Bioequivalence Study and Data Submission in FDA Abbreviated New Drug Application (ANDA)

Bioequivalence research is a key link in the development and application of generic drugs. As the pioneer and advocate of bioequivalence research, the U.S. Food and Drug Administration (FDA) has in-depth views on it. Starting with the history of equivalence and generic drugs, it introduces the FDA’s methodological considerations, experimental design, evaluation standards, and data submission of bioequivalence studies, providing references and basis for domestic generic drug companies’ bioequivalence studies.

1. Bioequivalence and Generic Drug Application
   1.1 History

Generic Drugs refer to replicas that are identical or bioequivalent (BE, bioequivalent) to brand-name drugs in dosage form, safety, dosage, route of administration, quality, performance characteristics, and uses. Since the difficulty and cost of developing generic drugs are far less than that of new drugs, their prices are also much lower than brand-name drugs. At the same time, except for the first generic drugs that have 180-day market exclusivity (Market exclusivity), general generic drugs also have no market and patent protection.

As early as the 1940s and 1950s, generic drugs appeared on the American market. At that time, the Federal Food, Drug, and Cosmetic Act (FD&C) did not have a definition of generic drugs, and because their active ingredients were consistent with brand-name drugs, generic drugs did not meet the definition of new drugs, so some early generic drugs were ” Impunity” entered the market without FDA supervision.

The Thalidomide incident in 1962 and the Kefauver-Harris amendment passed that year opened a new page in the history of the FDA, and the efficacy of the drug was listed as one of the contents of the FDA’s new drug review for the first time. Driven by the Kefauver-Harris amendment, the FDA initiated a “Drug Efficacy Study” to re-evaluate drugs approved before 1962. At the same time, the FDA requires that new drugs marketed after 1962 must submit a complete new drug application (NDA), and new drugs approved before 1962 can be simplified new drug application (ANDA) (the ANDA regulations at the time were not complete, and these generic drugs were also very Difficult to get approval). Although this measure effectively controls the safety and efficacy of generic drugs entering the market, it also greatly limits the industry’s enthusiasm for the development of generic drugs. To this end, on the one hand, the FDA adopted a “document-based new drug application policy (Paper NDA policy)”, which allowed the use of published literature and bridging data to support generic drug applications; The generic drug ANDA policy for marketed new drugs.

After years of hard work, the FDA finally passed the Drug Price Competition and Patent Term Restoration Act in 1984, which is often referred to as the Hatch-Waxman Act. The Hatch-Waxman Act regards bioequivalence as a good substitute for drug safety and effectiveness. Applicants for generic drugs no longer need to repeat animal and clinical trials, but only need to prove that the generic drug and the reference drug (RLD, Reference Listed) Drug) between bioequivalence. The Hatch-Waxman Act has epoch-making significance, and the simplified and new drug application procedures revised accordingly have been used today.

1.2 Therapeutic equivalence, pharmaceutical equivalence and bioequivalence

Pharmaceutical equivalent (Pharmaceutical equivalent), bioequivalence and therapeutic equivalent (Therapeutic equivalent) are common concepts in ANDA.

Pharmaceutical equivalence means that two drugs have the same active ingredient, dosage form, route of administration, and specification (or concentration), and the dosage of the active ingredient is the same, and meets the same pharmacopoeia or other applicable quality standards (such as specifications). , Quality, purity and identification). Bioequivalence refers to two pharmaceutical equivalent drugs given at the same dose under similar test conditions, showing comparable bioavailability (BA, Bioavailability, that is, the rate and extent at which the active ingredient of the drug is absorbed and utilized by the site of action). Therapeutic equivalence means that two medicines not only meet pharmacy equivalence, but also have the same clinical efficacy and safety when used in accordance with the drug instructions. The FDA believes that bioequivalence is an excellent substitute for the efficacy and safety of generic drugs. Therefore, in simple terms, therapeutic equivalence is to satisfy both pharmaceutical equivalence and bioequivalence.

An ANDA applicant must first prove that the generic drug is pharmaceutically equivalent to the reference drug through the data of API and formulation chemistry, production and control (CMC), and secondly, prove its bioequivalence through in vitro and/or in vivo studies. . When a generic drug is approved, it will receive an “Efficacy Equivalence” code, which is entered in the FDA’s “Drugs Approved by Therapeutic Equivalence Evaluation” (usually called the “Orange Book”).

1.3 Research methods of bioequivalence

Many methods can be used to measure bioavailability or prove bioequivalence. The research methods recommended by the FDA based on general conditions and priorities are: 1. In vivo pharmacokinetic studies (blood drug concentration and time relationship) or in vitro experiments that have established a corresponding relationship with in vivo BA; 2. In vivo tests (drug excretion and Time relationship); 3. In vivo studies with timely efficacy indicators; 4. Clinical comparative tests; 5. In vitro dissolution tests. The choice of specific methods also depends on the purpose of the test, whether the test method is available, the characteristics of the drug itself, and the risk-benefit situation of human trials. In short, the FDA requires applicants to choose the most accurate, sensitive and repeatable method to prove bioequivalence.

In 2013, the FDA issued the “Guidelines for Bioequivalence Research of Generic Drugs with Pharmacokinetics as the Endpoint Evaluation Index” (draft). This guiding principle revises and replaces two previous guiding principles (namely, “Overall Considerations for Oral Preparation Bioavailability/Bioequivalence (BA/BE) Studies” (2003) and “The Effect of Food on Bioavailability and Postprandial Bioavailability” The content of BE research on generic drugs in the “Guiding Principles of Bioequivalence Research Technology”). In addition, in order to help applicants better choose BE research methods, the FDA has established a “case-specific generic drug development guidance database.” Since 2007, the FDA has issued a total of 1,523 generic drug development opinions. In addition, the FDA has also established a “dissolution method database” to guide in vitro dissolution test methods that are not covered by the United States Pharmacopoeia (USP).

2. In vivo pharmacokinetics BE study
2.1 Experiment design and subjects

For drugs that act on the whole body through blood circulation, in vivo testing with pharmacokinetic indicators as the endpoint is the most reliable BE evaluation method. The standard design recommended by the FDA is a single-dose, dual-period, dual-sequence (2X2) randomized crossover trial, that is, each subject takes a different drug in the two medication cycles (first test drug and then reference preparation, or first reference Preparation retest drug), a cleaning period is set between the two cycles to ensure that the drugs taken in the first cycle are completely eliminated before the next administration. The cleaning period is at least three times longer than the half-life of the drug in plasma or urine . Parallel trial design can also be used in special circumstances, such as a longer half-life of a drug. For subjects, the FDA recommends that it be performed on 24-36 healthy adults, but if it is for safety reasons (such as drugs with high toxicity), patients can be selected for testing. In addition, the test population must be representative of the applicable population (age, gender, race, etc.) of the test drug. In addition to the instructions clearly stipulate that fasting administration is required, the FDA generally requires BE studies on both fasting and postprandial conditions.

2.2 Biological analysis methods

It is very important to select the appropriate biological analysis method to detect the concentration of the drug (metabolite) in the blood and urine in the BE test. The analytical method must be accurate, sensitive and repeatable. If the drug concentration after a single dose is too low to be detected, you can use two or several times the single dose to administer the dose. If the dose exceeds the instructions, you need to submit an investigational new drug application (IND). All analytical methods must be validated. The FDA’s guidance document “Industry Guidelines-Verification of Bioanalytical Methods” issued in May 2001 elaborated on the verification of bioanalytical methods in human pharmacokinetic tests. The basic verification elements include accuracy, precision, selectivity, Sensitivity, repeatability and stability.

2.3 Judgment criteria for BE

The criterion of BE is based on the results of statistical analysis of pharmacokinetic parameters. The two most important kinetic parameters can be obtained from the drug concentration-time curve: Area Under Curve (AUC) and drug peak concentration Cmax, which reflect the degree and rate of drug absorption, respectively. The FDA uses the two one-sided tests procedure to analyze the kinetic parameters of the test product and the reference product. If the 90% confidence interval of the geometric mean ratio of the AUC and Cmax of the two preparations falls between 80%-125%, the FDA determines that the two preparations are bioequivalent. The bioequivalence obtained here is called the average bioequivalence and is suitable for most BE tests. FDA has also established two concepts of group bioequivalence and individual bioequivalence to deal with changes between groups or individuals. The FDA’s guidance document “Guidelines for Industry-Statistical Methods for Establishing Bioequivalence” published in 2001 elaborated on FDA’s statistical consideration of bioequivalence.

3. Submission of BE research data in ANDA
3.1 Regulatory requirements

Proving the bioequivalence between the generic drug and the reference drug is the key to the ANDA review and approval. The FDA stipulates in 21CFR 314.1 that unless the FDA bioequivalence exemption conditions are met, the ANDA application must include a complete test report and all data used to prove bioequivalence. The results of all other BE studies conducted on the same prescription drug product (regardless of whether it supports bioequivalence) should be submitted in the form of a complete report or a summary report. The interpretation of “the same prescription drug” and the specific scope of application are detailed in the “Guidelines for Submission of Bioequivalence Data in ANDA” issued by the FDA in 2009.

3.2 Content and format of data submission

The key to the submission of human BE test data mainly includes four parts: in vitro dissolution test, biological analysis method, clinical test report and statistical analysis of results. These data are mainly reflected in Module 2 (CTD summary) and Module 5 (clinical trial report) in the ANDA application materials (Figure 1). Module 2 is mainly to summarize and summarize the results of BE research. And Module 5 contains a complete test report and related information.

In addition, the FDA official website provides editable PDF or Word format BE data summary form templates (Model Bioequivalence Summary Data Tables) to help ANDA applicants summarize and submit BE test designs, in vivo/in vitro test results, in vitro dissolution results, etc.

Concluding remarks
The quality consistency evaluation of generic drugs in China is in full swing. The core of consistency evaluation is to prove the equivalence of generic drugs and original drugs from the aspects of pharmacy and biology. From a small perspective, the consistency evaluation work is a comprehensive baptism of generic drug companies. On a large scale, it is an opportunity for the improvement of China’s entire generic drug industry. Therefore, drawing on and learning from the FDA’s regulatory system and empirical thinking in generic drugs and bioequivalence research is extremely important for our consistency evaluation work.