A summary of the BE test experience of Adamo monoantigen

On September 3rd, Xinda Bio's Adamo mono-anti-injection was approved by the State Drug Administration, becoming the third domestically produced Adamo mono-biologically similar drug after Baiotai and Haizheng Pharmaceuticals.
AbbVie's Shumeile (Adamo Mono-Resistance) was first approved for listing by the FDA on December 31, 2002 and first approved for domestic imports on February 26, 2010.
has been a global drug sales champion for six consecutive years since 2014, with sales of nearly $20 billion in 2019.
FDA has approved six companies for Adamo monobiotics (almost all of which use dual-report development and declaration strategies in Europe and the United States), and the EMA, in addition to the FDA-approved products of these six companies, also has an Adamo monobiotics-like drug to FessenYuscabi, which, although not yet FDA approved, is known through the review data published by the EMA, the company in the conduct of similar biological studies, while comparing European and U.S. products.
clinical pharmacology research plays a key role in the development of biosynthic products.
these studies are part of a step-by-step process to demonstrate biosynthics between proposed biosynthics and references.
these studies may help prove that there are no clinical differences between products.
These studies may address the uncertainty that remains after the evaluation of pharmaceutical studies, may improve the integrity of the evidence supporting biosynthic proof, and may also help to design any recommended follow-up clinical studies using selective and targeted methods to support biosynamic proof.
review of the clinical pharmacological trials of these Adamo monobial-like drugs, the basic design is the same, using healthy subjects, single-dose subsubtive injection of the drug (40 mg), double-blind randomized 3-arm trial.
But there are some differences in the specific details of the design, there are some differences between enterprises: although each enterprise has chosen healthy subjects for testing, but the more detailed requirements are different, mainly reflected in gender, age, weight, BMI and other requirements.
the size of the sample size estimated by enterprises is more obvious, the number of single-arm subjects from 60 to 120 people.
: Some trials were weight-layered before randomization.
Key Clinical Endpoints: The FDA's Clinical Pharmacological Evaluation Guidelines for Biosynthic Drugs, released in 2016, state that for single-dose studies, AUCinf should be compared when calculating AAUC, and Cmax and AAUC should be chosen as co-study endpoints for suppain injection studies.
Cmax and AUCinf are included in the main clinical endpoints of all enterprises, and most companies also include AUClast in the evaluation of major clinical endpoints.
the equivalent range agreed upon: 90% confidence interval (0.80, 1.25).
Point in time for final sampling: Most companies choose a final sampling point of about 60-70 days (except Pfizer, but the final sampling point for two trials is not 42 and 49 days, respectively).
first trial of three of the seven companies failed and did not reach the agreed clinical end of similarity.
the main clinical endpoints of the three failed clinical pharmacological trials, AUCinf and AUClast, exceeded the agreed ethonological range, resulting in the failure of the trial, and Grigg Ingham's Cmax exceeded the limit of ethonology.
the three companies analyzed the results of the first clinical pro-drug trial, adjusted the trial program and conducted the second clinical pharmacological trial, all of which were successful.
Bronger Ingham concluded that after the first Study 1297.1 failure, Grigg Ingham concluded that the reasons for the failure were high overall variability, the effect of weight on exposure doses, differences in the protein concentrations of compared preparations and experimental drugs, and unforeseen low exposure to European symelor.
in the second Study 1297.8, the company: increased the number of subjects (from 193 to 324) strictly stipulated that the injection site is limited to the abdomen in the programme pre-defined weight as a covariate into AN COVA analyzed the causes of the first GP17-101 failure and found no single root cause associated with the product or test, and observed that the actual variability of AUClast in the test was greater than 40%, higher than the applicant's pre-estimated variation of 31%.
a data review analysis of GP17-101, The formation of ADA also has an effect on the exposure of Adamo monoantigen.
In the second GP17-104 trial, Sanders: adjusting the number of subjects from 219 to 318 will also tighten the population of subjects, adjust from healthy adult subjects to healthy male subjects to group weight before randomization and reduce the main clinical endpoints from 3 (Cmax, AUCinf, AUClast) to 2 AusClast and AUCinf descriptive comparisons between ADA-positive and ADA-negative subjects in the trial scenario attributed to the failure of Pfizer's first clinical pharmacological trial (Study B5381001) due to a higher variability between subjects (up to 45%) than was assumed when the sample size was estimated (30%).
In the second clinical pharmacological trial (Study B5381007), the following adjustments were made to the design of the trial: the number of subjects was adjusted from 210 (70 with one arm) to the time range for blood sample collection from 360 (120 with one arm) from 42 days to 49 days when randomizing the grouping, increasing the number of subjects based on weight stratification: age range From 18-55 years to 18-45 years old, BMI from 17.5-30.5 kg/m2 to 19.0-30.5 kg/m2, minimum weight requirements from 50 kg to 60 kg clinical pharmacological trial failure mainly due to variability, 3 enterprises in estimating the sample size, underestimation of variability.
review of the 10 clinical pharmacological trials completed, the variation of Cmax was between 22.9 and 36.5 per cent (mostly around 30 per cent), AUClast between 30 and 52.6 per cent (mostly around 40 per cent) and AUCinf between 29.2 and 56.6 per cent (mostly above 40 per cent).
because the estimated sample size was small due to the underestimation of variability, all three companies re-estimated the sample size based on the variability calculated from the first failed trial, increasing the number of subjects.
To reduce the impact of variability on the trial, companies also tightened the subject population: companies thought weight might be a factor in increasing variability, so BI increased covariate weight analysis, Sanders and Pfizer increased weight-based groupings before randomizing, and Pfizer narrowed the weight range of the subjects.
sampling time range may also affect AUCinf's evaluation.
AUCinf represents the area between the start and the infinite time of the blood drug concentration curve, calculated as AUCinf, AUClast, Ct/kel (ct-lt; concentration at the last measurable point in time, divided by kel-lt; elimination rate constant, gt;), and is calculated using an appropriate method.
generally requires AUClast to cover at least 80% of AUCinf, and sampling time covers a long enough blood drug concentration time curve to provide a reliable estimate of the amount of the drug.
requires at least 3 to 4 samples during the end-of-1st-to-2 linear phase to reliably estimate the end-of-life rate constant, which is required to reliably estimate AUCinf.
, Pfizer increased the sampling time range from 42 to 49 days (but still less than the sampling time range for other companies).
complexity of biomedical large molecules has led to a lot of uncertainty in the development of biosynthic drugs.
The failure rate of clinical pharmacological trials of Adamo monobial-like drugs is high , and I hope that the valuable experience of other enterprises can reduce the failure rate , reduce costs and shorten the time , and make tomorrow's road smoother with the surprises accumulated .