单独立卷资料撰写指导建议(英文)_20090302

Annex 1Guidance on the Preparation of Standard-alone documents for Special Review Procedure (SRP) applicationsContents1. Foreword1.1 Background1.2 Objective1.3 Basic principles for authoring the dossier2. Basic contents of the "Standard-alone documents"2.1 Overview to justify the applied drug is in accordance with Article 2 inRegulation of New Drug Registration Special Review Procedure;2.2 Protocol for planned clinical trial(s) or summary of completed clinical trials;2.3 Evaluation of safety and efficacy based on the completed studies (pre-clinicaland clinical);2.4 Summary of finished pharmaceutical researches;2.5 Summary of other major studies;2.6 Risk control plan and implementation scheme;2.7 Conclusion and discussion.1．Foreword1.1 BackgroundOn January 9th, 2009, the State Food and Drug Administration (SFDA) issued the Notification to Publish the Regulation of New Drug Registration Special Review Procedure (SFDA-zhu [2009] No. 17) (hereinafter as "Regulations"), in which the Article 4 referred: “the applicant applying for special review procedure should fill in the Application Form for New Drug Registration Special Review Procedure and submit relevant data.The Application Form for New Drug Registration Special Review Procedure and relevant data should be filed in a separate dossier and submitted to the acceptance department for drug registration along with the application dossier required by the Drug Registration Regulation.”Therefore, the separated filed summaries are important documents to be submitted for a drug applying for special review process. Whether an application can be reviewed via SRP is based on whether the Separated Filed Dossier can scientifically and logically elucidate the research data reflecting the applied research phase.The Separated Filed Dossier for traditional Chinese medicine (TCM) and biological products can be prepared with reference to this guidance, in combination with their respective product characteristics. The corresponding items can be added or deleted as appropriate.1.2 ObjectiveThis guidance is intended to provide reference for authoring the Separated Filed Dossier for application of Special Review Procedure.It should be noted that in different drug research stage, the focuses of research and evaluation are different, so this guidance cannot cover all the contents and details in drug research (from preclinical to clinical). In addition, it is also unsuitable to consider the Separated Filed Dossier only as an abbreviated summary for the application dossier.1.3 Basic principles for authoring the dossierIt should be emphasized that the contents and conclusions in the Separated Filed Dossier need to be summarized based on the quantitative description and evaluation of research data.The following basic principles are the foundations of this guidance:●General information and target profile of the product;●Indications (or usage);●Completed Studies;●Purpose of this application and supporting data;●Risk control plan and implementation scheme.This guidance is prepared on the basis of characteristics of chemical drugs. The Separated Filed Dossier for TCM and biological products can be prepared withreference to this guidance, in combination with their respective product characteristics.2. Basic contents of the Separated Filed Dossier2.1 Overview to justify the applied drug is in accordance with Article 2 of Regulation of New Drug Registration Special Review Procedure.2.1.1 General Information of the ProductBriefly describe the drug name, structure, molecular formula and the major mechanisms of action, and etc.; for TCM combination preparations, describe the composition, source of the prescription; structure for effective parts and confirmation rationale.T o describe what is the treatment objective of the drug? Is this treatment targeted as the first-line or second-line treatment in clinical practice? Are there any other factors need to be considered related to the expected treatment outcome?2.1.2 Characteristics of target diseasesBriefly describe the epidemiology of the target disease, including the incidence, prevalence, mortality and related concomitant diseases. If data available, the differences of epidemiology in different regions should be discussed (because the epidemiology of indications may vary by region).Discuss the characteristics of the disease, including: what is are the hazardness of this disease? Is it lethal or caused disability? Is this disease (such as hypercholesterolemia, hypertension) a precursor or risk factor for other diseases (such as coronary artery disease, stroke)? If yes, how will this risk factor prognosticate the occurrence of more serious diseases? What are the expected outcomes for the early intervention of this disease?2.1.3 Existing treatmentsT o introduce if there are any other treatments for this disease, including drug and non-drug treatments?If there are other treatments existing, following aspects should be considered: (1) the characteristics of the existing treatment? Attention should be paid to whether the data comes from well-controlled studies to reach scientific conclusions. (2) Is there any comparison on the efficacy and safety of treatments, and how to conduct the comparison? What about the comparison results? (3) Is there any other factors impacting the efficacy of existing treatment, such as tolerability, convenience, or patient preference?If there is no treatment yet, to analyze what are the consequences without treatment?2.2 Protocol for planned clinical trial(s) or summary of completed clinical trials2.2.1 Introduction of protocol for planned clinical trial(s)This section is mainly required for applications for clinical trials. Should clearly describe the protocol for planned clinical trial.2.2.1.1 Description of the overall study design and protocolThe description of overall study design and protocol should be clear and concise. It is recommended to use tables, charts and other visual methods to describe the clinical trials to be conducted (see Table 1).Table 1: Description on the clinical trials to be conducted (adjusted according to thedrugs and type of the study)recruited?)Define the reasonable inclusion criteria, exclusion criteria and criteria to remove patient from treatment or assessment. Based on the study objective, to determine the inclusion criteria for the indication scope with justification, to select generally accepted diagnostic criteria, and pay attention to the severity and course of the disease, medical history characteristics, score of physical examination, the laboratorytest results, previous treatment, possible prognostic factors, age, sex, weight, race and so on.The reasons for defining the criteria should be justified.2.2.1.3 Determination of dosage regimen (dose and administration methods?)Indicate the dosage regimen, including the starting dose, route of administration, dose interval, dose exploration plan and the possible modification of dosage regimen.Rationales for dosage regimen should be justified.2.2.1.4 Considerations on the selection of control group (control treatment selection?)The basis and justification for selection of the control group should be indicated.If there is no control group in the study, the reasons should be provided; if randomized grouping is not adopted, detail reasons should be provided to explain any other technical measures applied to effectively minimize the selection bias.2.2.1.5 Determination and justification for efficacy and safety variables (What are the observational variables?)For the determination of efficacy variables: the primary endpoint shall be clearly explained, and corresponding justifications should be provided (such as literature, guidelines, etc.); if surrogated variables are used, corresponding justification should be provided. Other important secondary endpoints should also be explained.For the determination of safety variables: including the specific safety variables, the laboratory examinations, precautions, reasons for the determination of important safety variables (such as indicated by the pre-clinical study results). Describe the method of collecting the adverse event data, adverse events assessment criteria and management.If the efficacy or safety variables are unconventional, standardized parameters, theaccuracy, reliability and relevance should be justfied.2.2.1.6 Statistical plan and determination of sample size (What kind of statistical method is applied?)The statistical design and types of analysis should be clearly listed and explain with justification: such as superiority, equivalence or non-inferiority; the definition of primary ad secondary variables; statistical analysis methods for variables (with domestically and internationally well-recognized methods and software) and so on.To provide detail calculation method and calculation process of sample size, as well as the statistics estimations used in the calculation process and the basis of the estimation.Any protocol amendment for on-going studies and information outside of protocolshould also be described, and the statistical consideration involved in protocol amendment should be explained. To indicate whether a interim analysis will be conducted. If there is interim analysis planed, it should be conducted according to the protocol and explain the calculation methods for α consumption.2.2.1.7 Quality Assurance of Data (What is the data capture process?) Briefly describe the quality control process to ensure the accurate and reliable measurement of data, including the audit / inspection situation, the consistency of data entry, numerical range and logical inspection, and blind review process, etc.2.2.2 Situation for completed clinical trialsThis section is designed for the applications thatrelevant clinical trials finished.It is recommended to use tables, charts and other visual methods to describe the completed clinical trials (see T able 2).Table 2: Description of the completed clinical trials (adjusted according to drugs andtype of studies)Provide brief and clear description and evaluation to the completed clinical trials, such as design methodology, endpoint variables, statistical methods, efficacy and safety, etc.2.3 Evaluation of safety and efficacy based on completed studies(pre-clinical and clinical)2.3.1 SafetyThis section mainly describes the safety issues found in researches. According to the objectives and research phase of the application, the focuses would be different to support the future research (or application).2.3.1.1 Non-clinicalDescribe the general situation of non-clinical studies, such as the title of the studies, purpose, time, research institutions and responsible person, GLP implementation situation, batch number of test drug, quality specification of related bathes and the differences to the batches used in CMC researches, study protocol (animal, dosage, route of administration, period, etc.), and test results. It is recommended to be describe the studies by visual methods such as table and charts..The non-clinical findings, which need to be emphasized in the clinical trials or cannot be sufficiently explained by clinical trial data should be highlighted, such as genetic toxicity, reproductive toxicity, carcinogenicity, and drug interactions, etc.It is recommended to provide description and evaluation on liver toxicity, cardiovascular toxicity and renal toxicity, etc. If the product will be used in special populations (such as pregnant women, children), it should be considered whether specific non-clinical data needed.If the drug has not yet been used in human body, the justification and determination of first dose in human (first human dose) on the basis of animal test results should be indicated.2.3.1.2 ClinicalAdverse events (AEs) / adverse drug reactions (ADRs): list the important risks already identified in clinical trials and the potential risks. If possible, this information should include evidences of exposure, incidence, severity, reversibility and risk population. It is recommended to describe with tables, charts and other visual methods (see T able 3).Table 3: List of adverse events / adverse drug reactions occurred (can be adjustedaccording to the specific circumstances)Limitations of safety database: the limitations of database of safety should be indicated (for example, sample size of study population, populations excluded from the study (pregnancy or breast-feeding women, children, etc.), and related inclusion / exclusion criteria). The limitations predicating the safety in future clinical trials or post-marketing safety should be clearly discussed, especially for population intended or potentially exposed future studies and clinical application.Identified and potential interactions: including food - drugs and drug - druginteractions, to discuss the identified and potential pharmacokinetic and pharmacodynamic interactions. Summarize the evidences supporting the interaction and its possible mechanisms, and discuss the potential risks to health of patients for different indications and in different populations.2.3.2 EfficacyDescribe the results of efficacy evaluation, including the comparison of differences between groups for primary and secondary efficacy variables, and pharmacokinetic parameters. Conduct the FAS analysis and PP analysis according to the scheme defined in the study design.With analysis on primary and secondary endpoint variables, briefly summarize and evaluate the effectiveness and clinical significance of test drugs.2.3.3 ComplianceProvide the summary and analysis for patients' compliance. Describe the methods / indicators of compliance, such as drug counting, dairy cards, testing of drug concentrations in blood, urine and other body fluid sample.2.3.4 OthersThis section focuses on other important information reflecting the advantages of the clinical treatment.2.3.5 Evaluation of whether the results of clinical trials can support the advantages of the clinical treatment in the application?Combining the above-mentioned safety, efficacy and compliance analysis, in comparison with the control treatment and/or the existing treatment, discuss the advantages of the applied clinical treatment, such as: indicated to disease (and / or patient population) without effective treatment and method, or defects in existing treatment and method. Discuss the clinical characteristics or benifit of the applied drug.The evaluation and discussion could be derived from the benefits / risk assessment, but should not be too extensive, the evaluation should still be based on the analysisof research data.2.4 Summary for finished pharmaceutical researchesAccording to the type and purpose of the application, the description and evaluation on the research process and results for drug substance and drug product should be provided with quality control as the core, such as: production conditions of pre-clinical samples, whether the clinical trial samples are produced in GMP workshop, the relevance of its quality; production scale of drug substance and drug product; indicate whether the product quality can be well controlled by the process, quality specification and stability; the existing impurities limits and justifications, etc.For the above contents, drug substance and drug product should be described separately.2.5 Summaries of other major studiesIf there are other researches and results included in the previous studies, it can be explained and evaluated in this section.2.6 If the risk control plan and implementation scheme adequate for the application?2.6.1 Summary of safety issuesAt the beginning of the risk control plan and implementation scheme, an abstract should be prepared, including: (1) important confirmed risks that have been identified;(2) important potential risks; (3) Important missing data.It is encouraged to outline the important and special safety issues that already or potentially happened, including the non-clinical and clinical data related to the safety issues.2.6.2 Risk control plan and implementation schemeThe routine risk control plan should include: (1) internal assessment and reporting systems for suspected adverse reactions in the study; (2) reports to be submitted to health authorites: including expedited reports of adverse drug reactions (ADR) and periodic safety update report (PSURs).The Separated Filed Dossiershould include the risk control plan to address the plan to each important safety issue and assess its rationality:∙ Safety issues already identified in previous studies (or safety issues expected to be happened or need to pay attention);∙ Safety issues monitored by the sponsors and related plans;∙ Assessment and report for significant events.It should be clearly indicated that whether the investigator brochure (IB) is available; any target toxicity organs found in the previous studies and level of the toxicity; any monitoring measures for these toxicity taken into consideration in the clinical trial protocol; if the principle investigator (PI) has experience for clinical trials, and the situation of Ethics Committees (EC). Insurance situation for the clinical trial could also be included into the document.Important potential risks should be discussed, such as potential risks caused by changes to the course of treatment (for long term treatment), the target patient population (pregnant women, children), and drug interactions.It is recommended to include following events in the risk control plan: studies, evaluation, control and significant safety event reporting. When establishing these significant events, consideration should include: exposure to product reached a level, which is sufficient to identify the concerned AEs / ADRs, and / or obtain expected safety results.2.6.3 Other informationRisk control is always specific to individual products, indications, target populations and issues to be addressed. For a drug in clinical research stage, the current drug regulatory system and the measures are all effective measures to control the risks. The risk control plan in this guidance is to require the sponsors to apply administrative method and measures in drug development process based on their understanding to the investigational products.2.7 Conclusion and discussionThis section is intended to be a high-level summariy and analysis to the above-mentioned contents based on the type and purpose of applicationto discuss if the application submitted conform to the requirement for corresponding type in SRP.。