Understanding an impact of patient enrollment pattern on predictability of central (unstratified) randomization in a multi-center clinical trial.

In a multi-center randomized controlled trial (RCT) with competitive recruitment, eligible patients are enrolled sequentially by different study centers and are randomized to treatment groups using the chosen randomization method. Given the stochastic nature of the recruitment process, some centers may enroll more patients than others, and in some instances, a center may enroll multiple patients in a row, for example, on a given day. If the study is open-label, the investigators might be able to make intelligent guesses on upcoming treatment assignments in the randomization sequence, even if the trial is centrally randomized and not stratified by center. In this paper, we use enrollment data inspired by a real multi-center RCT to quantify the susceptibility of two restricted randomization procedures, the permuted block design and the big stick design, to selection bias under the convergence strategy of Blackwell and Hodges (1957) applied at the center level. We provide simulation evidence that the expected proportion of correct guesses may be greater than 50% (i.e., an increased risk of selection bias) and depends on the chosen randomization method and the number of study patients recruited by a given center that takes consecutive positions on the central allocation schedule. We propose some strategies for ensuring stronger encryption of the randomization sequence to mitigate the risk of selection bias.

Selecting a randomization method for a multi-center clinical trial with stochastic recruitment considerations.

BACKGROUND: The design of a multi-center randomized controlled trial (RCT) involves multiple considerations, such as the choice of the sample size, the number of centers and their geographic location, the strategy for recruitment of study participants, amongst others. There are plenty of methods to sequentially randomize patients in a multi-center RCT, with or without considering stratification factors. The goal of this paper is to perform a systematic assessment of such randomization methods for a multi-center 1:1 RCT assuming a competitive policy for the patient recruitment process. METHODS: We considered a Poisson-gamma model for the patient recruitment process with a uniform distribution of center activation times. We investigated 16 randomization methods (4 unstratified, 4 region-stratified, 4 center-stratified, 3 dynamic balancing randomization (DBR), and a complete randomization design) to sequentially randomize n = 500 patients. Statistical properties of the recruitment process and the randomization procedures were assessed using Monte Carlo simulations. The operating characteristics included time to complete recruitment, number of centers that recruited a given number of patients, several measures of treatment imbalance and estimation efficiency under a linear model for the response, the expected proportions of correct guesses under two different guessing strategies, and the expected proportion of deterministic assignments in the allocation sequence. RESULTS: Maximum tolerated imbalance (MTI) randomization methods such as big stick design, Ehrenfest urn design, and block urn design result in a better balance-randomness tradeoff than the conventional permuted block design (PBD) with or without stratification. Unstratified randomization, region-stratified randomization, and center-stratified randomization provide control of imbalance at a chosen level (trial, region, or center) but may fail to achieve balance at the other two levels. By contrast, DBR does a very good job controlling imbalance at all 3 levels while maintaining the randomized nature of treatment allocation. Adding more centers into the study helps accelerate the recruitment process but at the expense of increasing the number of centers that recruit very few (or no) patients-which may increase center-level imbalances for center-stratified and DBR procedures. Increasing the block size or the MTI threshold(s) may help obtain designs with improved randomness-balance tradeoff. CONCLUSIONS: The choice of a randomization method is an important component of planning a multi-center RCT. Dynamic balancing randomization with carefully chosen MTI thresholds could be a very good strategy for trials with the competitive policy for patient recruitment.

A Randomized，Double-blind，Multi-center Clinical Trial of Tengfu Jiangya Tablets Combined with Valsartan/Amlodipine in Treatment of Grade 2 Hypertension with Hyperactivity of Liver Yang / 中国实验方剂学杂志

ObjectiveTo observe the clinical efficacy and safety of Tengfu Jiangya tablets combined with valsartan/amlodipine in the treatment of grade 2 hypertension with liver Yang hyperactivity syndrome. MethodAccording to a randomized，double-blind，and placebo parallel control method，288 patients with grade 2 hypertension with liver Yang hyperactivity from 7 subcenters were included. They were randomly divided into an observation group （144 cases） and a control group （144 cases），and then treated with Tengfu Jiangya tablets combined with valsartan/amlodipine and placebo combined with valsartan/amlodipine，respectively. The efficacy was evaluated after four weeks of intervention. During the experiment，the safety indicators and adverse reaction events of the subjects were recorded for safety evaluation，and the efficacy indicators and TCM syndrome scores were recorded for effectiveness evaluation. Sensitivity analysis was also conducted on the statistical results of the main efficacy indicators such as blood pressure （BP） compliance rate to ensure the accuracy of the analysis results. 88 groups of blood samples from each of the treatment and control groups were included as test subjects. Fasting blood samples were collected from the patients in the clinical trial on the day before and after medication，and enzyme linked immunosorbent assay （ELISA） was performed on the treated serum. The levels of arachidonic acid （AA），thromboxane B2 （TXB2），and prostaglandin E2 （PGE2） in the serum of the patients before and after treatment were measured to explore the regulation of inflammatory factors in the body by Tengfu Jiangya tablets. ResultA total of 271 patients （133 in the observation group and 138 in the control group） completed the trial. There was no statistically significant difference before and after treatment in such safety indicators as the blood routine （white blood cells，red blood cells，and platelets），urine routine （urinary protein and urinary red blood cells），alanine aminotransferase，aspartate aminotransferase，creatinine，urea，and abnormal electrocardiogram，and no serious adverse reactions were observed. After four weeks，the systolic blood pressure （SBP） difference and diastolic blood pressure （DBP） difference of patients in the observation group were greater than those in the control group（P<0.01）. According to the criteria for determining the antihypertensive effect，the overall response rate in the observation group［89.47%（119/133）］ was higher than that in the control group［57.97%（80/138）］ （Z=2.593，P<0.01）. The SBP compliance rate was 61.65%（82/133） and 37.68%（52/138） in the observation group and control group， respectively. The DBP compliance rate in the observation group was 78.20%（104/133），while in the control group it was 55.07%（76/138）. The overall BP compliance rate in the observation group was 48.12%（64/133），while in the control group it was 23.19%（32/138）. The BP compliance rates in the observation group were all significantly higher than those in the control group（χ2=15.571，16.236，18.404，P<0.01）. According to the criteria for evaluating the therapeutic effect of TCM syndrome integration，the overall response rate of the observation group［57.89%（77/133）］ was higher than that of the control group［38.41%（53/133）］ （Z=-3.172，P<0.01）.Compared with those before treatment， the levels of serum AA and TXB2 in the two groups were significantly decreased after treatment （P<0.01）， and the level of PGE2 in the observation group was significantly increased （P<0.01）. Compared with those of the control group after treatment， the levels of AA and TXB2 in the observation group were significantly decreased， while the level of PGE2 was significantly increased （P<0.01）. The results suggest that Tengfu Jiangya tablets can effectively reduce inflammatory factors，reduce the production of inflammatory mediators，and thus prevent the occurrence of inflammatory reactions in the treatment of patients with grade 2 hypertension. ConclusionTengfu Jiangya tablets can more effectively reduce patients' SBP and DBP，improve their BP compliance rates，and improve their TCM syndromes in the treatment of grade 2 hypertension with liver Yang hyperactivity. Its clinical application is safe. Tengfu Jiangya tablets has outstanding clinical efficacy and can be used as an effective intervention method for the treatment of grade 2 hypertension with liver Yang hyperactivity syndrome.

A Phase Ⅲ Clinical Observation of Yishen Yangxin Anshen Tablets in Treatment of Insomnia with Deficiency of Heart Blood and Insufficiency of Kidney Essence / 中国实验方剂学杂志

ObjectiveTo confirm the clinical efficacy and safety of Yishen Yangxin Anshen tablets in the treatment of insomnia （heart-blood deficiency and kidney-essence insufficiency syndrome）. MethodA randomized block， double-blind， placebo-controlled， multi-center clinical trial design method was adopted， and a total of 480 patients with insomnia due to deficiency of heart blood and insufficiency of kidney essence （treatment group-control group 3∶1） from seven hospitals （Guang'anmen Hospital， China Academy of Chinese Medical Sciences， The First Clinical Hospital， Jilin Province Academy of Traditional Chinese Medicine（TCM）， The Second Affiliated Hospital of Liaoning University of TCM， The First Affiliated Hospital of Henan University of Chinese Medicine， Henan Province Hospital of TCM， Hebei General Hospital， The First Hospital of Hunan University of Chinese Medicine） were enrolled. The treatment group was given Yishen Yangxin Anshen tablets and the control group received placebo tablets （4 tablets/time， 3 times/day， 4 weeks of administration， 4 weeks of follow-up after drug withdrawal）. The sleep dysfunction rating scale （SDRS） score， pittsburgh sleep quality index （PSQI） score， TCM， polysomnography （PSG） indicators from four hospital （Guang'anmen Hospital， China Academy of Chinese Medical Sciences， Henan Province Hospital of TCM， Hebei General Hospital， The First Hospital of Hunan University of Chinese Medicine）， and other efficacy indicators were compared between the two groups before and after treatment. Through general physical examination， laboratory examination， and observation of adverse events， the safety of the drugs was evaluated. ResultThe baseline indexes of the two groups showed no significant difference and thus the two groups were comparable. After treatment， the total score of SDRS in the treatment group was lower than that in the control group （P<0.01）. After drug withdrawal for 4 weeks， the total score of SDRS demonstrated no significant change in the treatment group as compared with that at the end of treatment， indicating that the rebound change of curative effect was not obvious. After treatment， the total score of PSQI in the treatment group decreased as compared with that in the control group （P<0.01）， and the change of total score of PSQI in the treatment group was statistically significant （P<0.05） after drug withdrawal for 4 weeks but small， indicating that the rebound change of curative effect was not obvious. After treatment， the total effective rate about the TCM symptoms in the treatment group was higher than that in the control group （χ2=137.521，P<0.01）. After treatment， the disappearance rates of single indexes in the treatment group， such as difficulty in falling asleep， easily waking up after sleeping， early awakening， short sleep time， dreamfulness， palpitation， forgetfulness， dizziness， mental fatigue， and weakness of waist and knee， increased compared with those in the control group （P<0.01）. After treatment， the treatment group demonstrated fewer awaking times （AT）， longer total sleep time （TST）， lower ATA/TST ratio， and higher sleep efficiency （%） than the control group （P<0.05）. No abnormal value or aggravation related to drugs was observed in either group. The incidence of adverse events in the treatment group and the control group was 5.57% and 8.40% respectively. No serious adverse events or adverse events leading to withdrawal happened in either group. ConclusionYishen Yangxin Anshen tablets is effective and safe for patients with insomnia of deficiency of heart-blood and insufficiency of kidney-essence.

Ketogenic Diet Therapy for Drug-Resistant Epilepsy and Cognitive Impairment in Children With Tuberous Sclerosis Complex.

Objective: Tuberous sclerosis complex (TSC) is a rare disease with a high risk of epilepsy and cognitive impairment in children. Ketogenic diet (KD) therapy has been consistently reported to be beneficial to TSC patients. In this study, we aimed to investigate the efficacy and safety of KD in the treatment of drug-resistant epilepsy and cognitive impairment in children with TSC. Methods: In this multicenter study, 53 children (33 males and 20 females) with drug-resistant epilepsy or cognitive impairment caused by TSC were retrospectively recruited from 10 hospitals from January 1, 2010, to December 31, 2020. Intention-to-treat analysis was used to evaluate seizure reduction and cognition improvement as outcomes after KD therapy. Results: Of the 53 TSC patients included, 51 failed to be seizure-free with an average of 5.0 (range, 4-6) different anti-seizure medications (ASMs), before KD therapy. Although the other two patients achieved seizure freedom before KD, they still showed psychomotor development delay and electroencephalogram (EEG) abnormalities. At 1, 3, 6, and 12 months after the KD therapy, 51 (100%), 46 (90.2%), 35 (68.6%), and 16 patients (31.4%) remained on the diet therapy, respectively. At these time points, there were 26 (51.0%), 24 (47.1%), 22 (43.1%) and 13 patients (25.5%) having ≥50% reductions in seizure, including 11 (21.6%), 12 (23.5%), 9 (17.6%) and 3 patients (5.9%) achieving seizure freedom. In addition, of 51 patients with psychomotor retardation, 36 (36 of 51, 70.6%) showed cognitive and behavioral improvements. During the KD therapy, no serious side effects occurred in any patient. The most common side effects were gastrointestinal disturbance (20 of 53, 37.7%) and hyperlipidemia (6 of 53, 11.3%). The side effects were gradually relieved after adjustment of the ketogenic ratio and symptomatic treatment. Conclusion: KD is an effective and safe treatment for TSC-related drug-resistant epilepsy and cognitive impairment in children. KD can reduce seizure frequency and may potentially improve cognition and behavior.

Using crowdsourcing to understand patients attitudes toward a clinical trial for retinitis pigmentosa requiring 4 years of participation.

BACKGROUND: Clinical trials for retinitis pigmentosa (RP) likely require long follow-ups because of the slow progression of RP. Understanding patients' attitudes toward participation in a long trial and their acceptability of strategies aimed at promoting retention/compliance is important for assessing feasibility and resource needs and optimizing trial design. METHODS: A crowdsourcing survey to adult RP patients was administered on social media in 2020 July-November. Patient enthusiasm level of study participation, acceptability of attending clinic visits every 4-5 months for 45-months, tele-visits with doctors, and of receiving text messages for medication reminders and for reporting missed dosages were surveyed. RESULTS: Among the 1473 respondents, over 95% use email or a mobile phone and receive text messages; 1157 (79%) respondents were very/somewhat enthusiastic about participation, among them, 80.6% were "very willing" to attend clinic visits every 4-5 months for 45 months; 90.3% were "very willing" to have tele-visits; 64.7% and 77.1% were willing to receive text reminders to take medication and messages surveying missed doses, respectively. The youngest age group (18-30) (22.1%) and oldest age group (70+) (26.1%) compared to the 41-50 years age group (14%) and women (23.5%) compared to men (14.2%) were statistically significantly more likely not to report high willingness to participate in clinical visits for 45 months. CONCLUSIONS: A trial requiring 4-years of commitment is feasible although retention can be challenging. Strategies including supplementing in-clinic visits with tele-visits and frequent communications may facilitate retention. This study also demonstrates a methodology useful for planning clinical trials for chronic diseases.

Performance Assessment of a Commercial Continuous-Wave Near-Infrared Spectroscopy Tissue Oximeter for Suitability for Use in an International, Multi-Center Clinical Trial.

Despite the wide range of clinical and research applications, the reliability of the absolute oxygenation measurements of continuous wave near-infrared spectroscopy sensors is often questioned, partially due to issues of standardization. In this study, we have compared the performances of 13 units of a continuous wave near-infrared spectroscopy device (PortaMon, Artinis Medical Systems, NL) to test their suitability for being used in the HEMOCOVID-19 clinical trial in 10 medical centers around the world. Detailed phantom and in vivo tests were employed to measure the precision and reproducibility of measurements of local blood oxygen saturation and total hemoglobin concentration under different conditions: for different devices used, different operators, for probe repositioning over the same location, and over time (hours/days/months). We have detected systematic differences between devices when measuring phantoms (inter-device variability, <4%), which were larger than the intra-device variability (<1%). This intrinsic variability is in addition to the variability during in vivo measurements on the forearm muscle resulting from errors in probe positioning and intrinsic physiological noise (<9%), which was also larger than the inter-device differences (<3%) during the same test. Lastly, we have tested the reproducibility of the protocol of the HEMOCOVID-19 clinical trial; that is, forearm muscle oxygenation monitoring during vascular occlusion tests over days. Overall, our conclusion is that these devices can be used in multi-center trials but care must be taken to characterize, follow-up, and statistically account for inter-device variability.

[Consensus on collaborative ethical review of multi-center clinical trials of new drugs of traditional Chinese medicine (version 1.0)].

At present, the issues regarding multi-center clinical trials of new drugs of traditional Chinese medicine(TCM) remain: the lack of agreement on the content and scope of the ethical review among the ethics committee members of the center and the participating units results in repeated review, which leads to a time-consuming ethical review process. Moreover, the review capabilities of the ethics committees of various research centers are uneven, which is not necessarily beneficial to the protection of subjects' rights and safety. In view of the existing problems, to improve the efficiency of ethical review of multi-center clinical trials of new drugs of TCM and avoid repeated reviews, the TCM Clinical Evaluation Professional Committee of Chinese Pharmaceutical Association organized experts to formulate the "Consensus on collaborative ethical review of multi-center clinical trials of new drugs of TCM(version 1.0)"(hereinafter referred to as "Consensus"). The "Consensus" is formulated in accordance with the requirements of relevant documents such as but not limited to "the opinions on deepening the reform of the evaluation and approval system to encourage the innovation of pharmaceutical medical devices", "the regulations of ethical review of biomedical research involving human subjects". The "Consensus" covers the scope of application, formulation principles, conditions for the ethics committee of the center, sharing of ethical review resources, scope and procedure of collaborative review, rights and obligations, etc. The aims of the "Consensus" is to preliminarily explore and establish a scientific and operable ethical review procedure. Additionally, on the basis of fully protecting the rights and interests of the subjects, a collaborative ethical review agreement needs to be signed to clarify the ethical review responsibilities of all parties, to avoid repeated review, and to improve the efficiency and quality of ethical review in multi-center clinical trials of new drugs of TCM.

Consensus on collaborative ethical review of multi-center clinical trials of new drugs of traditional Chinese medicine (version 1.0) / 中国中药杂志

At present, the issues regarding multi-center clinical trials of new drugs of traditional Chinese medicine(TCM) remain: the lack of agreement on the content and scope of the ethical review among the ethics committee members of the center and the participating units results in repeated review, which leads to a time-consuming ethical review process. Moreover, the review capabilities of the ethics committees of various research centers are uneven, which is not necessarily beneficial to the protection of subjects' rights and safety. In view of the existing problems, to improve the efficiency of ethical review of multi-center clinical trials of new drugs of TCM and avoid repeated reviews, the TCM Clinical Evaluation Professional Committee of Chinese Pharmaceutical Association organized experts to formulate the "Consensus on collaborative ethical review of multi-center clinical trials of new drugs of TCM(version 1.0)"(hereinafter referred to as "Consensus"). The "Consensus" is formulated in accordance with the requirements of relevant documents such as but not limited to "the opinions on deepening the reform of the evaluation and approval system to encourage the innovation of pharmaceutical medical devices", "the regulations of ethical review of biomedical research involving human subjects". The "Consensus" covers the scope of application, formulation principles, conditions for the ethics committee of the center, sharing of ethical review resources, scope and procedure of collaborative review, rights and obligations, etc. The aims of the "Consensus" is to preliminarily explore and establish a scientific and operable ethical review procedure. Additionally, on the basis of fully protecting the rights and interests of the subjects, a collaborative ethical review agreement needs to be signed to clarify the ethical review responsibilities of all parties, to avoid repeated review, and to improve the efficiency and quality of ethical review in multi-center clinical trials of new drugs of TCM.

Design and analysis of stratified clinical trials in the presence of bias.

BACKGROUND: Among various design aspects, the choice of randomization procedure have to be agreed on, when planning a clinical trial stratified by center. The aim of the paper is to present a methodological approach to evaluate whether a randomization procedure mitigates the impact of bias on the test decision in clinical trial stratified by center. METHODS: We use the weighted t test to analyze the data from a clinical trial stratified by center with a two-arm parallel group design, an intended 1:1 allocation ratio, aiming to prove a superiority hypothesis with a continuous normal endpoint without interim analysis and no adaptation in the randomization process. The derivation is based on the weighted t test under misclassification, i.e. ignoring bias. An additive bias model combing selection bias and time-trend bias is linked to different stratified randomization procedures. RESULTS: Various aspects to formulate stratified versions of randomization procedures are discussed. A formula for sample size calculation of the weighted t test is derived and used to specify the tolerated imbalance allowed by some randomization procedures. The distribution of the weighted t test under misclassification is deduced, taking the sequence of patient allocation to treatment, i.e. the randomization sequence into account. An additive bias model combining selection bias and time-trend bias at strata level linked to the applied randomization sequence is proposed. With these before mentioned components, the potential impact of bias on the type one error probability depending on the selected randomization sequence and thus the randomization procedure is formally derived and exemplarily calculated within a numerical evaluation study. CONCLUSION: The proposed biasing policy and test distribution are necessary to conduct an evaluation of the comparative performance of (stratified) randomization procedure in multi-center clinical trials with a two-arm parallel group design. It enables the choice of the best practice procedure. The evaluation stimulates the discussion about the level of evidence resulting in those kind of clinical trials.

Exploration and Reflection on Improving the Efficiency and Quality of Ethical Review in Multi-center Clinical Trial / 中国药房

OBJECTIVE： To explore the ways to improve the efficiency and quality of ethical review in multi-center clinical trial. METHODS： After issuing the policy of Opinions on Deepening the Reform of Approval System and Encouraging the Innovation of Pharmaceutical Medical Devices and Measures for the Administration of Drug Registration （Revised Version）， combined with the practice of our center， the methods to improve the efficiency and quality of ethical review， the possible problems of complete filling system and the way to improve the efficiency and quality of ethical review in multi-center clinical trial were analyzed in our center. RESULTS & CONCLUSIONS： Our center adopted a variety of review methods （conference review， rapid review， filing system， etc.）， implemented hierarchical management and differential review process for research projects， and formulated defined rules of filling system operation and other ways to improve the efficiency and quality of review， doubled the review efficiency， increased the number of follow-up review and field visit. In the process of exploration， the ethics committee of our center believes that the complete implementation of the filing system will lead to problems such as the difficulty to evaluate the quality of the ethical review of the leader unit， different research qualifications and conditions of each center， etc. In order to improve the efficiency and quality of the ethical review of multi-center clinical research， the measures are can be adopted， such as improving the quality of the ethical review of the center， strengthening the communication and mutual recognition of the ethics committees of each center， and establishing the preliminary review system of the secretary of the ethics committee， so as to realize the balance of efficiency and quality.

Efficacy and safety of metyrosine in pheochromocytoma/paraganglioma: a multi-center trial in Japan.

To assess the efficacy, safety, and pharmacokinetics of metyrosine (an inhibitor of catecholamine synthesis) in patients with pheochromocytoma/paraganglioma (PPGL), we conducted a prospective, multi-center, open-label study at 11 sites in Japan. We recruited PPGL patients aged ≥12 years requiring preoperative or chronic treatment, receiving α-blocker treatment, having baseline urinary metanephrine (uMN) or normetanephrine (uNMN) levels ≥3 times the upper limit of normal values, and having symptoms associated with excess catecholamine. Metyrosine treatment was started at 500 mg/day and modified according to dose-adjustment criteria up to 4,000 mg/day. The main outcome measure was the proportion of patients who achieved at least 50% reduction in uMN or uNMN levels from baseline. Sixteen patients (11 males/5 females) aged 12-86 years participated. After 12 weeks of treatment and at the last evaluation of efficacy, the primary endpoint was achieved in 31.3% of all patients, including 66.7% of those under preoperative treatment and 23.1% of those under chronic treatment. Sedation, anemia, and death were reported in 1 patient each as serious adverse drug reactions during the 24-week treatment. Metyrosine was shown to be tolerated and to relieve symptoms by reducing excess catecholamine in PPGL patients under both preoperative and chronic treatment.

The development and improvement of ethical review of multi-center clinical trial / 中华医学科研管理杂志

Objective Improve the ethical review models of multi-center clinical trial.Methods Analyze the ethical review models of multi-center clinical trial in China,and summarize advantages and disadvantages of the different methods.Then,clarify the development of ethical review methods of multi-center clinical trial in our hospital.Results Four methods were used to review the multi center clinical trial in China,including independent ethical review,central institutional ethical review,central review made by committee cooperation,collaborative review.Each method has its advantages and disadvantages.Collaborative review about multi-center clinical trial is adopted now in our hospital.Conclusions Using collaborative review model of multi-center clinical trial,the ethical review could achieve timely and uniformly.

Retrospective Study on the Protocol Deviation in Drug Clinical Trial Implementation of Our Hospital / 中国药房

OBJECTIVE:To study the influencing factors of protocol deviation in drug clinical trial implementation,and pro-vide reference for improving the quality of drug clinical trial. METHODS:Quality verification was conducted for the drug clinical trial projects in the First Affiliated Hospital of Chongqing Medical University during 2010-2016,and protocol deviations in each year were retrospectively studied,classified and analyzed. Category,frequency,international and domestic pilot projects and the differences of protocol deviation after full-time research nurse participating in trail management were explored,and the measures were put forward. RESULTS:27 drug clinical trials were implemented in our hospital during 2010-2016,including 949 cases,176 cases with protocol deviation,accounting for 18.55％. Deviation protocol in drug clinical trial was decreased year by year for 7 years. The categories were mainly incompleteness of observation/records (30.11％),checking omission/broaden the window(28.41％),adverse drug events and improper combined medication (14.20％) and omission in drug management (11.93％). The proportion of protocol deviation with full-time research nurse participated was lower than the projects without full-time research nurse(11.11％ vs. 28.67％,P<0.01),and proportion of deviation protocol in international multi-center project was lower than the domestic projects(6.60％ vs. 28.84％,P<0.01). CONCLUSIONS:It is suggested to pointedly strengthen the weak links of drug clinical trial. For example,clinical trial institutions should establish the clinical trial data retention system,electronic data should be timely backed up in a different places,etc. Besides,clinical trial institutions should equip professional full-time research nurses as much as possible,learn the rigorous scientific experimental design,standard operational procedures and the authenticity of data pro-cessing from the international multi-center clinical trial projects to effectively reduce the incidence of deviation protocol and im-prove the quality of drug clinical trials.

Three measures of explained variation for correlated survival data under the proportional hazards mixed-effects model.

Measures of explained variation are useful in scientific research, as they quantify the amount of variation in an outcome variable of interest that is explained by one or more other variables. We develop such measures for correlated survival data, under the proportional hazards mixed-effects model. Because different approaches have been studied in the literature outside the classical linear regression model, we investigate three measures R(2) , Rres2, and ρ(2) that quantify three different population coefficients. We show that although the three population measures are not the same, they reflect similar amounts of variation explained by the predictors. Among the three measures, we show that R(2) , which is the simplest to compute, is also consistent for the first population measure under the usual asymptotic scenario when the number of clusters tends to infinity. The other two measures, on the other hand, all require that in addition the cluster sizes be large. We study the properties of the measures both analytically and through simulation studies. We illustrate their different usage on a multi-center clinical trial and a recurrent events data set. Copyright © 2016 John Wiley & Sons, Ltd.

Multi-center clinical trial of Xiao'er Feire Kechuan Granule on acute inflammation of pharynx and trachea with syndrome of pedo-anemopyretic cold with phlegm / 中草药

Objective: To evaluate the efficacy and safety of Xiao'er Feire Kechuan Granule in treating on acute inflammation of the pharynx and the trachea with syndrome of pedo-anemopyretic cold with phlegm. Methods: The stratified blocked randomization, positive drug (Jizhi Syrup) parallel contrast, double blind, double dummy, non-inferiority test, and multi-center research were applied to this study. Results: A total of 210 cases were collected, and each group with 105 cases. The total effective rates of disease in the treatment and control groups were 96.04% and 96.08%, respectively (per protocol analysis, PPS), and the total effective rates of syndrome in the treatment and control groups were 97.03% and 98.04% (PPS), respectively. The results of non-inferiority test indicated that the efficiency to the patients in the treatment group was no worse than that in the control group. The disappearance rate of sore red swollen throat in the two groups, respectively was 57.43% and 43.14% (PPS); The treatment group was superior to the control group, the difference between the two groups was significant (P<0.05). Compared with the disappearance rate of other single syndromes and the incidence of complications, the difference between the two groups was not significant. There was no clinical adverse reaction in both groups. Conclusion: The curative effect of Xiao'er Feire Kechuan Granule is not inferior to Jizhi Syrup, and compared with the disappearance rate of sore red swollen throat, it is superior to Jizhi Syrup. In addition to, Xiao'er Feire Kechuan Granule has high safety.

Bayesian Variable Selection under the Proportional Hazards Mixed-effects Model.

Over the past decade much statistical research has been carried out to develop models for correlated survival data; however, methods for model selection are still very limited. A stochastic search variable selection (SSVS) approach under the proportional hazards mixed-effects model (PHMM) is developed. The SSVS method has previously been applied to linear and generalized linear mixed models, and to the proportional hazards model with high dimensional data. Because the method has mainly been developed for hierarchical normal mixture distributions, it operates on the linear predictor under the Cox type models. The PHMM naturally incorporates the normal distribution via the random effects, which enables SSVS to efficiently search through the candidate variable space. The approach was evaluated through simulation, and applied to a multi-center lung cancer clinical trial data set, for which the variable selection problem was previously debated upon in the literature.

Analysis of Repeated Data of Multi-center Clinical Trial for Traditional Chinese Medicine by Hierarchical Linear Model / 中国中医药信息杂志

Objective To explore the applicability and feasibility of the hierarchical linear model in dealing with the repeated measurement data by applying it into multi-center clinical trials’ evaluation of new Chinese medicine. Methods The theoretical research described the basic concepts and principles of hierarchical linear model and compared the applying conditions of traditional statistical methods with hierarchical linear model. In the empirical study, the hierarchical linear model was used into a real multicenter clinical trial research of traditional Chinese medicine, with the TCM syndrome score as the analysis indicator. Results The hierarchical linear model added time, group and time×group as random variables into the model to get the final result. All of the three variables were significant in the result. The interaction (time×group) statistical result was t=2.65, P=0.008 1. During the whole treatment, the TCM syndrome mean score of trial group reduced 8.5 and the control group reduced 7.47. At the end of treatment, the TCM syndrome mean score of trial group was 2.46, and the control group was 3.31, which was higher than trail group. For this result, combining with the TCM syndrome score’s developing trend, we can see that the efficacy of trial group is not worse than the control group. Conclusion By comparing the data requirements, applying conditions and analysis results, the hierarchical linear model could be an effective method which can be used in multi-center trial to evaluate traditional Chinese drug.

Statistical approaches for evaluating and dealing with center effects in multi-center clinical trial / 中国临床药理学与治疗学

To search the statistical approaches for evaluating and dealing with the center effects in multi-center clinical trial. Breslow-Day test was used for evaluating the differences of the virtual rating among the centers whose responses were binary, Cochran-Mantel-Haenszel test for dealing with the center effects whose responses were binary or ordinal, and logistic regression for evaluating and dealing with the center effects simultaneously. The results showed that Breslow-Day test is invalid in evaluating the center effects whose response is ordinal, and Cochran-Mantel- Haenszel test can not be used for dealing with the effects of other covariates meanwhile.