Samantha Beneke – Accestra Consulting

New Guideline for Drug Master Filing (DMF) in China

Samantha Beneke — Thu, 28 Oct 2021 05:06:37 +0000

China DMF Inactive Number by CDE. Complete but not approved.

China DMF Active Number by CDE. Activated/Approved.

For Drug master filing (DMF) in China, there is a new guideline released by China’s NMPA (Formerly CFDA) in 2019 for the scope of active pharmaceutical ingredients (APIs), excipients and packaging materials. Similar to the systems of US DMF, Canadian DMF and EU CEP, the new guideline helps protect manufacturers from disclosing confidential information to their distributors and specifies a more direct route to communicating with China health authorities, e.g., Center for drug evaluation (CDE).

Applicants who already have US DMF, Canadian DMF and EU CEP will benefit from overlapping data, although they’re differences in local data requirements.

The new DMF filing system in China helps protect the supplier from disclosing unnecessary confidential data to the drug applicant which enables a direct path to exchange communication with China’s health authority namely Centre for drug evaluation (CDE).

What are inactive and active DMF numbers in China?

The applicant prepares China DMF dossier and file application to CDE for completeness review for allocation of DMF filing number with a status of “I” for “Inactive”.

Upon drug product registration, for example ANDA or new drug application; CDE will refer to the inactive DMF filing number and review the DMF dossier together with the drug dossier and then activate the DMF filing number shown as “A” for active. The “I” and “A” status will officially display on CDE database.

Steps to File DMF in China

The 7 steps for DMF filing process to obtain inactive and active DMF filing number is displayed in the flow graph above and correspondingly explained below:

The general steps for DMF filing include obtaining inactive and active filing number described below:
Step 1: Check material completeness to identify if the materials are generally complete.
Step 2: Conduct a more detailed data-gap analysis, providing guidance on supplementing missing data according to China CDE requirements.
Step 3: Prepare a DMF dossier in Chinese and file to CDE.
Step 4: CDE reviews dossier for completeness and feedback in 1 to 2 weeks.
Step 5: CDE issues the Inactive filing number in around 3-6 months counting from step 2 data gap analysis.
Step 6: CDE performs technical review. The queuing time at CDE may differ depending on the actual situation. It was slightly longer due to Covid-19 but now recovered back to normal processing times.
Step 7: CDE usually takes from start to finish 6-12 months for the technical review and will activate the DMF filing number If the finished product has already been approved.

Checklist for DMF filing in China

Costs & Timelines for DMF in China

China DMF Compared with US DMF, EU ASMF & CEP

Authorised Agent in China

Accestra Consulting has successfully helped overseas manufacturers to file drug master files (DMF) in China. We can be your trusted appointed agent by issuing us a letter of authorisation (LoA).

Find out more about China Drug Master file (DMF) Regulations and standards

We would be more than happy to arrange a teleconference call you share an overview of the China DMF process, requirements, costs and timelines. Email us to arrange a date and time to call (Info@accestra.com).

Contact Accestra Consulting Group

China Generic Drug Registration (ANDA): Understanding the Requirements

Samantha Beneke — Fri, 10 Sep 2021 23:39:14 +0000

To export a generic drug to China market, you need an Abbreviated New Drug Application (ANDA) for submission to China Center of Drug Evaluation (CDE) of National Medical Products Administration (NMPA formerly CFDA) for marketing authorization.

Highlights of China’s New Regulations for ANDA Submission

The requirements for China ANDA submission have changed and improved over recent years. These changes reduce complexity, shorten timelines, lower budget costs, and align closely with the international community. Highlights include:

Conditional acceptance of foreign clinical data,
Fast track review pathway,
Simplification of bioequivalence (BE) study application,
Adoption of ICH M4 CTD format for drug dossier.

Fig.1 Regulatory Reform and Impact on Generic Drug Import Market
TERM: BE Bioequivalence; ICH The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use; CTD Common Techincal Document

Who can apply for an ANDA in China?

According to the latest Provisions for Drug Registration (2020), a foreign applicant needs to choose a China domestic legal entity as the local representative to apply for and submit ANDA.

The foreign applicant can either choose to establish a legal entity or branch in China or appoint a qualified local agent as a representative. You can contact Accestra Consulting for local agent representation services.

Generic Drug Development Requirements

Reference Listed Drug (RLD)

China CDE requires that the reference product a generic drug refers to is on CDE’s RLD List. If you are submitting an ANDA while the reference product is not on the List, a RLD application will be required.

Clinical Trial/BE Study

China NMPA issued several guidelines for generics of different dosage forms and administration routes to assist applicants identify whether their drugs can be completely exempted from clinical studies.

If your drug needs clinical studies and you have finished them outside of China, your clinical data could be accepted by CDE, and additional clinical trial/BE study could be exempted in China.

According to CDE’s review of the drug dossier, there are four different scenarios for an imported generic where clinical studies are exempted or required:

Table 1. Clinical Study Requirements of An Imported Generic Drug

NO CLINICAL STUDIES REQUIRED IN CHINA
Clinical study exemption
CLINICAL STUDIES REQUIRED IN CHINA
Foreign clinical data available	Data fully accepted	Clinical study exemption
	Data partly accepted/rejected	Clinical trial*/BE study required
No foreign clinical data		Clinical trial*/BE study required

Clinical trial*: Certain clinical trial is required in China, incl. bridging study, confirmatory phase III clinical trial, and others.

Learn more about China Clinical Trial Exemption and IND Application.

ANDA Submission Requirements

The ANDA review and approval process are as below:

Fig.2 NMPA Workflow ANDA Review and Approval
TERM: ANDA abbreviated new drug application; NMPA National Medical products Administration; CDE Center for Drug Evaluation; CFDI Center for Food and Drug Inspection; NIFDC National Institutes for Food and Drug Control

Timeline

The overall timeline from ANDA submission to approval can take approximately 12-16 months.

CDE’s technical review part is around 200 working days, which could be extended to another 1/3 if material supplementation is required.

Costs

The administrative costs are approximately $80,000 if clinical studies have been or will be conducted,
or $60,000 if clinical studies are completely exempted.

Fast Track Review Pathway

A generic drug is reviewed by fast track if CDE determines that it could meet the market shortage or treat a rare or children’s disease.

Regardless of whether the drug has been market authorized in the US or EU, the applicant can apply for the fast track review pathway in China to speed up drug approval.

Our Tips

Fig.3 Activities an ANDA Application can do before Application.
TERM: CDE Center for Drug Evaluation

1. Have a Feasible & Strategic Plan for China Market

Make a feasible and strategic plan for ANDA submission and explore the most appropriate pathway options to China.

It is important to understand the pros and cons of different routes to market authorization.

A good market access strategy and implementation plan could not only save a significant amount of time and cost but most importantly reduce risks and increase the chance of success.

2. Apply for a CDE Communication Meeting (if needed)

If CDE’s requirements for your product are not explicit, a communication meeting can be applied to know CDE’s initial opinions on any critical issues relating to CMC (Chemical, Manufacturing, and Control), non-clinical and clinical studies, and to shorten the application timeline.

3. Mind the Gap and Close the Gap

After the regulatory reforms of ANDA submission, China regulations are now more aligned with the international requirements and ICH guidelines.

Except for the similarities, differences are still present between China, EU, and the US systems, especially in CTD Module 1 and CMC requirements .

It is important to conduct data gap analysis to identify and close gaps under China regulations.

4. Follow Regulatory Updates

China’s drug policy is young and significant changes happen frequently, so make sure to keep up with the regulatory updates.

Accestra Consulting can guide and assist you in fulfilling all the regulatory requirements for your generic drug product before, during, and after ANDA, including but not limited to the following services:

Authorized local agent,
Regulatory strategy plan,
RLD confirmation & application,
CDE communication meeting,
Data gap analysis,
ANDA dossier preparation, submission management & CDE review follow-up,
Annual report,
Pharmacovigilance (PV).

For more information and support with this process Contact Accestra Consulting Group.

Contact Accestra Consulting Group

2020 China Drug Evaluation Report – Part 3

Samantha Beneke — Sat, 14 Aug 2021 01:11:28 +0000

Part 3. Administrative Approval and Fast Track Review Pathways

Administrative approval.
Fast track review pathways.
2.1. Specialized pathway.
2.2. Breakthrough therapy.
2.3. Conditional approval.
2.4. Priority Review.

In 2020 CDE approved:

1,435 Investigational New Drug (IND) applications,
208 New Drug Applications (NDAs),
918 Abbreviated New Drug Applications (ANDAs).

This includes 59 drugs for the treatment of COVID-19.

As a follow-up on part 2 of the Drug Evaluation Report 2020, part 3 gives an overview of administrative drug approvals and fast track review pathways by CDE.

This includes specialized pathways, breakthrough therapy, conditional approval, and priority review.

1. Administrative Approval

CDE administratively approves a drug application regardless of whether it needs a technical review.

In 2020, there was a total of 8,646 approved applications, an increase of 44.51% year on year.

Most of these applications (5,647) were reviewed technically before approval, such as:

Clinical Trial Applications (CTAs),
New Drug Applications (NDAs),
Abbreviated New Drug Applications (ANDAs),
License renewal of imported drugs.

Other applications (2,972) were approved without technical reviews, such as temporary drug import applications.

Table 1 below gives an overview of applications administratively approved in 2020.

APPLICATION TYPE		NUMBER OF APPROVALS
		CHEMICAL DRUGS	BIOLOGICAL PRODUCTS	TRADITIONAL CHINESE MEDICINE	IN TOTAL
Approval after technical review	CTAs (incl. confirmatory clinical trials)	1,085	564	37	1,686
	Consistency Evaluations	623	0	0	623
	Supplementary Applications	1,955	615	290	2,860
	License Renewal of Imported Drugs	406	49	23	478
	Re-Review	17	3	7	27
Approval without technical review	Directly Approved Supplementary Applications	2,048	348	141	2,537
	Temporary Import Application	363	60	12	435
IN TOTAL		6,497	1,639	510	8,646

Comparing to 2019, 39.24% more applications were approved after technical review and 55.77% more applications were approved directly (without technical review).

View the diagram below for a comparison between the last three years (Fig. 1).

Fig. 1 Number of Administrative Approvals from 2018 to 2020.

2. Fast Track Review Pathways

CDE used several regulatory pathways to enhance efficiency as well as expedite drug development and approval in 2020.

According to the Provisions for Drug Registration (State Administration for Market Regulation [2020] Decree No. 27), the fast track review pathways are:

Specialized pathway,
Breakthrough therapy,
Conditional approval,
Priority review.

These pathways use a range of approaches, including:

More interactions between CDE reviewers and drug developers,
Greater application process flexibility,
Shortened timelines for review and approval.

During the COVID-19 pandemic, fast track review pathways advanced patient treatments in approving drugs for unmet clinical needs and significant improvements on medical care. This better protected the health of the Chinese public.

Specialized Pathway

A drug reviewed by the Specialized Pathway is used for the treatment or prevention of pandemic disease as part of a declared public health emergency.

The drug review is expedited with:

Increased flexibility:
Accelerated application acceptance,
Parallel proceeding of review,
On-site inspection/audit,
Product testing.

The drug can only be used in a specified period and is based on its medical need for controlling that pandemic disease.

During the COVID-19 pandemic, CDE reviewed 59 chemical drugs, biological products, and traditional Chinese medicines by the specialized pathway in 2020.

Among these:

1 novel drug (i.e., COVID-19 Vaccine (Vero Cell) Inactivated) was approved under controlled conditions,
53 novel drugs were approved for clinical trials,
5 listed drugs were approved to include a new indication of treating coronavirus.

2.2.Breakthrough Therapy

Breakthrough Therapy is a drug for a serious or life-threatening disease for which there is an unmet clinical need or for which there is preliminary clinical evidence demonstrating that the drug may have a substantial clinical improvement over other available therapies.

An application can be submitted to CDE in Phase I or II clinical trial for a drug to be designated as a Breakthrough Therapy.

Once accepted, a breakthrough therapy designation will have the following features:

Priority of advisory communication and meetings with CDE as well as more intensive CDE guidance on drug development.
Priority review with shortened approval timeline.
Priority of on-site inspection/audit and product testing.

In 2020, CDE designated 24 of the 147 applied drugs (16%) as breakthrough therapies.

2.3. Conditional Approval

A drug receives Conditional Approval if there is an urgent medical need for the drug to treat a serious, life-threatening, or public health emergency disease.

The drug can result in having surrogate endpoints, intermediate endpoints, or early clinical data as to efficacy measures.

If the clinical study demonstrates that the benefit of the drug overweighs its risk, it will be approved under controlled conditions.

In 2020, 15 novel drugs received conditional approvals from CDE and provided new therapies for:

COVID-19 pandemic,
Non-small cell lung cancer,
Ovarian cancer and more.

2.4. Priority Review

A drug receives a Priority Review if CDE determines that the drug could potentially provide significant advances in medical care or serve previously unmet medical needs.

The drug is reviewed in an expedited timeline, within 130 workdays instead of the standard 200 workdays, and within 70 workdays for a drug already approved overseas to treat a rare or “orphan” disease.

219 drugs were designated Priority Review by CDE in 2020, among which 42 drugs were pediatric and rare disease drugs.

Including the backlog of priority reviews of the previous year, 217 drugs (of 121 categories) were approved in 2020, an increase of 51.7% compared to 2019.

The highlight examples were:

Almonertinib mesylate tablets,
Agalsidase,
Concentrated injection,
Mulberry twig alkaloids tablets.

Table 2 gives an overview of priority review and approval in 2020 and compares the number of approvals from 2016 to 2020.

REGISTRATION APPLICATION	2016		2017		2018		2019		2020
	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO	NUMBER OF CATEGORIES	RATIO
Novel Drug with substantial clinical advance	0	14.30%	33	66%	39	47%	40	48.80%	36	29.80%
Parallel application	0	0%	4	8%	14	16.90%	7	8.50%	30	24.80%
AIDS Drug	0	0%	0	0%	0	0%	0	0%	3	2.50%
Orphan designation for rare disease	0	0%	0	0%	3	3.60%	6	7.30%	11	9.10%
Pediatric drug	4	57.10%	1	2%	9	10.80%	7	8.50%	8	6.60%
Re-application after generic consistency evaluation	0	0%	0	0%	5	6%	8	9.80%	20	16.50%
Major national R&D program drug	0	0%	0	0%	0	0%	5	6.10%	9	7.40%
Generic of coming off-patient drug	1	14%	2	4%	4	4.80%	7	8.50%	4	3.30%
Drug of urgent clinical need or of market shortage	0	0%	2	4%	3	3.60%	0	0%	0	0.00%
First generic drug approval	1	14.30%	8	16%	6	7.20%	2	2.40%	0	0.00%
IN TOTAL	7	100%	50	100%	83	100%	82	100%	121	100%

Accestra Consulting Provides China Regulatory Affairs Outsourcing for:

Drugs/Pharmaceutical,
Food and Feed products for China NMPA (Formerly CFDA).
Regulatory approval including product registration for China Investigational New Drug (IND),
China New Drug Application (NDA),
China Drug Master File (DMF) for APIs,
Excipients and Packaging Materials,
ANDA,
eCTD submission and others.

Read part 1 of the 2020 Drug Evaluation Report.

Read part 2 of the 2020 Drug Evaluation Report.

Contact Accestra Consulting Group

2020 China Drug Evaluation Report – Part 2

Samantha Beneke — Wed, 04 Aug 2021 22:40:14 +0000

Part 2. Chemical Drugs, Biological Products and Traditional Chinese Medicines

1. Chemical Drugs.
1.1. Application Overview.
1.2. Approval.
2. Biological Products.
2.1. Application Overview.
1.2. Approval.
3. Traditional Chinese Medicine.
3.1. Application Overview.
3.2. Approval.

Despite severe challenges from the COVID-19 pandemic, the Center for Drug Evaluation (CDE) of China reviewed 8,606 drug applications in 2020 and approved many new drugs to help patients suffering from different diseases.

As a follow-up on part 1 of the Drug Evaluation Report 2020, part 2 gives an overview of drug applications and approvals respectively for chemical drugs, biological products, and traditional Chinese medicines.

1. Chemical Drugs

1.1 Application Overview

In 2020, CDE reviewed 6,778 chemical drug applications, including:

1,086 Clinical Trial Applications (CTAs) for Investigational New Drugs (INDs) and confirmatory trials,
163 New Drug Applications (NDAs),
1,697 Abbreviated New Drug Applications (ANDA),
1,136 consistency evaluations,
2,248 supplementary applications.

Comparing to the previous year, the number of consistency evaluations has increased 103.22%

This is followed by CTAs (45.58%) and supplementary applications (23.72%).

View an overview of the chemical drug applications reviewed in 2020 below (Fig. 1).

Fig. 1 Number of Chemical Drug Applications Reviewed in 2020

1.2. Approval

907 INDs, 115 NDAs, and 918 ANDAs were approved with an increase of 51.42%, 30.68%, and 15.33% respectively compared to the previous year.

The table below (Table. 1) gives an overview of the chemical drug applications approved in 2020.

Table 1. Overview of Chemical Drug Application Approvals in 2020

APPLICATION TYPE	NUMBER OF APPLICATIONS
	APPROVAL (INCL. AFTER MATERIAL SUPPLEMENT)	NO APPROVAL SUGGESTED/NOT APPROVED	OTHERS*	TOTAL NUMBER
IND	907	39	14	960
Confirmatory Clinical Trial	108	11	7	126
NDA	115	3	45	163
ANDA	918	32	747	1,697
Supplementary Application	1,732	126	390	2,248
License Renewal of Imported Drugs	380	17	25	422
Consistency Evaluation	577	12	547	1,136
Re-Review	N/A			26
Total	4,737	240	1,775	6,778

Others*: herein refers to the applications which were withdrawn by the applicants or pending for material supplement after technical review, similarly hereinafter.

1.2.1. IND Approval

Under the classification of IND application, the approval rate of 694 Class 1 Innovative New Drugs increased by 40.77% compared to 2019.

Based on the Active Pharmaceutical Ingredients (APIs) of these drugs, 298 categories were approved for Class 1 Drugs with an increase of 57.67% comparing to the previous year.

View the following diagram for a comparison of IND and Class 1 drug IND approvals between the last five years (Fig. 2).

Fig. 2 Number of IND and Class 1 Innovative New Drug IND Approvals from 2016 to 2020

Among the IND approvals of Class 1 drugs, the following shared a large proportion of 80.69%:

Anti-neoplastic,
anti-infective,
circulatory system,
endocrine system,
gastrointestinal,
autoimmune disease,
immunosuppressant drugs.

The diagram below (Fig. 3) shows the number of Class 1 drug IND approvals for each therapeutic field in 2020.

Fig. 3 Number of Class 1 Innovative New Drug IND Approvals for Each Therapeutic Field in 2020

1.2.2. NDA Approval

CDE approved 115 chemical drug NDAs in 2020, among which Class 1 Innovative New Drugs covered 14 drug categories.

View a comparison of NDA approvals between the last five years below (Fig. 4).

Fig. 4 Number of NDA Approvals from 2016 to 2020

2. Biological Products

2.1 Application Overview

CDE reviewed a total of 1,410 Biologics License Applications (BLA) in 2020.

The number of reviewed IND applications and NDAs is given in the below table (Table 2) respectively for preventive and therapeutic biological products and in vitro diagnostics.

Table 2. Number of INDs and NDAs Reviewed for Biological Products in 2020

CLASSIFICATION	NUMBER OF INDs	NUMBER OF NDAs
Preventive Biological Product	27	9
Therapeutic Biological Product	537	108
In-vitro Diagnostics	0	1

The diagram below (Fig. 5) shows the number of BLAs reviewed for every application type.

Fig. 5 Number of BLAs Reviewed in 2020

2.2 Approval

Among the reviewed BLAs, 500 INDs and 89 NDAs were approved with an increase of 60.26% and 20.27% respectively compared to the previous year.

The number of approvals for each application type is summarized in the table below (Table 3).

Table 3. Overview of BLA Approvals in 2020

APPLICATION TYPE	NUMBER OF APPLICATIONS
	APPROVAL (INCL. AFTER MATERIAL SUPPLEMENT)	NO APPROVAL SUGGESTED/NOT APPROVED	OTHERS*	TOTAL NUMBER
Preventive IND	19	4	4	27
Therapeutic IND	481	45	11	537
Preventive NDA	7	0	2	9
Therapeutic NDA	81	1	26	108
In vitro Diagnostic NDA	1	0	0	1
Supplementary Application	551	22	102	675
License Renewal of Imported Drugs	45	0	4	49
Re-Review	N/A	N/A	N/A	4
In Total	1,185	72	149	1,410

For a comparison of biologics IND and NDA approvals between the last five years, please see the diagram below (Fig. 6).

Fig. 6 Number of Biologics IND and NDA Approvals from 2016 to 2020

2.2.1. IND Approval

Under the classification of biologics IND application, 294 cancer drugs were approved in 2020 which covered 58.8% of the total amount. The diagram below (Fig. 7) shows the number of IND approvals for each therapeutic field of biological products in this year.

Fig. 7 Number of Biologics IND Approvals for Each Therapeutic Field in 2020

2.2.2. NDA Approval

Under the classification of biologics NDA, cancer, endocrine, and cardiovascular drugs shared a large proportion of 65.17% of the total amount approved in 2020. The diagram below (Fig. 8) shows the number of NDA approvals for each therapeutic field of biological products this year.

Fig. 8 Number of Biologics NDA Approvals for Each Therapeutic Field in 2020

3. Traditional Chinese Medicines

3.1 Application Overview

CDE reviewed a total of 418 Traditional Chinese Medicine (TCM) applications in 2020, including 37 IND applications, 8 NDAs and 3 ANDAs. The diagram below (Fig. 9) shows the number of TCMs reviewed for each application type.

Fig. 9 Number of TCM Applications Reviewed in 2020

3.2 Approval

Among the reviewed TCM applications, 28 INDs and 4 NDAs were approved by CDE. The number of approvals for each application type is summarized in the table below (Table 4).

Table 4. Overview of TCM Approvals in 2020

APPLICATION TYPE	NUMBER OF APPLICATIONS
	Approval (incl. approval after material supplement)	No Approval Suggested / Not Approved	Others*	Total Number
IND	28	5	4	37
NDA	4	0	4	8
ANDA	0	2	1	3
Supplementary Application	220	42	65	327
License Renewal of Imported Drugs	17	6	4	27
Re-Review	N/A			16
In Total	269	55	78	418

For a comparison of TCM IND and NDA approvals between the last five years, please see the diagram below (Fig. 10).

Fig. 10 Number of TCM IND and NDA Approvals from 2016 to 2020

3.2.1. IND Approval

Under the classification of IND applications, 28 TCMs of 10 therapeutic fields were approved in 2020.

Respiratory, orthopedic, and gastrointestinal drugs shared a large proportion of 53.57%.

The diagram below (Fig. 11) shows the number of IND approvals for each therapeutic field of TCMs this year.

Fig. 11 Number of TCM IND Approvals for Each Therapeutic Field in 2020

Accestra Consulting Provides China Regulatory Affairs Outsourcing for:

Drugs/Pharmaceutical,
Food and Feed products for China NMPA (Formerly CFDA).
Regulatory approval including product registration for China Investigational New Drug (IND),
China New Drug Application (NDA),
China Drug Master File (DMF) for APIs,
Excipients and Packaging Materials,
ANDA,
eCTD submission and others.

Read part 1 of the 2020 Drug Evaluation Report.

Contact Accestra Consulting Group

2020 China Drug Evaluation Report – Part 1

Samantha Beneke — Wed, 28 Jul 2021 22:32:40 +0000

1. Summary.
2. Technical Review & Approval.
3. Reason For Application Rejections.
3.1 New Drug Application Rejections.
3.2 ANDA Rejections.
3.3 Supplementary Application Rejections.

3.4 Other Application Rejection.

In 2020, the Center for Drug Evaluation (CDE) of China reviewed and/or approved 11,582 drug registrations.

To summarize the accomplishments and failures of drug approvals, CDE released a China Drug Evaluation Report of the year.

Part 1 of the report gives an overview of drug approvals for:

All application types (incl. INDs, NDAs and ANDAs),
New drug approvals for hot topics in 2020,
Reasons for rejected applications.

1. China Drug Evaluation Report Summary

Under the impact of COVID-19 in 2020, the Center for Drug Evaluation (CDE) accelerated the drug review and approval process.

More drugs (incl. drug-device combinations) were reviewed and/or approved in 2020 than the previous year.

There were a total of 11,582 registrations (32.67% increase), among which 8,606 registrations required technical review and approval.

The others required only administrative approval. 4,882 registrations were also pending technical review.

For an overview of the registrations reviewed and/or approved (incl. rejections after technical review) in 2020, please see the table below (Table 1).

CATEGORY	REGISTRATION TYPE	NUMBER OF REGISTRATIONS
Drug Product	Requires Technical Review	8,606
	Only Administrative Approval	2,972
Drug-device Combination		4
Total Number		11,582

Among 8,606 registrations technically reviewed by CDE, there are:

6,778 chemical drugs (25.33% increase year on year)
418 traditional Chinese medicines (39.33% increase year on year),
1,410 biological products (27.72% year on year).

View the diagram below (Fig. 1) for a comparison between the categories and the total number of registrations reviewed between 2016 and 2020.

Fig. 1 Comparison of Drug Registrations Reviewed from 2016 to 2020.
(Note: There was no registration that required only administrative approval in 2016, i.e., all registrations required technical review & approval. From 2017, specific registrations could be approved without technical review under the new regulatory framework.)

2. Technical Review & Approval

Among 8,606 registrations technically reviewed by CDE, there are:

1,561 Investigational New Drug (IND) applications (55.94% increase year on year ),
289 New Drug Applications (7.04% increase year on year ),
1,700 Abbreviated New Drug Applications (2.16% increase year on year).

View the diagram below (Fig. 2) for a comparison between the categories and the total number of applications reviewed between 2016 and 2020.

Fig. 2 Number of Applications Reviewed from 2016 to 2020. (Note: CDE has started to conduct quality and efficacy consistency evaluation of generic drugs since August 2017.)

Among these applications, 1,435 INDs, 208 NDAs, and 918 ANDAs were approved after technical review.

These approved NDAs covered a total of 92 drug categories. This includes 20 categories of domestic new drugs and 72 categories of imported new drugs.

The drug category of a chemical drug is referred to as the Active Pharmaceutical Ingredient (API) of the drug, whereas the drug category of a biological product or traditional Chinese medicine is referred to as the International Nonproprietary Name (INN) of the drug.

29 Categories of NDAs were chosen and given below (Table 2). This provides an overview of the new drugs approved for hot topics in 2020, such as COVID-19 vaccines and anti-neoplastic drugs.

Table 2. Overview of New Drug Approvals for Hot Topics in 2020.

NO.	TOPIC IN DRUG THERAPY	INDICATION	DRUG CATEGORY
1	COVID-19 Vaccines and other treatments	SARS-CoV-2	COVID-19 Vaccine (Vero Cell) Inactivated
2	COVID-19 Vaccines and other treatments	Acute Lung Injury (ALI) / Acute Respiratory Distress Syndrome (ARDS)	Liahnhua Qingwen Tables/Capsules/Jinhua Qinggan Tables / Xuebijing Injection
3	COVID-19 Vaccines and other treatments	Non-small Cell Lung Cancer	Sivelestat Sodium Hydrate for Ijection
4	Anti-neoplastic Drugs	Non-small Cell Lung Cancer	Almonertinib Mesylate Tablets
5	Anti-neoplastic Drugs	Pancreatic and Non-pancreatic Neuroendocrine Tumors	Surufatinib Capsules
6	Anti-neoplastic Drugs	Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma	Bretunximab Vedotin for Injection
7	Anti-neoplastic Drugs	B-precursor Acute Lymphoblastic Leukaemia	Blinatumomab for Injection
8	Anti-neoplastic Drugs	Differentiate Thyroid Cancer	Lenvatinib Mesylate Capsules
9	Anti-infective Drugs	Chronic Hepatitis C	Coblopasvir Hydrochloride Capsules
10	Anti-infective Drugs	HIV-1 Pre-Exposure Prophylaxis	Emtricitabine / Tenofovir Disoproxil Fumarate Tablets
11	Circulatory System Drugs	Hereditary Angioedema	Lanadelumab-flyo Injection
12	Circulatory System Drugs	Transthyretin Amyloidosis	Tafamidis Soft Capsules
13	Respiratory System Drugs	Persistent Allergic Rhinitis	Bencycloquidium Bromide Nasal Spray
14	Respiratory System Drugs	Idiopathic Pulmonary Fibrosis (IPF)/Systemic Sclerosis Associated Interstitial Lung Disease (SSc-ILD)	Nintedanib Esylate Soft Capsules
15	Nervous System Drugs	Huntington’s Disease	Deutetrabenazine Tablets
16	Nervous System Drugs	Stage 1 Symptomatic Polyneuropathy	Tafamidis Meglumine Soft Capsules
17	Analgesics and Anesthetics	Painless Gastroenteroscopy	Ciprofol Injection
18	Dermatological and Otorhinolaryngological Drugs	Neurotrophic Keratitis	Cenegermin Eye Drops
19	Dermatological and Otorhinolaryngological Drugs	Atopic Dermatitis	Dupilumab Injection
20	Gastrointestinal Drug	Ulcerative Colitis/Crohn’s Disease	Vedolizumab for Injection
21	Surgical Drugs	Malignant Hyperthermia	Tacrolimus Granules
22	Surgical Drugs	Pediatric Transplant Rejection	Tacrolimus Granules
23	Rare Disease Drugs	Mucopolysaccharidosis 1	Laronidase Concentrate for Injection
24	Rare Disease Drugs	Mucopolysaccharidosis 2	Idursulfase-beta Injection
25	In Vivo Diagnostics	In-vivo diagnosis of mycobaterium tuberculosis infection	Recombinant ESAT-6:CFP-10 Fusion Protein
26	Preventive Biological Product (Vaccine)	Influenza	Influenza Vaccine, Live, Nasal, Freeze-dried
27	Traditional Chinese Medicine	Type 2 Diabetes	Mulberry Twig Alkaloids Tablets
28	Traditional Chinese Medicine	Knee Osteoarthritis	Jingu Zhitong Gel
29	Traditional Chinese Medicine	Acute Bronchitis and Tracheitis	Lianhua Qingke Tablets

3. Reasons for Application Rejections

367 Applications failed to get approved in 2020 because of:

Insufficient proof for drug safety,
Efficacy,
Quality control or delay in submitting the supplementary materials upon CDE’s requests.

The following reasons are identified from different perspectives of drug development and regulatory submission for INDs, NDAs, ANDAs, supplementary applications, and others.

3.1 New Drug Application Rejections

3.1.1. IND Application Rejections.

Lack of pre-IND meeting
Major data gaps were identified after IND applications were filed and couldn’t be supplemented in the given timeline.
Insufficient data for clinical development justification.
a. The IND-enabling (incl. pharmaceutical, nonclinical, preclinical) studies demonstrated that the drug efficacy was low and safety risk was high. The risk-benefit ratio was not suitable for first-in-human testing.
b. The clinical development purpose did not comply with the principles of clinical trials.
c. The IND-enabling studies were insufficient to start clinical trials.
Insufficient data to enable clinical studies or control safety risks in humans.
a. Major defects in the clinical trial protocol and insufficient risk control measures.
b. Insufficient nonclinical data for combination therapy drugs.
c. Insufficient data for each individual vaccine or different immunization procedures between the individual vaccines of a combination vaccine.

3.1.2. NDA Rejections

Major defects in the research quality control and management system. Thus the submitted data couldn’t prove the safety, efficacy, and quality of the drug.
Lack or regulatory compliance
a. Inconsistent study drugs were used for different phases of clinical trials.
b. Authenticity issues were identified in clinical data during on-site inspection/audit.

3.2. ANDA Rejections

Unsuitable justification for generic development: The reference listed drug (RLD) which the generic compared to has been withdrawn from the market. A new drug with improved safety has been authorized for marketing in China.
Insufficient data for quality consistency
a. Product specification review and sample inspection did not follow the requirements, or major defects were identified in the analytical methods.
b. The bioequivalence study demonstrated that the generic and RLD were not bioequivalent.
c. Lack of compliance with technical requirements for generics (such as stability testing and choose of API starting materials).
d. The APIs were not from legal sources.

3.3. Supplementary Application Rejections

Insufficient data to justify the change to an approved drug.
a. The submitted change had a major impact on the drug substance and caused substance change.
b. The submitted change to the drug label/insert did not follow technical requirements for drafting the drug label/insert.
The submitted data could not prove that the change to an approved drug had no impact on the drug safety, efficacy, and quality (such as insufficient reference literature and clinical data).

3.4. Other Application Rejection

Biosimilars.
a. Lack of similarity assessment or the choice of reference drug in the comparative study did not follow requirements.
b. Insufficient nonclinical/preclinical data to enable clinical studies.
Natural Medicines: The submitted data did not follow requirements for multi-regional clinical trials or the national guidelines for the review of natural medicines.

Accestra Consulting Provides China Regulatory Affairs Outsourcing for:

Drugs/Pharmaceutical,
Food and Feed products for China NMPA (Formerly CFDA).
Regulatory approval including product registration for China Investigational New Drug (IND),
China New Drug Application (NDA),
China Drug Master File (DMF) for APIs,
Excipients and Packaging Materials,
ANDA,
eCTD submission and others.

Contact Accestra Consulting Group

China Pharmacovigilance Regulations & Standards

Samantha Beneke — Mon, 19 Jul 2021 04:15:20 +0000

China pharmacovigilance regulations have been undergoing significant reform reinforced by recently issued Good Pharmacovigilance Practices (GVP) (2021, Decree No. 65).

In addition to the regulations, the National Medical Products Administration (NMPA), Center for Drug Evaluation (CDE) and National Centre for Adverse Drug Reaction (ADR) Monitoring (NCADRM) of China have also released guidelines and standards for implementing pharmacovigilance duties in China.

Under this framework, each drug Marketing Authorization Holder (MAH) requires to monitor drug safety and operate a pharmacovigilance system or by appointing a qualified service provider for carrying out pharmacovigilance activities to ensure that all the ADRs are being reported, evaluated and controlled.

For an overview of these requirements, we have summarized the pharmacovigilance regulations and standards in the table below.

CATEGORY	REGULATIONS	SUMMARY
General Law & Regulation	Drug Administration Law (2019, No. 31)	Regulatory basis for the establishment of pharmacovigilance system, requiring each drug MAH and health authority to monitor, identify, evaluate, and control ADRs and any other safety risks of a drug both before and after approval. https://www.nmpa.gov.cn/xxgk/fgwj/flxzhfg/20190827083801685.html(Chinese)
General Law & Regulation	Good Pharmacovigilance Practices (2021, No. 65)	General standards for the safety monitoring of drugs throughout their life cycle and guidance for drug MAHs, medical facilities, and health authorities on pharmacovigilance. https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20210513151827179.html (Chinese)
Premarketing Regulations	Good Clinical Practice (2020, No. 57)	Basic requirements for premarketing safety monitoring, incl. defining ADRs and Suspected Unexpected Serious Adverse Reactions (SUSARs), requiring drug MAHs to report ADRs in a timely manner and researchers to provide safety reports. https://www.nmpa.gov.cn/yaopin/ypggtg/20200426162401243.html (Chinese)
Premarketing Regulations	Announcement on Adapting Tier 2 ICH Guidelines (2018, No. 10)	A formal statement on adapting Tier 2 ICH Guidelines E2A, E2B, E2D, M4, M1 in China.https://www.nmpa.gov.cn/yaopin/ypggtg/ypqtgg/20180125175101686.html (Chinese)
Premarketing Regulations	Announcement on Adjusting Review and Approval Process of Drug Clinical Trials (2018, No. 50)	Requirements for a drug MAH to submit Development Safety Update Report (DSUR) after obtaining the clinical trial approval, file supplementary application for any change to the drug that could increase safety risks, and report SUSARs during clinical trials. https://www.nmpa.gov.cn/xxgk/ggtg/ywlchshyjgrdgg/20180727172901286.html (Chinese)
Premarketing Regulations	Standard and Process of Safety Data Fast Reporting during Drug Clinical Trials (2018)	Guidance for drug MAHs on identification and fast reporting of SUSARs and other serious safety risks during clinical trials, incl. responsibilities, timeline, and submission requirements.http://www.cde.org.cn/news.do?method=largeInfo&id=90755b9d6035c1b4 (Chinese)
Premarketing Regulations	Provisions for Safety Data Assessment and Management during Drug Clinical Trials (2020, No. 5)	Requirements for drug MAHs to assess and manage drug safety data during clinical trials under the review of CDE. For any clinical study suspended or terminated due to safety risks, the drug MAH can communicate with CDE about resuming the study. http://www.cde.org.cn/news.do?method=largeInfo&id=938b81c153eaf85e (Chinese)
Premarketing Regulations	Management Provisions for Development Safety Update Report (2020, No. 7)	DSUR drafting and submission requirements for drug MAHs. http://www.cde.org.cn/news.do?method=largeInfo&id=3cad3925b893ab31 (Chinese)
Postmarketing Regulations	Provisions for Reporting and Monitoring of Adverse Drug Reactions (2011, No. 81)	Fundamental requirements and systemic concept of ADR reporting and monitoring by drug manufacturers, distributors, medical facilities and health authorities.https://www.nmpa.gov.cn/yaopin/ypfgwj/ypfgbmgzh/20110504162501325.html (Chinese)
Postmarketing Regulations	Standard of Periodic Safety Update Report (PSUR) Drafting for Marketed Drugs (2012, No. 264)	Guidance for drug MAHs on drafting the PSURs. https://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjyp/20120906145901535.html (Chinese)
Postmarketing Regulations	Guidance on Periodic Safety Update Reports (PSUR) Review for Marketed Drugs (2012, No. 27)	Guidance for health authorities on reviewing these PSURs. http://www.cdr-adr.org.cn/drug_1/zcfg_1/zcfg_zdyz/201211/t20121123_35783.html (Chinese)
Postmarketing Regulations	Guidance for Drug Manufacturers on Intensive Drug Monitoring (2013, No. 12)	Guidance for drug manufacturers on intensive safety monitoring of new drugs within 5 years after approval and imported drugs within 5 years after first-time import. https://www.nmpa.gov.cn/xxgk/zhqyj/zhqyjyp/20130325113801579.html (Chinese)
Postmarketing Regulations	Guidance on Inspection of Adverse Drug Reaction Reporting and Monitoring (2015, No. 78)	Guidance for health authorities on inspection of ADR reporting and monitoring by drug manufacturers, incl. the purpose, plan, implementation and documentation requirements. https://www.nmpa.gov.cn/xxgk/fgwj/gzwj/gzwjyp/20150702120001584.html (Chinese)
Postmarketing Regulations	Announcement on Direct Reporting of Adverse Drug Reactions by Drug Marketing Authorization Holders (2018, No. 66)	A comprehensive regulation that specifies all the responsibilities and duties of a drug MAH in ADR reporting and monitoring. https://www.nmpa.gov.cn/yaopin/ypggtg/ypqtgg/20180930174301286.html (Chinese)
Postmarketing Regulations	Guidelines for Collection and Reporting of Individual Adverse Drug Reactions (2018, No. 131)	Guidance for drug MAHs on data collection, recording, reporting, verification, assessment and submission for Individual Case Safety Reports (ICSR), patient follow-up and case investigation. https://www.nmpa.gov.cn/xxgk/ggtg/qtggtg/20181221172901438.html (Chinese)
Postmarketing Regulations	Guidelines for Review of Literature about Marketed Drug Clinical Safety (2019, No. 27)	Guidance for drug MAHs on searching, screening, collection, review, and analysis of literature about clinical safety of marketed drugs and drafting the literature review reports. https://www.nmpa.gov.cn/yaopin/ypggtg/ypqtgg/20190618165701432.html (Chinese)
Postmarketing Regulations	Guidance on Annual Pharmacovigilance Report Drafting by Drug Marketing Authorization Holders (2019)	Guidance for drug MAHs on drafting the annual pharmacovigilance report, incl. content and format requirements for the report and a report template. http://www.cdr-adr.org.cn/drug_1/zcfg_1/zcfg_zdyz/201911/t20191129_46859.html (Chinese)
Postmarketing Regulations	Guidelines for Pharmacovigilance Authorization Agreement Drafting (2020)	Guidelines for drafting the pharmacovigilance authorization agreement, incl. principles, scope of work, responsibilities, etc. http://www.cdr-adr.org.cn/drug_1/zcfg_1/zcfg_zdyz/202006/t20200604_47472.html (Chinese)

For the English version of the above links, please contact us.

Except for the regulations and standards listed above, China has also adapted to several ICH guidelines for pharmacovigilance:

Premarketing Pharmacovigilance

SUSAR reporting in clinical trials: ICH E2A, E2B (R3) and M1 (MedDRA) guidelines
DSUR reporting in clinical trials: ICH E2F guideline

Postmarketing Pharmacovigilance

Safety reporting: ICH E2B (R3), E2D and M1 (MedDRA) guidelines
Periodic Benefit-Risk Evaluation Report (PBRER): ICH E2C (R2) guideline

For English translations or questions on China’s pharmacovigilance requirements, you may message us on: info@accestra.com

For further details on China pharmacovigilance history and MAH responsibilities, you may be interested in reading the following article: https://www.accestra.com/pharmacovigilance-pv-in-china/

Find out more about China pharmacovigilance history and MAH responsibilities

Contact Accestra Consulting Group

China Drug Master File (DMF) Regulations & Standards

Samantha Beneke — Sat, 26 Jun 2021 04:05:59 +0000

China Drug Master File (DMF) for APIs, packaging Materials, and pharmaceutical excipients are regulated by China NMPA formerly CFDA. The related DMF regulations and standards clarify the drug master file structure, process, requirements, timelines, and costings in the regulations listed below.

Contact Accestra Consulting Group for English translations or questions on China’s Drug Master File (DMF) requirements.

General Laws

Drug Administration Law (2019 No. 31)

The regulatory basis for the development, manufacture, business operation, practical use, supervision, and administration of drug products, substances, excipients, and packaging materials.

https://www.nmpa.gov.cn/xxgk/fgwj/flxzhfg/20190827083801685.html (Chinese)

Provisions for Drug Registration (2020 No. 27)

The regulatory basis for DMF approval pathways in Section 3 of Chapter 3.

https://www.nmpa.gov.cn/directory/web/nmpa/xxgk/fgwj/bmgzh/20200330180501220.html (Chinese).

DMF Standards

Announcement for Adjusting Evaluation and approval for APIs, Excipients and Packaging Materials (2017 No. 146)

Basic requirements for the binding review and approval of a drug and its related APIs, excipients, and packaging materials.

https://www.nmpa.gov.cn/yaopin/ypggtg/ypqtgg/20171130163301730.html (Chinese).

Announcement on Issues Concerning the Further Improvement of Drug-related Associated Review & Approval and Supervision (2019 No. 56)

Detailed requirements for DMF filing, incl. scope of DMF, dossier requirements, filing process and timeline under the framework of binding review and approval.

https://www.nmpa.gov.cn/yaopin/ypggtg/ypqtgg/20190716174501955.html (Chinese).

Provisions for Administration of Drug-related Associated Review & Approval for APIs, Excipients and Packaging Materials (2020 Draft for Comments)

Comprehensive administrative practices of DMF filing, incl. API independent review & approval, DMF holder responsibilities & obligations, changes to approved DMFs, and product supervision by the authorities.

http://www.cde.org.cn/news.do?method=largeInfo&id=5561f130fad55ba4 (Chinese).

Learn more about the China DMF filing approval process

China Clinical Trial Exemption and IND Application – Your Questions Answered

Samantha Beneke — Wed, 28 Apr 2021 02:41:54 +0000

Accestra Consulting Group has put together the top 10 most asked questions and answers to China’s clinical trial exemption and IND application (CTA).

China’s Center for Drug Evaluation (CDE) allows a drug Marketing Authorization Holder (MAH) to apply for clinical trial exemption in China if a drug is already approved for marketing in other countries.

How to qualify for a clinical trial exemption

Qualifying for a clinical exemption depends on:

An evaluation of the existing clinical data conducted overseas,
The drug clinical need and urgency in China, which can you can discuss with CDE before the Investigational New Drug (IND) application in a pre-IND meeting.

If no exemption is possible, clinical studies need to done in China according to CDE’s protocol. You will also need to register on the CDE database for government supervision and public review.

Samantha Beneke – Accestra Consulting

New Guideline for Drug Master Filing (DMF) in China

What are inactive and active DMF numbers in China?

Steps to File DMF in China

Checklist for DMF filing in China

Costs & Timelines for DMF in China

China DMF Compared with US DMF, EU ASMF & CEP

Authorised Agent in China

China Generic Drug Registration (ANDA): Understanding the Requirements

Highlights of China’s New Regulations for ANDA Submission

Who can apply for an ANDA in China?

Generic Drug Development Requirements

Reference Listed Drug (RLD)

Clinical Trial/BE Study

ANDA Submission Requirements

Timeline

Costs

Fast Track Review Pathway

Our Tips

2. Apply for a CDE Communication Meeting (if needed)

3. Mind the Gap and Close the Gap

4. Follow Regulatory Updates

2020 China Drug Evaluation Report – Part 3

Part 3. Administrative Approval and Fast Track Review Pathways

Table of contents

1. Administrative Approval

2. Fast Track Review Pathways

Specialized Pathway

2.2.Breakthrough Therapy

2.3. Conditional Approval

2.4. Priority Review

2020 China Drug Evaluation Report – Part 2

Part 2. Chemical Drugs, Biological Products and Traditional Chinese Medicines

Table of contents

1. Chemical Drugs

1.1 Application Overview

1.2. Approval

1.2.1. IND Approval

1.2.2. NDA Approval

2. Biological Products

2.1 Application Overview

2.2 Approval

2.2.1. IND Approval

2.2.2. NDA Approval

3. Traditional Chinese Medicines

3.1 Application Overview

3.2 Approval

3.2.1. IND Approval

2020 China Drug Evaluation Report – Part 1

Table of contents

1. China Drug Evaluation Report Summary

2. Technical Review & Approval

3. Reasons for Application Rejections

3.1 New Drug Application Rejections

3.1.1. IND Application Rejections.

3.1.2. NDA Rejections

3.2. ANDA Rejections

3.3. Supplementary Application Rejections

3.4. Other Application Rejection

China Pharmacovigilance Regulations & Standards

Premarketing Pharmacovigilance

Postmarketing Pharmacovigilance

China Drug Master File (DMF) Regulations & Standards

General Laws

Drug Administration Law (2019 No. 31)

Provisions for Drug Registration (2020 No. 27)

DMF Standards

Announcement for Adjusting Evaluation and approval for APIs, Excipients and Packaging Materials (2017 No. 146)

Announcement on Issues Concerning the Further Improvement of Drug-related Associated Review & Approval and Supervision (2019 No. 56)

Provisions for Administration of Drug-related Associated Review & Approval for APIs, Excipients and Packaging Materials (2020 Draft for Comments)

China Clinical Trial Exemption and IND Application – Your Questions Answered

How to qualify for a clinical trial exemption

Top 10 Questions to China’s clinical trial exemption and IND application