McDermott Will & Emery Henry (Litong) Chen April 5 2012 With increasing investment in research and development by foreign companies in China, assuring the reliability and efficiency of the drug and device development process is a critical priority. However, this investment comes at a time of increasing concern over the efficiency and integrity of the clinical trial process in China and of complaints that the drug-licensing process has become a bottleneck for the introduction of new drugs and devices in China. There are three phases to the drug licensing process in China. Stage 1: Apply to conduct a clinical trial. Stage 2: Conduct the trial. Stage 3: Apply for a license to import drugs (for non-Chinese drugs) or to manufacture drugs (for Chinese drugs). It takes around 155 working days to complete Stage 1. Typically, the Center for Drug Evaluation (CDE), a drug review body under the State Food and Drug Administration (SFDA), will require an applicant to provide supplementary documents within four months to support the application for the clinical trial. In Stage 3, the application for a license to import drugs takes approximately 185 working days, while a license to manufacture drugs takes even longer. Stage 2, the clinical trial, can easily take up to four years. Therefore, the entire process of obtaining a drug license could take between four and six painstaking years, although it is possible to speed up the process under some special circumstances. The Chinese Government has taken measures to reduce application procedures and increase the efficiency of the drug-approval process. CDE Reform Under the old system, technical evaluations of drugs were delivered to one of four CDE review departments, each operating its own pharmacology and toxicology divisions. The CDE is creating a single department in charge of both that will review all drugs. The CDE has also established an independent support division to conduct biostatistical analysis, and a management department that will oversee and coordinate nine divisions, and communicate with drug sponsors. In addition, a research and evaluation department has been added to draft technical review guidelines and conduct assessments of reviews. The CDE aims to approve an application for clinical trial within six months.
Encouraging Innovation Over Generics The SFDA has changed its system to adopt a strict review and approval policy on generic drugs and give more leeway to the review and approval of innovative drugs if the drugs have clinical value and can be massproduced. As a result of the new policy, in 2010 the SFDA approved 889 drugs, of which only 640 were generic drugs. Compared with 2005, approvals of generic drugs decreased 11-fold.
Improving Clinical Trials On 2 December 2011, the SFDA issued the Guiding Principles for Administration on Phase I Clinical Trials on Drugs (for Trial Implementation), which aim to regulate and streamline Phase I clinical trials in China. These principles became effective the same day they were issued and are an important development for industry and research facilities. Some observers take a sceptical view of the principles as just a compilation of existing clinical best practice statements. Other observers are more optimistic that the principles can have a positive impact on the life sciences sector.
Safety Considerations The principles are intended to protect more effectively the rights and safety of trial subjects and to enhance the research quality and management of Phase I clinical trials. To achieve these goals, the principles clearly delineate the rights and duties of sponsors, laboratories and ethics committees, which are the equivalent of an Independent Review Board in the United States. The principles require that a trial subject must sign a letter of informed consent that, generally speaking, must specify the objective of the Phase I clinical trial and describe the possible benefits and risks. The laboratory must maintain regular communication with trial subjects in order to uncover any adverse reactions quickly. A sponsor must give appropriate economic compensation to a trial subject and, if a subject is harmed on account of participation in the trial, the sponsor must assume the costs of treatment and provide reasonable additional compensation. The laboratory must meet the various requirements issued by the SFDA and be accredited by the China National Accreditation Service for Conformity Assessment. It must have adequate physical facilities and equipment, as well as quality management systems. The laboratory director and principal investigator, if they are different people, must have at least five years' experience each in handling clinical trials. The principles emphasise risk prevention and management. The sponsors, researcher and ethics committee have to work together closely to manage and control risks. The ethics committee must closely monitor trial risks, trial plans, the informed consent form and process, the qualification and experience of laboratories and associated researchers, trial subject recruitment and adverse events. A sponsor must evaluate any possible risk prior to a clinical trial and reach a consensus with each participating laboratory regarding risk management. In turn, the ethics committee has the responsibility of reviewing risk-control measures and monitoring their implementation. The committee also has the right to suspend or terminate a clinical trial.
Efficiency Considerations The principles require that sponsors and laboratories enter into a research agreement to specify the interests and rights of each party. Among other terms, the agreement must specify funding terms, the scope and process of clinical trials and any permitted sub-contracting. A sponsor may engage a Contract Research Organisation to carry out some work and tasks, but the sponsor remains responsible for the sub-contracted work and tasks. The original data must be first-hand information obtained from the trial and the equipment and methods used to generate study data must be inspected and verified. However, the principles do not specify which party is responsible for inspection and verification. The sponsor, principal investigator and laboratory director must each co-sign a final report that will be submitted to the CDE. In addition, the head of the laboratory must sign the analysis report on any biomedical samples, which will also be signed off by the laboratory. If nothing else, the principles are a prelude to the reform of the entire drug licensing system in China. Optimists are encouraged, for example, by ongoing efforts by the SFDA to draft two regulations: the Standards on the Administration of Quality of Drug Registrations and the Standards on the Administration of Drug Reviews to streamline further clinical trials and the agency's own review process. These rules establish an Expert Advisory Committee in respect to drug registration administration. In addition, internal and external supervisory mechanisms will be established to supervise the drug review and approval process. It remains to be seen whether the SFDA will issue similar principles for Phase II, III and/ or IV clinical trials.
Cross-Border Collaboration The Chinese Government attaches great importance to learning from and collaborating with other governments and international organisations. For example, in drafting the above principles, the SFDA referred to British Pharmaceutical Industry and European Medicines Agency clinical trials guidelines. The Chinese Government has also negotiated with the Taiwanese and other non-Chinese Governments on possible cooperation regarding clinical trials. According to Reuters, on 15 December 2010, the director of the Taiwan Food and Drug Administration explained that the Taiwan and Chinese Governments, after a cooperative agreement on pharmaceuticals is executed, will encourage Taiwanese and Chinese clinical facilities to cooperate with each other on clinical trials. Hopefully, the clinical trial data established in one country will be acceptable to the other. Similar dialogues are being held with other countries such as South Korea and Japan. Although there is no breakthrough in any of these dialogues yet, they do underscore the Chinese Government's commitment to speeding up market authorisation.
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