Objective To investigate the regulations and implementation effect for high-risk drugs of the FDA and MHRA on the basis of natalizumab, and to provide references for the risk regulation of the innovative drugs and high-risk drugs of China. Methods We searched MEDLINE, EMBASE.com, the official website of Food and Drug Administration (FDA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) for the marketing/withdrawal and risk regulation information of natalizumab as well as the relevant information of drug marketing/withdrawal and approval track. Results (1) Natalizumab was initially approved by the FDA through accelerated approval in November, 2004 with the phase three clinical trial still being conducted. But in February 2005, it was withdrawn after 3 patients developed PML. FDA resumed its marketing under a specially restricted distribution program called the Touch Prescribing Program in March, 2006. (2) Natalizumab was marketed in the European Union in April 2006. No cases of PML have been reported in the UK for this drug. (3) To speed the development of drugs that treat serious diseases, the FDA developed 3 distinct and successful approaches to make such drugs available as rapidly as possible: Priority Review, Accelerated Approval, and Fast Track. The proportion of new molecular entity and new biologic approved by fast tract were 45% and 74%, respectively between 2002 and 2009. (4) Drug regulation of MHRA contained: Yellow Card Scheme, Black Triangle products, Download Drug Analysis Prints (DAPs), and Defective Medicines Report Centre (DMRC). Self-reporting and monitoring system were fairly perfect, thus they can fulfill the close monitoring for high-risk drugs under the existing conditions and then realize the risk-minimization. Conclusion (1) The risk-minimization program of FDA for high-risk drugs is effective, and plays a role in the policy support for the researching and marketing of irreplaceable innovative drugs. (2) The risk regulation for high-risk drugs of MHRA is integrated into drug regulation program and enforces hierarchical management, and acquires risk-minimization effect. (3) We should learn from the policy and operational experience for the international new molecular entity and new biologic on the re-evaluation for innovative drugs and high-risk drugs. Combined with drug specific characteristics, evaluation indicators and criteria are developed base on evidence, risk management system and mechanism for innovative drugs are established and improved, and policy and administration security for the safety application of innovative drugs and high-risk drugs are provided.
Objective To analyze the withdrawal reason of natalizumab in depth based on the serious adverse reaction reports and approval channel, and to provide decision references for more safe and effective report method of other biologicals. Methods We searched MEDLINE, EMbase, and the official websites of Food and Drug Administration (FDA) for case reports, approval channel, and the relevant information of drug marketing or withdrawal. Results Four case reports and fourteen official reports were included. Three cases of progressive multifocal leukoencephalopathy (PML) were reported in the clinical trials after natalizumab’s initially approval with two dead and one disabled, which could be retrieved by hemodialysis (2 cases hitherto). Consequently, multiple sclerosis (MS) patients were willing to bear the risk. Two cases of natalizumab-related PML (0.06‰) were confirmed in 32 000 patients without death report after two years of its remarketing, in July 2008. Another PML patient was reported in October 2008. Because of its non-substitutability for treating MS and Crohn disease (CD), FDA announced that patients could still use natalizumab under the close monitoring. Conclusion (1) The most serious adverse reaction of treating MS and CD with natalizumab is PML, but it can be preventable and curable now. The monitoring findings of efficacy and adverse reaction during the postmarketing indicate that the review system is perfect and practicable relatively, and can give references for other high-risk drugs on the fast or standard approval channel, for example, Chinese medicine injection can draw lessons from it. (2) The remarketing of natalizumab not only provide significant risk management precedent for other drug-development firms, but also brings hope to the remarketing or relaunching clinical trials for the suspected sideeffect drugs. (3) Because of the fast-track reviewing of natalizumab and the overlap between the research of Good Clinical Practice (GCP) and the post-marketing evaluation, we should continue to track the information and provide new evidence.