英文譯稿《已上市化學(xué)藥品和生物制品臨床變更技術(shù)指導(dǎo)原則》

1、Technical Guidelines on Clinical Changes for Marketed Chemical Drugs and Biological ProductsFebruary, 2021 1 TABLE OF CONTENTSI.Overview3II.Classification of Clinical Changes3(1)Major changes3(2)Medium change5(3)Minor Changes6III.Clinical Change Procedure6(1)Supplementary Application6(2)Filing Manag

2、ement7(3)Annual Report7(4)Others7IV.Technical Requirements on Clinical Changes7(1)Technical Consideration on Change Study8(2)Requirements on Changes Submission Dossier9References10Author10I.OverviewThe clinical changes on the marketed drugs refer to the changes made by the drug marketing authorizati

3、on holders on the indications, indicated population, dosage administration, safety information in the drug package inserts, pharmacovigilance plans, and other matters due to the needs for safe and effective clinical use of the drugs in the clinical after the drugs are approved to be marketed. The cl

4、inical change administration on the drugs post-marketing is an important part of the drug life cycle administration.The Guidelines specify the clinical changes after drug approval in China, classify the changes according to the degree of change and possible effect on clinical safe and effective use

5、of drug, that is, degree of risk, and detail the submission procedures and technical requirements corresponding to different categories, aiming to provide beneficial technical guidance and reference for the marketing authorization holders to carry out study on the clinical changes after the drugs ma

6、rketed and for drug regulatory authorities to perform change management.This guideline is applicable to chemicals drugs, preventive biological products and therapeutic biological products. For addition of non-approved new indication of marketed drug in China and change of administration route, the s

7、ubmission, review and approval shall be conducted in accordance with the channel for drug clinical trial and marketing authorization application.II.Classification of Clinical ChangesThe clinical related changes are classified into three types: major changes, medium changes and minor changes based on

8、 the extent of impact and the risk of the changes on the drug safety, efficacy and the safe and effective use in the clinical as following:(1) Major changesThe changes in the drug safety and efficacy information, and changes in safety related information in package insert are major changes. Major ch

9、anges are classified into Class A and Class B based on complexity of the change and studies required.1. Class A Major ChangeThe changes in drug safety and efficacy information are major change Class A, referring to changes on the medication population, efficacy, safety, dosage and method of administ

10、ration, such as changes in medication population, dosage above or below the approved dosage and administration and changes in drug interaction, etc.Such changes mainly involve the expansion or reduction of target population or measurement range and other efficacy information, will affect the clinica

11、l use of the drugs directly and shall be supported with the clinical trial data and/or the relevant non-clinical research data, which shall be supplemental submitted and implemented after reviewed and approved. The corresponding amendments to the drug package inserts and/or label shall be carried ou

12、t for such changes.The Class A major changes mainly include the following scenarios:(1)Changes to Approved IndicationsThe changes in the applicable population, for example, the age range for the applicable population is expanded into the children on the basis of the adults.The indications shall be r

13、estricted or removed based on the insufficiency of the efficacy evidence as shown by the clinical study, or risks outweigh benefits.(2)Changes in dosage and administration, including the changes in the recommended dosage and/or administration scheme, etc., and the administration dosage after the cha

14、nge is above or below the approved dosage and administration range.(3)Changes in use in special populations, such as: changes in medication information for the pregnant and nursing women, children and the elderly; addition of the medication information for the patients with liver function damage and

15、 renal function impairment; addition of the medication information for the patients with the immune insufficiency disorders, etc.(4)Changes in drug interaction. The drugs used in combination for the treatment of a certain disease shall be administered as the new indications.(5)Addition of new streng

16、ths. The drug content in the new strengths is out of the dosage and administration range in the approved package inserts. The addition of new strength is generally proposed along with the change in dosage and administration.(6)Changes to the existing risk management measures, such as: removal of an

17、approved route of administration or strength due to the safety reasons; removal of the contraindication items (e.g. use in pregnant women, etc.); change the contraindications into precautions.(7)Addition of the approved indications for the same products within China or removal of the approved indica

18、tions.(8)Others: Other Class A major changes related to the safe and effective clinical use of the drugs.2Class B Major ChangesThe change in safety-related information in drug package inserts is a Class B major change, which refers to the change to content related to drug risk management in the pack

19、age insert. Such changes have a certain effect on the safe and effective use in the clinical, and a large-scale pharmacovigilance (post-marketing safety vigilance) data support is required. The supplementary applications for the changes in the drug package inserts information are required and can be

20、 implemented after reviewed and approved.For the scenarios where the clinical trial data or the non-clinical research data to support the change is required, the changes shall be classified as Class B major changes, not the changes in the drug package inserts safety-related information.The Class B m

21、ajor changes mainly include the following scenarios:(1)Standardize the text wording of the approved indications so as to avoid the misunderstanding. The change shall not involve the expansion or the narrowing of the range of the indications.(2)Revision to Adverse Reactions. For example, addition or

22、removal of the adverse reaction information; revision of the frequency of the known adverse reactions, etc.(3)Addition of Contraindications or Warnings. For example, define a specific subgroup of population at a high risk (e.g. the patients with a certain disease, the drugs used in combination, or p

23、atients in a specific age group). These changes also include clarification on the risk management measures (e.g. ensuring the patients aware of the certain risks).(4)Revision to Precautions, Drug Overdose and Pharmacology and Toxicology to direct the safe clinical administration.(5)Revision to the d

24、rug use description, including the drug preparation and dispensing methods, so as to optimize the safe use of the drugs.(6) Others: Other class B major changes related to safe clinical use of drugs.(2) Medium changeChanges in safety information in the package insert in accordance with information an

25、nounced or approved by National Medical Products Administration are medium changes. In most cases, such changes are made by the marketing authorization holder to safety information in package insert or package label of chemical generic or biosimilar with reference to the information announced or app

26、roved by the NMPA. These changes are generally accompanied by revisions to package labeling. Such changes can be submitted to relevant administrative authorities for filing.Medium changes mainly include the following scenarios:1. Revise package insert in a unified manner according to the requirement

27、s of the NMPA Announcement.2. Changes in the safety information in package inserts of chemical generic or biosimilar by referring to the latest package insert of innovative drug and modified new drug approved by NMPA or the latest package insert of chemical generic or biosimilar listed in the Catalo

28、gue of Reference Preparations of Chemical Generic Drugs and marketed in China. Changes to safety information include:(1) Revise adverse reactions.(2) Revise contraindications or warnings.(3) Revise precautions, drug interactions, overdose, pharmacology and toxicology, etc.(4) Revise the instructions

29、 for administration, including medication preparation, dispensing method, etc., to optimize the safe use of drug.3. Revise the package labeling according to the approved package insert.(3)Minor ChangesThe changes in the administrative information in drug package inserts are the minor changes, which

30、refers to the change that do not change the safety and efficacy for the drug. These changes are generally accompanied by revisions to package labeling. The changes in this category are not required to be reviewed and approved, or filled. The marketing authorization holder should report it in the ann

31、ual report.The minor clinical changes include the following scenarios:1.Changes made according to the approval documents from National Medical Products Administration, such as changes in the drug name or the trade name, etc.2.Changes to name of marketing authorization holder and/or manufacturer or n

32、ame of address while not changing the actual entity or address (for example, the name is changed due to the merging without the changes to the main body).3.Update of the contact information of the marketing authorization holders (e.g. telephone number, website address).III.Clinical Change ProcedureF

33、or clinical changes on the marketed drugs, the classification of changes shall be determined by the marketing authorization holders according to the item of the changes, which shall be submitted, filed or annually reported according to the corresponding procedures. The classification of changes and

34、the main items of changes in the application form shall be clarified when the application is submitted.(1)Supplementary ApplicationFor the major clinical changes on the marketed drugs, the marketing authorization holders shall submit a supplementary application to National Medical Products Administr

35、ation before the changes implemented with the changes and the justification clarified, and the corresponding changes can made only after the approval obtained.The marketing authorization holders shall carry out the corresponding study based on the different scenarios of the changes; in general, the

36、different submission procedures are required depending on the different study contents used to support the Class A and B major changes. Specifically, the following procedures are included:1.Class A Major changes, there is a high impact and risk on the safe and effective use of the drugs, where a str

37、ict design and the support with the data from the implemented clinical trial and/or non-clinical research data are required in general. Before the clinical trials carried out, the marketing authorization holders shall first submit a supplementary application, and the clinical trials can only be carr

38、ied out after the approval obtained. When the marketing authorization holders completes the clinical trials and the clinical trial data can support the corresponding changes as assessed, the supplementary application may be submitted to National Medical Products Administration.2.Class B major change

39、s, there is a certain impact on the safe and effective use of the drugs, where the support with the pharmacovigilance (safety alert) data after drugs put into the market is required in general. The marketing authorization holders shall submit a supplementary application after a comprehensive evaluat

40、ion and demonstration on the pharmacovigilance data.(2)Filing ManagementModerate changes can be administrated by the means of filing because the basis of change has been reviewed and approved by the NMPA. The marketing authorization holders shall provide the relevant materials to support the filing.

41、(3)Annual ReportMinor changes generally do not affect the safe and effective use of drug, and can be managed as annual reports. The marketing authorization holder shall provide supporting documents for the annual report.(4)OthersWhen the clinical changes in various scenarios are submitted at the sam

42、e time, the supplemental application or filing shall be carried out according to the procedural requirements for the strictest type of the changes.IV.Technical Requirements on Clinical ChangesBefore the clinical changes submitted for the drug post-marketing, the marketing authorization holders shall

43、 evaluate the potential impact of the changes on the safety, efficacy, the safe and effective use in the clinical for the drug and other aspects at first. For those with the potential impacts, the relevant study shall be carried out in a targeted manner. Under the prerequisites where the study data

44、has been obtained and evaluated as the relevant changes can be supported, an application shall be submitted with the supporting technical data together. For those where there is no potential impact, the changes can be annually reported with the relevant supporting materials submitted.(1)Technical Co

45、nsideration on Change StudyWhether and to what extent the clinical changes need to be studied depends on the potential impact of changes on drug safety, efficacy and the safe and effective use in the clinical. It shall be analyzed on a case-by-case basis. The marketing authorization holders are enco

46、uraged to communicate with National Medical Products Administration in advance on the adequacy of clinical and/or non-clinical data needed to support the major changes.In general, for the Class A major change, the type and the scope of supportive non-clinical and/or clinical safety and efficacy stud

47、ies required shall be determined based on a comprehensive assessment on the different aspects, such as the benefits/risks related to changes, drug characteristics, approved indication characteristics (morbidity, mortality, acute or chronic diseases, accessibility of current disease treatment, etc.),

48、 safety factors, etc. For example, for the approved indications with the population expanded from the adults to the children, the necessary non-clinical and/or clinical studies shall be carried out in accordance with the requirements of relevant guidelines for pediatric medication studies, taking th

49、e factors such as indication characteristics, etc. into account; for the change to the dosage and administration, relevant studies shall be carried out, such as a comparative study on the safety and efficacy with the different dosages and administration before and after the change, on the basis of e

50、valuating the existing dose-related safety and efficacy data and ensuring the safety of the subjects; for the changes to existing risk management measures, the existing clinical trials, post-market observational studies or large-scale post-market safety data may be required to obtain the supporting

51、evidence, etc.For the Class B major changes, it is necessary to provide the pharmacovigilance reports (e.g., periodic safety update reports) to support changes in safety information related to package inserts in general.For medium changes, it usually requires the relevant announcements issued by NMP

52、A or the approved package insert for use of the same variety and other supporting materials.For minor changes, it is generally requires relevant supporting documents in the annual report. If not provided, it should be explained.The marketing authorization holders shall carry out the studies in a tar

53、geted manner based on the types and extents of the clinical changes with reference to the relevant pharmacological, toxicological and clinical technical guidelines issued by the State Drug Supervision and Administration Authorities. For example, when the marketing authorization holder intends to cha

54、nge the drug interaction information for the drug, the study shall be carried out in a targeted manner according to “Guidelines on Drug Interactions Study”.(2)Requirements on Changes Submission Dossier1.Major Changes(1) Class A Major ChangeThe content and the reason of the change.Summary of relevant

55、 studies on the changes. The main study methods used to evaluate the impact of the changes on the drug efficacy and/or the safety and the information on the completed studies shall be provided.Non-clinical research data and the necessary domestic and foreign literature related to the change.Drug cli

56、nical trial data related to the change, including the review data, clinical trial plans and protocols, statistical analysis plans, clinical study reports, etc.; the clinical testing method and the validation information shall be detailed in the clinical research report.The samples manuscripts of the

57、 package inserts and the packaging labels applied to change, package insert and package labeling attachments in drug approval letter, the revision clarification, and the comparison table before and after the revision.Pharmacovigilance plan, whether it is necessary to prepare and provide the relevant

58、 pharmacovigilance plan regarding to the changed contents and the study data.The above , and relevant materials can be written according to relevant module requirements in M4: Common Technical Document (CTD) for Registration Application of Human Drugs.(2)Class B Major ChangeThe content and the reason of the change.Clinical relevant supporting data (pharmacovigilance report, etc.) and statistical analysis results.Sample manuscripts of package inserts and packaging labels applied to change, package insert and packaging label attachments in drug approval letter,