Introduction to Clinical Trials
SAS We Program for Life
Objectives
– What What ar aree cli clini nica call tria trials ls?? – Import Important ant terms terms used used in the the phar pharma ma indu industr stry y – Role Role of a SAS SAS progr program ammer mer in clin clinica icall trial trialss – Re Repo port rtss in pha pharm rmaa indu indust stry ry – Intr Introd oduc ucti tion on to CDIS CDISC C
Introduction to Clinical Trials • Definition : – The answer to WHAT • a research study in human volunteers to answer specific health questions. – The answer to WHY • to determine if a new drug or treatment will work on a disease or will potentially be of benefit to patients
Introduction (FYI) Types of clinical trials? – Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy – Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes – Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. – Screening trials test the best way to detect certain diseases or health conditions. – Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.
Introduction (contd.) Phases in clinical trials? Phase I trials , researchers test a experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. Phase II trials , the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. Phase III trials , the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. Phase IV trials , post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
Important Terms • • • • • • • •
Adverse Events – AE Arm Baseline Blinded Trial Control Group Double-blind trial Efficacy Inclusion /Exclusion Criteria
• • • • •
IND Placebo Protocol Randomization Serious Adverse Events SAE • Toxicity • Treatment Group
Big Words • CRF (Case Report Form) / eCRF • Protocol – SOP (Standard Operating Procedures) • SAP (Statistical Analysis Plan) • CRT (Case Report Tabulation) • CSR (Clinical Study Report) • eSUB (electronic Submission)
CRF / eCRF •
Regular forms with questions given to the patients (subjects) participating in the CT
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Examples: – – – – –
Demographic (PTID/Sex/Race/DOB etc) Lab (Sodium/ Potassium/Chlorine/PH/Visit date/) Vitals ( SBP/DBP/ Height/ Weight/ BMI ) Adverse Events-AE (Start date/ End date/ AE-Name/Duration) Concomitant Medications (Start Date/ End Date/Medications)
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Response of the patients is then transferred to a database -------raw dataset-------analysis dataset--------reports
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Paper / eCRF
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Annotated CRF (CRFs with variable names)
Protocol • The Protocol ( A- Z of a Study) – It is a document that describes the objective's, design, methodology, statistical considerations, and organization of a clinical trial. – The protocol contains a study plan on which all clinical trials are based. The plan is designed to safeguard the health of the participants as well as answer specific research questions. The protocol describes what types of people may participate in the trial; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical trial, participants following a protocol are seen regularly by the research staff (medical doctors and nurses) to monitor their health and to determine the safety and effectiveness of their treatment.
SAP • Statistical Analysis Plan (SAP) – Prepared by study biostatistician – Summarize the protocol from an analysis point of view including the study population definitions, data definitions, and also statistical analyses to be performed. – Provides details about the statistical procedure to be performed for primary and secondary endpoints. – Provides information about tables, graphs and listings to be generated as a part of the Clinical Study Report.
Other… •
Study Designs – Multi-site Vs. Single Site clinical trials – Placebo vs. Active Control – Blinded vs. Open Label – Randomized
SAS ® •
Definition : – The answer to WHY • Recommended by FDA • SAS ® is a robust tool for reporting and analysis • SAS ® is available in various platform and can be easily used to produce highly customized reports
Data Flow •Data Extracts SITE
Database •EDC System, e.g.. eCRF •Paper CRF followed by manual data entry
•SAS Datasets Raw Data
Derived Data
•Data Cleaning / Querying •Database Lock / Freeze
•TGL Programming CSR
eSUB
Role of a SAS Programmer Either a source programmer or developer OR a verification or validation programmer •
Data Extraction / Cleaning – Extraction of clinical data from various sources. – SAS ® Tools used • SAS ® /Access, SAS ® /Connect
– Edit Checks, Cross-form edit checks, Validation reports, Summary reports – Transfer files per sponsor specifications, company specifications, CDISC standards – SAS ® Tools used • Base SAS
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Data Analysis / Reporting –
Analysis Datasets
– TLGs / TFLs – In-Text Tables – Tools Used • • • •
Base SAS MACROS SAS/STAT SAS/GRAPH
Role …. • • • •
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Data Extraction Edit Checks & Dataset Creation (Analysis Files) TFL generation Validation – Independent Programming – Output Review / Check numbers using SAS Procedures – Code Review Submission Work – Define Documents
Data Domains • • • • • • • • • •
Inclusion \ Exclusion Demographics Labs Vital Signs Adverse Events / Serious Adverse Events ECG Physical Exam Concomitant Medication Medical History Study Completion / Early Termination
Data Domains (contd.) •
ECG Data: – – – – –
ECG Core Labs ECG done at the site ECG Collection form Sample Data Sample CSR
Reports •
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Tables / Summary Tables – Numbers Only – No patient details – Independent Programming / Number Check Listings – All details – Output Review / Code Review Graphs / Figures – Frequency / Number Checks
Sample Table Scheduled Timepoint
Placebo (N=XXX)
Treatment A xx.xmg (N=XXX)
Total (N=XXX)
N
XX
XX
XX
Mean (SD)
XX.XX (X.XXX)
XX.XX (X.XXX)
XX.XX (X.XXX)
Median
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
N
XX
XX
XX
Mean (SD)
XX.XX (X.XXX)
XX.XX (X.XXX)
XX.XX (X.XXX)
Median
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
N
XX
XX
XX
Mean (SD)
XX.XX (X.XXX)
XX.XX (X.XXX)
XX.XX (X.XXX)
Median
XX.X
XX.X
XX.X
Min, Max
XX.X, XX.X
XX.X, XX.X
XX.X, XX.X
Baseline
At Week 4
Change from Baseline at Week 4
NOTE Mock / Shell Tables: Usually provided by statistician – General layout – how the report should look Typical Tables to take care of: •Adverse Events tables – collapsing the most severe AE, related to drug, 1 patient showing two AEs in an SOC is counted only once, which sometimes causes confusion about the numbers not matching on the summary table •Shift Tables – Clinically significant grades for LAB shift tables, also done shift tables for ECHO (echocardiography sub-study)
CDISC WHAT: Clinical Data Interchange Standards Consortium (CDISC) is a non-profit organization WHY: To develop industry standards to support acquisition, exchange, submission and archiving of clinical trials data for medical and biopharmaceutical product development. MODELS: ODM : ADAM : SDTM : LAB :
Operational Data Model Analysis Data Model Study Data Tabulation Model Laboratory Standard Model
CDISC - Models ODM – Operational Data Model • Facilitates the movement of clinical data collected from multiple sources to one operational database • Sources – Paper CRF / eCRF / Diaries etc • The ODM is a specification of a standard XML schema for the interchange and archive of clinical trials data and metadata. • define.xml
CDISC - Models ADaM - Analysis Dataset Model • Defines a standard for analysis datasets that are used to generate statistical reports fro regulatory submissions (To ensure the datasets are driven by the objective of the study) • One step away – as they are called, this means the dataset should be ready for analysis to be performed using SAS procedures directly without any further work on the data. • Typical Dataset names: Names should have more descriptive labels in case of more than one dataset • SBCAD – Subject baseline Characteristics Analysis Dataset • ADCFB – Analysis Dataset Change from Baseline • Metadata is required to be submitted at each level for all the datasets involved • Metadata – “Data about Data” Description/Attributes/Structure • Domain level / Variable level / Table level • ISO8601 type of date and time – e.g.. 2006-06-18T10:00:00
CDISC - Models SDTM - Study Data Tabulation Model • Defines a standard structure for data tabulations that are to be submitted as part of a product application to a regulatory authority such as the FDA. • Current version: 3.1.1 SDTMIG LAB – Laboratory Study Model • Work towards developing a standard model fro acquisition and interchange of lab data (largest component of CT data) • Example – To standardize the test codes SAS® resources: PROC CDISC
Further Reading • • • •
www.fda.gov www.cdisc.org www.clinicaltrials.gov www.google.com ☺
