On May 28, CDE issued the guiding principles for clinical trial design of biological analogues for Liraglutide injection, which explained the requirements for research and development of biological analogues forLiraglutide injection and the key points for clinical trial design.
Liraglutide injection is a human glucagon like peptide-1 (GLP-1) analogue product developed by Novo Nordisk for the treatment of type 2 diabetes. It was approved for import registration in 2011. Many domestic pharmaceutical enterprises have started the research and development of biological similar drugs of Liraglutide. Up to now, there is no approval for the release ofLiraglutide biological analogues in the world, and there is no guiding principle for the research and development of this variety of biological analogues.
Since 2016, domestic enterprises have successively obtained the approval documents for clinical trials of Liraglutide injection. At the same time, with the deepening of the global understanding of the characteristics of biological similar drugs, the technical standards for evaluation are also constantly clear. In the process of communication with many enterprises, we found some common problems in clinical trial design. In this context, the research group started to write this guiding principle.
Attachment: guidelines for clinical trial design of biological analogues for lilalutide injection
1、 Overview
Liraglutide injection is a kind of human glucagon like peptide-1 (GLP-1) analog product developed by danmeno and Nord company. The GLP-1 (7-37) peptide chain of precursor, i.e. the 34th arginine replacing lysine, was prepared by Saccharomyces cerevisiae expression system, and then the fatty acid side chain containing 16 carbon was acylated by glutamic acid at the 26th lysine ε amino group. Since 2009, it has been approved to be listed in Europe and the United States [1-2] for the treatment of type 2 diabetes. In 2011, it was approved to be imported for registration. Currently, the listed license holder is Novo Nordisk A / s, with the trade name of Victoza / Novelli [3].
With the expiration of the patents of the original products, many domestic pharmaceutical enterprises have started the research and development of biological similar drugs. Up to now, there is no biological similar drug of Liraglutide approved for market in the world.
In February 2015, the former State Food and Drug Administration issued the technical guidelines for research, development and evaluation of bio similar drugs (Trial) [4] (hereinafter referred to as the “guidelines for bio similar drugs”). This guiding principle is based on the guiding principle of bioequivalent drugs, combined with the progress of drug research, relevant technical guiding principles and current communication and exchange experience, to form suggestions on the clinical research strategy and clinical trial design of Liraglutide bioequivalent drugs, for the reference of the drug developers and researchers.
This guideline only represents the current opinions and understandings of drug regulatory authorities, and does not have mandatory legal binding force. With the development of scientific research, the relevant contents of the guiding principles will be continuously improved and updated. When applying these guidelines, please also refer to GCP, ICH and other relevant guidelines issued at home and abroad.
2、 Requirements for clinical research and development of biological analogues of Liraglutide
In principle,Liraglutide biological analogues should take the original research drug (Novolin) of Novo Nordisk Co., Ltd., which is listed in China as the reference drug, and carry out pharmacokinetic comparison test and clinical safety effectiveness comparison test.
Pharmacokinetic comparison test needs to complete a single dose bioequivalence study compared with the original drug in healthy subjects to verify the similarity of PK characteristics between the candidate drug and the original drug. The clinical comparison study needs to select the adult type 2 diabetes patients, and carry out a comparative clinical equivalence study with the original research drug to support the registration and listing of biological similar drugs.
3、 Key points of clinical trial design of biological analogues of Liraglutide
The clinical trials of biological analogues should be designed scientifically and reasonably to prove the similarity of candidate drugs and reference drugs.
（1） Pharmacokinetic comparison test of healthy subjects
Trial design: PK comparative study of single dose is recommended to compare the characteristics of drug exposure. If cross design is adopted, the influence of immunogenicity on the results should be considered and a reasonable cleaning period should be established [5].
Study population: healthy volunteers are ideal homogeneity test population, which can better reflect the PK characteristics consistency between the candidate drug and the original drug, but it is still recommended to control the factors that may affect the pharmacokinetic parameters, such as age, body weight / body mass index, through inclusion exclusion criteria.
Dosage and route of administration: the recommended dosage approved by the original research drug at home and abroad is 0.6mg per day, which should be increased to 1.2mg at least one week later. In order to further improve the hypoglycemic effect, the dosage can be increased to 1.8mg at least one week later. In order to protect healthy subjects and meet the requirements of the minimum quantitative limit of detection methodology, it is suggested to choose a relatively sensitive low dose 0.6mg subcutaneous injection and try to choose a unified injection site.
End point index and boundary value: the PK comparison test of biological similar drugs usually adopts the equivalence design, with Cmax and auc0-t as the main end point index, the equivalence judgment boundary value of 90% confidence interval of 80% – 125% [6], and other important pharmacokinetic parameters such as auc0 – ∞ as the secondary end point. The sampling time t is required to be greater than 3-5 half lives, and the auc0-t / auc0 – ∞ ratio is required to be greater than 80% to ensure adequate sampling and auc0-t is enough to identify the difference between the two preparations [5].
Sample size: before the test, it is necessary to fully estimate the sample size required. Generally, α is 0.1 on both sides (0.05 on both sides), and the test efficiency is 80%. In the estimation of sample size, the individual variation should be fully considered, and the corresponding adjustment can also be made according to the pre test results.
（2） Clinical effectiveness comparison test
Trial design: the purpose of clinical effectiveness comparison is to prove that the clinical efficacy of similar drugs is similar to that of the original research drug. The original research drug should be used as the control, and randomized, parallel control and equivalence design should be carried out.
Study population: Patients with poor blood glucose control after metformin alone or sulfonylurea alone and metformin combined with sulfonylurea were selected as the study population, and the previous dose of metformin and sulfonylurea were limited in the inclusion and exclusion criteria. Generally, the recommended dose of metformin is 1500-2000 mg / day For sulfonylureas, such as glimepiride, 4 mg / day or the maximum tolerable dose determined by the doctor.
Dosing plan / dose: it is recommended to give the drug according to the approved dose and method of the original research drug, and determine the time of dose titration, such as the initial dose of 0.6 mg per day, and the dose will increase to 1.2 mg and 1.8 mg after 1-2 weeks (unless intolerable). During the treatment, the corresponding concomitant treatment should maintain a stable dose.
Evaluation index: the change of HbAlc from baseline at least 24 weeks after treatment with stabilizer amount is recommended as the main endpoint in clinical effectiveness comparison test, and the secondary index is recommended to include the change of HbAlc and body weight at 12 weeks. It is suggested that HbAlc should be tested in the central laboratory.
Equivalence boundary value: at present, the recognized non inferior boundary value of HbAlc at home and abroad is 0.3% or 0.4% [7-9]. The hypothesis of equivalence test needs two unilateral tests in two directions, so the equivalence boundary value can be set as 95% confidence interval ± 0.4%.
（3） Other issues to focus on
- Study on safety and immunogenicity
The type, severity and frequency of adverse reactions should be compared in the study of pharmacokinetic and efficacy comparison tests, especially the specific adverse reactions that are focused on.
Anti drug antibody (ADA) and neutralizing antibody (NAB) may be produced after subcutaneous injection of Liraglutide. Therefore, the anti drug antibody (ADA) and neutralizing antibody (NAB) should be detected in clinical comparative study, and the positive rate, titer and time of antibody emergence should be evaluated. It is suggested that the sampling points of all subjects should at least include before the first administration, half course treatment and after the last administration.
- Pharmacokinetic study of patients
In the clinical comparison test, we should carry out the analysis of the pharmacokinetic characteristics of patients after multiple administration. The sampling point should be set to clearly reflect the overall characteristics of the two, so as to further evaluate the similarity between the biological similar drugs and the original research drugs. Considering the absorption process of subcutaneous injection, it is recommended to take samples when the drug reaches steady state, and compare key parameters such as auc0 -? , CSS, min.
4、 Summary
The research and development of biological analogues of Liraglutide should follow the general requirements of the guiding principles of biological analogues. At present, it is considered that clinical similarity evaluation should include at least one pharmacokinetic comparison test and one clinical comparison test. This paper expounds the key points of the research design, represents the understanding of the current review, and sincerely expects the industry to put forward valuable opinions and suggestions for the follow-up improvement.
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