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Generic bioequivalence evaluation

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If the drug concentration is related to the therapeutic effect, it is assumed that the same subject takes different preparations and then measures the drug concentration in the blood at different time points. If the same blood drug concentration-time curve is obtained, it means that the same effect can be produced at the site of action. The drug concentration produces the same therapeutic effect, so pharmacokinetic parameters can be used as alternative endpoint indicators to establish the equivalence between different preparations, that is, bioequivalence (BE).

Bioequivalence test

The purpose of equivalence research is to distinguish between the following two clinical situations: prescribability; switchability.

1. Pharmaceutical equivalence

If the two drugs contain the same amount of the same active ingredient, have the same dosage form, and meet the same or comparable quality standards, they can be considered to be pharmaceutically equivalent. Pharmaceutically equivalent preparations do not necessarily mean bioequivalence, because different excipients or differences in production processes may result in changes in the rate of drug dissolution or absorption.

2. Therapeutic equivalence

If the two preparations contain the same active ingredient, and clinically show the same safety and effectiveness, the two drugs can be considered to be therapeutically equivalent. If the excipients used in the two preparations do not themselves cause problems in effectiveness and safety, bioequivalence studies are the most appropriate method to confirm the therapeutic equivalence of the two preparations. If the absorption rate of the drug has nothing to do with the clinical efficacy, drugs with the same degree of absorption but different absorption rates may also achieve therapeutic equivalence. Drugs containing the same active ingredient, but with different active ingredient chemical forms (such as salts and esters of a compound) or different dosage forms (such as tablets and capsules) may also have therapeutic equivalence.

3. Essentially similar products

If two preparations have the same quantity of active ingredients that meet the same quality standards, have the same dosage form, and are proven to be bioequivalent, the two preparations can be considered to be substantially the same drug. Broadly speaking, this concept also applies to different dosage forms containing the same active ingredient, such as tablets and capsules. Drugs that are basically the same as original drugs should be used instead of original drugs.

Bioequivalence research methods

Bioequivalence research methods include in vitro and in vivo methods, which are ranked as pharmacokinetic research methods, pharmacodynamic research methods, clinical test methods, and in vitro research methods according to the priority of the methods.

1. Research methods of pharmacokinetics

That is, the method of comparative study of human bioavailability is adopted. Because BA is defined as the degree and speed of absorption of the active ingredient to the systemic circulation, the concentration of the drug in the biological sample (such as whole blood, plasma, serum or urine) at different time points can be obtained by measurement to obtain the drug concentration-time curve (concentration -time curve, Ct curve), and after appropriate data processing, calculate the pharmacokinetic parameters related to the degree and speed of absorption, such as the area under the curve (AUC), peak concentration (Cmax), peak time ( Tmax), etc., to reflect the dynamic process of drug release from the preparation and absorption into the systemic circulation, and then through statistical comparison to determine whether the two preparations are therapeutically equivalent.

2. Research methods of pharmacodynamics

When there is no feasible pharmacokinetic research method to establish a bioequivalence study (such as no sensitive blood drug concentration detection method, there is no linear correlation between concentration and effect), you can consider using a clear, graded quantitative, Objective clinical pharmacodynamic indexes are established through comparison of the effect-time curve to establish equivalence. The use of this method should also strictly abide by the clinical trial management regulations and be confirmed by sufficient methodology.

3. Methods of randomized controlled clinical trials

When there is no suitable drug concentration detection method, and there is no clear quantitative grading and objective clinical pharmacodynamic indicators, randomized controlled clinical comparative tests can also be used to verify the equivalence of the two preparations with a comprehensive efficacy endpoint indicator Sex. However, as a bioequivalent research method, controlled clinical trials may be inefficient due to limited sample size and insensitive detection indicators, and expanding the sample size will also bring economic costs, so when feasible, you should try to Adopt the pharmacy method.

4. In vitro research methods

It is generally not recommended to use in vitro methods to establish bioequivalence, because in vitro processes cannot completely replace in vivo behaviors, but in some cases, if sufficient evidence can be provided, in vitro methods can also be used to conduct bioequivalence studies. The FDA stipulates that oral preparations that are classified as high solubility, high permeability, and rapid dissolution according to the classification of biopharmaceutics can be verified by the method of in vitro dissolution comparative study to verify the bioequivalence, because the dissolution and absorption of such drugs are no longer drugs entering the body Speed limit steps. For drugs that are poorly soluble but have high permeability, if a good correlation between in vivo and in vitro has been established, in vitro dissolution studies can also be used to predict in vivo dissolution and avoid ex vivo studies. Therefore, many companies usually conduct in-vivo and in-vitro research early in the new drug development process to provide support for later R&D processes and product changes after launch.

The research method using pharmacokinetic parameters as the end point index is the commonly used bioequivalence research method. A complete bioequivalence study includes four aspects: biological sample analysis, experimental design, statistical analysis, and result evaluation.

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