Last year, several inquiries to us at Modular R&D, where I am a managing partner, were from companies new to China, on the subject of filing clinical trial applications. We hear comments such as “It’s taking too long,” “I cannot give out this information,” and “Why do I need to do an expensive long-tox study for a phase II?” These are usually expressed in great frustration. So we did a workshop recently at the ChinaTrials conference, and worked with experts in regulatory affairs and preclinical studies from US, Europe and China, to look at the Chinese IND process in detail, especially how it compares to the US investigational new drug (IND) application and EU Clinical Trial Application (CTA).
In order to conduct clinical trials in China, one needs to obtain approval from the State Food and Drug Administration (SFDA). The process for doing this is called ????????, and is translated either as Clinical Trial Application (CTA) or Chinese IND (CIND).
The Chinese IND is functionally similar to the IND in the U.S. and the CTA in EU. The application process is like any other: You fill out an application form, supply required materials, submit them to the relevant agency, then wait for approval, or lack of disapproval in the case of the US IND.
The required materials are similar across the regions, with minor differences. The materials supporting clinical trial conduct are organized into four parts: Summary, CMC (Chemistry, Manufacturing, and Controls) data, pharmacology and toxicology data, and clinical trial information. Each region has its guidelines on content and format of the application materials, but the Common Technical Document (CTD) format is accepted worldwide.
Then there are the differences.
One is that the review and approval of a Chinese IND application takes a lot longer. A regular new drug application takes at least seven months, and could sometimes go to a year. This compares to the 30 day review time by the FDA and 60 day review time for the EMEA.
The reason given for the long timeline is usually the lack of personnel in the Chinese Center for Drug Evaluation (CDE), the agency under the SFDA responsible for the technical review of the application. There are around 120 reviewers in the CDE to review over six thousand applications per year. The State Council sets employment quotas at the SFDA, so hiring more people is not as simple as a corporation adding head count. The CDE went through a reform early last year, to increase the efficiency of the approval process. However, there are parts of the timeline that are not under the control of the CDE, and the published official review time is still the same as before the reform.
Another issue is that the China IND application has high CMC requirements. This is shown in two aspects. One is that sample testing is required for several types of drugs, including imported drugs being submitted for market registration. For local drug IND, not only does the drug need to be tested, the manufacturing facilities are also inspected at the time of IND submission. The other aspect, which is more challenging for international companies, is that the China IND requires extremely detailed manufacturing protocols that many drug development companies may consider sensitive or even trade secrets.
The Chinese drug approval system was developed in the context of a large generics manufacturing industry. At the beginning the agency was faced with ensuring the production quality of thousands of small manufacturing facilities, instead of the drug safety and efficacy concerns of innovative new drugs. The regulations have been improved upon four times in the past two decades, yet one still find vestiges of this generics background. The high CMC requirements are one of these.
In a way, the long timeline issue is one of the easier to deal with, since it is predictable – you should simply plan ahead if you want to integrate China into your global development plan. In working with high CMC requirements, it’s necessary to decide the company’s comfort level in terms of sharing protocols and know-how. If what is asked for goes beyond that threshold, then China plans may need to be put on hold.
Then there are sentiments such as, “Our IND is approved and we have already started clinical trials in the States, why is SFDA still asking us to do…” which are based on generalized assumptions that the SFDA will operate like the more familiar FDA or EMEA. The Chinese regulatory system adopted many parts of US and EU system, but have adaptations and adjustments based on China’s preexisting conditions. Understanding and working with these differences is a good way to avoid frustration.
We learn to drive on the left in Britain and Japan, we learn to use inches and yards in America, and when we go to Rome, we do what Romans do. The globalization of drug development sometimes requires dexterity of mind, to understand how things come to be the way they are, and when in China, do what SFDA asks you to do.