable to the branded drug compounds with similar therapeutic and side effect profiles. What is the difference between bioavailability and bioequivalence? Why are bioequivalence studies required?

What is the significance of bioavailability? How is drug bioavailability calculated? How is bioequivalence determined? Is bioequivalence study a clinical trial?