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 But in February 2005, it was withdrawn after 3 patients developed PML.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.
ObjectiveTo investigate the effects of hypoxia inducible factor 1α (HIF-1α) overexpression on the differentiation of stem cells derived from human exfoliated deciduous teeth (SHED) into vascular endothelial cells.MethodsSHED was isolated from the retained primary teeth donated by healthy children by using collagenase digestion method. The third generation cells were identified by flow cytometry and alizarin red and alkaline phosphatase (ALP) staining after osteogenic differentiation culture. The SHED were divided into blank control group (SHED without any treatment), empty group (SHED infected with empty lentivirus), HIF-1α overexpression group (SHED infected with HIF-1α overexpression lentivirus), Wnt inhibitor group (SHED interfered by IWR-1), and combination group (HIF-1α overexpressed SHED interfered by IWR-1). Real-time fluorescence quantitative PCR (qRT-PCR) and Western blot were used to analyze the expressions of HIF-1α mRNA and protein in the SHED of blank control group, empty group, and HIF-1α overexpression group. Then the SHED in 5 groups were induced differentiation into vascular endothelial cells for 14 days. The expressions of cell surface marker molecule [von Willebrand factor (vWF) and CD31] were detected by flow cytometry. The mRNA expressions of vascular cell adhesion protein 1 (VCAM-1), KDR (Kinase-inserted domain containing receptor), and VE-cadherin (VE) were analyzed by qRT-PCR. The protein expressions of phosphate-glycogen synthasc kinase 3β (p-GSK3β) and β-catenin were analyzed by Western blot. The tube forming ability of induced cells was detected by Matrigel tube forming experiment. The ability of endothelial cells to phagocytic lipid after differentiation was detected by DiI-labeled acetylated low density lipoprotein (DiI-Ac-LDL) phagocytosis.ResultsAfter identification, the cells were SHED. After lentivirus transfection, compared with the blank control group and the empty group, the expressions of HIF-1α mRNA and protein in the HIF-1α overexpression group increased significantly (P<0.05). Compared with the blank control group and the empty group, the expressions of VCAM-1, KDR, and VE mRNA, the percentages of vWF positive cells and CD31 positive cells, and the relative expression of β-catenin protein were significantly higher (P<0.05), the relative expression of p-GSK3β protein was significantly lower (P<0.05), the number of tubules formed and the ability to phagocytic lipids significantly increased (P<0.05) in the HIF-1α overexpression group; while the indicators in the Wnt inhibitor group were opposite to those in the HIF-1α overexpression group (P<0.05). Compared with the HIF-1α overexpression group, the expressions of VCAM-1, KDR, and VE mRNA, the percentages of vWF positive cells and CD31 positive cells, and the relative expression of β-catenin protein were significantly lower (P<0.05), the relative expression of p-GSK3β protein was significantly higher, and the number of tubules formed and the ability of phagocytosis of lipids significantly reduced, showing significant differences between groups (P<0.05).ConclusionOverexpression of HIF-1α can promote SHED to differentiate into vascular endothelial cells by activating Wnt/β-catenin signaling pathway.
Objectives We conducted a literature review of 33 kinds of Traditional Chinese medicine injections (CMIs) on the national essential medicine list (2004 edition) of China in ADR articles to retrieve basic ADR information and research trends related to CMIs and to provide evidence for the research and development as well as the rational use of CMIs, particularly pharmacovigilance and risk management of CMIs. Methods We electronically searched Chinese Biomedical Literature Database (CBM, Jan. 1978-April 2009), the China National Knowledge Infrastructure Database (CNKI, Jan. 1979-April 2009), Chinese Science and Technology Periodical Database (VIP, Jan. 1989-April 2009) and the Traditional Chinese Medicine Database (Jan. 1984 April 2009). We also retrieved the websites of Ministry of Health and State Food and Drug Administration, to collect data about CMIs ADRs reports and regulations from “Newsletter of Adverse Drug Reactions” (Issue 1 to 22). Then we descriptively analyzed all the results on the year published, periodicals and types of study design of included ADR literatures, the major CMIs as well as the regulations about their ADRs. Results (1) There were 5 405 citations found in total and 2160 were removed because of duplication. After screening the title, abstract and full text of the selected papers, 1 010 studies finally met the eligible criteria. (2) The total and cumulative amount of research articles published about CMIs ADRs significantly increases over time. (3) The included 1,010 articles were scattered among 297 periodicals. A total of 55 journals on pharmaceutical medicine, containing 399 articles, accounted for 39.50% of total; 64 journals on traditional Chinese medicine and pharmaceutical medicine, containing only 197 articles, amounted for 19.50% of total. Only 22 periodicals were included on the core journals of the Beijing University List (2008 edition) (8.94% of the total journals in the list), which published 129 articles (12.77% of the total articles published). (4) We categorized the articles included into eight categories based on their content and study methodology. There were: 348 case reports and 254 case series which accounted for 34.46% and 25.15% of the total articles, 119 overviews (11.78%), 116 randomized controlled trials (11.49%), 78 cross-sectional studies (7.72%), 61 ADR literature analyses (6.04%), and 28 non-randomized controlled clinical studies (2.77%). (5) In the three of top ten journals, "Adverse Drug Reactions Journal", "China Medical Herald", and "Chinese Pharmaceuticals" published literature accounted for 5.84%, 3.76% and 2.67% of the total respectively. (6) The reports of ADRs to Shuanghuanglian, Qingkailing and Yuxingcao injections were the most in all reports for CMIs (All the three injections had more than 200 articles, accounting for 41.95% of the total). The Ministry of Health and the State Food and Drug Administration took measures to supervise them. (7) The four kinds of CMIs (Shuanghuanglian, Ciwujia, Yuxingcao, and Yinzhihuang injections) among the top 5 reported ADR literatures were removed from the market or were suspended for sale. The varieties and numbers of reports for CMIs ADRs have relationship with the supervision to them. Conclusions (1) Articles published on CMIs ADRs increased year by year, but overall the research is of low quality and is scattered in a large number of sources. (2) It is very urgent to create a clear standard to grade ADRs of CMIs for the risk management. (3) It is necessary to enforce safety re-evaluation work for CMIs and to promote the clinical rational use.
ObjectiveThe application of the coefficient of variation (CV) in the development of clinical practice guidelines is limited to evaluating the consistency of the consensus panel in clinical questions rating, and the application of variability was limited. This study presents the application and results of variability evaluation in the development of guidelines. MethodsWe conducted a large-scale clinical survey through questionnaire survey, and conducted two rounds of questionnaire survey and face-to-face consensus meeting for the consensus group. Means and CV were calculated for clinical questions and outcome importance ratings. We performed the summary and analysis by SPSS and Microsoft Excel. ResultsA total of 356 clinical survey questionnaires and two rounds survey in consensus panel were collected. We found that in the clinical survey and the first-round of the consensus panel, the CV was greater than 25% for all clinical questions regardless of the overall importance score. In the consensus panel, the results of the second-round were greatly changed. On the one hand, compared with the first-round, the CV of almost all clinical questions was smaller in the second-round, and the CV of high-priority clinical questions was less than 25%, while the clinical questions with a CV greater than 25% were of low-priority. In view of the CV of outcome importance, the clinical survey was similar to the results of the first-round of consensus panel. The CV of very important outcomes was less than 30%. In the second-round of consensus panel, the variability of very important outcomes was less than 20%. The higher the importance level of the outcome was, the smaller the CV was. ConclusionThe study of variability evaluation has practical methodological value, which can assist clinical questions and outcomes priority selection, and help to fully consider the influence of different factors and values, and develop high-quality guidelines.
Currently, there is a lack of clarity and standardization regarding the implementation details of interventions in traditional Chinese medicine clinical practice guidelines (CPGs). This in methodological guidance for standardizing the implementation prescription adversely impacts the quality of implementation and hinders the clinical application rate of recommendations. Through in-depth analysis of implementation prescription of evidence-based CPGs in traditional Chinese medicine, we identified the challenges associated with standardization. In response, we propose enhancing the technical specifications of implementation prescriptions, advocating for improved formulation processes, diverse reporting approaches, and standardizedological guidelines. These recommendations aim to serve as a methodological reference and guidance for clinical practice guideline developers.
Objective The Chengdu initiative essential medicine policy is part of the Special Healthcare Program of Comprehensive Reform for Coordinated and Balanced Urban-rural Development. We aimed to investigate the current situation of medicine use in rural hospitals and community health service centers, so as to provide evidence for policy-makers to select essential medicines and facilitate rational use of medicines. Method We selected 7 township/community health institutions from which to collect medicine use information, including medicine category, number of medicine categories, cost and consumption. Descriptive analysis and the ABC classification method were applied for statistical analysis. Results The number of medicine categories used in the community health institutions was four times greater than that in the township health institutions. Traditional Chinese medicine preparations accounted for 40% of the total medicine cost. Polypharmacy, overuse of injections, and improper use of antibiotics were major manifestations of the irrational use of medicines. Conclusion The selection and use of essential medicines should be base on high quality evidence as well disease burden, the economic situation and specific demands in different areas. Drug and therapeutics committees should be set up to perform dynamic monitoring, education, evaluation and continual improvement of an essential medicines list.