Analysis of Ornidazole Injection in Clinical Use at Post-marketing Stage by Centralized Hospital Monitoring System

This study aims to analyze the clinical use of ornidazole injection at the post-marketing stage by centralized hospital monitoring system method,and investigate its widespread use in patients,in order to regulate and guide the rational drug use,improve the drug specificity and provide a basis for drug therapy.The study adopts a prospective,multi-center,large sample size,centralized hospital monitoring system.We selected five leading hospitals in Hubei province,and observed the inpatients who received the ornidazole injection from July 1,2015 to October 31,2015.The basic information of patients was recorded,as well as the drug use and adverse events.The statistical analysis was performed based on these data.A total of 4396 individuals were enrolled in this study,most of them were middle-aged female patients and the ornidazole injection was mainly used as prophylactic prior to surgery to prevent the infections,and surgical treatment of anaerobic infections,abdominal infections and pelvic infections.The irrational drug use existed mainly in the prescribing and administration process,including unreasonable dosing frequency,rapid intravenous drip speed and extended duration of drug use.Eleven cases of adverse reactions were collected during the monitoring,incidence rate of adverse reactions was 2.5‰;adverse drug reactions occurred within 30 min.The study results fully reflected the usage of ornidazole injection in the real world.Based on the study,we calculated the adverse reaction incidence of ornidazole and identified the risk factors which may affect the safety of ornidazole injection.Study results strongly recommend that the manufacturers should publish standards for inpatient use and doctors should prescribe with caution accordingly.

How to establish precise proprietary Chinese medicine in post-marketing reappraisal?

The clinical efficacy and safety of proprietary Chinese medicine has become a more prevailing public health concern.The China Food and Drug Administration has pushed drug companies to conduct post-marketing reappraisal for proprietary Chinese medicine to provide additional evidence supporting the efficacy and safety of these medicine.In this paper,we propose a reappraisal protocol called“precise proprietary Chinese medicine”to precisely i)define the therapeutic aim;ii)design the protocol;iii)control the quality of proprietary Chinese medicine;iv)implement the protocol in the trial;v)study the mechanism-of-action of the proprietary Chinese medicine and vi)describe the indications of the proprietary Chinese medicine.We hope that these steps facilitate the post-marketing reappraisal of proprietary Chinese medicine.

Safety and Efficacy of Combination Therapy with Insulin Glargine and Oral Hypoglycaemic Agents Including DPP-4 Inhibitors in Japanese T2DM Patients: ALOHA 2 Study, a Post-Marketing Surveillance for Lantus^®

Aims: In the Add-on Lantus®?to Oral Hypoglycaemic Agents 2 (ALOHA 2) Study in Japanese adults with type 2 diabetes mellitus (T2DM), data on the safety and efficacy of combination therapy with insulin glargine (Lantus®) and oral anti-hyperglycaemic drugs (OADs) including dipeptidyl peptidase-4 (DPP-4) inhibitors in a real-life setting were collected and analyzed. Methods: This postmarketing surveillance was a prospective, observational, 24-week study that complied with the pharmaceutical affairs law and the ministerial ordinance of “Good Post-Marketing Study Practice (GPSP)” in Japan. Safety, efficacy and patient-reported outcomes (PROs);patients’ satisfaction with treatment (DTSQs and DTSQc) and patients’ self-reported health (EQ-5D and EQ-VAS) of combination therapy of insulin glargine and OADs were evaluated. Results: A total of 2,630 patients were enrolled. Of the 2,602 patients in the safety analysis population, 161 patients experienced 175 cases of adverse drug reactions, and the major adverse drug reaction was hypoglycaemia (140 patients, 5.38%). Out of those with hypoglycaemia, 11 patients (0.42%) had severe hypoglycaemia and the incidence rate (episodes per patient-year) was 0.019. Basal supported oral therapy (BOT) with insulin glargine substantially reduced the HbA1c, FPG and 2 hour-PPG levels for 24 weeks by -1.61%, -54.4 mg/dL and -74.5 mg/dL respectively. The mean weight was increased, however the change was +0.50 kg. In addition, the treatment satisfaction scores of DTSQs (mean treatment satisfaction score increased 3.6 from baseline to last observation) and DTSQc, EQ-5D index scores and EQ-VAS scores were significantly improved. Conclusion: Insulin glargine and OADs combination therapy was suggested to be effective and well tolerated. Patients’ satisfaction with treatment and their self-reported health improved in spite of the addition of injections to oral agents. The combination therapy of insulin glargine and OADs including DPP-4 inhibitors is likely to be considered an important therapeutic option in the diabetic patients.

Regulations and Guidelines Should Be Strengthened Urgently for Re-evaluation on Post-marketing Medicines in China

This paper reviewed the situation of regulations and guidelines on post-marketing medicines in the developed countries and in China. The developed countries have accumulated a lot of empirical principles and techniques on post- marketing surveillance （also named pharmacovigilance）, therefore, their regulation systems are nearly perfect. In China, the regulations on post-marketing re-evaluation and relative technical guidelines do not cover the whole aspects, even lack in some important aspects, and long-term risk management mechanisms have not been established. So it is urgent to establish new regulations and improve the regulatory system in China based on the existing regulations and guidelines, by learning from the ideas of foreign advanced regulations, then fully integrating them with China＇s actual conditions, and cooperating with multidisciplinary researchers.

Post-marketing Re-evaluation of Tongxiening Granules (痛泻宁颗粒) in Treatment of Diarrhea-Predominant Irritable Bowel Syndrome:A Multi-center,Randomized,Double-Blind,Double-Dummy and Positive Control Trial

Objective: To evaluate the efficacy and safety of Tongxiening Granules(痛泻宁颗粒, TXNG) in the treatment of irritable bowel syndrome with predominant diarrhea(IBS-D). Methods: A randomized, double-blind, double-dummy, and positive paral el control ed clinical trial was conducted from October 2014 to March 2016. Total y 342 patients from 13 clinical centers were enrolled and randomly assigned(at the ratio of 1:1) to a treatment group(171 cases) and a control group(171 cases) by a random coding table. The patients in the treatment group were administered oral y with TXNG(5 g per time) combined with pinaverium bromide Tablet simulator(50 mg per time), 3 times per day. The patients in the control group were given TXNG simulator(5 g per time) combined with pinaverium bromide Tablets(50 mg per time), 3 times per day. The treatment course lasted for 6 weeks. The improvement of Irritable Bowel Syndrome Symptom Severity Score(IBS-SSS) was used to evaluate the primary outcome. Secondary outcomes included adequate relief(AR) rate, Irritable Bowel Syndrome-Quality of Life Questionnaire(IBS-QOL), Hamilton Anxiety Scale(HAMA), Hamilton Depression Scale(HAMD), and the recurrence rate at fol ow-ups. Safety indices including the adverse events(AEs) and related laboratory tests were evaluated. Results: Primary outcome: IBS-SSS at baseline, weeks 2, 4, 6 showed no statistical significance in both full analysis set(FAS) and per protocol set(PPS, P>0.05). After 6 weeks of treatment, the total effective rate of IBS-SSS scores in the treatment group(147/171, 86.0%) was higher than the control group(143/171, 83.6%) by FAS(P>0.05). In regard to secondary outcomes, after 6-week treatment, there was no significant difference in AR rate, total score of IBS-QOL, improvement of HAMD and HAMA total scores between the two groups(P>0.05). The recurrence rate at 8-week fol ow-up was 12.35%(10/18) in treatment group and 15.79%(12/76) in control group, respectivery(P>0.05). A total of 21 AEs occurred in 15 cases, of which 11 occurred in 8 cases in the treatment group and 10 AEs in 7 cases in the control group. The incidence of AEs had no statistical significance between the two goups(P>0.05). Conclusion: Tongxiening Granules could relieve the symptoms of patients with IBS-D and the treatment effect was comparable to pinaverium bromide.(No. ChiCTR-IPR-15006415)

Methodological Approaches to Developing and Establishing the Body of Evidence on Post-marketing Chinese Medicine Safety

ABSTRACT Evidence based medicine demands the highest form of scientific evidence to demonstrate the efficacy and clinical effectiveness for any therapeutic intervention in order to provide best care. It is however accepted that in the absence of scientific evidence, personal experience and expert opinion together with professional judgement are critical. Obtaining evidence for drug safety, post- marketing surveillance （PMS） has focussed on follow up of observational cohorts exposed to a particular drug in order to estimate the incidence of adverse drug reactions （ADRs）. Evidence on PMS of Chinese herbal products is still limited, in particular for herbal injections. The aim of this article is to suggest a new model of ascertaining the safety of Chinese medicine using a more comprehensive approach for collecting data. To collect safety data on the Chinese herbal injection, Kudiezi, a mixed methods approach is proposed using 18 hospital information systems to detectADRs in order to prospectively observe 30,000 patients over 3 years. Evidence will also be collected using a questionnaire survey and through a sample of semi structured interviews. This information based on the expert opinion and the experience of clinicians will produce additional data on the frequency and types of side effects in clinical practice. Furthermore semi structured interviews with a random sample of patients receiving the injection will be carried out to ascertain any potential side effects missed. It is hoped that this comprehensive approach to data collection will accumulate wider evidence based on individual traditional Chinese medicine care and treatment and provide important feedback to the national data collection system to ensure completeness of ADR data recording, monitoring and any potential wider effects through developing improved ADR guidelines.

Post-marketing safety monitoring of Shenqifuzheng injection: a solution made of Dangshen(Radix Codonopsis)and Huangqi(Radix Astragali Mongolici)

OBJECTIVE:Toidentify the potential risk factors associated with Shenqifuzheng injection(SFI), a solution made of Dangshen(Radix Codonopsis) and Huangqi(Radix Astragali Mongolici), for the timely provision of information to regulatory authorities.METHODS: A comprehensive analysis of the production process, quality standards, pharmacology,post-marketing clinical studies, and safety evaluation using the primary literature of adverse reactions(ADR), case analyses, and systematic reviews,intensive hospital safety monitoring of post-marketing drugs, and data provided by the hospital in-formationsystem(HIS).RESULTS: Sub-acute toxicity tests suggesting that a dose of 15 mL/kg(concentrated solution) had specific biological effects, whereas a smaller dose engendered no observable effects. Long-term toxicity testing in domestic rabbits showed that after SFI was administered for 90 days, the animals in each dosing group showed no chronic toxic reactions. Among 20 100 cases observed, the incidence of an ADR was 1.85‰. From March to November 2013,of the leading institutions and 22 sub-centers involved in the post-marketing clinical safety intensive hospital monitoring, 21 units completed 8484 cases of monitoring, and reported 23 cases of adverse reactions. No damage to renal function was found using SFI ata dosageanda treatment course larger and longer than that recommended for the adjuvant treatment of tumors. This could reduce the mortality rate of admitted patients based on the analysis of the data provided by the HIS. A total of 16 clinical case reports of adverse reactions related to SFI in 1999-2012 were obtained through literature retrieval. These reports contained information concerning 17 cases, with adverse reaction symptoms including thrombocytopenia, rash,chills,feeling cold,palpitation,dyspnea,edemaofa lower extremity, palpebral edema, and superficial vein in flammation,among others.CONCLUSION: This study introduces "get full access" to the flow of information on medicines regarding their ADR incidence rate and characteristics and factors.It supports the safety of SFI for clinical, research, and production uses based on objec-tive, reliable, and scientific information to provide safe medication.

Post-Marketing Surveillance of Qishe Pill(芪麝丸)Use for Management of Neck Pain in a Chinese Patient Cohort to Determine Its Safety,Tolerability and Effectiveness

Objective:To evaluate the safety and effectiveness of Qishe Pill(芪麝丸)on neck pain in realworld clinical practice.Methods:A multi-center,prospective,observational surveillance in 8 hospitals across Shanghai was conducted.During patients receiving 4-week Qishe Pill medication,Visual Analogue Scale(VAS)and Neck Disability Index(NDI)assessments have been used to assess their pain and function,while safety monitoring have been observed after 2 and 4 weeks.Results:Results from 2,023 patients(mean age 54.5 years)suggest that the drug exposure per unit of body mass was estimated at 3.41±0.62 g/kg.About 8.5%(172/2,023)of all participants experienced adverse events(AEs),while 3.8%(78/2,023)of all participants experienced adverse reaction.The most common AEs were gastrointestinal events and respiratory events.The VAS score(pain)and NDI score(function)significantly decreased after 4-week treatment.An effect-quantitative analysis was also conducted to show that the normal clinical dosage may be consider as 3–4 g/kg,at which dosage the satisfactory pain-relief effect may achieve by 40-mm reduction in VAS.Conclusion:These findings showed that patients with cervical radiculopathy who received Qishe Pill experienced significant improvement on pain and function.(Registration No.NCT01875562).

Design and Analysis of Post-marketing Research

A post-marketing study is an integral part of research that helps to ensure a favorable risk-benefit profile for approved drugs used in the market. Because most of post-marketing studies use observational designs, which are liable to confounding, estimation of the causal effect of a drug versus a comparative one is very challenging. This article focuses on methodological issues of importance in designing and analyzing studies to evaluate the safety of marketed drugs, especially marketed traditional Chinese medicine （TCM） products. Advantages and limitations of the current designs and analytic methods for postmarketing studies are discussed, and recommendations are given for improving the validity of postmarketing studies in TCM products.

Clinical Application Analysis of Andrographolide Total Ester Sulfonate Injection,a Traditional Chinese Medicine Licensed in China

Andrographolide total ester sulfonate（ATES） injection is one of the products of traditional Chinese medicine（TCM） currently used against viral infection in China.ATES injection was approved for manufacturing and marketing in January 2002.It is indicated for acute respiratory infections,tonsillitis,chronic obstructive pulmonary disease,influenza,foot and mouth disease,bronchiolitis,herpangina,mumps,infectious mononucleosis and psychosis.However,its usage also carries risk.We investigated the use of ATES at the Wuhan Union Hospital from January 2014 to December 2014 and evaluated its real-world clinical application using the hospital centralized monitoring method.A total of 848 cases were enrolled in this study.In these cases,it was mainly used for postoperative anti-inflammation and treating upper respiratory infection,pneumonia and bronchitis.Among them,39.86% were contraindicated.Irregular medication of adults and children accounted for 1.91% and 23.38%,respectively.Improper choice of solvent accounted for 3.18%.The choice of intravenous drip versus aerosol inhalation was reasonable.A case of adverse events（AEs） was observed in the monitoring period,and the incidence of adverse drug reaction（ADR） of ATES injection was 0.12%.ATES injection in our hospital is relatively safe with a low incidence of adverse reactions.The study assesses the clinical usage and adverse reactions of ATES injection,and provides suggestions for rational use in clinical practice.

Safety and Diagnostic Image Quality of Ultravist^®in an Unselected Sub-Set of Chinese Patients: Data Analyses from a Previous Post Marketing Surveillance

Background: Iopromide (Ultravist&reg) has been shown to be a very safe CM agent in previous post-marketing surveillance studies on Western and Asian populations. Our study aimed to analyse data pertaining to the safety, tolerability and diagnostic image quality of Iopromide in an unselected sub-set of the Chinese population. Methods: we analysed data for Chinese ambulatory and in-patients who received Iopromide for an imaging procedure (in accordance with the local package insert and routine clinical practice), as part of an international post-marketing surveillance study. Use of premedication was at the discretion of the attending physician. Patient demographics, clinical history, type of examination, contrast quality and tolerability, including pre-specified adverse drug reactions, were recorded. All statistical analyses were descriptive. Results: case report forms for 20,000 Chinese patients (61.3% men) were analysed, of whom 153 patients (0.77%) had risk factors for idiosyncratic contrast media reactions (at-risk group). Use of premedication, most commonly corticosteroids, was recorded for 5658 patients (28.3%) and 86 at-risk patients (56.2% of the at-risk group), respectively. The mean (±standard deviation) dose of iodine administered was 29 ± 5.5 g. During the physician’s evaluation of image parameters, contrast quality was considered to be “good” (64.7%) or “excellent” (29.3%) in the majority of patients. 571 patients (2.9%) experienced at least one adverse drug reaction [most frequently nausea (0.70%) and dysgeusia (0.62%)], which were typically transient and of mild intensity. Two serious adverse drug reactions were reported [edema (n = 1), decreased blood pressure and dyspnea (n = 1)]. The incidence of adverse drug reactions was increased in the at-risk group versus the overall patient population, and tended to reduce with premedication (mainly corticosteroids). Conclusions: Iopromide was well tolerated and proved to be an efficient contrast agent in a large, non-selected sub-set of Chinese patients undergoing different types of diagnostic imaging procedures.

ADRs and Children： Knowledge and Methodological Standard in PASS （Post Authorization Safety Studies）

PhV （pharmacovigilance） knowledge has the outcome of being inadequate in particular due to the lack of instruction. Pediatricians have to face the realization that over-the-counter medicines increments the peril of ADRs （adverse drug reactions） has become a public health concern. The purpose of this article is to disseminate knowledge of the PhV and to highlight the cultural and organizational difficulties for its implementation. The objectives of promoting the organization of specific training courses and research projects aimed at： （1） to foster the culture of iatrogenic disease in pediatrics; （2） to improve the appropriateness of prescribing drugs in children; （3） to enco.urage spontaneous reporting of ADRs in children; （4） to involve Pediatricians in PASS （post-authorization safety studies） according to GCP, GVP and ENCEPP Code of Conduct. An up to date proposal of PhV, a procedure of preparation improves the productivity of creating novel informative reports which can be utilized for a benefit/risk scrutiny making strides in medicine prescription. In this context, FP-MCRN （family paediatficians-medicines for children research network） established with the aim of developing competence, infrastructure and education for paediatric clinical trials, plays a crucial role in paediatric PhV, through an improvement of PhV training, a correct research methodology and very strong relationship with the families. The initial necessity is cultural, implementing culture of iatrogenic illnesses and a watchful evaluation of the importance of PASS by FPs （family pediatricians）. Participation in clinical trials that generates a precise database administered by FPs together with follow-up outcomes becomes relevant and vital for a scrupulous and accurate assessment of ADRs. PASS can foresee on one hand training and information regarding the proper use of drugs in children and possible iatrogenic pathologies caused by their improper use, the other to constitute a territorial survey in the prescriptive appropriateness and safety of pediatric drugs aimed at evaluating the risk-benefit balance on usage.

Bias in multiple-treatments meta-analysis： a case on comparative efficacy and tolerability of 15 antipsychotic drugs for schizophrenia

Multiple-treatments meta-analysis is thought to be a feasible method to compare the efficacy and safety among different treatments, especially when there was no head-to-head research among some treatments. But sometimes some conclusions are inconsistent with the clinical experience. Recently, we read a multiple-treatment meta-analysis finished by Stefen Leucht et al, which was published in Lancet） The authors summarized the results of the RCT studies on 15 antipsychotics commonly used in practice; they also horizontally compared the efficacy and safety profile by the recta-analysis. We believe that the results provide more solid evidence for the rational usage of antipsychotics to the psychiatrists, also for the government to distribute health resources in a more reasonable way.