Generic drugs comprise a significant part of China's pharmaceutical market. In 2020, 63% of drugs marketed in China were generics. The Chinese generic drug market size reached 970.7 billion yuan (143.85 billion USD) in 2019 and fell to 808.7 billion yuan1 (circa 119.84 billion USD) in 2020 due to the economic slowdown brought by the COVID-19 pandemic.
However, China's generic drug market is expected to grow. One reason is that generics usually have lower prices than patented originator drugs, so that generics have advantages in the volume-based procurement where the price competition is fierce.
Another reason is that generics' quality has improved remarkably since 2015 as China mandates that generics should be equivalent with originator drug/reference listed drug in quality and therapeutic effects.
Furthermore, China encourages the development of clinically-needed and high-quality generics. In the drug patent linkage system, China awards the first generic to successfully challenge the relevant patent drug with 12-month market exclusivity. Thus, generics have remarkable market potential in China.
This article introduces China's regulations on generic drug's marketing authorization application, also known as abbreviated new drug application (ANDA).
Article Contents:
Definition and Classification of Generic Drugs
Reference Listed Drug (RLD)
Quality and Therapeutic Equivalence
ANDA Dossier
ANDA Procedures
ANDA Fees
BaiPharm Service of Generic Drug Registration
Related Webinar
ChemLinked BaiPharm Webinar: Generic Drug Application Procedures in China
1. Definition and Classification of Generic Drugs
Generic drugs are copies that are equivalent with originator drugs in dose, safety, strength, quality, efficacy, and indication. In China, there are five general classes of chemical drugs. Generic chemical drugs are divided into Class 3, Class 4, and Class 5.2. Generic drugs only refer to chemical drug copycats, not including biosimilars.
Classification of Generic Drugs2 | |
Class 3 domestic generic drug manufactured in China | The relevant originator drug/RLD has been approved overseas only, but has not approved in China; The generic drug has the same active pharmaceutical ingredient (API), dosage form, strength, indications, administration route, and dosage with the RLD. The generic drug can demonstrate quality and therapeutic equivalence to the RLD. * The generic drug's strength and dosage can be different from those of RLD if the differences are supported by sufficient and reasonable data. |
Class 4 domestic generic drug manufactured in China | The relevant originator drug/RLD has been approved in China; The generic drug has the same API, dosage form, strength, indications, administration route, and dosage with the RLD. The generic drug can demonstrate quality and therapeutic equivalence to the RLD. |
Class 5.2 overseas generic drug imported to China | The generic drug has been approved overseas; The generic drug has the same API, dosage form, strength, indications, administration route, and dosage with the RLD. The generic drug can demonstrate quality and therapeutic equivalence to the RLD. |
Notes:
* Original drug refers to the first drug that obtains Chinese or overseas marketing authorization supported by sufficient safety and efficacy data.
* For a generic drug in the joint research in China and overseas but manufactured overseas, it should be registered as a Class 5.2 generic drug. If such drug applies for clinical trials in China, it is not required to provide the overseas certificate of pharmaceutical product (CPP).
2. Reference Listed Drug (RLD)
A generic drug applicant should choose an appropriate RLD to approve the generic drug's equivalence to the RLD in quality and therapeutic efficacy.
(1) NMPA recommends drug applicants to choose RLDs in the following order of priority:
Originator drug approved in China →
Drug manufactured by the confirmed foreign originator pharmaceutical company in China or manufactured with technology transferred from overseas to China →
Originator drug not imported to China.
(2) When the production of the originator drug is discontinued, or the originator drug is not appropriate to be an RLD, the generic drug applicant can choose an internationally recognized drug as the RLD. Internationally recognized drug refers to the drug that have received marketing approval and RLD status countries and regions with standardized management, such as the the U.S., Japan, and the EU.
(3) Other drugs can be chosen if they are confirmed by the NMPA to be qualified in safety, efficacy, and quality controllability.
China NMPA has released the Catalog of Reference Listed Drugs and will continue selecting and adding drugs to the catalog. To add a new RLD to the catalog, a generic drug applicant, drug research/manufacturing company, or industry association should submit an RLD listing application to the Center for Drug Evaluation (CDE), an office under NMPA.3
RLD Listing Application Procedures in China
3. Quality and Therapeutic Equivalence
Generic drugs need to be equivalent with the originator drug/RLD in both in vivo and in vitro performances:
3.1 Pharmaceutical equivalence for in vitro performance
Generic drugs must have the same API, dosage, administration route, and dosage form with the originator drug/RLD, and comply with drug quality standards on API content, purity, homogeneity, disintegration time, dissolution profile, etc.
In terms of non-API ingredients, generics do not have to be the same with the originators/RLDs. But for special cases, for example, an injection's excipient needs to have the same type and amount with those of the originator/RLD.
3.2 Therapeutic equivalence for in vivo performance
For oral generic drug, bioequivalence (BE) studies usually suffice to prove its therapeutic equivalence. Detailed BE requirements are specified in CDE's guidelines, e.g., Bioequivalence Guidelines on Ebastine Tablets.
However, for special oral drugs and complex dosage forms, clinical trials are required to provide efficacy data.
In 2018, NMPA made No. 32 and No. 136 Announcements to allow trial simplification or exemption of BE studies for some drugs, e.g., BCS (Biopharmaceutics Classification System) I or III oral drugs. Applicants of the listed drugs should conduct comparative chemistry, manufacturing, and controls (CMC) study and other required researches according to the Guidelines on Exempting BE Studies for Human Body. If the drug is qualified, the applicants can submit BE study exemption application with the ANDA.
4. ANDA Dossiers
Applicant should prepare the dossiers according to CTD format:
M1: Regional Administrative Information • 1.0 Cover letter • 1.1 Tablet of contents • 1.2 Application form • 1.3 Product information • 1.4 Application status (if applicable) • 1.5 Application for expediting approval (if applicable) • 1.6 Meeting (if applicable) • 1.7 Change during the clinical trial (if applicable) • 1.8 Risk management • 1.9 Post-approval studies (if applicable) • 1.10 Post-approval change (if applicable) • 1.11 Applicant's/MAH's certificate and qualification documents • 1.12 Small-and-micro enterprise certificate (if applicable) For imported drugs: • Appointment letter for the Chinese agency • Drug approval from the authority of country of origin • GMP and production authorization letter from the country of origin • Application form filled out by the Chinese agency |
M2: Summary Table for Main Study • 2.3 Quality overall summary (QOS) • 2.5 Clinical overview: analysis of clinical data in the CTD documents • 2.7 Clinical conclusion: conclusion of all the clinical data in the CTD documents |
M3: Pharmaceutical Study • 3.2.S. Drug substance • 3.2.P. Drug product • 3.2.R. Regional information |
M5: Clinical Study • BE (if applicable) • Clinical (if applicable) |
5. ANDA Procedures
China Abbreviated New Drug Application (ANDA) Procedures in China
6. ANDA Fees
Generic drug | Application | Domestic | Imported |
ANDA with clinical trial | ¥318,000 | ¥502,000 | |
ANDA without clinical trial | ¥183,600 | ¥367,600 |
RELATED: Drug Application Fees for FY 2022 in China and the U.S.
7. BaiPharm's Generic Drug Registration Service
Analyze the feasibility of registering the drug in China according to Chinese regulations;
Assist the drug applicant to add its reference drug to the RLD catalog;
Evaluate whether the drug can apply for exempting the BE study and expediting review and approval;
Help the drug applicant contact a Chinese CRO to conduct the BE study; monitor the BE study process;
Provide the list of ANDA documents;
Review the documents, conduct gap analysis, and give advice on improving the documents;
Compile, translate, review, and submit the documents in CTD format;
Track CDE's review progress, respond to CDE's deficiency letter, and submit supplemental data.
Contact BaiPharm for drug registration services.
