China Prepares Site For First-In-Human Studies But Safety Concerns Remain

Multinational companies have long urged China to allow first-in-human studies for innovative drugs developed outside the country. Now that wish could be getting close to reality.

BEIJING – China’s State FDA plans to identify a clinical trials site for first-in-human studies from 52 facilities that have received millions of renminbi in grants from China’s cabinet, the State Council, under its new drug development project. The agency could announce the site by year-end, disclosed Jianming Li, director of SFDA’s Center for Drug Certification.

Noting an unprecedented amount of clinical trial applications for new chemical entities from both international and domestic firms, Li said that Chinese drug regulators are increasing manpower by contracting out some review processes to third parties and beefing up the role of ethical committees through training at U.S. universities.

Although SFDA has cleared roughly 330 facilities to conduct clinical trials, vast differences exist among them, and many can only do bioequivalence testing, acknowledged Li, who is in charge of the division that conducts inspections for good clinical practices and good laboratory practices.

The agency has completed a guideline on certifying a first-in-human study site and will gather industry comments, he said. Among well-run facilities, he mentioned Peking Union Medical College (PUMC) Hospital, Peking University No.1 Hospital, Huaxi Hospital and Nanchang University Medicinal Institute.

Despite a late start, China now realizes the importance of Phase I studies to new drug development and acknowledges its large gap with international standards. In a speech given during the China GCP conference last December in Beijing, SFDA Deputy Commissioner Zhen Wu said the agency hoped to catalyze Phase I studies and categorize trial facilities to improve the overall level of drug innovation.

Facility And Investigator Uncertainty

Early-phase studies in China such as first-in-human (FIH) trials are laden with uncertainties, noted Dan Zhang, CEO of Beijing-based clinical research organization Fountain Medical Development Ltd. Zhang is a member of SFDA’s Expert Committee and former VP and GM for Quintiles Transnational Holdings Inc. in China.

China established Phase I study guidelines less than a year ago, and it has yet to establish guidelines for Phase 0 microdose studies (Also see "China Issues New Guidelines On Phase I Trials – Will It Speed Up Approvals?" - Scrip, 5 Jan, 2012.).

Uncertainties include the challenges of choosing a starting dose. Chinese regulators have concerns about the safety profiles of new drugs particularly liver toxicity. Although there is no evidence to support it, there is a long-held view among physicians that Chinese people are more vulnerable to liver damage than Caucasians, Zhang noted.

Another challenge is limited experience in conducting early-stage studies. More than 90% of GCP-compliant Phase I centers in China have little exposure to innovative drug testing, Zhang said, adding that only domestic companies have been allowed to conduct FIH studies and very few have focused on new drug development. Even Peking Union Hospital conducts studies mostly for me-too and me-better products, he noted.

In addition, no qualified principal investigators exist in China for FIH studies, he emphasized. Out of the pool of PIs at the flagship PUMC hospital, only four work full-time, while 50 work on a temporary basis. The lack of a clear career path for PIs is a key reason for shortcomings in human capacity.

For sponsors, Chinese PIs also behave more like authority figures than working partners, observed Yuhong Chen, manager of clinical research at Merck & Co. Inc. in China.

Even with a FIH study site on the horizon, “where will the PIs come from and how will they accumulate the necessary experience?” Zhang inquired, noting such worries could have been a driving force behind SFDA’s shift to consider opening such studies to foreign firms.

Furthermore, institutional review boards at Chinese facilities also lack experience reviewing studies for innovative products, noted Zhang, drawing upon his experience sitting on a review committee for Beta Pharma Inc.’s lung cancer drug icotinib. For icotinib, the IRB had concerns about the study protocol’s starting dose and the range of dosage escalation, and it took two years and 19 steps to bridge the differences, he said (Also see "Meet China’s New Innovators: Beta Pharma Redefines Innovation With “Me-Too, Me-Better” Strategy" - Scrip, 3 Aug, 2012.).

Despite the uncertainties, promising signs are emerging. According to Zhang, China is identifying IRBs and ramping up training on standards from the International Conference on Harmonization and World Health Organization. The goal is to have IRBs simultaneously review applications for clinical trial authorizations and new drug applications independent of CDE.

Backed by deep pockets, China’s Ministry of Science and Technology has granted on average RMB 15 million ($2.4 million) to each of the 52 selected GCP sites; part of the funding goes to IRB training, he added.

In fact, SFDA is also ramping up training to strengthen the role of ethical committees, Li noted, acknowledging gaps in ethical committee reviews among different facilities. Ethical committees have been singled out by the Research & Development Pharmaceutical Association Committee (RDPAC) as one area for needed enhancement (Also see "China Enhances Data Management, Communication For IND Approvals" - Scrip, 4 Jun, 2012.).

One proposal is to establish regional ethical committees, instead of current site-based committees, and encourage well-run university committees to take on bigger roles. Meanwhile, the agency also received training assistance from Harvard and Duke Universities, Zhang said.

Using third parties to ease CDE’s severe staffing shortage has been one of SFDA’s priorities, Li added. Two laboratories, one in Shanghai and one in Beijing, have been approved to conduct toxicology tests for registration purposes.

China’s State Council, eager to showcase breakthroughs in major drug development, will also increase headcount at CDE and SFDA to accelerate the approval process, predicted Zhang.

Benefit From Local Partnerships

However, challenging the perception that foreign companies could use Chinese people as human guinea pigs has been another priority for SFDA, said Zhang.

For multinationals, the best way to proceed is to partner with local firms, he said. Local R&D focused companies such as Simcere Pharmaceutical Group and Jiangsu Hengrui Medicine Co. Ltd. have built up their research capacity in the last few years.

Simcere, for example, inked a second development deal with Bristol-Myers Squibb Co. earlier this year after a similar deal was signed in 2010 (Also see "Simcere Teams Up Again With Bristol-Myers For Co-Development In China" - Scrip, 14 Dec, 2011.).

MNCs will also benefit from collaborating with academics and key opinion leaders through early-stage studies in China. Such partnerships demonstrate commitment to China as an important market, noted Merck’s Chen.

Given the acute CDE staffing shortage, where roughly 80 reviewers handle thousands of applications, early familiarization and collaboration with regulators and key opinion leaders is especially important in China, she stressed.

“Collaboration will have a good impact early on,” she said. “For pharmaceutical companies, it helps for well-prepared dossiers to address safety issues. And that’s why Merck has its R&D center in Beijing.” One year ago, Merck unveiled its $1.5 billion R&D investment in China, the largest ever for Big Pharma (Also see "Merck Unveils $1.5 Billion Expansion In China With New Beijing R&D Center; Plans To Double R&D Team By 2014" - Scrip, 7 Dec, 2011.).

China has seen clinical trial applications surge in recent years; SFDA granted a record 39 CTAs in 2011, a three-fold increase from 13 in 2009 (Also see "Five NCEs Approved In China In 2011: A Closer Look At SFDA’s Progress Report" - Scrip, 11 Oct, 2012.).