上海罗氏关于SAS programmer的讲座

Pharmaceutical IndustryContentsClinical trial protocol introductionThe statistical programmer’s working environment Guiding principles for the statistical programmer Preparing clinical trial dataClassifying clinical trial dataHow to be a good programmerCRO VS. PharmaClinical Trial ProtocolWhy do a Clinical Trial?To answer a clinical problemTo gain new knowledge about a new or established treatment To support a “claim”–for gaining government regulatory approval–for marketing a drug, device, or techniqueThe Scientific Method Applied To MedicineGuiding PrincipalsWhat is step one?Research involving humans should be scientifically justified and described in a clear, detailed protocol.“The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol.”(Declaration of Helsinki)SynopsisThe information should be included in a study protocolGeneral InformationBackground InformationTrial Objectives and PurposeTrial DesignSelection and Withdrawal of SubjectsTreatment of SubjectsAssessment of EfficacyAssessment of SafetyThe information should be included in a study protocol(cont.)StatisticsDirect Access to Source Data/DocumentsQuality Control and Quality AssuranceEthics Description of ethical considerations relating to the tri al Data Handling and Record KeepingFinancing and InsurancePublication PolicySupplementsGeneral InformationProtocol title, protocol identifying number, and date, any amendment(s), amendment number(s) and date(s)Name and address of the sponsor and monitorName and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsorName, title, address, and telephone number(s) of the sponsor’s medical expert (or dentist when appropriate) for the trial.General Information (cont.)Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephonenumber(s) of the trial site(s)Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for al l trial-site related medical (or dental) decisions (if other than investigator)Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/orinstitutions involved in the trial.Background InformationName and description of the investigational product(s)A summary of findings from nonclinical studies that potentiallyhave clinical significance and from clinical trials that arerelevant to the trialSummary of the known and potential risks and benefits, if any, to human subjectsDescription of and justification for the route of administration, dosage, dosage regimen, and treatment period(s)Background Information(cont.)A statement that the trial will be conducted in compliancewith the protocol, GCP and the applicable regulatoryrequirement(s)Description of the population to be studiedReferences to literature and data that are relevant to the trial, and that provide background for the trialTrial Objectives and PurposeA detailed description of the objectives and the purpose of thetrial–Primary objectives / Secondary objectives–Primary endpoints / Secondary endpointsTrial Designthe type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stagesthe measures taken to minimize/avoid bias, including: (a) Randomization. (b) Blindingthe trial treatment(s) and the dosage, dosage regimen of the investigational product(s), dosage form, packaging, andlabelling of the investigational product(s)Trial Design(cont.)Expected duration of subject participation, and the sequence and duration of all trial periods, including follow-up, if anyThe “stopping rules”or “discontinuation criteria”for individual subjectsAccountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if anyMaintenance of trial treatment randomization codes and procedures for breaking codesThe identification of any data to be recorded directly on the CRFsParallel designCrossover DesignEach patient receives both treatments (drug / placebo) Order of treatment is randomizedComparison is “within”patients not “between”patientsSelection and Withdrawal of SubjectsSubject inclusion criteriaSubject exclusion criteriaSubject withdrawal criteriaTreatment of SubjectsThe treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), theroute/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for eachinvestigational product treatment/trial treatment group/arm of the trialMedication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial Procedures for monitoring subject complianceSubjectsClinical research uses “convenience samples”–Individuals coming to your hospital and attending your clinic.–Individuals that are available.–VolunteersStudy FlowsheetAssessment of EfficacySpecification of the efficacy parametersMethods and timing for assessing, recording, and analysing of efficacy parametersAssessment of SafetySpecification of safety parametersThe methods and timing for assessing, recording, and analysing safety parametersProcedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnessesThe type and duration of the follow-up of subjects after adverse eventsStatisticsThe statistical methods to be employed, including timing of any planned interim analysis(ses)The number of subjects of each site planned to be enrolled, reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justificati on The level of significance to be usedCriteria for the termination of the trialStatistics (cont.)Procedure for accounting for missing, unused, and spurious dataProcedures for reporting any deviation(s) from the original statistical planThe selection of subjects to be included in the analyses (e.g.all randomized subjects, all dosed subjects, all eligiblesubjects, evaluable subjects)Direct Access to SourceData/DocumentsThe sponsor should ensure that it is specified in the protocol or other written agreement that theinvestigator(s)/institution(s) will permit trial-relatedmonitoring, audits, IRB/IEC review, and regulatoryinspection(s), providing direct access to sourcedata/documentsRelative DocumentInvestigator’s Brochure–The investigator’s brochure is a “compilation of the clinical and nonclinical data on the investigational product(s) thatis relevant to the study of the investigational product(s) inhuman subjects.”(ICH E6, 1.36)The Statistical Programmer’sWorking EnvironmentPharmaceutical Industry VocabularyExample:–ICH CDISC–NDA IND–MedDRA WHODD–SAE–CRF SAP ProtocolStatistical Programmer Work Descriptionworks in a pharma or contract research organization (CRO) conduct programming to perform statistical analysis efficiently Involving the tasks as belowDrug Approval ProcessPre-clinical studiesPhase 1 trialsPhase 2 trialsPhase 3 trialsPhase 4 trialsIndustry Regulations and StandardsInternational Conference on Harmonization (ICH)Clinical Data Interchange Standards Consortium (CDISC)–Study Data Tabulation Model (SDTM).–Analysis Dataset Models (ADaM).–Operational Data Model (ODM).–Case Report Tabulation Data Definition Specification (Define.xml).Food and Drug Administration (FDA) Regulation and Guidance21 CFR–Part 11 Electronic Records; Electronic SignaturesE3 Structure and Content of Clinical Study ReportsE9 Statistical Principles for Clinical TrialsE6 Good Clinical Practice: Consolidated GuidancePart 312.33 of Title 21 of the Code of Federal Regulations; Annual ReportsProviding Regulatory Submissions in Electronic Format –General ConsiderationsProviding Regulatory Submissions in Electronic Format –NDAsElectronic Common Technical Document SpecificationYour Clinical Trial ColleaguesScientistStatisticianData managerClinical programmerStatistical programmerCRA/ MonitorProject ManagerQuality AssuranceRegulatory AffairsMedical WriterInformation TechnologyGuiding Principles for theStatistical ProgrammerUnderstand the Clinical StudyA good statistical programmer takes time to understand thesubject matterseveral areas of study that will help you understand the research topic–read the clinical protocol–read the statistical analysis plan(SAP)Program Reusepreventing you from “reinventing the wheel.”For a clinical trial you may have anywhere from a few dozen to a couple hundred different SAS programs, depending on the nature of the projectProgram ReuseExample:If you were to copy the LIBNAME statements above into 200 different programs, you might realize two things:– 1. You had to copy three common lines of SAS code into 200 different places– 2. You now have a code maintenance problemClinical Trial Data Are DirtyPeople and their behavior are uniqueThe data that describe a patient’s activities tend to be unique as wellNot well designed turns out to be junk dataIt’s impossible to secure all data fields by data management The best way to protect yourself against dirty clinical trial data is to use good defensive programming techniquesUse SAS Macros JudiciouslyThe SAS macro language is a very powerful toolgreat power comes the potential for great abuseThe SAS macro language can be abused when it is used to such an extent that a SAS program becomes unreadableA SAS macro can become unreadable when it is too densewith macro invocations, is poorly documented, or involvestoo many nested macro callsStrive to Make Your Programming ReadableIt is guaranteed that someone other than you will have to read your program at some pointA well-written SAS program has an ample supply ofcomments, employs white space to make the code pleasing to the eye, and uses a consistent case and indention styleFor more information about basic SAS programming style, you may want to refer to The Little SAS Book: A Primer, by Lora Delwiche and Susan SlaughterPreparing Clinical Trial DataPreparing Clinical Trial DataClinical trial data type: numeric variables and character string (text) variablesTwo considerations for all numeric and text variables –All data should be cleaned if they are needed for analyses, –Any data entered as free-text variables should be coded or categorized if they are needed for analyses“Clean”the DataBefore the statistical programmer receives data that are ready for analysis, the clinical data management group cleans the data through a query process.Data Cleaning ProcessThe clinical data management query process usually looks like this:– A programmatic or manual investigation finds an errant data point– A “query”or data clarification form (DCF) for that data point is sent to the clinical site–The clinical site responds to the query–The clinical data management group updates the database or CRF based on the response from the clinical siteProgrammer’s responsibility in data cleaning ProcessEdit check programming / DQCPay attention to the data issue when you do any program test Dig out all the storyCategorize Data If NecessaryCategorize the numeric dataeg: Age group; BMICategorize the free-text dataeg: Adverse EventMedical History / DiagnosisConcomitant MedicationCoding ThesaurusDictionaries related to Clinical Trials Coding。