By Cathy Yarbrough
Over the past decade, China has overhauled its regulations governing drug development and approval. In addition to encouraging medical innovation, China’s regulatory reforms are designed to improve the quality of the drugs developed in the country and the efficiency and transparency of the nation’s review process for Investigational New Drug (IND) applications and New Drug Applications (NDAs), said Fan Jin, Head of Covance China Bioanalytical Lab, which is located in Shanghai.
China’s overarching goal is to be included at any stage in global biopharmaceutical companies’ clinical trials, said Fan, who spoke at the AAPS webinar, Challenges and best practices in supporting clinical bioanalysis in China, on March 20, 2020.
Global biopharmaceutical companies can now obtain priority review and fast-track approval for investigational compounds that target unmet or urgent medical needs as well as for drugs with obvious therapeutic advantage against such diseases as cancer, AIDS, and pulmonary tuberculosis.
China also allows global companies to obtain conditional approval for drugs against life-threatening diseases for which an effective therapy is not available. Drugs that are significantly more effective than existing therapies also can obtain conditional approval, Fan said.
In addition, China has reduced the time period between IND submission to patient enrollment in a clinical trial to 8 to 10 months. The country also joined the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and has adopted several ICH guidelines.
The biopharmaceutical industry is paying attention to China’s new drug regulations. “The establishment of fast-track processes and alternative regulatory paths have created greater interest from multi-national pharmaceutical companies seeking to expand their development programs in China,” Fan said.
As a result, global pharmaceutical companies have been obtaining more drug approvals in China. Drug approvals achieved by global companies totaled 3 in 2016, 39 in 2017, 40 in 2018, and 41 in 2019. China-based pharmaceutical companies’ drug approvals totaled 2 in 2016, 1 in 2017, 11 in 2018, and 12 in 2019.
Both global and local biopharmaceutical companies are conducting more clinical trials in China.
In 2017, China was the site of 1,500 clinical trials, more than double the number of trials that were held during the previous year. Since 2015, most of the growth in China from global companies has occurred in preclinical research and phase 1 trials.
In 2018, over 350 INDs for new chemical entities (NCEs) and over 150 INDs for biologic drugs were submitted to the National Medical Products Administration (NMPA), China’s version of Federal Drug Administration (FDA) and European Medicines Agency (EMA). The NMPA, formerly known as the China Food and Drug Administration, reviews and approves clinical trial applications for drugs to be registered in China.
For a global biopharmaceutical company, the first step in China’s IND application process is a communications meeting with the NMPA’s Center for Drug Evaluation. NMPA uses the meeting to determine the integrity of the data in the company’s IND application as well as the company’s ability to ensure the safety of clinical trial participants, Fan said.
All pre-IND documents must be written in Chinese. In addition, the IND applications must be reviewed and approved by an ethics committee (EC) in China. A global pharmaceutical company cannot initiate a clinical trial in the country without the approval of not only the NMPA and EC but also the Human Genetic Resources Administration of China (HGRAC), said Fan.
Because about three months is needed for the HGRAC review process, global companies should apply immediately to HGRAC after securing IND and EC approval, she added.
A global biopharmaceutical company that wants to export human samples such as plasma, serum, and tissue slides from a clinical study in China must obtain export permits from both the HGRAC and the Chinese Customs Bio-Sample Exportation (CCBSE). Permits must be obtained for each shipment. CCBSE’s review of a permit application can require more than two months.
Obtaining permits to export biological samples is a challenging and time-consuming process, said Fan. “There is almost no way to export human wet tissues or tissue blocks out of China,” she said. As a result, she recommended that global biopharmaceutical companies conduct their bioanalysis work in China if they sponsor a clinical trial in that country or have a Chinese study arm in an international trial.
The minimal likelihood of securing export permits for biological samples is not the only reason that high quality, comprehensive bioanalytical services must be available in China, said Fan. To register a new drug in China, global companies are required by NMPA to conduct pharmacokinetics and phase III studies in the Chinese population.
All bioanalysis work in an international clinical trial must be consistent. Thus, method transfer and validation followed by cross validation should be conducted in China to ensure that the bioanalysis data generated in the country are comparable to the data produced at other clinical trial sites.
Over the past decade, NMPA has issued new guidance to bring China’s bioanalysis regulations in line with international standards. For example, in 2011, the agency issued guidance for clinical trial bioanalytical laboratory management that is very similar to Good Clinical Laboratory Practices (GCLP). Four years later, the China Pharmacopeia issued guidance for bioanalytical method validation that is like FDA and EMA guidances.
Fan said that these and other changes in China’s regulation of bioanalysis work have resulted in self-inspection and verification of clinical data for NDA submissions. In addition, clinical trial on-site inspections now routinely occur for NDA applications in China.
China’s drug regulatory reform has improved the country’s capabilities in regulated bioanalysis, she said. Before July 2015, clinical sample analysis was conducted primarily by hospitals and research institutes in China, and the quality of their bioanalysis work varied. After NMPA mandated self-inspection and data verification of clinical studies in 2015, Fan said that “high quality standards and routine inspections became the norm.” Today, GCLP compliant contract research organizations (CROs) conduct most of the clinical sample bioanalysis in China, and the quality of their work is at an international scale, she said.
For their bioanalysis work in China, Fan recommended that global companies select a lab that has extensive experience in supporting clinical studies in that country and that is knowledgeable about NMPA’s requirements for IND submissions and NDAs.
Fan said that quality standards and technical expertise vary among bioanalytical suppliers in China. Thus, global companies should select a CRO with technical expertise and a strong track record in international regulatory inspection.
For CROs in China, the training and retention of experienced staff are a challenge, she said. “Because the Chinese biopharmaceutical development sector is expanding, qualified employees have many job options at pharmaceutical companies and CROs in the country,” she said. To retain experienced staff, CROs in China should provide career development opportunities including training in new technical capabilities, drug development, client communication and project management.