What Is Bioequivalence?

Chinese name: Bioequivalence
Foreign name: bioequivalency

Analytical method: Chromatography immunoassay
Definition: Dosage changing products
Types of: experiment method

Bioequivalence I. Concept

Bioequivalency (BE) refers to the statistical difference in the degree and rate of drug absorption between the test preparation and the control standard preparation under the same test conditions. When the difference in absorption rate is not clinically significant, some pharmaceutical preparations have the same degree of absorption but different rates can also be considered bioequivalent. Bioequivalence is different from pharmaceutical equivalents. Pharmaceutical equivalence refers to the same dosage of the same drug in the same dosage form, but the inactive ingredients are not necessarily the same. The content, purity, uniformity, disintegration time, Formulations whose dissolution rates meet the same prescribed standards. The equivalence of a medicament cannot reflect the condition of the drug preparation in vivo.

Bioequivalence 2. Definition

Research on bioavailability or bioequivalence reflects the biological standards of pharmaceutical preparations and provides direct evidence for clinical efficacy. There are two main types of drugs that actually require bioequivalence studies.

1. Product that changes the dosage form.

2. Products that change prescriptions and processes.

Bioequivalence

Bioequivalence is used to evaluate whether the effects (safety and effectiveness) of two drugs on patients with a disease are the same or similar. For example, generic and standard medicines, natural medicines and chemical medicines, oral medicines and injections, long-acting medicines and short-acting medicines, and the comparison of low-dose and high-dose of a drug need to be evaluated by bioequivalence methods. FDA stipulates that if there is bioequivalence between a generic drug and a registered drug, the notification process can be performed in accordance with the abbreviated new drug application (ANDA) instead of the new drug application (NDA). Avoid time-consuming and expensive Phase I and III clinical trials. Therefore, bioequivalence testing plays an extremely important role in clinical trials of new drugs.

Bioequivalence

There are three types of equivalence: average bioequivalence (ABE), population bioequivalence (PBE), and individual bioequivalence (IBE).

Mean bioequivalence : The effect of using T drug and R drug in the population is the same. Although ABE guarantees that the average effect is the same, it does not necessarily guarantee that the variation of the effect is the same, that is, the mean of the two populations is the same, but the variance is not necessarily the same.

Population bioequivalence: The effects of using T drug and R drug in the population not only have the same average value, but also the same degree of variation in the effect, that is, the marginal distribution of the two populations is the same. Although PBE guarantees the same edge distribution, for each individual, the effects of using T drug and R drug are not necessarily the same. That is, there may be subject-byformulation interactions between individuals and drugs.

Individual bioequivalence: For each individual, the effect value obtained by using T drug and R drug is close.

Obviously, if the individuals are equivalent, the groups are equivalent; if the groups are equivalent, the average is equivalent, and vice versa. In terms of equivalence, individual bioequivalence is the strongest, group bioequivalence is second, and average bioequivalence is the weakest. From an application perspective, two drugs with individual bioequivalence have switchability, that is, if a patient takes a drug for a period of time, if he switches to another, it has individual equivalence. Drugs can get the same effect; while drugs with group bioequivalence have prescribability, that is, doctors can choose arbitrarily when prescribing drugs to patients for the first time, which has an effect on this type of patient group Are the same. It can be seen that the three equivalence statements have different problems, so the inspection methods are different, and the design requirements are also different.

[1]

Bioequivalence

5.1 Setting the background

At present, the most commonly used method for BE evaluation at home and abroad is the pharmacokinetic method, that is, the use of Bioavailability (BA) indicators for BE evaluation. Generally, BA refers to the extent and speed at which the active ingredient is absorbed in the formulation. The pharmacokinetic method for BE evaluation is to examine whether a pharmaceutical equivalent formulation or a replaceable drug takes the same dose under the same test conditions, and whether the degree and speed of active ingredient absorption meet the preset equivalent standard. Among the pharmacokinetic parameters, the parameters that characterize the extent and speed of absorption are mainly AUC, _Tmax, and _Cmax . Therefore, the use of pharmacokinetics to evaluate whether there is bioequivalence between the preparations is to statistically evaluate whether the AUC, T _max and C _max measured by the test preparation and the reference preparation meet the preset equivalent standard. How to set the equivalent standard in advance becomes one of the key factors affecting the BE evaluation.
According to the recommendations of clinicians and the past experience of the FDA, for most drugs, if the difference in drug exposure in the circulatory system is within 20%, it will not have a significant impact on the clinical treatment effect. Based on this, the FDA has set the pharmacokinetic parameters (AUC and C _max ) of the test preparation and the reference preparation as "the difference should be less than 20%" as the criterion for determining equivalence. The specific determination method is: Test and (1-2%) confidence interval method to obtain the 90% confidence interval (Confidence Interval, CI) of the geometric mean ratio of the AUC or C _{max of the} two preparations. For drugs without a narrow therapeutic window, this 90% CI must fall within 80.00% to 125.00%. In addition, the FDA and EMEA guidelines also emphasize that this confidence interval must retain two significant digits and must not be rounded to make the BE test pass for the test drug, that is, the minimum value of the lower limit is 80.00%, and the upper limit cannot exceed 125.00%. For example, if the result of a bioequivalence test is 79.96% 110.20%, it is determined to be biologically unequivalant ^{[2, 3]} . As a non-normally distributed T _max , non-parametric statistical methods are required to prove that there is no statistically significant difference between the preparations.

5.2 Bioequivalence criteria adopted by major countries, organizations and institutions around the world

Consistent with FDA requirements, drug regulatory agencies in other major countries and regions (including European Union EMEA, Japan's Ministry of Health and Welfare) and the World Health Organization (WHO) use 80.00% to 125.00% as the standard for determining the equivalence of AUC and C _max 90% CI. . In the guidelines formulated by the above agencies, the criteria for determining the equivalence of AUC are strict and usually can only be narrowed down (for example, for certain drugs with narrow therapeutic windows, EMEA recommends that the scope be reduced to 90.00% to 111.11%) . ^[3,4] Relatively speaking, C _max 's equivalence determination standard has certain flexibility. For example, the Canadian Drug Regulatory Agency (Health Canada) only requires that the ratio of C _max's mean value fall between 80% and 125%. ^[6] EMEA and WHO have proposed that for certain special cases of drugs (such as highly mutated drugs, that is, the intra-individual difference in pharmacokinetic parameters is more than 30%), the scope of the equivalence criterion can be appropriately expanded according to the situation. For example, EMEA recommends that for drugs with an _intra- individual variation (CV _intra ) of 35%, the equivalence criterion can be expanded to 77.23% to 129.48%. When the CV _intra is 40%, the range can be expanded to 74.62% to 134.02%. When the CV _intra is 50% or more, it can be expanded to 69.84% to 143.19%. However, the sponsor must provide evidence to prove that under this criterion, there will be no drug safety problems and ensure that there is no significant difference in the clinical efficacy of the drug, that is, it is necessary to prove that the increase in C _max difference will not cause a significant increase in adverse reactions. It will not significantly affect the efficacy. In addition, the expansion of the C _max equivalence criterion must be set before the start of the BE test and provide corresponding evidence. It cannot be changed based on the test results after the test.
The Japanese Ministry of Health and Welfare suggests that if the scope of the C _max equivalence determination criteria is expanded, the following three conditions must be met:

(1) The number of subjects is not less than 20, or the total number of subjects after increasing the number of subjects is not less than 30;

(2) The logarithmic difference of C _max mean is between log (0.9) log (1.1);

(3) For an in vitro dissolution test, under any test conditions, when the in vitro dissolution of the reference preparation is 30%, 50%, and 80%, the dissolution difference between the test preparation and the reference preparation is within 10%. ^[5]

5.3 China's current current standards

In the "Guiding Principles for the Research on the Human Bioavailability and Bioequivalence of Chemical Drug Preparations" promulgated in China in 2005, the 90% CI equivalence determination standard of AUC is consistent with international standards, while the C _max standard is due to the then technology Due to the relatively low level and the conditions of clinical trials, in order to facilitate the management and review of BE trials, a relatively loose equivalence determination standard has been set uniformly, that is, 70% to 143%. ^[7]
In recent years, with the advancement of China's clinical pharmacokinetic test level and the improvement of formulation research level, the requirements for drug quality control will be more stringent to ensure the development of high-quality generic drugs. Therefore, referring to the regulations of advanced countries and organizations, it is necessary to increase the requirements of the C _max equivalence determination standard, that is, 80.00% -125.00% is adopted as the equivalence determination standard. Under this standard, special drugs, such as highly mutated drugs, can appropriately expand the scope of the equivalence criteria, but the sponsor must provide evidence of relevant safety and clinical efficacy, as well as evidence of intra-individual variability, before the BE trial. On this basis, the criteria for determining equivalence are reset, such as: 75.00% -133.00% or 70.00% -143.00%. After the end of the test, even if it is found that the organism is not equivalent due to the large intra-individual differences, the range of the equivalence criterion cannot be enlarged again based on the results. Bioequivalence should be re-determined by expanding the number of participants to re-run the clinical trial and reduce the standard deviation.

Bioequivalence

Chromatography: for most drug tests

Immunoassay: mostly used for protein peptide detection.

Microbiological method: It can be used for the determination of antibiotic drugs.

Bioequivalence

7.1 Test design and operation

1. Cross design

2. Subject selection

3. Administered dose

4. sampling

5. Parameter calculation.

6. standardization

7.2 Data processing and statistical analysis

1. Data representation

2. Pharmacokinetic parameters

3. Statistical Analysis

7.3 Evaluation of results.

Bioequivalence reference

[1] Chinese Journal of Clinical Pharmacology and Therapeutics. Statistical Analysis Methods for Bioequivalence Evaluation Chen Feng, Yu Hao, Lu Jingjing, Zhao Yang, Liu Yuxiu

[2] US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 2002. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products-General Considerations.
[3] Committee for Proprietary Medicinal Products (CPMP), the European Agency for the Evaluation of Medicinal Products (EMEA). 2010.
[4] World Health Organization, WHO Expert Committee on Specifications for Pharmaceutical Preparations, WHO Technical Report Series 937, Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.
[5] Guideline on the Investigation of Bioequivalence. Japan National Institute of Health, Division of Drugs, 1997. Guideline for Bioequivalence Studies of Generic Products,
[6] Health Products and Food Branch, Minister of Health, Canada, 1992. Guidance for Industry: Conduct and Analysis of Bioavailability and Bioequivalence Studies-Part A: Oral Dosage Formulations Used for Systemic Effects.
[7] State Food and Drug Administration, Drug Evaluation Center, 2005. Technical guidelines for human bioavailability and bioequivalence of chemical drug preparations.