Research status of biological equivalent trials of tadalafil tablets in China and its review requirements

Tadalafil is a selective phosphodiesterase type 5 (PDE5) inhibitor that catalyzes the degradation of cyclic guanosine phosphate (cGMP), increases cGMP concentration, promotes relaxation of smooth muscles in cavernous bodies, pulmonary blood vessels, prostate, and bladder, and increases blood flow into the cavernous corpus of the penis, thereby enhancing erectile function [1-2]. After consulting the European MedicinesAgency (EMA) and the WEBSITES OF the U.S. Food and Drug Administration (FDA), tadalafil tablets were developed by Lilly ICOS and approved for marketing in 15 EU member states in November 2002; approved for marketing by the US FDA in November 2003, with specifications: 2.5, 5, 10, 20 mg, indications: for the treatment of erectiledysfunction (ED) in men; in May 2009, the product was approved by the FDA to increase the indications: for the treatment of pulmonary hypertension (PAH, WHO Group I), improve exercise capacity, the trade name of this indication: ADCIRCA®, specifications: 20 mg. In October 2011, the FDA approved CIALIS to increase indications®: the treatment of benign prostatichyperplasia (BPH) and ED with BPH. After searching the website of the State Drug Administration, tadalafil tablets (10 and 20 mg specifications) produced by the original research company were approved for import into China in December 2004, and the company's 2.5 and 5 mg specifications tadalafil tablets were approved for import into China in March 2013.

As of December 30, 2021, after searching the website of the State Drug Administration, China has approved 38 tadalafil tablet generic drug approval numbers and 6 approval numbers (different packaging specifications) for the original research import, involving 4 specifications of the variety (2.5, 5, 10, 20 mg); the Chemical Drug Catalogue of the Drug Evaluation Center of the State Drug Administration (https://www.cde.org.cn/hymlj/listpage/ 9cd8db3b7530c6fa0c86485e563f93c7) contains a total of 35 tadalafil tablets information, including 4 original imported products (marked as reference preparations), 31 domestic approval numbers passed or are deemed to pass the chemical generic drug consistency evaluation. As of December 30, 2021, the Drug Clinical Trial Registration and Information Publicity Platform (http://www.chinadrugtrials.org.cn/index.html) has registered a total of 80 biological equivalent trials of tadalafil tablets, of which 45 are registered as completed, 31 are in progress, and 4 are actively suspended.

In this study, by combing the bioequivalence (BIOEquivalence) test requirements of domestic and foreign drug regulatory agencies, combined with the current situation of BE test research on Tadalafil tablets in China in recent years, this study preliminarily analyzes the main characteristics of the BE test of this variety, and puts forward general considerations in combination with a variety of situations encountered in the review process of BE tests, in order to provide a basis and reference for the BE test in the research and development of generic drugs of this variety.

1 BE test requirements for tadalafil tablets by drug regulatory agencies in the United States, the European Union and China

1.1 U.S. FDA Technical Requirements

The FDA has been released in March each year since 1980, when the first edition of approved drug with therapeutic equivalence evaluation (often referred to as the Orange Book) was issued, and the current edition of the Orange Book is the 41st edition [3], which explicitly specifies reference formulations for generic pharmacology and BE research. Since June 2010, the FDA has successively published and updated the Guidance for Industry Bioequivalence Recommendations for SpecificProduces, which provides guidance and reference for BE studies in the consistency evaluation of chemical generic drugs in China and the listing application of generic drugs[4].

1.1.1 FDA Orange Book Tadalafil tablets in the FDA Orange Book listed ELI LILLY Co. Company's CIALIS® (Application No. N021368) and ELI LILLY Co. ADCIRCA® (Application No. N022332) as BE Study Reference Preparations (RS) with a specification of 20 mg.

1.1.2 FDA Guidelines for BE Research on Individual Drugs FDA Tadalafil Tablets BE Research Guidelines [5] (recommended in May 2007, revised in September 2012 and October 2017) The BE study of this product is designed for fasting and postprandial double cross in vivo studies, using healthy male subjects, examining the area under the curve (AUC) and the maximum blood concentration (Cmax) 90% of the main pharmacokinetic parameters after a single dose. The confidence interval (90% CI) is 80.00% to 125.00%, as shown in Table 1.

Table 1 FDA Individual Drug Guidelines Tadarafil Tablets BE Study Recommendations

Table 1FDA Draft guidance on Tadalafil Tablet bioequivalence

project	BE study specific requirements
Type of study	Fasting and post-meal (2 studies)
Research design	Single-dose, two-cross in vivo study
Formulation specifications	20 mg
Subjects	Male, general population
Other requirements	not
To be measured	Tadalafil in plasma
BE Judgment Object (90%CI)	Tadalafil (90% CI value)
In vivo studies can be exempted from specifications	2.5, 5, and 10 mg simultaneously meet the following conditions: (1) 20 mg specification BE study is acceptable; (2) in vitro dissolution test nodes of all specifications (3) The proportion of prescriptions for all formulation specifications is similar

1.2 EMA technical requirements

In the EMA Guidelines for the STUDY of Tadarafil Tablets BE (drafted in October 2013 and effective in August 2018), the BE study in this product is recommended to be designed for fasting and postprandial double-crossed in vivo studies, using healthy male subjects, examining the area under the curve (AUC0-72 h) and Cmax 90% CI at 80.00% to 125.00% of the main pharmacokinetic parameters after a single dose. It is also required that the median and range of the peak time (tmax) of the subject formulation and the reference formulation be compared, as shown in Table 2.

Table 2 EMA Drug Guidelines recommendations for the study of tadarafil tablets BE

Table 2EMA Draft guidance on Tadalafil Tablet bioequivalence

project	Contents
BCS classification	BCS Classification: □ I □ II ■ Neither Background: Tadalafil is considered a low-solubility compound
BE study design If the BCS BE waiver is not feasible or does not apply	Single dose, crossover
Healthy volunteers
□ Fasting □ After Meals ■ Both include □ fasting Or after a meal
Specification: 20 mg Background: Linear pharmacoplastic and low solubility drug adoption Highest specifications
Number of studies: 2 single-dose studies (20 mg on an empty stomach and after a meal)
Analytes	■ Mother drug □ metabolites □ both are included
■Plasma/serum □ blood □ urine
Enantioselective analysis: □ Yes ■ No
BE rating	Main pharmacokinetic variables: AUC0-72 h, Cmax, and tmax
90% CI: AUC0-72 h and Cmax 80.00%~ 125.00%, the median and range of tmax is comparable

1.3 Technical requirements of China

China has not yet released guidelines for BE trials of tadalafil tablets. Most of the domestic TADALAFIL BE studies refer to the FDA and EMA guidelines for the study of bee drugs of this variety, and carry out relevant research in combination with the overall technical requirements of the "Technical Guidelines for Human Bioequivalence Research of Chemical Drug Generic Drugs with Pharmacokinetic Parameters as the Endpoint Evaluation Index" [7] issued by China in 2016.

2 Analysis of evaluation results of the Tadarafil tablets BE trial

The author refers to the BE research declaration data of more than 10 applicants of tadalafil tablets and related literature reports [8-9] of the Drug Review Center in recent years, and summarizes the statistics based on the main pharmacokinetic parameters Cmax, AUC, tmax, etc., and forms the results of the BE test of tadalafil tablets as follows.

Main pharmacokinetic parameters: BE findings showed that the lower limit of Cmax's lowest 90% CI was 82.12%, the upper limit of the highest 90% CI was 124.20%, the lower limit of AUC0-t's lowest 90% CI was 89.35%, the upper limit of the highest 90% CI was 119.92%, the lower limit of 90% CI of AUC0-∞ was 89.44%, and the maximum 90% CI upper limit was 116.01%. In terms of tmax, the tmax (median) range of the test preparation was 1.5 to 4.0 h, and the reference formulation was 1.5 to 4.3 h; 8 of the 13 companies (accounting for 61.54%) carried out tmax nonparametric test with reference to the EMA tadalafil tablet BE drug guidelines, and the sign rank and test results showed that there was no statistical difference between the test preparation and the reference preparation (P<0.05), the minimum value was 0.051, and the maximum value was 0.991.

Coefficient of Variation (CV): The results of the BE study showed that the CV range of Cmax was 8.04%-19.42%, the CV range of AUC0-t was 8.71%-15.89%, and the CV range of AUC0-∞ was 8.68%-16.80%.

3 Review considerations for the TADARAFIL BE trial

3.1 Selection of reference formulations

As of December 30, 2021, after searching the NmEDA has issued the eighth batch [10], the sixteenth batch [11], the twenty-sixth batch [12], the twenty-seventh batch [13] and the forty-first batch [14] of the Catalogue of Chemical Generic Drugs Reference Preparations, tadalafil tablets have issued a total of 13 reference preparations, involving 2.5, 5, 10, and 20 mg four specifications, including tadalafil tablets imported from the original research, listed in the European Union and listed in the United States.

Referring to the relevant instructions of the US FDA TADALAFIL TABLETS BE Drug Guidelines [5], tadalafil tablets BE research needs to select the corresponding reference preparation to carry out BE testing, and for different reference preparations, applications need to be submitted separately, and most domestic applicants currently choose the original research imported products that have been approved in China (licensee Eli Lilly Nederland B.V., trade name CIALIS®) to carry out relevant research. From the published "Catalogue of ChemicalLy Generic Reference Preparations (41st Batch)[13] Tadalafil Tablets Reference Formulations, it can be seen that the American Orange Book lists another tadalafil tablet original research product (licensee Eli Lilly CO, trade name ADCIRCA®) as a reference preparation, and there are also applicants who have applied for and carried out imitation studies.

3.2 Number of subjects, sampling points and cleaning period

It can be seen from the BE study data that the overall variation in tadalafil tablets is less than 20%, if the significance level of the test is set to 0.05, the power of study of the bioequivalence of the subject preparation and the reference preparation is detected to be 0.9, the equivalent limit is set to 80.00% to 125.00%, assuming that the geometric mean ratio of the main endpoint of tadalafil is 0.95 to 1.05, and the sample size is calculated using PASS, the estimated sample size on an empty stomach is 28 cases, considering about 20% Risk of shedding, about 30 cases of male healthy subjects were enrolled in the general fasting and postprandial trials, and single-dose, fasting and postprandial medications, two preparations, two cycles, two sequences, randomized, open, self-intersecting biological equivalent trials were carried out.

In terms of sampling points and cleaning period, with reference to the relevant requirements of the "Technical Guidelines for Human Bioequivalence Research of Chemical Drug Generic Drugs with Pharmacokinetic Parameters as the Endpoint Evaluation Index" [7] issued by Mainland China in 2016, it is recommended that each subject sample 12 to 18 blood collection points per cycle, the sampling time is not less than 3 end elimination half-life, and the corresponding terminal elimination is collected at least 3 to 4 samples to ensure accurate estimation of the end elimination phase slope, AUC0-t covers at least 80% of AUC0-∞. The results of existing studies show that the in vivo half-life of tadalafil tablets [15] is about 18 h, and most researchers generally choose 0 h (within 1 h before taking the drug) and 18 to 20 blood collection points after taking the drug to 96 h. The cleaning period should generally not be shorter than 7 half-lives, and 10 to 14 days should be selected.

3.3 Pharmacokinetic parameter selection and BE evaluation

According to the FDA and EMA Tadalafil Tablets BE Trial Drug Guidelines, the BE research requirements of this variety are different between the European Union and the United States. The FDA requires that the main pharmacokinetic parameters of the subject preparation and the reference preparation AUC0-t, AUC0-∞, and Cmax 90% CI be within 80.00% to 125.00%; the EMA requires the subject formulation to be within 80.00% to 125.00% of the main pharmacokinetic parameters of the reference formulation AUC0-72 h and Cmax 90% CI, and the median and range of the subject preparation and the reference preparation are required to be compared.

The existing domestic research results show that most of the reporting units refer to the FDA Tadalafil Tablets BE Trial Drug Guidelines, submit the statistical results of 90% CI of the main pharmacokinetic parameters AUC0-t, AUC0-∞, and Cmax, and at the same time refer to the requirements of the EMA Tadalafil Tablets BE Trial Drug Guidelines, submit the non-parameter test results of the median and range of the subject preparation and the reference preparation tmax, if not submitted, the applicant is generally required to supplement.

4 Conclusion

Tadalafil tablets are commonly used clinical drugs, is one of the hot varieties of imitation and development of domestic enterprises after the expiration of the patent of the original research product, and the drug clinical trial registration and information publicity platform shows that as of December 30, 2021, the bioequivalence test of this variety has reached 80. It can be seen from because of the existing BE study data that the overall variation in tadalafil tablets is less than 20%, and the number of subjects can generally be selected from about 30 male healthy subjects to carry out double-cross, two-cycle fasting and postprandial BE tests. The test preparation and the reference preparation in BE to study the TMAX of the Chinese medicine kinetic parameter can reflect the peak time of the two preparations in vivo to a certain extent, and then reflect the clinical efficacy.

From the FDA, EMA tadalafil tablets BE trial drug guidelines can be seen that the BE research requirements of this variety are different between the European Union and the United States, the EMA requires the main pharmacokinetic parameters (AUC, Cmax) of the subject preparation and the reference preparation 90% CI on the basis of 80.00% to 125.00%, and at the same time requires the median and range of the tmax of the subject preparation and the reference preparation to be compared, although the trial and most of the trials that have been approved for this variety have compared tmax, However, a unified requirement for BE research on this variety has not yet been formed in China. In order to further standardize the be research of tadalafil tablets in mainland China and ensure that the clinical efficacy of the generic drugs declared by tadalafil tablets and the reference preparations is consistent, the guidelines for the be test of Chinese tadalafil tablets SHOULD be formulated in a timely manner to provide a basis and reference for the subsequent development of tadalafil tablets BE tests.

Conflicts of Interest All authors declare that there is no conflict of interest

Bibliography

Source: Liu Dong,Han Hongxuan,Wang Jun. Research status and review requirements of biological equivalence tests of tadalafil tablets in China[J]. Drug Review & Research, 2022, 45(5): 828-833.