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Bioequivalence Criteria and Requirements Explained

Bioequivalence is defined as the lack of a significant difference between the extent and rate with which the active ingredients or active moieties of two pharmaceutical alternatives or pharmaceutical equivalents reach their site of action in the body.

Two pharmaceutical products can be compared only when administered at the same molar dose, under similar conditions, and in the context of an appropriately designed study. The comparison can be made with single and multiple doses. The ascertainment of bioequivalence indicates that the two pharmaceutical equivalents or alternatives will also deliver equivalent therapeutic effects.

What Is the Goal of Bioequivalence Studies?

There are two main scenarios in which bioequivalence studies are conducted;

Assessment of Generic Drug Candidates

The rising costs of pharmaceutical products have exacerbated the need to develop cost-effective therapeutic alternatives. Generic drugs have been widely implemented in clinical practice because they cost 80% to 85% less than the corresponding brand name drugs. Regulatory agencies worldwide have defined requirements for the approval of generic drug candidates. 

These requirements encompass the comparison of the bioavailability of products, called bioequivalence. The results of bioequivalence studies are then used as a surrogate for therapeutic equivalence between the two pharmaceutical alternatives or pharmaceutical equivalents. 

Evaluation of Changes in Pharmaceutical Formulations or Manufacturing Procedures, pre- and post-drug approval.

Drug development is associated with high costs and failure rates of drug candidates. Modifications in the pharmaceutical formulations and the manufacturing procedures of drug candidates or pharmaceutical products pre- or post-drug approval may lead to differences in their systemic exposure. Therefore, bioequivalence studies should be conducted before or after implementing changes. 

Pharmacokinetic Bioequivalence Studies

Bioequivalence studies using pharmacokinetic evaluations are the preferred method to assess bioequivalence because they are considered the most sensitive approach. Pharmacokinetic studies are to measure the concentration of the drug in the blood (or in another relevant body fluid, such as plasma or serum) and ensuring that the systemic absorption of the drug is relevant for its action.

The pharmacokinetic parameters employed to assess bioequivalence include Cmax, AUC0-t, AUC0-inf, and Tmax. Cmax (the maximum or peak concentration) measures the maximum observed concentration and indicates the rate with which the drug becomes available at its target site. AUC0-t (area under the curve 0-t) indicates the extent of drug exposure to the body from time zero until the last time point with a measurable drug concentration. 

AUC0-inf (area under the curve 0-inf) indicates the total drug exposure to the body from time zero until time infinity. Tmax is defined as the time to reach Cmax and provides information regarding the rate of drug absorption. If there are differences in the Tmax of two drug products being compared, additional partial AUC analyses, clinical studies, or exposure-response assessments may be required for certain products. Typically, the drug product’s highest-marketed strength is evaluated unless safety concerns preclude it.

Study Design and Subject Recruitment 

Three types of study design are generally recommended for the performance of pharmacokinetic bioequivalence studies for most of the jurisdictions:

  1. A two-period, two-sequence, two-treatment, single-dose crossover study design, which is the most commonly used paradigm;
  2. A single-dose parallel study design; and
  3. A single-dose replicate study design.
  4. A two-period, two-sequence, two-treatment, multiple-dose crossover study design for certain products intended to EMA submission

Did You Know?

Bioequivalence Studies are generally conducted in individuals at least 18 years old and may be healthy volunteers or other appropriate populations for which the investigated pharmaceutical alternatives or equivalents are intended.

Bioequivalence Criteria

Specific bioequivalence criteria have been proposed to assess the bioequivalence between two drug products based on differences in the achieved systemic exposure. The AUC and Cmax, which are the main pharmacokinetic parameters indicative of the extent and rate of drug absorption, respectively, are utilized to establish these bioequivalence requirements.

The 80%-125% Bioequivalence Criterion

The 80%-125% bioequivalence requirement has been accepted as a threshold for bioequivalence based on the assumption that differences in the systemic exposure of the evaluated pharmaceutical alternatives or pharmaceutical equivalents smaller than 20% would not be clinically significant.

How was this criterion established? Two pharmaceutical alternatives or pharmaceutical equivalents are considered bioequivalent if the 90% confidence intervals (CIs) of the ratios of the geometric means of the AUC and Cmax after a logarithmic transformation are within the bioequivalence limits of 80% and 125%.

Why is a Logarithmic Transformation Performed?

The pharmacokinetic exposure measures AUC and Cmax are not normally distributed and require a logarithmic transformation to achieve normal distribution. After a logarithmic transformation, the bioequivalence criterion is symmetric around 0 on the logarithmic scale within the range of -0.2231 (corresponding to 80% systemic exposure) to 0.2231 (corresponding to 125% systemic exposure).

Challenges Associated with the Bioequivalence Criteria

The generally accepted 80%-125% bioequivalence requirement has been challenged in some instances, such as for pharmaceutical products with a narrow therapeutic index or high intra-subject drug variability.

Drugs with a Narrow Therapeutic Index
Are drugs for which a small modification in their dose or blood concentration may cause therapeutic failures or severe adverse reactions that lead to significant or persistent disability or are life-threatening. Certain variations exist in the strategies different regulatory agencies employ to ensure that the bioequivalence requirements for pharmaceuticals with a narrow therapeutic index are sufficiently stringent.

“A reference-scaled average bioequivalence approach with a four-way, fully replicated, crossover design study that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products” has been recommended. In addition, stricter bioequivalence requirements, defined as narrower bioequivalence limits, have been proposed by some regulatory agencies.

Highly Variable Drugs
Are drugs with consistently high intra-subject variability for a particular pharmacokinetic parameter that is not caused by outliers. There are also distinctions in the approaches different regulatory agencies undertake to account for drugs’ high variability when conducting bioequivalence studies, using strategies that follow the same principles but differ in certain details.

Efforts for Global Harmonization of Bioequivalence Criteria and Requirements

Substantial efforts have been focused on the global harmonization of bioequivalence requirements, with important contributions made by the Global Bioequivalence Harmonization Initiative (GBHI) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

One of the focus areas is searching for opportunities to harmonize the selection criteria for reference products among regulatory agencies to reduce the need for repetitive bioequivalence studies. Another focus area relates to harmonizing the requirements for waivers for bioequivalence studies. And an ICH guideline (M9) has been published that addresses the Biopharmaceutical Classification System (BCS)-based biowaiver concept. Stay tuned for more global harmonization information related to bioequivalence conduct.

A Global Leader in Bioequivalence Studies

BioPharma Services, Inc. has extensive expertise in the design and conduct of bioequivalence studies, both as a part of the development of generic products and to assess the effects of changes in drug formulation or manufacturing. As a full-service CRO, we have experience in all aspects of bioequivalence studies, including trial design, recruitment, conduct, bioanalysis, statistical analysis, and regulatory support. In addition, we have already studied over 300 generic compounds for our sponsors’ programs. 

By partnering with BioPharma Services for your next bioanalytical study, you’ll receive end-to-end support from our:

Modern in-house bioanalytical laboratory

Regulatory expertise

Full-service CRO with an expert multidisciplinary team

Experienced with various drug formulations & routes of administration

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