1. Overview of Drug Administration in China
1.1 Regulatory Affairs Profile
China has established a quite streamlined drug regulatory system from nearly zero base during the last thirty years along with its national policy of reform and opening-up. SFDA and its affiliates play a key role in this system; they make decisions on approvals, additional requirements or exemptions. However, there are still many defects and loopholes in both process and regulations such as that provisions and guidelines are found vague or lack of explanations; and these flaws are part of the reason that regulation time takes longer than other countries. Knowing its deficiency, Chinese regulatory system is continuing evolving; it is trying to keep up with the standards of EU, USA and Japan.
With protection of IPs, quality standards embodied by GxPs, efforts on regulatory clarity and more and more emphasis on innovation, China is striving hard to make progress on drug regulation to ensure safe and effective usage in medication. Following the national strategy of innovation, it inclines to encourage “real” new drugs and get more and more stringent on generic drugs, and a more science driven regulatory system with enough clarity is expectable in China.
1.2 Regulatory Agencies
In 2003, State Food and Drug Administration (SFDA) was established to replace the State Drug Administration (SDA) with expanded functions. The SFDA was modeled after the US FDA, and operates under supervision of the Ministry of Health.
With its provincial, municipal and county branches, the SFDA is the governing body that regulates all drugs, medical devices, food, health food and cosmetics and controls all registrations, inspections, sales, researches and advertisings for these products. The SFDA is also in charge of all new drug registration approvals.
Among its affiliated units, National Institute for the Control of Pharmaceutical and Biological Products (NICPBP), Center for Drug Evaluation (CDE), Certification Committee for Drugs (CCD), Center for Drug Reevaluation (CDR) and Chinese Pharmacopoeia Commission (CPC) take very important roles in registration and manufacturing regulation process.
1.3 Laws and Regulations
1.3.1 Laws
The basic regulations for the government’s administration of the pharmaceutical industry in China are outlined in two fundamental laws. These laws regulate all pharmaceutical areas, including drug manufacturers, drug distributors, pharmaceutical use in medical institutions, new drug registrations, drug packaging, pricing, advertising, and post-marketing surveillance.
First, the Drug Administration Law of the People’s Republic of China was revised at the 20th Session of the Standing Committee of the 9th National People’s Congress on February 28, 2001 and became effective on December 1, 2001. This law controls all pharmaceutical areas from R&D, manufacturing to marketing and circulation of drugs. Since its first edition in 1985, it is the basis of whole Chinese drug regulation system.
Second, the Regulation for the Implementation of the Drug Administration Law of the People’s Republic of China was approved by the State Council and became effective on September 15, 2002. It is a corresponding law for maneuverable operation of Drug Administration Law.
1.3.2 Regulations, Guidance Related to Product Registration
1.3.2.1 Drug Registration Regulation
The Drug Registration Regulation in China has undergone four revisions since its first version in 1985. After that, it went through version 1999, 2002, 2005 and the latest fifth version (Order 28), which was enacted on October 1 2007. The regulation has been changed significantly over the twenty-year development. The newly revised regulation emphasizes on safety, efficacy and quality control of drugs, as well as ensures the registration processes and procedures judicial, fair and open. The current regulatory system is built on joint accountability system, staff briefing and challenge system, and responsibility assigning system. The most important improvement is that all regulatory processing activities should be under the public surveillance. Compared to the previous versions, the newly revised regulation encourages innovation and sets a lot of limitations for the generic drug applications.
1.3.2.2 Special Evaluation and Approval Procedure
The introduction and implementation of Special Evaluation and Approval Procedure, issued on January 1st 2009, outlines detailed regulations on the special review and approval process for innovative new drugs. Other than raising GMP standards in more facilities and more stringent IP protection, Special Evaluation & Approval Procedure shows the government’s commitment to encourage research and development of new drugs and to treat difficult and life threatening diseases by exercising the approval via a special process designated for innovative new drugs, as outlined in SDFA order 28. For drugs meeting following criteria, the applicant can win more support from the government. The threshold for applying this special process is to meet at least one of the following criteria:
a) New drug material and its preparation, active ingredients and its preparation extracted from plant, animal and minerals, which have not been marketed in China ;
b) Chemical drug substance and its preparations, and/or biological product that have not been marketed domestically and outside China;
c) New drugs for treatment of AIDS, cancer and orphan disease and have significant efficacy
d) New drugs for treatment of the diseases which have no effective therapy.
Special Evaluation and Approval Procedure grant applicants 10 days less than normal evaluation (90 working days) and chances to make easy communication with CDE evaluation staff.
1.3.2.3 Rules for Registration of Drug Technology Transfer
Besides 20 years protection by Chinese patent law, five-year market exclusivity and six years of protection for the data from local clinical trials are granted to new drugs.
In 2009, a new regulation on Rules for Registration of Drug Technology Transfer was published for public opinion. The objective of this regulation is to facilitate licensing of new drug product and technology and transfer of manufacture process. The government is expecting to optimize and upgrade Chinese pharmaceutical industry and product structure. According to this regulation, it is permitted to transfer the production process of imported drug to domestic manufacturer in China. Although execution detail of this process is not yet to become available, this regulation opens a new pathway for the development of imported drug.
1.3.2.4 Technical Guidance Related to Drug R&D
In order to improve and standardize drug R&D activities in China, SFDA has promulgated 80 technical guidelines, covering guidance to chemical drug, TCM, biological product, integrated disciplines and general principles. Although it is a long way to establish a comprehensive guidance system like FDA who has more than 500 technical guidelines, SFDA is continuing working on it. Introduction of ICH guidelines and promoting international mutual recognition are also on SFDA’s to-do list.
2. Drug Registration
2.1 Drug Category and Classification
In Drug Registration Regulation SDFA order 28, a drug should be fallen into one of the following 3 categories, namely small molecule, biological product and traditional Chinese medicine. Under these 3 categories, there are various classes. There are 6 classes for new Chemical Drugs, 15 classes for Biological Drug, and 9 classes for Traditional Chinese Medicine. The provisions define these classes mostly by demonstrating and distinguishing how a drug and its preparation process have been marketed, especially in regards to China. For example, Class 1 of Chemical Drugs refers to a new drug which has never been marketed in any country, while Class 3 of Chemical Drugs refers to a new drug which has only been marketed outside of China.
2.2 Drug Registration Application Category
Besides the drug category and classification, according to Article 11 of SDFA order 28, drug registration applications themselves are also divided into three different types, namely (1) Domestic New Drug Application, (2) Domestic Generic Drug Application, and (3)Imported Drug Application. These three types of applications are described as below.
2.2.1 Domestic New Drug Applications
A new drug application means a registration application for a drug that has not been marketed in China, and the drug should be produced within China mainland. Applications for a change in dosage form, or route of administration, additional new indication of marketed drugs shall be regulated as new drug application procedure too. Classes that fall into this category include Class 1 to 5 for new Chemical Drugs, Class 1 to 14 for new Biological Drugs, and Class 1 to 8 for new Traditional Chinese Medicine.
2.2.2 Domestic Generic Drug Applications
Generic Drug Application means a registration application of drugs for which SFDA has already established the official standards; Generic Drug Application can be used for drugs class “that already have a national standard in China”, which are Class 6 of Chemical Drugs, Class 15 of Biological Drugs, and Class 9 of Traditional Chinese Medicine.
2.2.3 Imported Drug Registration
Chinese regulations take the manufacturer as main body of an application, thus if the manufacturer is located out of China mainland, the drug will be under the administration of Imported Drug Registration. According to SDFA order 28, the precondition for approval of Imported Drug Registration is that the drug should have obtained marketing authorization approval in other country or region.
1) For imported drug application, in case CPP (Certificate of Pharmaceutical Product) is not available at beginning of CTA(clinical trial application) submission, it will be under the administration of New Drug Application category 1 for requirement on dossier, clinical trial and timeline;
2) For imported drug under original brand, in case CPP can be available at beginning of CTA submission, it will be under the administration of New Drug Application category 3 for requirement on dossier, clinical trial and timeline;
3) For imported generic drug, even the CPP can be available at beginning of CTA submission; SFDA will only regulate it as Generic Drug Application on requirement of dossier, clinical trial and timeline.
2.3 Drug Registration Requirement
2.3.1 Application Documents
The application documents of drug registration application consist of four sections:
> Summary materials
> Pharmaceutical research materials
> Pharmacological and toxicological research materials
> Clinical research materials
For each section, the SFDA has issued detailed documents list for (1) Chemical Drugs, (2) Biological Drugs and (3) Chinese Traditional Medicine. Different drug classes have different requirements for the above documents. Registration document requirements in China all follow ICH guidelines, meaning that requirements are fairly similar for China, the United States, and the European Union.
Overall, during the registration process, pharmaceutical companies should not encounter problems with different data requirements in China vs. in other foreign countries. However, when an applicant is reluctant to submit sensitive, proprietary info, or to divulge information about the manufacturing process or quality control of raw materials, problems often arise.
2.3.2 Specification Verification
Drug Registration Testing is mandatory for all kinds of drug registrations, the difference only lies on when and how many batches sample will be requested. For example, for imported drug registration, the applicant should submit 3 batches sample automatically to NICPBP for testing at CTA stage; For domestic New Drug Application, for chemical entity, 3 batches sample will be sampled by the PFDA only at the beginning of Production Application stage; while for the biological product, 3 batches sample will be sampled by the PFDA both at the beginning of CTA and Production Application stage.
For Drug Registration Testing, first, NICPBP will develop a Chinese specification based on the proposed in-house specification and Chinese pharmacopoeia, then NICPBP will carry out a QC testing according to the Chinese specification draft. When the product is granted marketing authorization by SFDA, the Chinese specification draft will become as the official Drug Registration Specification and will be used as specification for quality control of commercial goods.
Additionally, local Quality Control testing repot is requested by CDE to draw final conclusion of the evaluation; failing to submit the QC testing report to CDE will leads to delay of the evaluation timeline.
2.3.3 Requirement on Local Registration Trial
Drug registration in China is getting regulated more stringently over last two decades. Local drug clinical trials are requested mandatorily to get product registration.
SDFA order 28 has detailed the clinical requirement for different drug categories, drug classifications and application types accordingly. Additionally, clinical trials can only be conducted in China after obtaining CTA approval from the SFDA, and are only permitted to be done at hospitals that have been accredited by SFDA. Effective on March 1, 2005, no registration clinical trials in China can be conducted in non-accredited clinical research centers.
For imported drugs, only data from local clinical trials can be counted in local registration. Even a product is approved elsewhere in the world, SFDA most likely still requires the foreign manufacturer to conduct at least one study in China before approval. Results from overseas clinical trials can only be regarded as referential clinical data.
Requirements on clinical trial for different situations of imported drugs are shown as below:
Regulatory Status
Clinical Requirement
New drug never marketed in any country at CTA stage
1) Phase 1, phase 2 and Phase 3 trial
2) The sample size should meet the statistic power
Drug marketed ex-China but not yet marketed domestically
1) Pharmacokinetics study and abbreviated phase 3 trial with 200 cases
2) Or abbreviated phase 3 trial with 100 cases for treatment arm only
Drug product with changed dose form, but no change of administration route, and the original preparation already approved in China
1) Bioequivalence study only
Drug substance or product following a national standard
1) Clinical trial waived
2) Or BE study
3) Or Clinical trial with 100 cases for treatment arm
2.4 Drug Registration Process
In China, the drug registration process is different from that in EU and North America, also different from other Asia Pacific countries. The process includes two applications, before and after the clinical trial.
The first step in this process is to submit an application to the SFDA for a Clinical Trial Application (CTA). The SFDA will conduct a preliminary review of the submission package and then transfer the dossier to the Center for Drug Evaluation (CDE). Reviewers with background in pharmaceuticals, pharmacology and clinical study will run a technical review, while local sample testing will also be conducted in parallel. Few CTAs would pass through the CDE review in one single round. However, most applications will receive supplement notice(s) in writing to request additional information for further assessment. In such case, CDE will allow a 4-month period for applicant to gather and submit additional requested information to CDE. This entire CTA step usually takes at least 125 working days.
The second step in drug registration is Production Application (or Imported Drug License Application), which involves submitting a clinical report and other relevant dossiers to obtain an imported drug license. The process itself is basically the same as the CTA step. This second step will take approximately 145 days.
In general, Clinical Trial Application (CTA) is analogous to the IND in US; and Production Application (or Imported Drug License Application) is comparable to NDA in US.
2.4.1 Different CTA Approaches
As mentioned above, in China, it is not possible to get marketing authorization without local registration clinical trial. In addition, no clinical trial can be initiated without SFDA’s approval on CTA. Hereafter are a brief summary of all kinds CTA falling into the different Drug Registration Application Category.
2.4.1.1 CTA under Name of Imported Drug Registration
If the sponsor starts the CTA under the name of Imported Drug Registration with CPP, requirement of clinical trial is plain and straight, usually a local bridging study (data of 100 pairs of subjects and/or a PK study) is sufficient to move forward to the marketing authorization stage. It is the most common scenario for products already marketed in other countries.
If the sponsor starts the CTA under the name of Imported Drug Registration without CPP, an entire clinical trial program from Phase I to Phase III is required to move forward to the marketing authorization stage. It is an aggressive scenario for imported drugs not marketed anywhere in the world.
2.4.1.2 CTA under Name of Domestic New Drug Application
This CTA pathway follows requirement of domestic New Drugs Application, on-site inspection from provincial FDA is a must. It is the common scenario for product developed by domestic company, and local benefits and sometimes support from local government are possible.
While since controlling system of drugs in China is based on manufacturer location, if the manufacture of final product is transferred to subsidiary or JV or a third party in China, CTA from this entity is regarded as the first stage of domestic NDA no matter the subsidiary or JV is 100% owned by a foreign company. Thought it is a full local clinical program independent to global development, it provides an alternative R&D development path.
2.4.1.3 International Multi-center CTA (Int’l CTA)
In Article 44 of order 28, if the drug has been already registered abroad or entered into phase 2 or phase 3 clinical trials in other country, and the foreign applicant who would like to conduct an international multi-center clinical trial in China, Chinese Drug Registration Regulation provides a channel under of International Multi-center Clinical Trial Application (Int’l CTA). The only difference between Int’l CTA and imported drug registration is that the purpose from the regulatory perspective for Int’l CTA is to conduct clinical trial in China only. Upon completion of the study, the applicant shall submit the final study report to SFDA, and then this regulatory procedure is over automatically. However, Int’l CTA for First-in-Human (FIH) study or vaccine study is forbidden.
3. Drug Registration Strategy for Imported Drug
Though differ types of CTA provide different ways to conduct clinical trial in China, for any sponsor, the ultimate goal is to receive marketing authorization. Because of the long regulatory process and duration, it leads to a long registration lag compared to other countries. Meanwhile, China’s growing pharmaceutical market has provided many new opportunities for drug companies to conduct clinical trials in China. The greatest incentive for these opportunities is the enormous potential for cost-savings in clinical study as well as a large population pool, which is translated into a faster enrollment.
Chinese SFDA doesn’t currently engage in a simultaneous IND submission process, so for applicants who are seeking a short cut within the existing regulations to shorten the registration lag, the only way is to add China to the global development and start CTA under different name as earlier as possible after overseas clinical program enters Phase II,. Optimally it is possible to obtain imported drug license within one year after getting marketing authorization one year after the approval in original country.
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