The Study Of EDC Building And Simulation, Forecast & Evaluation Methods For Adaptive Clinical Trials

Adaptive design has been attached much importance to by biostatisticians in their studies due to its flexibility. In the past few years, with the development of computer and network technology, the obstacles which block the application of adaptive design were removed and its advantages have been paid more and more attention by regulatory agencies, sponsors and investigators. IVRS, EDC and clinical trial simulation, forecast & evaluation system have been regarded as three key modules of promoting application of adaptive design. IVRS and IWRS, which can inform the investigators the random number of test drug instantly, offer the possibility of adjust the random allocation scheme in adaptive design. The application of EDC, can not only cut down the trial time and obtain high quality data in time, but reduce the costs, improve the efficiency and ensure its reliability. In clinical trial simulation, forecast & evaluation system, the whole trial process and conceivable scenarios can be simulated by computer simulation and the possible results will be forecasted and evaluated to guide the investigators and biostatisticians to optimize the trial design and improve the power of clinical trial.EDC, which has the direct relationship with the implementation and quality of adaptive clinical trial, is the key factor of promoting the application of adaptive design in clinical trials. The difficulty of EDC building is the reusability of e-CRF design, which is to make use of the commonness of case report forms as much as possible to improve the efficiency when designing different e-CRFs. Moreover, the system of simulation, forecast & evaluation has to be paid much attention to due to the application of adaptive design. In the system of simulation, forecast & evaluation, the whole trial flow can be simulated and the corresponding results will be forecasted and evaluated to help the investigators and biostatisticians choose the optimal trial design. However, the basis of this system is the study of simulation, forecast & evaluation method. Considering what we have discussed above, this study focuses on the methods of EDC building,simulation, forecast and evaluation method for two stage adaptive design. The main works are introduced as follows:(I)Study of EDC building based on structural case repot formAccording to the structural characteristic of case report form, which is investigated systematically based on the clinical trials in our country, general database model and e-CRF metadata repository have been built to deal with the problem of reusability. The structure of general database model, which is constructed by using EAV structure and traditional relational structure, does not change with the change of indexes in different clinical trials. It simplifies the process of e-CRF database building for each clinical trial and solves the reusability of EDC database. The data type, format in Web page, check condition, option for categorical variable, label, etc are include in e-CRF metadata repository, which is composed of XML file, XSL file and JavaScript check file. Due to e-CRF metadata repository, the XML file and XSL file for the whole case report form can be written easily to build the Web page of e-CRF for data entry.Furthermore, XML is not only to construct e-CRF metadata repository, but a medium between e-CRF and EDC database for storing and reading. It can help the data transportation between EDC and other related systems in clinical trials. Besides, in virtue of XML, the XSL file can be used for Web page generation repeatedly and the efficiency of programming is improved.(II)Study of simulation, forecast & evaluation method for two-stage adaptive designTaken adaptive two-stage double-arm clinical trial for dichotomous variables as an example, Monte Carlo simulation is performed at the stage of protocol design to simulate multiple conceivable scenarios and adaptations. Then the corresponding results could be forecasted and evaluated to determine the optimal parametersα1,α0,α2and sample size of stage II. This method, in which the sample size of stage II can be adapted based on the accrued data at the interim stage, enhances the flexibility of the clinical trial. Besides, the integrity of the trial can also be ensured much more by preplanning the possible sample size adaptation in protocol design. Moreover, this method is generalized when sample size constraint, unequal sample size and different distribution for endpoint variables are considered.The methods of overall analysis are also compared by Monte Carlo simulation. It has been found that the method of pooled data analysis have a higher overall test power and better constraint on overall type I error due to additive rule. Among the methods of combining p-values, although the overall test powers of INM method and MSP method are higher than Bauer-K?hne method, their overall type I error are not controlled finely. However, the overall type I error of Bauer-K?hne method, which has its inferiority in overall test power, is accepted in adaptive two-stage designIn this paper, the studies of EDC building method based on structural case report form and simulation, forecast & evaluation method for adaptive two-stage design provide theoretic and arithmetic basis for the building of EDC and simulation, forecast & evaluation system, which will further promote the application of adaptive clinical trials in our country.