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1、A Statistical Reviewers PerspectiveStephen E. Wilson Division Director Feng Zhou Statistician Food and Drug Administration Views expressed in this presentation are those of the speaker and not, necessarily, of the Food and Drug Administration. Presentation Outline Background Information Review of SD
2、TM and ADaM datasets: An Example Pre-NDA Submission NDA Review Comments and Closing Thoughts 2Background InformationCDISC Clinical Data Interchange Standards Consortium ODM Operational Data Model SDTM Study Data Tabulations Model ADaM Analysis Data Set Model 3Background Information WebCarcin (for ca
3、rcinogenicity study) eStable (for stability study) DataSmart(TM) (for data restructuring) OBPS Office of Business Process Support Standardizes information management processes to support electronic submissions eCTD - Electronic Common Technical Document WebSDM FDA Web based Submission Data Managemen
4、t tool Check for data errors Run the standard reports Merge/reformat the data sets eReview (Ted Guo, Feng Zhou) Reviewers developed and managed web-based review tools: Publishes regulations, Guidance Documents and MaPPs 45 Pre-NDA Submission An Example Pre-NDA MeetingThe Pre-NDA briefing package inc
5、luded: Questions about eCTD Questions about data elements according to CDISC standards (SDTM and ADaM) CD ROM “sampler”: eCTD module define.xml and define.pdf SDTM sample data ADaM (analysis) sample data 6An Example Pre-NDA meetingSome discussion at the Pre-NDA meeting Questions regarding sample dat
6、aset: a. Are the Statistical Reviewers in agreement with the content, structure and format of the ADaM dataset? Do the Statistical Reviewers have other comments regarding any dataset (ADaM or SDTM) or presentation of the metadata? b. Does the FDA wish to receive the programming code for statistical
7、analyses performed? 7An Example Pre-NDA meeting Sample eCTD structure Datasets Analyses Programs Define.xml IN.xpt RE.xpt Tabulations Define.xml DM.xpt LB.xpt ADaM data include the primary efficacy analyses SDTM data mirror the observed data 89 An Example Pre-NDA meeting Sample analysis dataset (ADa
8、M) 10 An Example Pre-NDA meeting Some discussion at the Pre-NDA meeting 11 An Example Pre-NDA meeting Some discussion at the Pre-NDA meeting An Example Pre-NDA meeting Some discussion at the Pre-NDA meeting: The company referred to the Divisions first comment, noting that the differences would be mo
9、dified to conform with the CDISC SDS version 3.1 specifications. The Division stated that this is acceptable. The company referred to the Divisions second comment, noting that they had not planned to include these data in the application submission. The company did not analyze the AM and PM data ind
10、ividually (the analysis was based on 24 hour averages). This information is included in the clinical data. The Division suggested that the company include the AM and PM measurements in the submission, in addition to providing the average values. 12An Example Pre-NDA meeting Some discussion at the Pr
11、e-NDA meeting: The Division commended the company on the quality of the statistical portion of the meeting package, noting that the sample ADaM analysis datasets were extremely helpful tools for reviewing the anticipated submission. 1314 NDA Review 15 An Example Review SDTM Datasets using WebSDM Rev
12、iewing SDTM datasets using WebSDM (Lincoln Technologies) An Example Review ADaM (Analysis) DatasetsStatistical Review Approach Check the primary outcome Reconstruct the primary outcome from observed datasets (SDTM) according to the Statistical Analysis Plan (SAP) Check SAS code that created the prim
13、ary outcome (derived variables) Check the SAS code for Primary Analysis Check study sites records Check interpretation difference of ITT Perform additional analyses to assess the robustness of a certain efficacy model 1617 An Example Review ADaM Datasets The approach used to handle duplicated record
14、s should be captured in the metadata An Example Review ADaM Datasets SAS code that created the RE.xpt (ADaM) data | PROGRAM: D_TNSS_REFL| PROTOCOL: xxxxxx| VERSION: xxxxxx| SOURCE(optional): TNSS Intermediate dataset | PURPOSE: | REQUIREMENTS: | INPUTS: IMED.TNSS_W.sas7bdat | SDTM.DM.sas7bdat | SDTM
15、.DS.sas7bdat| OUTPUTS: ADAM.RE.sas7bdat | EXAMPLE(optional): | PROGRAMMER: xxxxxx| DATE: xxxxxx| SAS VERSION: 9.1.3 | NOTES: 24 Hour Reflective Total Nasal Symptom Score (TNSS)| REVISION HISTORY:| BY: xxxxxx| DATE: xxxxxx*-Create CDISC ADaM TNSS dataset There is no document about this dataset in the submission 18An Example Review ADaM Datasets“The SDTM datasets were derived from the raw data after the analy
