mona.zhang – Accestra Consulting

Restructure of 2 Trillion RMB pharmaceutical market: Major Update of China National Reimbursement Drug List

mona.zhang — Thu, 22 Aug 2019 03:59:09 +0000

On August 20th, China State Medical Insurance Administration issued the 2019 version of the National Reimbursement Drug List (for Basic Medical Insurance, Work Injury Insurance and Maternity Insurance).

The general composition of the list is as follows:

The newly added drugs include the drugs listed in the National Essential Drug List, drugs to treat cancer and rare diseases, drugs for chronic diseases and pediatric drugs. In terms of the drugs that are removed from the previous 2017 version, they are mainly the drugs which the license was withdrew by the NMPA, low clinical value drugs, the drugs with obvious abuse and the drugs with better alternatives.

In addition, 128 drugs were included in the proposed negotiation list and to be negotiated about the price. The therapeutic fields of these drugs mainly involve cancer, rare diseases, hepatitis C, hepatitis B, and chronic diseases such as hypertension and diabetes. Most of them are innovative drugs approved by the China NMPA in recent years.

And there is another important adjustment issued together with the National Reimbursement Drug List: the local health bureau in China will no longer allowed to adjust the local reimbursement list. Which means, for pharmaceutical companies, if its product is not listed in the National List, it can no longer enter the medical insurance system through local bureau channels. The product can only be paid by patients themselves then, which pushes the pharmaceutical companies to reconsider their product strategy in the future.

The public release of the National Reimbursement Drug List was delayed by about one month comparing to the original working plan (see our previous news link https://www.accestra.com/2019/04/25/china-initiating-2019-health-insurance-drug-list-adjustment/). This also reflects the Chinese authority have a lot of considerations for the new version of the national list. After all, for a long time, Reimbursement Drug List has large impact on the pharmaceutical market. Taking Herceptin (trastuzumab) as an example, it enters into the Reimbursement Drug List in 2017 after the price negotiations with the price decline at 65%, but the sales growth in 2018 reached 259% instead. A dramatic change of China’s 2 trillion pharmaceutical market is foreseeable.

Questions and Answers on biosimilar development published by China CDE: Part II

mona.zhang — Sat, 10 Aug 2019 10:25:42 +0000

On July 31^st, China CDE has published 7 Questions and Answers on biosimilar development to industry on its website. It mentioned that these Q&As respond to the most-commonly-asked-questions from applicants, and these Q&As also describe CDE’s considerations and requirements.

Q4: Consideration in immunogenicity assessment

A4: Sponsors are encouraged to collect immunogenicity data in any clinical study, including human PK or PD studies.

The timing and duration of follow-up evaluation should be determined according to the immunogenic characteristics of different products. Factors such as the length of administration of the product, pharmacokinetics of the product, and the time course for the generation of immune responses should also be considered. It is recommended to discuss with CDE before initiating the study.

Sponsor should pay attention to any differences in human immune responses between proposed products and reference products, and evaluate the effect of the differences on effectiveness and safety.

Q5: How to determine the equivalence margins of a comparative clinical study for a biosimilar?

A5: In the comparative clinical study of biosimilars, it is necessary to select the rational ratio or difference as the effect size of primary study endpoints. The equivalence margin is generally estimated based on the confidence interval of the efficacy of the originator product, and is determined in combination with clinical significance. The efficacy of the originator product is usually based on the meta-analysis of the randomized control superiority study of the originator product and the standard treatment (or placebo). The selection of meta-analytical literature, the use of analytical results need to consider factors such as clinical practice, ethnic differences, and sample size feasibility of the target indications.

Q6: Consideration in extrapolation of clinical data across indications

A6: If comparative study demonstrates the proposed product is clinically similar to reference product, the applicant may seek licensure of the proposed product for one or more additional conditions of use for which the reference product is licensed. The extrapolation of indications needs to be considered on the basis of the characteristics of the products and the sufficiency of similarity research data.

The following issues should be addressed:

clinically relevant pathological mechanisms and/or related receptors, and the function and target are the same;
in the clinical comparison study, appropriate indications are selected, and the safety and immunogenicity are fully assessed.

The applicant would need to provide sufficient scientific justification for extrapolating clinical data to support a determination of biosimilarity for each condition of use for which licensure is sought.

Q7: Recommendations on package insert of biosimilar product

A7: The general principles for writing of biosimilar product package insert should be “not affect clinical use” and “facilitate post-marketing safety monitoring”.

It is recommended to add the header on the front page like ” [BIOSIMILAR PRODUCT’S PROPRIETARY NAME (XYZ mAb)] is biosimilar to [REFERENCE PRODUCT’S PROPRIETARY NAME (XYZ mAb)]”; and add the definition of a biosimilar product in the front page footer as: ” Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an NMPA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. The package insert of this product is consistent with the one of originator product.”

Clinical trial data in the package insert of biosimilar product should demonstrate effectiveness and safety rather than the similarities with reference product. in the package insert, the difference between the proprietary name of reference drug, the proprietary name of similar product and the proper name. When clinical studies of reference product is described, the reference product’s proper name instead of proprietary name should be used.

Questions and Answers on biosimilar development published by China CDE: Part I

mona.zhang — Thu, 08 Aug 2019 10:20:12 +0000

Q1: The scope of ‘biosimilars’

A1: ‘Biosimilars’ applies to the therapeutic recombinant protein products with a definite structure and function. The amino acid sequence of the proposed product should in principle be the same as the reference product. Host cells and expression systems similar to the reference product are recommended because different cell types can affect patterns of post-translational modifications, such as glycosylation.

If a different expression system comparing to the reference product is used, a sufficient CMC study is required to demonstrate that the expressed protein of proposed product has the same amino acid sequence, comparable higher order structure and post-translational modification, and biological activity; after comparison, if the degree and type of post-translational modification between the proposed product and reference product are found to be different, the potential impact on safety and efficacy must be demonstrated. If a new expression system is adopted for proposed product, it usually increases the difference in glycosylation patterns and new process-related impurities, and the impact on clinical immunogenicity should also be considered.

Q2: Approaches to developing a biosimilar

A2: The general idea of similar product development is to demonstrate similarity based on data directly comparing the proposed product with the reference product, and further to support its safety, efficacy and quality. A stepwise approach include the CMC, non-clinical, and clinical comparison studies.

After the CMC and non-clinical comparison studies finished, it is recommended that the sponsor have a pre-IND communication and with CDE to confirm the follow-up research content and research design. It is suggested that the PK study should be carried out in the clinical research stage. After completing the PK study, the communication with CDE is recommended. If PK study supports a demonstration of biosimilarity after preliminary assessment, the head-to-head comparative trial can be continued to prove the efficacy and safety.

Q3: How to choose reference product and the origin

A3: The originator biological product approved in China should be selected as the reference product. The reference product used in each stage of the whole development program should from the same origin.

Other suitable pathways may be considered for those that are not commercially available in China, but bridging comparison studies of reference products from different origins or comparative evidence for reference products from different origins should be provided, with a focus on the source of the drug substance.

Sponsor should, as far as practicable, select the originator biological product that has been approved for importation or clinical trial in China as a reference for clinical trials of biosimilars. For the safety of the subjects consideration, if the sponsor intends to select the originator product of the same enterprise but from the different origins as the reference, before the start of the clinical trial, the comparative data between the original products of different origins should be provided to CDE first, otherwise comparative research on the originator products of different origins should be carried out in accordance with the relevant technical guidelines published by China NMPA and information should be submitted to CDE as supplement application. After review and approval by CDE, the sponsor may use the reference product from a different origin for clinical trial use. However, the comparison research at various stages of development program should be conducted with the originator product from the same origin.

China enters the era of innovative drug

mona.zhang — Fri, 02 Aug 2019 07:05:04 +0000

The information published on China CDE public platform showed that there are 8 innovative drug (Class 1) IND applications accepted by CDE on the day Aug 1^st, 2019.

According to the new classification system for chemical drugs lunched by China former CFDA since 2016, Class 1 new drugs are defined as “innovative drugs that contain new chemical entities with clinical value and have never been marketed anywhere in the world”. The new classification system provides more incentives to China domestic companies to develop innovative drugs because of the favorable policies both for drug approval and hospital procurement.

Looking back at IND statistics published by CDE from Jan to Jul 2019, there are 57 IND applications of Class 1 new drugs got approved in total. So it is expected that the number of IND applications for the whole year of 2019 will be consistent with last year.

And just on Jul 31^st, the China Ministry of Science and Technology and the National Health Commission held a major press conference on China local innovative drugs development, and summarized the achievement of national project “Major New Drug Creation”, which is special project established early in 2008 to encourage the local development of innovative drugs. According to the information released at this press conference, 14 innovative drugs developed by China domestic pharmaceutical companies and supported by this project have been approved by China NMPA since 2017 (see below).

In addition to the guiding of innovative drug approval policy, the tremendous change of China’s drug procurement system has also led to the increasingly fierce price competition of generic drugs, that’s the reason why China domestic corporations are adjusting themselves to the innovative drug market. It can be seen that the number of Class 1 new drugs applications are increasing year by year, indicating China’s domestic pharmaceutical market are entering the era of drug innovation.

China NMPA published New DMF Requirement

mona.zhang — Thu, 18 Jul 2019 04:07:34 +0000

On 16 July 2019, the China NMPA issued the Announcement on Further Improving the Binding Review, Approval and Supervision of Drugs (Announcement No. 56, 2019).

This included updates to requirements for the filing and binding review of APIs, excipients, and pharmaceutical packaging materials.

With this new announcement, Announcement No. 146, 2017 will be invalidated.

What changes are being made to China DMF

According to Announcement No. 56, 2019, China continues to implement the “individual filing, binding review” way for APIs, excipients and pharmaceutical packaging materials, and the new adjustments include the following:

1. “If the APIs/excipients/pharmaceutical packaging materials is not able to be registered on the platform for special reasons, the information of APIs/excipients/pharmaceutical packaging materials is also allowed to submit together with the finished drug application dossier”.

Compared to the previous description in Announcement No. 146, 2017 “only the APIs, excipients and packaging materials for self-use or designed for specific finished drug holders, may submit the information together with the drug application dossier instead of the separated filing”, the filing of APIs/excipients/pharmaceutical packaging materials is no longer mandatory, which means the joint submission with the finished drug is generally acceptable.

2. The following conditions will apply to the DMF platform. to A filing number will be produced and an “Active” status granted;

APIs with the approval licenses and expiry date no earlier than November 27, 2017;
APIs completed for review, including the API transfer application reviewed by the provincial bureau in accordance with the NMPA No. 38 Notice, 2013;
Excipients and pharmaceutical packaging materials that have completed for review;
Excipients that have obtained approval licenses;
Pharmaceutical packaging materials with approval licenses and expiry date no earlier than August 10, 2016.

3. Add the case in which a separated review application is applicable: the APIs used for generics in which the same drugs are already approved on the market. For these APIs, it’s possible to bypass the binding review with finished drugs. A single application can be submitted for review and approval instead. After that, the status of the APIs will also be changed to “Active”;

4. Update the filing data requirements for excipients and pharmaceutical packaging materials;

5. A list of excipients is issued, including the names of certain flavors, essences, pigments, inorganic salts, pH regulators, and benzene free ink for printing which can waive the filing work to China NMPA ;

6. Clarify the time of annual report submission for APIs/excipients/packaging materials companies in Q1 of each year, and the basic content is given (the template of the annual report is still not available).

The new announcement came into effect on 15 August 2019.

China Drug Master File (DMF) VS US DMF

mona.zhang — Wed, 17 Jul 2019 14:37:38 +0000

China has implemented a separate filing and review regime with drug products since December 2017.

This was announced in the publication “Announcement on adjusting the review and approval system of drug substance, pharmaceutical excipients and pharmaceutical packaging materials (No. 146, 2017)” by CFDA (the new rule was published as Announcement No. 56, 2019).

The regime covers:

APIs,
Excipients,
Packaging materials.

The new filing system is referred to as the China Drug Master File (DMF) system.

While the current management system is more like the US DMF, there is still some significant differences between the two.

1- The scope

The FDA Drug Master File (DMF) is a voluntary submission of information to the FDA.

It is used to provide confidential, detailed information about the facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drug products.

It is not mandatory that manufacturers submit information to the FDA in a DMF.

But in China, the filing work is more forceful.

All the APIs (except the API of innovative drug), excipients (except the exemption list), and packaging materials need to be registered to CDE.

They will then be published on the CDE platform.

Only the APIs, excipients, and packaging materials for self-use or designed for specific finished drug holders can submit the information together with the drug application dossier instead of separate filing.

According to Announcement No. 146, 2017, in the follow-up Announcement No.56, 2019 the phrase “for special reason” is used to accept submission of APIs/excipients/packaging materials together with finished drugs ) .

In US, around 90% of the DMFs are API and Packaging Material DMF. Some non-pharmaceutical ingredients, like excipients, can also submit DMF. Generally, though, the CMC information of used excipients listed on the USP-NF will not be reviewed by FDA.

In China, the same filing rule applies to excipients as API and Packaging Material.

There is only one exemption list given of items that can waive the filing work to China NMPA:

The names of some flavors,
essences,
pigments,
certain inorganic salts,
pH regulators,
and benzene-free ink for printing.

2- Types of DMF

US FDA

Type 1 Manufacturing site, facilities, operating procedures, and personnel (no longer applicable.
Type 2 Drub Substance, Drug Substance Intermediate, and Material used in their preparation, or Drug Product.
Typ 3 Packaging Material.
Typ 4 Excipient, Colorant, Flavor, Essence, or Material Used in their Preparation.
Typ 5 FDA Accepted Reference Information.

China NMPA

Drug Substance.
Excipient, Colorant, Flavor, Essence, or Material used in their preparation.
Packaging material.

*There is no number given to each DMF category.

3- Submission pathway

In the United States and China, the DMFs for drug substances should both be prepared in the format of CTD M4Q.

From May 5, 2018, new DMFs other than Type III DMFs, as well as all documents submitted to existing DMFs other than Type III DMFs, must be submitted using the Electronic Common Technical Document (eCTD) to FDA.

For Type III DMFs, this eCTD requirement came into effect on May 5, 2020.

In China, the eCTD is not enforced yet so the whole dossier must be submitted in CD form and paper formats still.

4- Fees

In US, under the Generic Drug User Fee Amendments of 2012, DMF holders of Type II API are required to pay a DMF fee when first authorizing the reference of their DMF in a generic application.

In China it’s similar, the registration fee for API in the linked review process is retained while the filing of excipients and packaging materials is free of charge now.

But, unlike US, the fee will still be changed if API DMFs are used to support NDAs in China.

5- Review of DMFs

In the US, after receipt, the original DMF undergoes an administrative review to determine whether it is has been sufficiently completed.

Elements checked during the process are administration-related, including:

The information of holder,
Manufacturing facility,
Contact,
Agent,
Statement of Commitment.

If the DMF is acceptable from an administrative point of view, an Acknowledgement Letter will be issued, notifying the holder of the DMF number.

Only Type II DMFs to support ANDAs under GDUFA that have passed the Administrative review (have an active status) and have had the user fee paid is placed in the queue for a “Completeness Assessment”.

In China, the review of all DMFs begins with the “Completeness Assessment”, which means the DMF number will only be issued after CDE makes sure the holder submitted all required information (both administrative and technical).

The linked technical review procedure after the application of the finished drug is generally the same in China and US.

Although, China CDE seems to have much stricter standards in the technical review process, especially:

Impurity research,
Quality control of starting materials,
The package material information of the APIs.

The close cooperation and timely communication between DMF holders and drug product manufacturers are important to pass the technical review in China.

6- The different meaning of the status mark

In the US the status of DMF conveys no information about whether it has been reviewed for technical content or whether it has undergone a Completeness Assessment.

In China, all the DMF published with a DMF number indicates the Completeness Assessment is done, and the status shows the technical review progress.

US FDA

A: Active. This means that the DMF was found acceptable for filing, administratively, and has not been closed.
I: Inactive. This means a DMF that has been closed either by the holder or by the FDA.

CHINA NMPA

A: Active. This means that the APIs, excipients or packaging materials are approved to be used in finished drugs.
I: Inactive. This means the MDF was found acceptable for filing after complete assessment, but the technical linked review with finished drugs is not completed yet.
A#: Active. This means that the APIs, excipients or packaging materials were approved to be used in finished drugs, but there are technical amendments that may significantly affect the quality, and the amendments are not reviewed yet.
A*: Active. This means that the APIs, excipients or packaging materials are registered and reviewed solely, but the technical linked review with finished drugs is not completed yet.

7- Confidentiality

In the US, there is a DMF list covering all DMF information and an Available for Reference List containing Type II DMFs that have passed the Completeness Assessment and are available for reference by ANDAs under GDUFA.

In China, there is no such list but all the information will be available on the China CDE website platform:

DMF filing number,
APIs/Excipients/Packaging Material name,
Company name,
Company address,
Packing specification,
Announcement date and approval status.

Like the US, there are no “open” or “closed” parts of DMFs filed in China as well.

If the APIs/Excipients/Packaging Material hasn’t been filed to CDE already, the DMF holder only needs to send the LoA to drug product manufacturers and the linked review can begin.

8- Annual report

In China, there is also an annual report obligation according to the No. 146 “Announcement” but no template so far.

It’s mentioned that DMF holders should submit the annual report, including the amendment summary and also the authorized drug product/company information, in Q1 of each year.

2018 Drug Review and Approval Report of China CDE (Part III- Traditional Chinese Medicine)

mona.zhang — Fri, 12 Jul 2019 06:25:40 +0000

On 2^nd July, 2019, China CDE-NMPA published the 2018 working Report, summarizing the drug review and approval statistic data in the past year.

See below for the details.

8- Statistic of Traditional Chinese Medicine – Overall

Figure 17. Traditional Chinese medicine application total number from 2015 to 2018

Figure 18. Traditional Chinese medicine application statistics in 2018

Figure 19. Number of completed traditional Chinese medicine review by CDE in 2018

Table 3 Detailed information of completed traditional Chinese medicine review by CDE in 2018
Note: “other” refers: 1) the applicant withdrawal the application, 2) Supplementary information is required from applicant after the review, 3) the application directly submitted to Drug Registration Management Bureau of NMPA instead of CDE, 4) the combination application of medical device, 5) API/excipient/package material application for linked review procedure.

9- Statistic of Traditional Chinese Medicine -IND

Figure 20. Approved number of traditional Chinese medicine IND application from 2015 to 2018

Figure 21. Indication distribution of traditional Chinese medicine IND approved in 2018

10- Statistic of Traditional Chinese Medicine -NDA

Figure 22. Approved number of traditional Chinese medicine NDA application from 2015 to 2018

2018 Drug Review and Approval Report of China CDE (Part II-Biological products)

mona.zhang — Fri, 12 Jul 2019 05:17:36 +0000

On 2^nd July, 2019, China CDE-NMPA published the 2018 working Report, summarizing the drug review and approval statistic data in the past year.

See below for the details.

5- Statistic of Biological Products – Overall

Figure 11. Biological products application total number from 2015 to 2018

Figure 12. Biological products application statistics in 2018

Figure 13. Number of completed biological products reviewed by CDE in 2018

Table 2 Detailed information of completed biological products review by CDE in 2018
Note: “other” refers: 1) the applicant withdrawal the application, 2) Supplementary information is required from applicant after the review, 3) the application directly submitted to Drug Registration Management Bureau of NMPA instead of CDE, 4) the combination application of medical device, 5) API/excipient/package material application for linked review procedure.

6- Statistic of Biological Products -IND

Figure 14. Approved number of biological products IND application from 2015 to 2018

Figure 15. Therapeutic areas distribution of biological products IND applications in 2018

7- Statistic of Biological Products -NDA

Figure 16. Approved number of biological products NDA application from 2015 to 2018

K-REACH: Pre-registration window opens for another two weeks

mona.zhang — Thu, 11 Jul 2019 07:24:19 +0000

The Ministry of Environment (MoE) of South Korea issued a notice on Jul 5^th that the pre-registration system will re-open to applicants from Jul 8^th to Jul 19^th to allow the industry to update their pre-registration information. At the same time, companies can also submit new pre-registrations in this period.

According to the requirement of “The Act on Registration and Evaluation of Chemicals of Korea”, i.e. “K-REACH”, all existing chemical substances manufactured or imported at ≥ 1 t/a in Korea shall submit pre-registration before Jun 30^th, 2019 to obtain the grace period for standard registration. And because many companies are rushing to submit pre-registration right before the deadline, there are quite a few error information submitted in the pre-registration system. That’s the reason why Korea MoE made this decision to re-open the system for another two weeks. However, the company which missed the pre-registration deadline can take this opportunity to submit its chemical information. The registration procedure is just like the original one.

2018 Drug Review and Approval Report of China CDE (Part I-Chemical Drug)

mona.zhang — Wed, 10 Jul 2019 10:27:04 +0000

On 2^nd July, 2019, China CDE-NMPA published the 2018 working Report, summarizing the drug review and approval statistic data in the past year.

See below for the details.

1- Overall Statistic

It can be seen from Figure 1, 2, 3 and 4, the backlog of drug applications in CDE has been greatly alleviated: the application number waiting in line has dropped from nearly 22,000 at the peak of year 2015 to 3,440 in year 2018; the review completion rate for all types of drug applications in 2018 has exceeded 90%.

Figure 1. Drug application total number from 2015 to 2018

Figure 2. Total number of completed drug review by CDE from 2015 to 2018
(By different drug category)

Figure 3. Total number of completed drug review by CDE from 2015 to 2018
(By different application type)

Figure 4. The drug application number waiting in line for CDE review

2- Statistic of Chemical Drugs -Overall

Figure 5. Chemical drug application statistics from 2015 to 2018

Figure 6. Number of completed chemical drug review by CDE in 2018

Table 1 Detailed information of completed chemical drug review by CDE in 2018

*Note: “other” refers: 1) the applicant withdrawal the application, 2) Supplementary information is required from applicant after the review, 3) the application directly submitted to Drug Registration Management Bureau of NMPA instead of CDE, 4) the combination application of medical device, 5) API/excipient/package material application for linked review procedure.

3- Statistic of Chemical Drugs -IND

Figure 7. Therapeutic areas distribution of chemical drugs IND applications in 2018

Figure 8. Indication distribution of innovative chemical drugs IND approved in 2018

4- Statistic of Chemical Drugs -NDA

Figure 9. Chemical drug NDA applications from 2015 to 2018

Figure 10. Approved NDA number from 2015 to 2018 (chemical drugs)