Drug examination center: soliciting opinions on technical guidelines for clinical trials of drugs for the treatment of nonalcoholic steatohepatitis (for Trial Implementation)

To provide technical guidance for clinical trials of drugs for the treatment of nonalcoholic steatohepatitis, our center has organized the drafting of technical guidelines for clinical trials of drugs for the treatment of nonalcoholic steatohepatitis (for Trial Implementation) Now we are open to comments and sincerely welcome all sectors of the society to put forward valuable opinions and suggestions Our center will further revise and improve according to the feedback and suggestions Time for consultation: March 14, 2019 to June 13, 2019 Contact: Lu Shuang, Chen Ying email: lush@cde.org.cn cheny@cde.org.cn directory of technical guidelines for clinical trials of non-alcoholic fatty hepatitis treatment drugs 1 Scope of application 2 Overview 2 2 1 definition 2 2 epidemiology 3 2 3 treatment drugs 3 3 Clinical trial design 3 1 total body consideration 3 1 1 subject 3 1 2 endpoint index evaluation 4 3 1 3 methodological considerations 6 3.2 specific considerations for different research and development stages 7 3.2.1 clinical pharmacology 7 3.2.2 exploratory clinical trials 7 3.2.3 confirmatory clinical trials 9 3.2.4 trials to confirm clinical benefits 9 3.3 safety evaluation 9 1 Scope of application The guiding principles are jointly discussed and formulated by the drug regulatory department and clinical researchers to provide suggestions for the research and development of drugs for the treatment of nonalcoholic steatohepatitis (NASH) This guideline is only for adults with significant fibrosis of Nash, not for patients with Nash related decompensated cirrhosis and children This guideline is applicable to drug research and development of chemicals and therapeutic biological products, only as a recommendation When applying these guidelines, the International Council for harmonization of technical requirements for pharmaceuticals for human use (ICH) and other relevant technical guidelines issued at home and abroad should also be referred to This guideline will be further updated based on the progress of scientific research In view of the rapid progress and update of key elements in NASH clinical trials, this guideline represents only current recommendations 2 Overview this guideline mainly discusses the focus of clinical trial design in NASH treatment drug development, and does not discuss the general issues of clinical trial design or statistical analysis 2.1 definition Nonalcoholic fatty liver disease (NAFLD) is a kind of metabolic stress liver injury closely related to insulin resistance (IR) and genetic susceptibility The disease spectrum includes nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and Nash related liver stiffness Chemokines and HCC Nash showed more than 5% steatosis with intralobular inflammation and ballooning degeneration No or only mild fibrosis (F0 ~ 1) was the early Nash; significant or septal fibrosis (F2 ~ 3) was the fibrotic Nash; cirrhosis (F4) was the Nash cirrhosis 2.2 epidemiological NAFLD is one of the main liver diseases in the world It has been reported that the global prevalence rate is 25.24% (95% CI: 22.10-28.65), and the prevalence is increasing year by year Cardiovascular disease, malignant tumor and liver cirrhosis decompensation are the common causes of death in patients with NAFLD Nash has a high detection rate in NAFLD patients with metabolic syndrome and type 2 diabetes Nash is one of the main causes of cirrhosis The incidence of cirrhosis in NASH patients is as high as 15% - 25% in 10-15 years 2.3 treatment objectives: the ultimate goal is to delay, prevent and reverse the progress of Nash, improve the clinical outcome, including reducing the incidence of cirrhosis and its complications, reducing the demand for liver transplantation, improving the survival rate, improving the quality of life, etc Therapeutic drugs: at present, there are no therapeutic drugs that have been confirmed to be effective and safe through randomized controlled clinical trials 3 Clinical trial design 3.1 overall consideration: the design of clinical trial for drug research and development is based on the purpose of clinical trial According to the different targets of Nash, the clinical trial plan was made 3.1.1 Nash diagnosis: Although there are some limitations in liver histology, such as invasive, sampling and evaluation error, it is still the "gold standard" for NASH diagnosis In NASH drug research and development, liver histology is the evaluation index of subject diagnosis and main end point in confirmatory clinical trial The histological evaluation system of NAFLD / NASH mainly includes brunt system, NASH-CRN system in the United States, the fatty liver occlusion of progress (flip-saf) system in Europe, etc It is encouraged to explore noninvasive markers as a method for early screening of Nash subjects, including not only serum biochemical indicators such as alt, but also simple imaging indicators such as abdominal ultrasound 3.1.2 the efficacy evaluation end point of endpoint index includes clinical outcome end point and liver histology alternative end point, as well as other exploratory end points such as serum biochemical examination and imaging examination 1) Evaluation of clinical outcomes in patients without cirrhosis of Nash, the clinical endpoints included progression to cirrhosis, liver transplantation, HCC or liver related death / all-cause death For patients with Nash cirrhosis in compensatory phase, the clinical end points included the occurrence of cirrhosis decompensation (ascites, esophageal variceal bleeding or hepatic encephalopathy, etc.), liver transplantation, HCC or liver related death / all-cause death 2) Histopathological evaluation of the currently acceptable end points of histopathological alternatives to liver include improvement of inflammation or / and fibrosis The quality of histopathological evaluation is affected by many factors, including biopsy method, biopsy type (coarse needle / wedge biopsy), puncture site, puncture needle specification and pathological expert evaluation In order to ensure the quality of histological samples, it is required to strictly follow the SOP (standard operation procedure) procedure for pathological samples In order to reduce the difference of histopathological evaluation, the central reading should be used for pathological film reading It is suggested that more than two liver pathologists should read single blind or double blind films 3) Mri-pdff (magnetic resonance imaging – derived proton density fat fraction) can be used to quantitatively evaluate liver fat content On the premise of training and good quality control, we can use the absolute value or relative percentage of mri-pdff changes to evaluate the drugs with liver fat as the treatment target Noninvasive techniques such as magnetic resonance elastography (MRE) and transient elastography (TE) can be used to evaluate the changes of liver fibrosis Among them, the simultaneous detection of the controlled attenuating parameter (CAP) by te can help to evaluate the liver steatosis However, due to the influence of liver inflammation, cholestasis, operation standard and other factors, histopathological evaluation can not be replaced in the diagnosis of Nash fibrosis degree and the evaluation of curative effect before and after treatment 4) In the non-invasive indexes of serological evaluation, there are body weight, body mass index (BMI), waist to hip ratio, fasting blood glucose, glycosylated hemoglobin, insulin resistance (such as HOMA-IR), blood lipid and so on There are alt, AST, CK18 fragments related to liver inflammation / injury Related to the evaluation of liver fibrosis were FibroTest, ELF (enhanced liverfibrosis), NAFLD fibrosis score (NFS), pro-c3, FIB-4, AST / PLT index (Apri) 5) Other indicators used to evaluate the clinical outcome of cirrhosis include the changes of hepatic venous pressure gradient (HVPG), child Pugh and model for end stage liver disease (MELD) scores 3.1.3 methodology shall consider accepting both traditional clinical R & D design and novel design, such as adaptive / seamless design, but shall be explained in advance in the scheme If novel design is adopted, it is suggested to communicate with drug regulatory department in advance It is suggested to adopt the method of stratified randomization in random grouping, such as considering the coexisting disease factors such as diabetes The introduction period of 6-8 weeks was set before the random grouping to educate the subjects, optimize the diet and exercise arrangement, improve the lifestyle, help to evaluate the compliance of the subjects, and ensure the stability of weight and metabolic parameters A stable weight is defined as a change of no more than 5% If there is a combination of drugs, there should be a stable dose for at least 6 months If the study involves multiple drugs and multi-target combination treatment or fixed dose compound preparation, it is necessary to provide sufficient basis for the combination of drugs If the study involves the combination of drugs, including traditional Chinese medicine, etc., it needs to be clearly defined in the study plan, and relevant information should be recorded in detail In international multicenter clinical trials, ethnic differences (including differences in clinical pharmacology and clinical practice) should be paid attention to because Nash is related to lifestyle and genetic and metabolic factors such as diet It is suggested to join global R & D at an early stage to fully ensure that the subjects can represent the Chinese population 3.2 specific consideration for different research and development stages 3.2.1 clinical pharmacology research usually includes human tolerance test, human pharmacokinetics and pharmacokinetic / pharmacodynamic test As the drugs for NASH treatment need to be administered for a long time, the administration time should be long enough in the multiple administration tolerance test, at least one week in a row, unless contraindicated by the toxicity or pharmacological effect of the drugs If the blood concentration of the drugs and their metabolites cannot reach the steady state, it should be extended appropriately Before the pharmacokinetic data of patients with liver dysfunction are obtained, this part of the population should be excluded In the early stage of drug research and development, we can consider imaging, serology, Nash liver fibrosis non-invasive discrimination model as pharmacodynamic indicators to conduct small sample, short course of pharmacokinetic / pharmacodynamic evaluation, fully understand the characteristics of drug exposure / effect, and provide guidance for follow-up clinical trials NASH patients often have diabetes, hypertension, hyperlipidemia, gout and other metabolic diseases at the same time In the early clinical trials of Nash drugs, we should at least study the drug interaction with common antidiabetic drugs, antihypertensive drugs, lipid-lowering drugs and so on 3.2.2 exploratory clinical trial 1) early concept validation of Nash drugs should conform to the general principles of this phase Provide preliminary evidence to support follow-up clinical trials, including enrollment criteria, clinical trial cycle and endpoint setting The subjects can be selected by serum biochemical examination or imaging method The main efficacy indicators can be non-invasive markers, including mri-pdff, MRE and other imaging changes, as well as the changes of liver disease-specific serum biochemical indicators, etc., or combined with the changes of histopathology, imaging and serum biochemical examination and other non-invasive markers to evaluate the liver fat content and inflammation / fibrosis The dosage and treatment duration should be designed according to the mechanism of action and the expected effect on the selected efficacy index, and there should be a long enough end-point observation time It is suggested that multiple dose explorations should be included in this phase as a follow-up design option 2) In the later exploration, placebo-controlled, randomized, double-blind design is recommended Subjects: age, gender, diagnostic criteria, disease severity, combined disease, etc should be considered for inclusion It is suggested that the time window from liver biopsy to admission of NASH patients confirmed by liver histopathology should not exceed 6 months In this time window, it is necessary to pay attention to whether the patients accept the intervention that may affect the changes of liver histology Inclusion criteria: NAS score ≥ 4, including inflammation and