Quick view! Guidelines for clinical trials of antipsychotic drugs published by the State Food and Drug Administration

In order to guide and standardize the clinical trials of antipsychotic drugs, the State Drug Administration has organized and formulated the technical guidelines for clinical trials of antipsychotic drugs, which are hereby promulgated Notice is hereby given Annex: technical guidelines for clinical trials of antipsychotic drugs annex to SFDA Circular No 114 of 2018 on November 6, 2018 Doc (see the end) Annex: technical guidelines for clinical trials of antipsychotic drugs I overview Antipsychotics refer to a kind of drugs that can alleviate the psychotic symptoms and prevent the recurrence of psychotic symptoms According to dsm-5 diagnostic system, all kinds of diseases in schizophrenia spectrum and other mental disorders may be treated with antipsychotics In this guideline, antipsychotics refer to the drugs used to treat schizophrenia This guideline is mainly applicable to the research and development of innovative antipsychotic drugs in China, focusing on the key points for consideration of confirmatory clinical trial design, for the reference of drug research and development applicants and researchers The contents with common principles with other types of innovative drug research and development, such as the requirements of clinical pharmacology research, exploratory clinical trials, post marketing research, etc., are not covered by this guiding principle When applying these guidelines, please also refer to the good clinical practice (GCP), the International Council for harmonization of technical requirements for pharmaceuticals for human use (ICH) and other relevant technical guidelines published at home and abroad 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 2、 The basic principle is that, like other innovative drugs, the clinical research and development of antipsychotics should also be based on the clinical research mode of "specification oriented" The whole clinical research plan should set a clear ultimate goal and research path, and each specific clinical trial should have a clear research purpose At the end of each clinical trial, staged benefit and risk assessment shall be conducted in time to decide to terminate or continue the clinical study The clinical trial should be designed, implemented and analyzed scientifically to ensure that the trial process is standardized, the results are scientific and reliable, and completely and truly presented in the clinical trial report When designing clinical trials of antipsychotics, it is suggested to consult with clinical experts and statistical experts with clinical research experience to discuss and determine the trial scheme 3、 The main points of confirmatory test design (1) objective schizophrenia is an unknown disease, which is composed of different symptom groups caused by complex pathological mechanism At present, the diagnosis of schizophrenia mainly depends on the symptomatology and course of disease, and the clinical treatment is mainly aimed at relieving symptoms The clinical manifestations of schizophrenia are mainly composed of positive symptom group, negative symptom group, cognitive dysfunction, emotional symptoms and agitation, which can be one of the main, but also a variety of both Therefore, the main research purposes of confirmatory clinical trials of antipsychotics can be divided into the following two situations: the first is to prove the therapeutic effect of drugs on the overall symptoms of schizophrenia (the overall symptoms do not refer to all symptoms of the disease, but refer to the choice of no positive or negative symptoms in the research purpose) At the same time, according to the characteristics of pharmacological mechanism, positive symptoms, negative symptoms or cognitive dysfunction can be regarded as the key secondary research purposes On the basis of proving that the drug has therapeutic effect on the overall symptoms, it can be further analyzed which symptom group is the improvement leading to the production of therapeutic effect The second is to prove the therapeutic effect of drugs on one or several symptom groups (positive symptoms, negative symptoms, cognitive dysfunction, agitation, etc.) of schizophrenia According to the suggestion in the guideline for the prevention and treatment of schizophrenia (Second Edition), schizophrenia needs long-term treatment in the whole process, including acute stage, consolidation stage (stable stage) and maintenance stage (rehabilitation stage) The main purpose of treatment in the acute phase is to reduce the severity of psychotic symptoms and related symptoms; the main purpose of treatment in the consolidation phase is to use the effective drugs and doses used in the acute phase to consolidate treatment for at least 6 months to prevent the recurrence of relieved symptoms; the main purpose of treatment in the maintenance phase is to maintain the continuous remission of symptoms and prevent recurrence The duration of maintenance treatment is at least 2 years for the first patients, 3-5 years for the patients with one relapse, and more than 5 years or even a lifetime for the patients with multiple relapses Therefore, the confirmatory clinical trials of antipsychotics should prove that the drugs can achieve good control of symptoms and have acceptable safety in the "whole course treatment" recommended by the diagnosis and treatment guidelines The trial should include two parts: proving that the drug can relieve symptoms and maintain efficacy, and providing evidence of short-term safety and relatively long-term safety In principle, on the basis of confirming that the drug can relieve symptoms and has good short-term safety, further clinical trials should be carried out to prove the efficacy and relative long-term safety of the drug （2） The subjects were selected according to the purpose of the study If the purpose of the study is to prove the therapeutic effect of drugs on the overall symptoms of schizophrenia In general, it is recommended to select patients who have first or multiple episodes, are in acute phase and are not currently receiving antipsychotic treatment If it is necessary to use patients who are receiving antipsychotic treatment, a sufficient lead-in period should be designed to clean the previous drugs If the purpose of the study is to prove the therapeutic effect of drugs on one or several symptom groups of schizophrenia Reasonable entry and discharge criteria should be designed to select the subjects who meet the purpose of the study The factors included but not limited to the condition of medical history, the condition of course of disease and the scoring condition of symptom severity scale If the loading test design is adopted, the condition of basic treatment drugs should also be considered It is suggested that the international classification of diseases (ICD) or the diagnostic and Statistical Manual of mental disorders (DSM) diagnostic system be used to screen the test population It is suggested to use diagnostic scale developed based on ICD and DSM system, which has been widely verified, as a diagnostic standardized tool, such as structured clinical interview for DSM disorders (SCID) or Mini International Neuropsychiatric Interview (m.i.n.i.) The severity screening based on the scale score was related to the purpose of the study If the purpose of the study is to prove the therapeutic effect of drugs on the overall symptoms of schizophrenia, generally, it is recommended that the total score of the positive and negative symptom scale (PANSS) be ≥ 70; the Clinical Global Impressions scale severity (CGI-S) be ≥ 4 The requirements for items in the measurement form can be clearly specified in the test plan according to the research purpose If the purpose of the study is to prove the therapeutic effect of the drug on one or several symptom groups of schizophrenia, the scoring standard of symptom groups in the scale should be determined according to the correlation with the purpose of the study Generally, it is suggested that the single score of key items related to or strongly related to the research purpose in PANSS should be ≥ 4 points, and if necessary, the single score of key items not related to or weakly related to the research purpose should be ≤ 3 points If other diagnostic systems, diagnostic standardization tools and severity screening criteria based on scale scores are selected, the basis shall be described in the test scheme （3） The confirmatory clinical trial of test type antipsychotics should include two parts: proving that the drug can relieve symptoms and maintaining efficacy 1 The main purpose of short-term trial is to prove the effect of drugs on relieving symptoms The observation period (double-blind treatment period) usually takes at least 6 weeks 2 Long term trial the main purpose of long term trial is to prove the effect of drug maintenance Generally, there are two design methods for long-range test: parallel control test: it can be a continuation of short-range test The observation period is usually not less than 6 months Random withdrawal test: the random withdrawal test is divided into two stages The first stage: all subjects took the test drug, using an open, non control design, and it is recommended to continue the treatment for 12 weeks (including titration introduction period and dose stabilization period of at least 6 to 8 weeks) The second stage: the eligible subjects entered the double-blind period and were randomly divided into the trial drug group or placebo group to observe the recurrence of the two groups Subjects continued to receive treatment until they met the pre-defined recurrence criteria or end of study criteria, such as the end of the trial after observing how many recurrence events or when the interim analysis results were positive (the trial drug group was better than the placebo group) When entering the double-blind period from the stable period, the subjects must meet the following criteria: there is no change in dose during the stable period, or the dose change is within the allowable range specified in the plan in advance; there is no recurrence event; the total score of PANSS is less than 70 (corresponding adjustment is allowed according to the research purpose); and / or the single score of the symptom group related to or strongly related to the research purpose in PANSS scale is less than or equal to 3 (according to the research purpose Corresponding adjustment is allowed) The observation period suggested in the guidelines is not a mandatory deadline It is suggested to determine a reasonable observation period according to the drug characteristics and research purposes, and elaborate the basis in the test plan （4） At present, no matter in clinical diagnosis and treatment or in drug clinical trials, there is no reliable objective index to evaluate the severity of schizophrenia and the efficacy of antipsychotics It is a popular evaluation method to use the scale with good reliability and validity PANSS can distinguish different symptom groups of schizophrenia It can not only evaluate the improvement of the overall symptoms and severity of schizophrenia, but also the improvement of each symptom group and severity It has a detailed operation standard of symptom severity and good reliability and validity It is the most widely used scale in the research and development of antipsychotics At present, it is suggested that PANSS should be used as the evaluation tool of efficacy index in the confirmatory clinical trials of antipsychotics, including the main efficacy index and the secondary efficacy index with symptom group as the object The evaluation tools of secondary efficacy indexes include clinical general impression scale, cognitive function evaluation scale, sexual function evaluation scale, quality of life evaluation scale, social economy evaluation scale, etc In the test plan, the rationality basis of the selected scale should be described Generally, it is recommended to take the change value of the primary efficacy index (scale score) of the observation end point relative to the baseline as the most important statistical analysis object, and its statistical analysis results as the most important basis for evaluating the efficacy of drugs In the long-term trial with the purpose of maintaining the efficacy of drugs, according to the design of the trial, the continuous observation of the main efficacy indicators of the short-term trial or the recurrence related indicators can be used as the main efficacy indicators Effective rate, remission rate and relapse rate, as indicators of population benefit, have important guidance and reference significance in clinical diagnosis and treatment practice after the drug is put on the market