Smoother Regulatory Process for China

In August 2015, the China State Council issued opinions on reforming the evaluation and approval system for drugs and medical devices to set up goals for the China Food and Drug Administration (CFDA).¹ The CFDA was pushed to accelerate its activities to promulgate new or updated regulations and guidelines. Nearly one year has passed, and after a glance at all the new policies, we can see the reforms are really rebuilding smoother processes for innovative drug development in China.

Optimizing clinical trial application evaluation and approval

In addition to international multi-regional clinical trials, stand-alone synchronous clinical trials for imported new drugs not yet marketed overseas are allowed in China. Although first-in-human trials for imported new drugs are still not encouraging in China, some big pharmaceutical companies have received approval this year to conduct stand-alone synchronous clinical trials in China for imported new drugs not yet marketed overseas.

Meanwhile, the one-time approval model has been adopted for clinical trial applications of new drugs and the phased application-evaluation-approval approach has therefore been abandoned.² The CFDA will place emphasis on the evaluation of scientific clinical protocol and control of safety risks for clinical trial applications. Applicants should submit the research results and next-phase clinical trial protocol after completing Phase I and II studies. Those applicants without safety issues can move into the next-phase trial after communicating with the Center for Drug Evaluation (CDE). However, applicants must report serious adverse drug reaction events truthfully and submit timely research reports annually. Those trials failing to control safety risks will be stopped immediately.

For an imported drug intended to treat special clinical needs (especially for pediatric drugs or rare disease drugs) and already marketed in the U.S., EU or neighboring regions of China, relevant clinical trial data completed overseas may be used for the drug registration applications. Conditional market authorization approval will be considered by the CFDA on a case-by-case basis without requiring additional trials in Chinese patients or requiring only limited trials in Chinese patients.

As of Dec. 1, 2015, bioequivalence studies have been made subject to a filing system instead of the approval system used before. The formula, process and production line used for bioequivalence study samples should be the same as those in the commercial production. Dossiers for bioequivalence studies should be filed with the CFDA 30 days in advance of studies. The CFDA may terminate the bioequivalence study anytime if it determines the study failed to meet relevant requirements.

Strengthening Communications between applicants and CFDA CDE

In June 2016, the CFDA promulgated a regulation to streamline the drug development and technical review communication between the agency’s Center for Drug Evaluation (CDE) and the applicant.³ The CFDA adopted communication procedures similar to those used in U.S., with some small differences. Previously, the application channel for the communication meeting between the CFDA CDE and the applicant was not clear; only meetings for drugs under special review were commonly approved. With this new regulation, it is easier for applicants to get the opinions of CDE reviewers to guide their drug research and development processes.

Shortening the application timeline

1. Backlog reductions of registration applications

Multiple measures have been taken by the CFDA to resolve the backlog of registration applications. The CFDA is trying to clear the backlog inventory before the end of 2016 and is attempting to meet the regulation-specified timelines in 2018.

Since the CFDA increased the drug registration fee significantly⁴ (hiking fees for various applications by approximately 1,000%), the CFDA CDE has been recruiting more technical reviewers to resolve the resources issue. The number of CDE reviewers is expected to reach 500 by the end of 2016, up from only around 100 in early 2015. In addition, depending on the needs of the evaluation, relevant external experts may be hired to take part in relevant technical evaluations. The CFDA also plans to assign some evaluation tasks to provincial review centers and may establish one CDE sub-center in Shanghai.

For new drug applications that have already been accepted by the CFDA, the applicants need to file a self-inspection report on their registration trial to the CFDA. Then the CFDA will carry out a separate on-site inspection for each drug registration based on the review process. If a falsification issue is found, an investigation shall be initiated and the corresponding registration applications shall not be approved. Additionally, the direct responsible persons will be subject to severe punishments by law, and research institutions issuing false trial results will be prohibited from conducting trials in China with the punishment results to be disclosed to the public.

However, if an applicant actively withdraws the application before the CFDA inspection, the CFDA will not investigate the potential falsification. This policy was implemented first in July-August 2015; at that time, the CFDA asked sponsors to self-audit 1,622 NDAs.⁵ Since then, nearly 80% of NDAs have been withdrawn by applicants.

For accepted applications of the same type of products, the CFDA conducted a centralized review based on the unified evaluation criteria and standards. This policy facilitated the review of clinical trial applications: The CDE has completed the technical review on thousands of CTAs since September 2015.

2. Implementation of priority review procedure

To expedite the review and approval of innovative drugs with clinical value, the CFDA released its opinion on the priority review for drug applications in China in February 2016.⁶ Priority review can be granted to applications:

• For innovative drugs not yet launched in domestic and overseas markets

• For innovative drugs such as for the prevention and treatment of HIV/AIDS, malignant tumors, major communicable diseases, rare diseases and diseases with a high incidence in, or is unique to, elderly people, etc.

• For pediatric drugs

• Requested by an applicant who has both filed the same application and received approval to conduct a clinical trial in the U.S. or EU.  

If priority review is granted for the applications, the review timeline will be significantly shortened. It is expected approval could be obtained within about six months after submission for both the clinical trial application (CTA) and the new drug application (NDA). In comparison, the current timeline is 12 to 18 months for the CTA and around 24 months for the NDA in China. It is important to note that having pre-application communications with the CDE seems critical to ensure the quick review initiation within the CDE.

Conducting pilot program of MAH system

The current legal framework in China only permits drug manufacturers to obtain regulatory approvals and has been perceived as an obstacle to innovation. R&D-based companies have had to commit to a substantial investment in manufacturing facilities in order to commercialize their assets.

To create a more supportive regulatory framework for innovation, the Standing Committee of the National People’s Congress authorized the State Council to roll out a three-year pilot program of the MAH system in 10 provinces.⁷ Under the CFDA’s proposed MAH pilot program, domestic drug manufacturers, domestic R&D institutions and research personnel of Chinese nationality can obtain regulatory approvals to commercialize pharmaceuticals in principle and completely outsource the actual manufacturing to contract manufacturing organizations. Nevertheless, MAH applicants must arrange for insurance or financial guarantee to cover product liabilities.

Conclusion

In the upcoming months, China’s drug administration law and drug registration regulations will be updated again, and there will be more regulations related to the implementation of the country’s new policies to streamline drug development. As the regulatory environment of China is being improved gradually, it is expected more and more sponsors of international multi-country clinical trials (IMCTs) will consider including China for good reasons: more patients to accelerate the trials, lower costs and quicker imported drug registrations in China for the IMCT pathway. Similarly, more foreign companies will start to develop products mainly in China for some specific indications with high incidence rates in Chinese patients such as hepatitis C and stomach cancer. 

For companies with development activities in China, now is good opportunity to change your strategy to that you will be able to market your product in China earlier. 

Kai Zhang, Regulatory Affairs Associate Director, AP Region, Chiltern

References:

1. Opinions of the State Council on Reforming the Evaluation and Approval System for Drugs and Medical Devices, available from link: http://www.gov.cn/zhengce/content/2015-08/18/content_10101.htm
2. Announcement of China Food and Drug Administration (“CFDA”) on Certain Policies for Drug Registration Review and Approval, available from link: http://www.sfda.gov.cn/WS01/CL0087/134665.html
3. Drug Development and Technical Review Communication Administration (trial version), available from link: http://www.cfda.gov.cn/WS01/CL0087/155022.html
4. Announcement of CDFA on the Registration Pricing Standards of Drugs and Medical Devices, available from link: http://www.sfda.gov.cn/WS01/CL1411/120201.html
5. Announcement of CFDA on conduct self-check and inspection on drug clinical trial data, available from link:  http://www.sda.gov.cn/WS01/CL0087/124800.html
6. Opinions on Implementing Priority Review and Approval and Resolving the Backlog of Drug Registration Applications, available from link: http://www.sfda.gov.cn/WS01/CL0844/145260.html
7. Announcement of the State Council on drug market authorization holder (MAH) policy pilot protocol, available from link: http://www.gov.cn/zhengce/content/2016-06/06/content_5079954.htm