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제목 2016년 상반기 중국 의약품 규제의 큰 변화 (Highlights of Regulatory News in China) 등록일 2016.09.23 11:42
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Highlights of Regulatory News in China

Notice of Basic Principles for Priority Review and Approval for Pediatric Drug Application for Urgent Unmet Medical Needs and the first batch of priority review varieties(29th Jan. 2016, CDE, notice)

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To implement the spirit from CFDA "Notice on review and approval of drug registration policy " (2015 No. 230) , CDE released a notice of basic principles for priority review and approval for pediatric drug application for urgent unmet medical needs and the first batch of priority review varieties on 29 January 2016 . The notice include two appendixes, the first one is basic principles for priority review and approval for pediatric drug application for urgent unmet medical needs, the other is the priority review varieties (first batch). Granted priority review varieties will be under arrangement plan for review.

First of all, the notice states three basic principles apply to the evaluation of applications of pediatric drug products in urgent unmet medical needs for priority review:

  1. 1. Variety of the pediatric drug has been newly added. This kind of drug should concerning life-threatening diseases or for diseases affecting the growth and development of children, with no effective treatment drugs or therapeutic methods currently available; or can show significant treatment advantages compared with existing therapeutic drug.
  2. 2. Varity of changing dosage form or newly added strength. This kind of drug should existing package inserts already have clear message of “administration and dosage for children” and whose existing dosage form or strength is not appropriate to children yet the newly added dosage form or strength is applicable to children.
  3. 3. For pediatric drugs that are currently in the shortage of market supply, priority review and approval should be granted.


For the variety that compliance to the principle 2 and 3, if multiple manufacturers of apply at the same time, priority review shall be granted to the first applicant according to the queuing of applications by the sequence of the time of submission; if an application does not meet requirements after the review, its priority will be disqualified, and the subsequent application of the same product may supplement and replace based on the order in queue. Also, the notice list the catalog of the first batch for priority review and approval for pediatric drug, which involve a total of 5 varieties, one of these is imported drug, the others are all domestic drugs that are either the first application or the first generic drug application. Following the announcement of a month later, CFDA released “Opinions on Implementing Priority Review and Approval and Resolving the Backlog of Drug Registration Applications”, which emphasized the priority review and approval would be used for pediatric drugs again.

Source : http://www.cde.org.cn/news.do?method=viewInfoCommon&id=313519

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Announcement of the CFDA on Relevant Matters of Drug Registration Testing(No.36, 2016) Important Notice of National Institutes for Food and Drug Control on Drug Registration Test Matters(2016/2/5,CFDA,Notice;2016/2/22,NIFDC,Important Notice)

CFDA released the “Announcement of the CFDA on Relevant Matters of Drug Registration Testing” on Feb 5, 2016. In this announcement, drug registration applicants should deliver the drug registration test dossiers, samples and related reference standard to relevant drug test institutes in six months from receiving “Test Notice” issued by acceptance department. If necessary, applicants should deliver the supplemental dossiers, samples and reference standards to relevant drug test institutes in four months from receiving “Deficiency Letter” issued by drug test institutes. CDE will not approve the application based on situation description issued by drug test institutes if related dossiers, samples and reference standards are not delivered in a timely manner for above situations. 

Source : http://www.sfda.gov.cn/WS01/CL0087/144101.html

NIFDC released an important notice about drug registration test matters on Feb 22, 2016, further emphasized the new requirements on delivery time for imported drug registration test. Once exceeded delivery deadline, relevant drug test institutes won’t accept samples and dossiers and execute based on the principle of announcement exactly.

Source : http://www.nifdc.org.cn/CL0832/7826.html

Notice of the state on the import of drugs in accordance with the relevant matters of the Pharmacopoeia of the people's Republic of China Notice on the provision of microbiological validation data for the 2015 edition of the Chinese Pharmacopoeia

CFDA issued the notice on related matters that the imported drugs should comply with Pharmacopoeia of the People’s Republic of China ([2016] No.18) on February 19th 2016 and has emphasized the requirements for port inspection of imported drugs: the imported drugs should be tested according to the related requirements of Pharmacopoeia 2015 in the port inspection. The products included in Pharmacopoeia 2015 should also comply with the related requirements of Pharmacopoeia 2015 besides the registration specification of the imported drugs. The products not included in Pharmacopoeia 2015 should comply with the related general requirements. The products have already done the supplementary submission but not been approved, port inspection should comply with the old specifications.

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Shanghai Institute for Drug Control issued the notice on providing the validation documents of sterile and microbial limit test according to Chinese Pharmacopeia on Jan 11th 2016, due to the sterile and microbial limit test are revised, the old validation documents do not comply with new Pharmacopeia, so the import drugs should follow the new test method and its validation, also provide the documents of test results and validation during port inspection.
Guangzhou Institute for Drug Control issued the notice on providing the validation documents of sterile and microbial limit test according to Chinese Pharmacopeia on February 2nd 2016, due to the sterile and microbial limit test are revised, the old validation documents do not comply with new Pharmacopeia, so the import drugs should follow the new test method and its validation, also provide the documents of test results and validation during port inspection.
Beijing Institute for Drug Control issued the notice on providing the validation documents of microbial limit test according to Chinese Pharmacopeia on Mar 1st 2016, due to the sterile and microbial limit test are revised, the old validation documents do not comply with new Pharmacopeia, so the import drugs should follow the new test method and its validation, also provide the documents of test results and validation during port inspection. 

Source : http://www.sda.gov.cn/WS01/CL0844/144720.html

CFDA Opinion on Implementing Priority Review and Approval and Resolving the Backlog of Drug Registration Applications Notice about submitting ‘Implementing Priority Review and Approval Application Form’ (2016/2/26,CFDA,Nitoce;2016/2/29,CDE,Notice)

For the implementation of Opinions of State Council on Review and Approval of Drug & Medical Devices (GUO FA [2015] No. 44), Opinion on Implementing Priority Review and Approval and Resolving the Backlog of Drug Registration Applications (hereinafter referred to as “the Opinion”) was issued by CFDA on Feb 26th, 2016, which gives the priority review and approval for the registration applications of drugs with significant clinical value, ability to prevention and treatment of major diseases and significant clinical advantages.

According to the Opinion, the scope of priority review and approval covers the following 17 conditions fell under the under-mentioned 3 categories:

  1. (I) Drug with significant clinical value satisfying following conditions:
    1. 1. Innovative medicines not yet registered in domestic and overseas market
    2. 2. Innovative new drugs with manufacturing site transferred to China
    3. 3. Drugs with advanced formulation technologies, or innovative therapies, or significant clinical advantage
    4. 4. Clinical trial application for drugs whose originator patent will be expired within 3 years; marketing application for drugs whose originator patent will be expired within 1 year.
    5. 5. New drug CTA that applicant simultaneously filed the same application and got permitted to conduct clinical trial in EU or US; New drug NDA manufactured the product in China, which is undergoing simultaneous filing in EU or US and passed GMP/GCP inspection by EMA/FDA (products manufactured with same production line)
    6. 6. Traditional Chinese Medicine with clear clinical therapeutic purpose in prevention and treatment for major diseases.
    7. 7. New drug listed in the National Major Science and Technology Projects and National Key R&D Plan.
  2. (II) For below diseases prevention and treatment and can show significant clinical advantage
    1. 1. AIDS
    2. 2. TB
    3. 3. Hepatitis
    4. 4. Rare disease
    5. 5. Malignant tumor
    6. 6. Pediatric drug
    7. 7. Diseases with high incidence or unique in elderly people
  3. (III) Others
    1. 1. Post approval manufacturing process change of a generic drug with the aim to meet generic drug quality consistency compared with reference products
    2. 2. For ANDAs which had been listed in CFDA GCP self-inspection Notice (CFDA notice No. 117 in 2015), if the applicant withdraw the application and then complete research to show quality and efficacy consistency compared with reference product, the later ANDA submission will be eligible for priority review.
    3. 3. Urgent unmet medical needs and drugs in shortage. The List should be provided by NHFPC and Ministry of Industry and Information Technology. The list should also be reviewed by CDE and related agencies/ experts invited by CDE.

Simultaneously, the Opinion specifies the definite procedures of priority review and approval and corresponding timeframe. According to the Opinion, the procedures of priority review and approval includes application, review and confirmation, CDE review, transfer to CFDA and approval. Corresponding timeframes are specified for the following four steps, which includes review and confirmation of application of priority review and approval, initiation of technical review, supplementation of dossiers and on-site inspection. Besides, the Opinion also limits the review period of “three-in-one” report, which is to submit to CFDA for approval within 8 days; and the approval period, which is to make CFDA to decide approval or disapproval within 10 days upon the reception of dossier submitted by CDE. For enhancement of communication, the Opinion defines the communication opportunities involved before or after the procedures of priority review and approval and requires the establishment of meeting mechanism for communication with applicants and online consulting platform by CDE, encouraging and facilitating communication during the IND application, NDA application as well as the priority review and approval of innovative drug with major clinical significance to the unsatisfied clinical needs. Additionally, the Opinion shows that for the applications of new drugs used for treatment of severe life-threatening diseases without effective treatment, or the applications of new drugs with significant value to meet medical needs, a conditional approval before completion of Phase III study could be allowed. For imported pediatric drugs in clinical needs and already marketed in the United States, the European Union and neighboring regions of China, relevant clinical trial data completed overseas may be used for the drug registration applications in China. 

Source : http://www.sda.gov.cn/WS01/CL0844/145260.html 
http://www.cde.org.cn/news.do?method=largeInfo&id=313524

CFDA Announcement on the Release of Work Plan for the Reform of Chemical Drug Registration Classification(4th Mar. 2016, CFDA, Final)

China Food and Drug Administration (CFDA) has formulated the Work Plan for the Reform of Chemical Drug Registration Classification and hereby promulgates the Plan since 4th Mar. 2016 after the approval of the State Council. Where inconsistencies exist between the Drug Registration Regulation and this Work Plan, the requirement of this Work Plan shall prevail. 

The new classification of chemical drugs includes the following five categories:

Registration
classification

Classification
explanations

Conditions

1Innovative drugs not marketed in and outside ChinaDrug substances and their drug products containing new compounds with definite structure and pharmacological actions, and possessing clinical value.
2Improved new drugs not marketed in and outside China2.1 Drug substances and their drug products containing optical isomers with known active ingredients made through such methods as resolution or synthesis, or esterification of known active ingredients, or saltification of known active ingredients (including salts containing hydrogen bond or coordinate bond), or the alteration of the acid radicals, basic groups or metal elements, or the formation of other non-covalent bond derivatives (complex, chelate or clathrate) and possessing significant clinical advantages
2.2 Drug products applying for new dosage forms containing known active ingredients (including new administration systems), new formulation processes and new routes of administration and possessing significant clinical advantages.
2.3 New compound products containing known active ingredients and possessing significant clinical advantages.
2.4 Drug products applying for new indications containing known active ingredients
3Generic drugs imitating originator drugs that are marketed overseas yet not marketed in ChinaDrug substances and their preparations possessing the same active ingredients, dosage forms, strength, indications, routes of administration and dosage and method of administration with original drugs.
4Generic drugs imitating originator drugs that have already been marketed in ChinaDrug substances and their drug products with possessing the same active ingredients, dosage forms, strength, indications, routes of administration and dosage and method of administration with original drugs.
5Overseas-marketed drugs apply for marketing in China5.1 Overseas-marketed originator drugs (including drug substances and their drug products) apply for marketing in China
5.2 Overseas-marketed non-originator drugs (including drug substances and their drug products) apply for marketing in China

The new category 3 in new chemical drug in original classification corresponds to category 3 in new classification, but belongs to generic drug range. While compared to the draft for comments, oversea-marketed drugs of category 5 do not belong to generic drug range any more, moreover they are further divided into 2 sub-categories based on whether they are originators. In the relevant requirements of registration management in this new work plan, the application procedure has been stipulated for drugs in new classification; new drugs (category 1 and 2) are subject to a monitoring period of 3 to 5 years. In addition, drug approval numbers issued according to new registration classification (Import Drug License/ Pharmaceutical Product License) for registration applications shall have the same effect with the drug approval numbers (Import Drug License/ Pharmaceutical Product License) issued according to the original registration classification for registration applications. CFDA interpreted the related issues regarding the work plan on 16th Mar. 2016. Both “innovation”, i.e. a structure of matter “new to everyone”, and clinical value are emphasized for innovative drugs; on the other hand, “superiority” is emphasized for improved drugs, i.e. with significant clinical advantages over the existing drugs; for generic drugs, “consistency” is the key, i.e. they must reference the originator drugs and be consistent with the originator drugs in quality and efficacy.

Source : http://www.sfda.gov.cn/WS01/CL0051/146140.html 
http://www.sfda.gov.cn/WS01/CL1297/147302.html

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The General Office of the State Council issue Opinion on the Implementation of Consistency Evaluation for the Quality and Efficacy of Generic Drugs(2016/03/05, General Office of the State Council, Final Edition)

The General Office of the State Council issued a new policy, Opinion on the Implementation of Consistency Evaluation for the Quality and Efficacy of Generic Drugs, on March 5 2016, to deploy quality and efficacy consistency evaluation relevant work for approved generic drugs.

This Opinion requires:
For generic drugs approved before the implementation of new registration classification of chemical drugs, consistency evaluation shall be conducted if any of them was approved without consistency evaluation for the quality and efficacy with brand-name drugs. Consistency evaluation shall be completed by the end of 2018 for chemical generic drugs (with oral solid forms) that were approved before October 1, 2007 and have also been listed in the National Catalogue of Essential Medicines (2012 edition). Different with draft version, in the final version, of which, for products that need to complete clinical efficacy trials and products with special circumstances, the consistency evaluation should be completed before the end of 2021, otherwise their reregistration will not be granted.

This Opinion emphasis:
Drug manufacturers are the entities for the consistency evaluation and shall take the initiative to select and purchase reference drugs and conduct relevant studies to ensure quality and efficiency consistency with reference products. For domestic drug manufacturers, if their drugs have already been marketed in European Union, the United States or Japan, they may use the dossier for overseas registration applications as the basis and submit the marketing application in accordance with the new registration classification of chemical drugs. Consistency evaluation will be deemed as passed once the drug is approved by the CFDA for marketing. Drugs manufactured using the same production line in China and approved for marketing in the European Union, the United States and Japan shall be deemed as passed the consistency evaluation.
The Opinion also raises many policy measures to encourage manufacturers to conduct consistency evaluation.
Afterwards, in order to regulate the work of quality and efficacy consistency evaluation of generic 6 drugs, the CFDA released Technical Guideline for Selection and Determination of Reference Products for Common Oral Dosage Form Drug Formulations; Technical Guidelines for Measurement and Comparison of Dissolution Curve of Common Oral Dosage Form Drug Formulations; andTechnical Guidelines for Human Bioequivalence Study of Chemical Generic Drugs with Pharmacokinetic Parameters as Appraisal End Points on March 18 2016. 

Source : http://www.sda.gov.cn/WS01/CL0051/146201.html

CFDA’s Notice regarding publication of Guidelines for Pediatric Drug Clinical Trial (Order 48, 2016) (2016/03/07, CFDA, Notice)

CFDA issued the notice on related matters that the imported drugs should comply with In order to formulate and guide the pediatric drug clinical trial in China, CFDA organized CDE to draft for public consideration on Aug. 4, 2015 and published formal guideline on March 7, 2016. Guidelines for Pediatric Drug Clinical Trial elaborate 8 perspectives, separate as “Overview, Ethical Considerations, Data and Safety Monitoring, Subjects Age Groups, Time Points to Initiate Pediatric Drug Clinical Trials, Designing Pediatric Drug Clinical Trials, Choosing Dosage Forms for Pediatric Drugs, Clinical Trials for Rare Pediatric Diseases”. This guideline is applicable to the new drugs clinical trials which are developed for pediatric population in China (including addition of pediatric indications for the marketed drugs). When implementing these guidelines, the requirements of the Good Clinical Practice (GCP), the International Conference on Harmonization (ICH) and other related domestic and overseas guidelines should be taken into account as well. 

Source : http://www.sfda.gov.cn/WS01/CL0087/146408.html

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Application Document Requirements based on New Chemical Drug Registration Classification (Trial), 04-May-2016

CFDA issued and implemented the guidance on May 4, 2016 to instruct applicants to prepare the required documents based on new chemical drug classification released on Mar 6, 2016. This is one of the measures to implement the Reform Work Plan. This document contains the check list of application documents, explanations, and writing guide for registration Class 1, 2, 3, 5.1 in Section 1, Class 4 and Class 5.2 in Section 2.This report is about on section 1.There are total 34 document items involved in this new released guidance. Please refer to the annex, the items with * are the new added ones and marked in blue. These are some of the aspects for added new items: 1.The most challenge new added item could be the item 4 “Self-evaluation reports, self-inspection reports on research reports”. According to the explanation in the context, applicants are required to establish a scientific committee to review product research and development process and results, to make sure the data is scientific, completed and integrity. But there is no definition for “scientific committee” , no information about its composition. 2.New added item no. 5, 33,34 would not be the issues to MNCs; 3.New item 29 Data management plan and statistical analysis plan may not be available at the time of first IND submission; The aspects of Tabulated Summaries of Main Study Data

  1. 1.For the tabulated summary of CMC part, table 1-3 need to be drafted individually but not complicated; annex 1 &2 are for batch analysis data which are similar to the ones in CTD documents, but Chinese HA ask for more information such as the process, equipment and critical quality data;
  2. 2.For the tabulated summary of pe-clinical part, the required tables are similar but China HA ask for more information than CTD format documents, such as information of project leader, status of GLP, batch no. for the samples, how to prepare the sample solution, the drug concentration etc.


For the items with same or similar names in current and past versions:
More information is asked by China HA for these items especial for CMC part. The overall comparison results can be concluded between new guidance vs the previous one:

  1. 1. The requirements are set separately for IND/NDA (section 1) and generics (section 2) in this guidance, while in the past they were covered by one document;
  2. 2. This structure of the guidance looks not so complicated for a lot of requirements in detail are asked to refer to amount of individual technical guidelines, and the guidelines in ChP. While in the past, all requirements are almost within one piece of the document;
  3. 3. Summary tables are formally required for pre-clinical, CMC and clinical researches, the format and/or content are provided by this guidance;
  4. 4. Now the full package of the submission will be composed of application forms plus 5 volumes (Summary part, tabulated summaries on main researches, CMC part, pre-clinical part, clinical part); in the past, there were 4volumes for summary, CMC, pre-clinical and clinical part;
  5. 5. There are the document requirements for MAH accordingly;
  6. 6. More detail technical information is needed on pre-clinical, CMC and clinical part than before;
  7. 7. HA agreed to accept the entire ICH CTD format dossiers for all imported originator drugs if it is approved somewhere in the world, with the summary part defined by this document as well;
  8. 8. There is no minimal case number required for clinical trials in this guidance.
  9. 9. HA doesn’t recognize which are the necessary items for IND or NDA this time.

In conclusion, HA intends to use this document to guide chemical drug applications in China and for long time to guide the high quality drug development. Although CFDA ask for more detail information than ICH CTD at some points, the entire outline of the package still looks similar. And they now can accept ICH CTD format documents for 5.1 products, while in the past, ICH CTD was recommended to submit for domestic and imported generics only. Although it is not a precise guide book to applicants, China HA still delivery the strong message to encourage innovation, to improve the drug and evaluation quality. 

Source : Application Document Requirements for New Chemical Drug Registration Classification

Annex
  1. (I) Summary
    1. 1. Name of drug
    2. 2. Approval documents
    3. 2.1 Relevant approval documents for Category 1, 2 and 3 of registration classification (such as administrative certificate of the company, GMP certicicate, GLP certificate etc )
    4. 2.2 Relevant approval documents for Category 5.1 of registration classification (such as CPP, legalized authorization letter in origin, non-infringement statement etc.)
    5. 3.Objectives and justifications of the application
    6. *4. Self-evaluation reports, self-inspection reports on research reports
    7. *5. Information of marketing authorization holder (MAH)
    8. *6. Informaiton of originator product (if applicable)
    9. 7. Drug package insert, drafting explanations and relevant reference literatures
    10. 8. Sample draft of package and label design
  2. (II)Tabulated Summaries of Main Study Data
    1. *9. Tabulated Summaries of pharmaceutical study data
    2. *10. Tabulated Summaries of nonclinical study data
    3. *11. Tabulated Summaries of clinical study data
  3. (III) Pharmaceutical Study Data
    1. 12. (3.2S) For drug substance
    2. 13. (3.2P) For drug product
  4. (IV) Nonclinical Study Data
    1. 14. overview of nonclinical research data.
    2. 15. Main pharmacodynamic study data and literature data.
    3. 16. Safety pharmacology study data and literature data.
    4. 17. Single-dose toxicity study data and literature data.
    5. 18. Repeated dose toxicity study data and literature data.
    6. 19. Genetic toxicity study data and literature data.
    7. 20. Reproductive toxicity study data and literature data.
    8. 21. Carcinogenicity study data and literature data.
    9. 22. Dependence study data and literature data.
    10. 23. Data and literature data of special safety studies including allergy (regional, full-body and phototoxicity) and hemolytic and regional (blood vessel, skin, mucosa, muscle, etc.) irritation studies
    11. 24. Other safety study data and literature data.
    12. 25. Nonclinical pharmacokinetic study data and literature data.
    13. 26. Data of studies and literature data on the efficacy, toxicity and pharmacokinetic interactions of multiple ingredients of compound preparations.
  5. (V) Clinical Study Data
    1. 27. overview of clinical studies.
    2. 28. Clinical study plan and protocol.
    3. *29. Data management plan and statistical analysis plan.
    4. 30. Clinical investigator’s brochure.
    5. 31. Sample draft of informed consent and approval of ethical committee; review report of scientific committee.
    6. 32. Clinical study reports.
    7. *33. Electronic files of clinical study database (original database, derivative analysis database and the document of variable explanations).
    8. *34. Data management report and statistical analysis report.

CFDA Notice on Record-Filing and Recommendation Procedures for the Reference Products Used in the Quality and Efficacy Consistency Evaluation of Generic Drugs (2016/05/20, 2016 Notice No. 99)

This Record-Filing and Recommendation Procedures for the Reference Products Used in the Quality and Efficacy Consistency Evaluation of Generic Drugs (CFDA 2016 Notice No.99) is formulated to implement the tasks and requirements of the Opinions on the Implementation of Consistency Evaluation for the Quality and Efficacy of Generic Drugs (Guo Ban Fa [2016] No. 8) and further clarify the process for the selection of reference products.

1. The Notice defines the entities of reference products record-filing and recommendation procedures and their respective reference product selection pathways. Drug manufacturers, industry associations, original drug manufacturers and manufacturers of the same type of international recognized drugs act as applicants or recommending entities in selecting reference products through such approach as record-filing, recommendation and application in accordance with the Guiding Principles for the Selection and Determination of Reference Products for Ordinary Oral Solid Dosage Forms (CFDA 2016 Notice No.61) .
2. The Notice clarifies that manufacturers of original drugs or the same type of drugs with the international recognition can voluntarily apply their products as reference products and specifies both imported and<