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Introduction to Clinical Trials SAS We Program for Life

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Page 1: SAS Clinical Trials

Introduction to Clinical Trials

SASWe Program for Life

Page 2: SAS Clinical Trials

– What are clinical trials?– Important terms used in the pharma industry – Role of a SAS programmer in clinical trials– Reports in pharma industry– Introduction to CDISC

Objectives

Page 3: SAS Clinical Trials

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

Page 4: SAS Clinical Trials

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 (FYI)

Page 5: SAS Clinical Trials

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.

Page 6: SAS Clinical Trials

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

Page 7: SAS Clinical Trials

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)

Page 8: SAS Clinical Trials

CRF / eCRF• Regular forms with questions given to the patients (subjects)

participating in the CT

• 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)

• Response of the patients is then transferred to a database --------raw dataset-------analysis dataset--------reports

• Paper / eCRF

• Annotated CRF (CRFs with variable names)

Page 9: SAS Clinical Trials

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 areseen regularly by the research staff (medical doctors and nurses) to monitor their health and to determine the safety and effectiveness of their treatment.

Page 10: SAS Clinical Trials

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.

Page 11: SAS Clinical Trials

Other…

• Study Designs– Multi-site Vs. Single Site clinical trials– Placebo vs. Active Control– Blinded vs. Open Label– Randomized

Page 12: SAS Clinical Trials

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

Page 13: SAS Clinical Trials

•TGL Programming

Data Flow

SITE Database Raw Data Derived Data

CSR

•EDC System, e.g.. eCRF•Paper CRF followed by

manual data entry

•Data Extracts

•Data Cleaning / Querying•Database Lock / Freeze

•SAS Datasets

eSUB

Page 14: SAS Clinical Trials

• 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

Role of a SAS Programmer

• Data Analysis / Reporting– Analysis Datasets– TLGs / TFLs– In-Text Tables– Tools Used

• Base SAS• MACROS• SAS/STAT• SAS/GRAPH

Either a source programmer or developer OR a verification or validation programmer

Page 15: SAS Clinical Trials

Role ….• 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

Page 16: SAS Clinical Trials

Data Domains

• Inclusion \ Exclusion • Demographics• Labs• Vital Signs• Adverse Events / Serious Adverse Events• ECG• Physical Exam• Concomitant Medication• Medical History• Study Completion / Early Termination

Page 17: SAS Clinical Trials

Data Domains (contd.)• ECG Data:

– ECG Core Labs – ECG done at the site– ECG Collection form– Sample Data– Sample CSR

Page 18: SAS Clinical Trials

Reports• Tables / Summary Tables

– Numbers Only– No patient details– Independent Programming / Number Check

• Listings– All details– Output Review / Code Review

• Graphs / Figures– Frequency / Number Checks

Page 19: SAS Clinical Trials

Scheduled Timepoint

Placebo(N=XXX)

Treatment A xx.xmg(N=XXX)

Total(N=XXX)

Baseline

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

At Week 4

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

Change from Baseline at Week 4

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

Sample Table

Page 20: SAS Clinical Trials

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)

Page 21: SAS Clinical Trials

CDISCWHAT:Clinical Data Interchange Standards Consortium (CDISCCDISC) 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 : Operational Data ModelADAM : Analysis Data ModelSDTM : Study Data Tabulation ModelLAB : Laboratory Standard Model

Page 22: SAS Clinical Trials

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

Page 23: SAS Clinical Trials

CDISC - ModelsADaM - 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

Page 24: SAS Clinical Trials

CDISC - ModelsSDTM - 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

Page 25: SAS Clinical Trials

• www.fda.gov• www.cdisc.org• www.clinicaltrials.gov• www.google.com ☺

Further Reading