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▲TG-Bio has joined hands with more than 600 industry colleagues and will open in April ▲Randomized control is the gold standard for clinical trials, because randomization reduces confounding factors and bias at baseline.
However, after the start of the clinical trial, the occurrence of concomitant events will affect the analysis of the results.
For example, the concomitant incidents of salvage treatment often encountered in clinical trials of diabetes, which cannot be resolved randomly.
Clinical trials usually use intentional analysis (ITT) to assess the effectiveness of drugs under investigation.
The ITT principle requires the data of all random subjects to be included in the analysis and no concomitant events are considered.
The ITT principle can reflect the actual situation of clinical practice, because in the real world, not all patients have good compliance.
However, the analysis according to the protocol (PP) only included the data of subjects who did not have major protocol deviations for analysis.
Regarding the use of ITT principles to estimate whether the treatment effect can always represent the treatment effect most relevant to regulatory and clinical decision-making, the question remains unresolved.
The framework outlined by ICHE9 (R1) of the estimation objective provides a basis for describing different treatment effects, and provides important points to be considered in trial design and analysis in order to estimate treatment effects and provide a reliable basis for decision-making.
The core issue of drug development and approval is to determine whether the therapeutic effect exists and to estimate its magnitude.
The estimated goal is an accurate description of the treatment effect, reflecting the clinical questions raised for the purpose of the clinical trial.
It summarizes and compares the results of the same patients under different treatment conditions at the group level.
The construction of the estimation target involves three levels: First, the estimation target is incorporated into a coordinated framework of clinical trial planning, design, implementation, analysis and interpretation.
(Figure 1) What scientific issues are clinically concerned about? What needs to be estimated? What is the main analysis method? What is the method of sensitivity analysis? Second, determine the attributes of the estimated target.
The estimated target has five attributes: treatment (treatment), population, variables (or endpoint), concomitant events, and group-level summary.
Concomitant events are events that occur after treatment that can affect the interpretation or existence of observations related to clinical problems.
When describing relevant clinical problems, concomitant events need to be addressed in order to accurately define the treatment effect that needs to be estimated.
Concomitant events are different from missing data.
Missing data is data that is meaningful for the analysis of the established goals, but not collected.
For example, termination of treatment (EOT) represents a concomitant event, which needs to be resolved by the precise description of the estimated target in the trial purpose; while exit from the study (EOS) leads to missing data, which needs to be resolved in statistical analysis.
Third, according to the clinical problem corresponding to the estimated target, choose an appropriate strategy for solving concomitant events.
When defining clinical problems, there are five strategies for solving concomitant events: 1) Therapy strategy: The occurrence of concomitant events under the treatment strategy has nothing to do with the treatment effect, that is, regardless of whether concomitant events occur, the value of related variables will be used .
The analysis of this strategy is the ITT analysis used before; 2) The hypothetical strategy is to assume that all subjects comply with the protocol and no concomitant events occur; 3) The compound variable strategy is that concomitant events themselves can provide information on patient outcomes , So it is included in the definition of variables.
4) The treatment strategy focuses on the treatment effect that occurred before the concomitant event.
5) The main-level strategy can be considered that the target population is the "main-level" where concomitant incidents occur, or the target group is the main level where no concomitant incidents occur.
The clinical problem is only related to the treatment effect in this main layer.
These five strategies are not part of the plan analysis (PP).
Case analysis In the guidelines for the clinical development of diabetes drugs issued by the EMA in 2018, the recommendations for the strategies for the treatment of concomitant events in diabetes clinical trials are as follows: When studying the therapeutic effect of changes in HbA1c from baseline, it is recommended to deal with the concomitant events of remedial treatment False image strategy; recommended treatment strategies for the concomitant events of early termination of study drug treatment.
When studying the therapeutic effect of the blood glucose compliance rate, such as the percentage of patients with blood glucose compliance, it is recommended to use the two concomitant strategies that have neither remedial treatment nor early termination of the study drug at the end of the study.
Case 1: The Dulaglycotide AWARD-11 study is a randomized double-blind parallel controlled study.
The purpose of the study was to compare the efficacy and safety of the new dosing regimen of 3.
0 mg and 4.
5 mg once a week of dulaglutide with the approved dosing regimen of 1.
5 mg once a week in patients with poorly controlled metformin type 2 diabetes.
.
The main purpose of the study is to verify that the therapeutic effect of 3.
0mg and/or 4.
5mg of duraglutide in reducing HbA1c is better than 1.
5mg after 36 weeks of treatment.
The secondary research objectives include verifying that the weight reduction achieves superior results.
The concomitant events defined in the study are new hypoglycemic drug treatment for >14 days (regardless of whether it is due to salvage treatment or other reasons) and termination of study drug treatment.
If two concomitant events occur in the same subject, choose to occur first Analysis of concomitant events.
The estimated goals of the primary efficacy endpoint are: 1) the estimated target of therapy; 2) the estimated target of treatment.
These two estimated targets cover four groups of people, and no concomitant events occurred during the study (A); the study drug was stopped during the study but the study continued (B); the hypoglycemic drug treatment was added and the study continued (C); Withdraw from the study before the primary endpoint (D).
(Figure 2) Figure 2: AWARD-11 study treatment estimated target and treatment estimated target treatment estimated target evaluation does not consider the efficacy of any concomitant events, and all data are included for analysis.
For subjects who discontinued study drug treatment early before 36 weeks, the missing data was filled in with the HbA1c value of subjects who discontinued drug treatment early but continued to maintain the study at 36 weeks.
For subjects who did not terminate study drug treatment early but lacked 36 weeks of data, the 36 weeks data of subjects who maintained study drug treatment were used to fill in.
The main analysis method uses analysis of covariance model.
The goal of treatment estimation is to evaluate the efficacy of dulaglutide under the premise of the established hypoglycemic medication regimen and the normal use of the study drug.
Only the data before the occurrence of concomitant events were included for analysis.
The primary analysis uses the mixed-model for repeated measures.
The efficacy results of using two different estimation targets are different.
In general, the hypoglycemic efficacy of the estimated target of treatment is slightly greater than the estimated target of treatment (Figure 3).
Figure 3: AWARD-11 study two estimated target HbA1c and weight loss results Case 2: Oral semaglutide PIONEER 1 study is a randomized double-blind placebo-controlled study to evaluate oral semaglutide and placebo Compared with the efficacy and safety of type 2 diabetes patients with poor blood glucose control based on lifestyle intervention.
The primary endpoint was the change in HbA1c from baseline at 26 weeks of treatment.
The concomitant events defined in this study are: early termination of study medication and remedial treatment during the study.
This study uses two types of estimation targets: therapy estimation targets and hypothetical estimation targets.
The clinical question answered by the goal of therapy estimation is to disregard the two concomitant events of stopping study medication and using remedial treatment.
What is the effect of oral semaglutide? The hypothetical objective to answer the clinical question is, if all subjects maintain the established regimen of study medication and no salvage treatment occurs, what is the efficacy of oral semaglutide? There are also four types of population in the PIONEER1 study: no concomitant events occurred during the study (A); remedial treatment occurred and the study continued (B); the study medication was stopped during the study but the study continued (C); the study was withdrawn before the primary endpoint (D). (Figure 4) Figure 4: PIONEER 1 study therapy estimation target and hypothetical estimation target therapy estimation target The main analysis method uses the analysis of covariance (Analysis of covariance).
Missing data were imputed by a pattern mixture model using multiple imputation.
Missing data were imputed by a pattern mixture model using multiple imputation.
The results of the study showed that the hypoglycemic effect of oral semaglutide hypothetical estimated target was slightly better than the estimated therapeutic target.
(Figure 5) Figure 5: Two estimated targets for HbA1c and weight loss efficacy results NMPA issued a decision on January 21 this year to apply "E9 (R1): Estimated Targets in Clinical Trials to Sensitivity Analysis" ICH guidelines Announcement, E9 (R1) is applicable to clinical studies initiated after 12 months from the date of announcement.
Although E9 (R1) has not yet been implemented in China, in the current clinical research process, CDE has required companies to prepare for the implementation of E9 (R1).
The implementation of E9 (R1) puts forward higher requirements for drug R&D companies, especially medicine and statistics.
It is necessary to fully consider and plan at the design stage, and communicate with regulatory agencies in a timely manner. Dr.
Xinxu Li of CDE of the 3rd Supervision-Biostatistics Summit Forum gives a speech for more details of the conference, please poke the QR code below! By Aogu Store-around Wenchuang, the interesting soul of biomedicine is here! (Click on the QR code, long press to go) Gathering is a group of fire, the real-name reader group of Bai Aogu, scan the code to add a WeChat editor, please note [Job position + work unit] to facilitate communication and collision of ideas! The copyright statement welcomes personal forwarding and sharing. Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Biopharmaceutical Editor" in a prominent position.
However, after the start of the clinical trial, the occurrence of concomitant events will affect the analysis of the results.
For example, the concomitant incidents of salvage treatment often encountered in clinical trials of diabetes, which cannot be resolved randomly.
Clinical trials usually use intentional analysis (ITT) to assess the effectiveness of drugs under investigation.
The ITT principle requires the data of all random subjects to be included in the analysis and no concomitant events are considered.
The ITT principle can reflect the actual situation of clinical practice, because in the real world, not all patients have good compliance.
However, the analysis according to the protocol (PP) only included the data of subjects who did not have major protocol deviations for analysis.
Regarding the use of ITT principles to estimate whether the treatment effect can always represent the treatment effect most relevant to regulatory and clinical decision-making, the question remains unresolved.
The framework outlined by ICHE9 (R1) of the estimation objective provides a basis for describing different treatment effects, and provides important points to be considered in trial design and analysis in order to estimate treatment effects and provide a reliable basis for decision-making.
The core issue of drug development and approval is to determine whether the therapeutic effect exists and to estimate its magnitude.
The estimated goal is an accurate description of the treatment effect, reflecting the clinical questions raised for the purpose of the clinical trial.
It summarizes and compares the results of the same patients under different treatment conditions at the group level.
The construction of the estimation target involves three levels: First, the estimation target is incorporated into a coordinated framework of clinical trial planning, design, implementation, analysis and interpretation.
(Figure 1) What scientific issues are clinically concerned about? What needs to be estimated? What is the main analysis method? What is the method of sensitivity analysis? Second, determine the attributes of the estimated target.
The estimated target has five attributes: treatment (treatment), population, variables (or endpoint), concomitant events, and group-level summary.
Concomitant events are events that occur after treatment that can affect the interpretation or existence of observations related to clinical problems.
When describing relevant clinical problems, concomitant events need to be addressed in order to accurately define the treatment effect that needs to be estimated.
Concomitant events are different from missing data.
Missing data is data that is meaningful for the analysis of the established goals, but not collected.
For example, termination of treatment (EOT) represents a concomitant event, which needs to be resolved by the precise description of the estimated target in the trial purpose; while exit from the study (EOS) leads to missing data, which needs to be resolved in statistical analysis.
Third, according to the clinical problem corresponding to the estimated target, choose an appropriate strategy for solving concomitant events.
When defining clinical problems, there are five strategies for solving concomitant events: 1) Therapy strategy: The occurrence of concomitant events under the treatment strategy has nothing to do with the treatment effect, that is, regardless of whether concomitant events occur, the value of related variables will be used .
The analysis of this strategy is the ITT analysis used before; 2) The hypothetical strategy is to assume that all subjects comply with the protocol and no concomitant events occur; 3) The compound variable strategy is that concomitant events themselves can provide information on patient outcomes , So it is included in the definition of variables.
4) The treatment strategy focuses on the treatment effect that occurred before the concomitant event.
5) The main-level strategy can be considered that the target population is the "main-level" where concomitant incidents occur, or the target group is the main level where no concomitant incidents occur.
The clinical problem is only related to the treatment effect in this main layer.
These five strategies are not part of the plan analysis (PP).
Case analysis In the guidelines for the clinical development of diabetes drugs issued by the EMA in 2018, the recommendations for the strategies for the treatment of concomitant events in diabetes clinical trials are as follows: When studying the therapeutic effect of changes in HbA1c from baseline, it is recommended to deal with the concomitant events of remedial treatment False image strategy; recommended treatment strategies for the concomitant events of early termination of study drug treatment.
When studying the therapeutic effect of the blood glucose compliance rate, such as the percentage of patients with blood glucose compliance, it is recommended to use the two concomitant strategies that have neither remedial treatment nor early termination of the study drug at the end of the study.
Case 1: The Dulaglycotide AWARD-11 study is a randomized double-blind parallel controlled study.
The purpose of the study was to compare the efficacy and safety of the new dosing regimen of 3.
0 mg and 4.
5 mg once a week of dulaglutide with the approved dosing regimen of 1.
5 mg once a week in patients with poorly controlled metformin type 2 diabetes.
.
The main purpose of the study is to verify that the therapeutic effect of 3.
0mg and/or 4.
5mg of duraglutide in reducing HbA1c is better than 1.
5mg after 36 weeks of treatment.
The secondary research objectives include verifying that the weight reduction achieves superior results.
The concomitant events defined in the study are new hypoglycemic drug treatment for >14 days (regardless of whether it is due to salvage treatment or other reasons) and termination of study drug treatment.
If two concomitant events occur in the same subject, choose to occur first Analysis of concomitant events.
The estimated goals of the primary efficacy endpoint are: 1) the estimated target of therapy; 2) the estimated target of treatment.
These two estimated targets cover four groups of people, and no concomitant events occurred during the study (A); the study drug was stopped during the study but the study continued (B); the hypoglycemic drug treatment was added and the study continued (C); Withdraw from the study before the primary endpoint (D).
(Figure 2) Figure 2: AWARD-11 study treatment estimated target and treatment estimated target treatment estimated target evaluation does not consider the efficacy of any concomitant events, and all data are included for analysis.
For subjects who discontinued study drug treatment early before 36 weeks, the missing data was filled in with the HbA1c value of subjects who discontinued drug treatment early but continued to maintain the study at 36 weeks.
For subjects who did not terminate study drug treatment early but lacked 36 weeks of data, the 36 weeks data of subjects who maintained study drug treatment were used to fill in.
The main analysis method uses analysis of covariance model.
The goal of treatment estimation is to evaluate the efficacy of dulaglutide under the premise of the established hypoglycemic medication regimen and the normal use of the study drug.
Only the data before the occurrence of concomitant events were included for analysis.
The primary analysis uses the mixed-model for repeated measures.
The efficacy results of using two different estimation targets are different.
In general, the hypoglycemic efficacy of the estimated target of treatment is slightly greater than the estimated target of treatment (Figure 3).
Figure 3: AWARD-11 study two estimated target HbA1c and weight loss results Case 2: Oral semaglutide PIONEER 1 study is a randomized double-blind placebo-controlled study to evaluate oral semaglutide and placebo Compared with the efficacy and safety of type 2 diabetes patients with poor blood glucose control based on lifestyle intervention.
The primary endpoint was the change in HbA1c from baseline at 26 weeks of treatment.
The concomitant events defined in this study are: early termination of study medication and remedial treatment during the study.
This study uses two types of estimation targets: therapy estimation targets and hypothetical estimation targets.
The clinical question answered by the goal of therapy estimation is to disregard the two concomitant events of stopping study medication and using remedial treatment.
What is the effect of oral semaglutide? The hypothetical objective to answer the clinical question is, if all subjects maintain the established regimen of study medication and no salvage treatment occurs, what is the efficacy of oral semaglutide? There are also four types of population in the PIONEER1 study: no concomitant events occurred during the study (A); remedial treatment occurred and the study continued (B); the study medication was stopped during the study but the study continued (C); the study was withdrawn before the primary endpoint (D). (Figure 4) Figure 4: PIONEER 1 study therapy estimation target and hypothetical estimation target therapy estimation target The main analysis method uses the analysis of covariance (Analysis of covariance).
Missing data were imputed by a pattern mixture model using multiple imputation.
Missing data were imputed by a pattern mixture model using multiple imputation.
The results of the study showed that the hypoglycemic effect of oral semaglutide hypothetical estimated target was slightly better than the estimated therapeutic target.
(Figure 5) Figure 5: Two estimated targets for HbA1c and weight loss efficacy results NMPA issued a decision on January 21 this year to apply "E9 (R1): Estimated Targets in Clinical Trials to Sensitivity Analysis" ICH guidelines Announcement, E9 (R1) is applicable to clinical studies initiated after 12 months from the date of announcement.
Although E9 (R1) has not yet been implemented in China, in the current clinical research process, CDE has required companies to prepare for the implementation of E9 (R1).
The implementation of E9 (R1) puts forward higher requirements for drug R&D companies, especially medicine and statistics.
It is necessary to fully consider and plan at the design stage, and communicate with regulatory agencies in a timely manner. Dr.
Xinxu Li of CDE of the 3rd Supervision-Biostatistics Summit Forum gives a speech for more details of the conference, please poke the QR code below! By Aogu Store-around Wenchuang, the interesting soul of biomedicine is here! (Click on the QR code, long press to go) Gathering is a group of fire, the real-name reader group of Bai Aogu, scan the code to add a WeChat editor, please note [Job position + work unit] to facilitate communication and collision of ideas! The copyright statement welcomes personal forwarding and sharing. Any other media or website that needs to reprint or quote the copyrighted content of this website must be authorized and marked "Reprinted from: Biopharmaceutical Editor" in a prominent position.
