Major Clinical Trial Reforms Underway in China’s Regulatory Environment

Bill Wang, director of regulatory affairs, discusses China’s regulatory environment.

As the second-largest pharmaceutical market in the world, China offers great opportunities. However, historically, the country’s regulatory environment has been considered a highly challenging one with:

• Heavy backlogs of drug applications
• Long regulatory review timelines
• Quality issues of local drugs

In response, the central government issued its notification “Opinions on Reforming the Review and Approval System for Drugs and Medical Devices” in August 2015, which many consider as the start of major China regulatory reform. Its main purposes are to:

• Eliminate the backlog
• Upgrade the quality of generic drugs
• Encourage new drugs R&D in line with global development
• Improve the quality and transparency of the review and approval process

Actions to benefit drug development

Accordingly, the China FDA (CFDA) has taken the following actions:

1. Clinical trial data self-inspection — To upgrade data quality to avoid any inauthentic or incomplete clinical data, CFDA now requires all NDA applicants to perform self-inspections on their clinical trial data and submit an inspection report along with their NDA package, after which CFDA will conduct its own inspection or audit.
2. Hire more drug reviewers in the Centre for Drug Evaluation (CDE) — The primary reason for the long review timeline and the heavy backlog is the limited number of CDE reviewers. In 2015 there were only around 70 reviewers to handle 8,000+ applications. Following a new hiring program, 600 drug reviewers had been put in place by the end of 2016 and more hirings are planned over the next few years.
3. Priority review process — Encouraging new drug innovation, the CFDA launched a priority review process in 2016 for IND and NDA applications. Scope includes new chemical entities (NCE) not yet approved anywhere, approval for global clinical trials in China (trials that also include the U.S. and/or EU) and new drugs for rare diseases, HIV, oncology and pediatrics. Since being implemented, the IND approval process has reduced the timeline from around 12 months to less than six months.
4. Generic drug quality and efficacy consistency evaluation – In order to tackle the high variability in quality of generic drugs marketed in China, CFDA has started requiring generic drug makers to perform consistency research on the quality and efficacy of their products. CFDA requires the comparator product to be the “innovator drug,” or a globally recognized similar drug. A generic company may have previously performed the comparative study, but if the comparator was not the innovator drug, they need to repeat those studies.
5. New programs for the market authorization (MA) holder — Previous regulation did not allow the new drug innovator to hold the market authorization if it did not have its own manufacturing plant. This change is a major incentive that makes it possible for local new drug innovators to hold the MA independently, while, on the other hand, assuming all the responsibility for drug quality.
6. New classification and definition of new drugs — That includes “new to the world” instead of “new to China” based on the global marketing approval status and the location of the manufacturing site. This removes the previous definitions that were based on the specific status in China, and becomes closer to other countries’ regulatory agencies.

Changes announced by the CFDA

On March 15, 2017, the CFDA announced its decision to change the requirement on import drug registration. The main purpose of this change, which is still under public consultation and not yet effective, is to encourage foreign-developed new drugs to hold clinical trials in China and outside China in parallel, and to minimize the drug lag.

Other changes include:

• Open first-in-human Phase I trials to global companies
• Simplify unreasonable processes for foreign-drug registration, such as changing from “3-submission-3-approval” to “2-submission-2-approval.” This change can shorten the whole process by at least one year
• No longer need to wait for approval in any other country. The applicant can make the NDA submission in China without the foreign country’s certificate of pharmaceutical product (CPP).

These three changes have the potential to offer significant positive impact for foreign-developed new drug innovators. They can have a full clinical development program inside China with a much shorter regulatory review process, and China MA approval can be conducted in parallel with the U.S. or EU.

On May 12, 2017, CFDA announced four new guidelines to further encourage innovation in drugs and medical devices. These seek to:

• Reform clinical trial management
• Accelerate the drug and medical device registration review process
• Enhance drug and medical device lifecycle management
• Protect innovator’s rights

These, too, are under public consultation and are not effective yet.

China’s increasingly confident market

In mid-June, the ICH Assembly approved CFDA as a new regulatory member, and Pharmaceutical Inspection Co-operation Scheme (PIC/S) as a new observer. Joining ICH means China will follow all ICH guidance and requirements.

In conclusion, these regulatory reforms exemplify the China government’s confidence in opening the pharmaceutical market and encouraging new drug innovation. Shorter review timelines and more harmonized or globalized requirements and processes make it possible for local innovators in China and foreign new drug companies to have clinical development in China and to have drug registration and approval in China in parallel with other countries.

Global companies with headquarters outside China may not be familiar with what has happened in China and how it may impact the global industry. Strong local China regulatory expertise is increasingly important to closely monitor these changes and ensure accurate and timely communication to all stakeholders.

In addition, regulatory strategy consultation and assessment for China will need to be prepared and agreed upon to have a clear understanding of all the global scenarios. This could include many opportunities, challenges, benefits and difficulties. But, it will enable an expanded understanding of how China can be effectively integrated into the global program.

Bill Wang is a director of regulatory affairs for PPD in China.