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Introduction to Clinical Trials

We Program for Life

– 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
Introduction to Clinical

• 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

– 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

– 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

of people (20-80) for the first time to evaluate its safety, determine a safe
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
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 • IND

• Arm
• Baseline • Placebo
• Blinded Trial • Protocol
• Control Group
• Randomization
• Double-blind trial
• Efficacy • Serious Adverse
• Inclusion /Exclusion Criteria 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)
• 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)


• 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.

• 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.

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

• 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 •SAS Datasets

SITE Database Raw Data Derived Data

•EDC System, e.g.. eCRF •Data Cleaning / Querying

•Paper CRF followed by •Database Lock / Freeze
manual data entry


Role of a SAS
Either a source programmer or developer OR a verification or validation programmer

• Data Extraction / Cleaning • Data Analysis / Reporting

– Analysis Datasets
– Extraction of clinical data from
– TLGs / TFLs
various sources.
– In-Text Tables
– SAS® Tools used – Tools Used
• SAS®/Access, SAS®/Connect • Base SAS
– Edit Checks, Cross-form edit • MACROS
checks, Validation reports, • SAS/STAT
Summary reports
– Transfer files per sponsor
specifications, company
specifications, CDISC standards
– SAS® Tools used
• Base SAS
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
Data Domains
• Inclusion \ Exclusion
• Demographics
• Labs
• Vital Signs
• Adverse Events / Serious Adverse Events
• 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
• 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 Placebo Treatment A xx.xmg Total

Timepoint (N=XXX) (N=XXX) (N=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



Median XX.X XX.X XX.X

Min, Max XX.X, XX.X XX.X, XX.X XX.X, XX.X

Change from Baseline at Week


Median XX.X XX.X XX.X

Min, Max XX.X, XX.X XX.X, XX.X XX.X, XX.X


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)
Clinical Data Interchange Standards Consortium (CDISC)
CDISC is a non-profit

To develop industry standards to support acquisition, exchange, submission and
archiving of clinical trials data for medical and biopharmaceutical product

ODM : Operational Data Model
ADAM : Analysis Data Model
SDTM : Study Data Tabulation Model
LAB : 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:
Further Reading

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