Download SAS Clinical Programming In 18 Easy Steps

SAS Clinical Programming
In 18 Easy Steps
FOR M.Pharm / M.Sc (Life Sciences) /M.sc (Stats)/
M.C.A/M.Tech / B.Pharm /Bio-Tech/B.Tech.
SAS Clinical Programming
In 18 Easy Steps
FOR M.Pharm / M.Sc (Life Sciences) /M.sc (Stats)/
M.C.A/M.Tech / B.Pharm /Bio-Tech/B.Tech.
Mr. Y. Lakshmi Prasad
Notion Press
5 Muthu Kalathy Street, Triplicane,
Chennai - 600 005
First Published by Notion Press 2014
Copyright © Mr. Y. Lakshmi Prasad 2014
All Rights Reserved.
ISBN: 978-93-84381-63-9
This book has been published in good faith that the work of the author
is original. All efforts have been taken to make the material error-free.
However, the author and the publisher disclaim the responsibility.
No part of this book may be used, reproduced in any manner whatsoever
without written permission from the author, except in the case of brief
quotations embodied in critical articles and reviews.
This book is dedicated to
P. V. Narasimha Rao
(Patriotic statesman who believed that
the nation is bigger than the political system)
Preface
Finally, An Indian author created an indispensable guide focuses on
SAS Clinical Programming, in an instructive and conversational tone
which helps them who want to make their career in SAS Clinical
Programming and entry level programmers for their day to day tasks
with practical, real world examples, detailed description, work flows,
Issues, Resolutions, key techniques and many more.
This book is like your personal trainer, explains the art of SAS
clinical Programming in 18 easy steps which covers from basics to
ADS, TLF Creation, as well as CDISC SDTM, ADaM. Many statistical
Concepts are explained in an easy way so that you feel confident while
using Statistical Procedures. If you are already working as a SAS
Clinical Programmer, still you need this book to sharpen your skills.
This book will be an asset to you and your career by making you a
better SAS clinical Programmer.
Authors’ Note
One interesting thing in SAS Clinical Programming, it is the career
Option for people with various study backgrounds. I have seen SAS
Programmers with different qualifications like Pharmacy, Statistics,
M.C.A, M. Tech, M.Sc Life sciences, Bio Tech, Mathematics and
many more. It is wonderful to see people with different backgrounds
working on the same project, but how can we expect Clinical Research
and Biostatistics knowledge from a person with technical qualification.
Every person might be strong in their own subject but SAS Clinical
Programmer needs to know more than one subject (Programming
(Tech), Clinical Research (Pharma) and Biostatistics (Stats)). This
might be the reason I thought it would be beneficial to have a resource
that brings together all these aspects in one volume so that it would
help everybody who wants to make SAS Programming as their career
Option.
This book was written to assist learners in getting started, while at
the same time providing techniques that I have found to be useful to
Entry level SAS Clinical programmers. This book is aimed more at the
SAS Clinical programmer who is responsible for producing submission
ready Reports.
This book assumes that the reader has no prior knowledge of
clinical research and SAS programming. Each one of us has our own
style of approach to an issue; it is likely that others will find alternate
solutions for many of the issues discussed in this book.
The clinical trial data that appears in a number of examples
throughout this book was just an imaginary phase 2 Diabetic study, any
resemblance was simply accidental.
This book was organized in 18 easy steps from introduction to
creating final reports, which resembles the SAS Clinical programmer’s
work environment.
viii Author’s Note
The solutions to some of the questions are not written fully but only
some steps of hints are mentioned. It is just for the sake of recalling the
memory involving important facts in common practice.
I shall ever be thankful, grateful and eager to accept the insightful
suggestions from my colleagues make this work more worthy.
Y L Prasad
Acknoweldgements
A great deal of information was received from the numerous people
who offered their time. I would like to thank each and every person
who helped me in creating this book.
I heartily express my gratitude to all of my peers, colleagues,
friends and students whose sincere response geared up to meet the
exigent way of expressing the contents. I am very much grateful to our
Press, editors and designers whose scrupulous assistance completed
this work to reach your hands.
Finally, I am personally indebted to my wonderful partner
Prajwala, and my kid Prakhyath, for their support, enthusiasm, and
tolerance, without which this book would have never been completed.
Y.L.Prasad
Contents
Prefacevi
Authors’ Note
vii
Acknoweldgements ix
Step 1: INTRODUCTION TO CLINCAL RESEARCH
1
Drug Development Process
Clinical Research
Clinical Trials
Clinical Research Process
Industry Regulations and Standards for Clinical Trials
Departments and Roles in a CRO
Process Flow in a Typical Clinical Trial
1
2
3
3
6
8
12
Step 2: INTRODUCTION TO SAS
15
Basic SAS Program Requirements
Rules for User-Supplied SAS Names
SAS WINDOWS
Reading Data into a SAS Data Set
Introduction to SAS/Library 16
17
18
19
20
Step 3: INTRODUCTION TO OUR STUDY 23
Diabetes Mellitus
23
Types of Diabetes Mellitus
23
Pathophysiology24
Diagnosis 24
WHO Diabetes Diagnostic Criteria
25
Study Details
25
Study Design
26
Efficacy Measures
27
Analysis Populations
28
Treatment Compliance
29
Contents xi
Baseline Definition Efficacy Evaluation
Safety Evaluation
29
30
30
Step 4: STUDY DATASETS
32
List Input Method
Double Trailing AT Method (@@)
Reading Non Standard Data (Format Input Method)
Column Input, Column Pointer Method
Column Pointer At Method
33
34
36
40
45
Step 5: INTRODUCTION TO PROC STEP
56
Proc Print (PRINT Procedure)
Proc Contents (CONTENTS Procedure)
Proc Sort (SORT Procedure)
Proc Format (FORMAT Procedure)
57
65
67
72
Step 6: COMBINING DATASETS
81
Concatenating Datasets
Appending Datasets
Interleaving Datasets
Merging Datasets
82
83
87
88
Step 7: SAS FUNCTIONS
98
Arithmetic Functions
Character Functions
DATE/TIME Functions
99
101
122
Step 8: UNDERSTANDING DATA STEP
PROCESS AND PDV
128
Flow of Action in a Datastep
Processing a DATA Step, a Walkthrough
Types of Errors in SAS
Common Automatic Variables
128
130
131
132
Step 9: MODIFYING SAS DATASETS
133
Conditional Processing
Using UNTIL and WHILE Clauses
133
149
xii Contents
Debugging154
Creating User Generated Log Messages
154
RETAIN Statement
155
Array158
Step 10: STATISTICAL CONCEPTS
165
Common Statistical Terms
Types of Variables
Types of Data
Types of Clinical Studies
Selection of an Appropriate Statistical Test
Proc Freq (FREQ Procedure)
CHI-Square Test
Fisher’s Exact Test
Mantel-Heanszel Chi-Square Test
Cochran-Mantel-Heanszel Chi-Square Test (CMH Test)
Proc Means (MEANS Procedure)
Proc Univariate (UNIVARIATE Procedure)
Proc Univariate in Data Cleaning
ODS (Output Delivery System)
Proc Ttest (TTEST Procedure)
Two Sample Ttest
Proc Npar1way (NPAR1WAY Procedure)
Wilcoxon Signed-rank Test
Wilcoxon Rank Sum Test
Proc ANOVA
Kruskal-Wallis Test
CORR Procedure Regression Analysis
Multiple Linear Regressions
LOGISTIC Regression
165
166
167
172
174
175
179
182
183
184
184
188
191
192
199
201
203
204
205
206
208
209
213
218
219
Step 11: SAS MACROS
222
Macro Terminology
Macro Variables %LET Statement
Creating Macro Variables from Data Step
222
223
225
228
Contents xiii
Symget and Symgetn Functions
Building a Better Macro
Macro Parameters
Steps in Creating Macro
Macro Functions
Macro Debugging
Storing Macros
230
233
235
236
237
242
244
Step 12: PROC SQL
248
SQL Terminology
SELECT Clause
INTO Clause Joining Tables
Performing Inner Join
248
249
256
257
259
Step 13: CDISC SDTM
264
CDISC Standards
SDTM Domains
DM Domain
CM Domain AE Domain
LB Domain
264
266
274
281
287
294
Step 14: CDISC ADaM
301
Structure of Analysis Dataset Specifications
ADSL Specification
ADAE Specifications
ADCM Specifications
ADLB Specifications
Data Definition Tables (Define.pdf)
301
303
315
320
326
332
Step 15: CREATING ANALYSIS DATASETS
337
Study Populations / Analysis Populations
Study Day Variable
Change from Baseline
Visit Windowing
Basic Lab Pre-Processing
339
339
343
344
346
xiv Contents
Dealing with Partial Dates
348
Time to Event Analysis
349
Duration of Response
350
Determining Value for VISFWDID in Adverse Events
351
Proc Transpose (Transposing Datasets)
351
Flagging Concomitant Medications
354
TEAE Flag
356
LOCF358
Duration Calculation
362
TABLE Shells
365
Step 16: CREATING REPORTS 376
TABULATE Procedure
Proc Report (REPORT Procedure)
Using the Column Statement
Using the Define Statement
Using the Break /Rbreak Statements
Using Compute Block
376
384
386
388
392
392
Step 17: SAS/GRAPH397
Proc Gchart (GCHART Procedure)
GPLOT Procedure
397
400
Step 18: DOCUMENTATION & STANDARD
OPERATING PROCEDURES
405
Different Documents we use while Performing
SAS Clinical Programming
405
Standard Operating Procedures
412
Validation and QC Guidelines
420
Messages to be Checked in the Log Window
421
Proc Compare
422
Check Your Understanding
426
Index432
We all have dreams. But in order to make dreams
come into reality, it takes an awful
lot of determination, dedication,
self-discipline, and effort.
---Jesse Owens
Step 1
INTRODUCTION TO
CLINCAL RESEARCH
The Process from discovering a new drug to registering it for
marketing is very complex and lengthy. There are several people
involved in the Process of drug discovery and development includes
Scientists, Clinicians, Statisticians as well as Data managers and SAS
Programmers. It is estimated that, on average, a drug takes 10-12
years from initial research to reach the market. Drug discovery and
development are mainly carried out by pharmaceutical companies and
research agencies. The pharmaceutical market is very competitive. It is
imperative that pharmaceutical companies discover and develop drugs
efficiently and within the shortest time span to remain competitive.
Drug Development Process
The Drug development Process has different stages:
Drug Discovery

Drug Development

Clinical Trials

Manufacturing

Marketing Approval
The Drug Discovery Process involves in finding out the target that
causes the disease, chemical or biological compounds are screened and
tested against these targets to find leading drug candidates for further
development.
The Drug Development Process involves Tests performed on the
lead compounds in test tubes (laboratory, in vitro) and on animals (in
vivo) to check how they affect the biological systems.
2 SAS Clinical Programming
The development Process includes pharmacological studies
of the lead compound and its effects on toxicity, carcinogenicity,
mutagenicity and reproductive development. These data are important
for determining the safety and effectiveness of the lead compound as a
potential drug.
Typically, tens of thousands of compounds are screened and tested,
and only a handful makes it into the market as drug products. The
statistics are such that, of 5000 compounds that show initial promise,
five will go into human clinical trials, and only one will become an
approved drug.
Clinical Research
Clinical research is a branch of healthcare science that determines the
safety and effectiveness of medications, devices, diagnostic products
and treatment regimens intended for human use.
Clinical research includes:
Medical and behavioral research involving volunteer participants
Investigations that are carefully developed and conducted with
clinical outcomes recorded
Identification of better ways to prevent, diagnoses, treats, and
understands human disease
Trials that test new treatments, clinical management and clinical
outcomes, and long–term studies
Strict scientific guidelines
There are ethical and regulatory constraints for the design and
conduct of a clinical trial that have to be considered. Ethical principles
are to protect participants before a drug is put forward for a clinical
trial.
The United States National Institutes of Health (NIH) has stipulated
seven ethical requirements:
1. Social value
2. Scientific validity
3. Fair subject selection
4. Informed consent
5. Favorable risk-benefit ratio
Y Lakshmi Prasad 3
6. Independent review
7. Respect for human subjects
Clinical Trials:
Clinical trials are prospective studies on human subjects that are
designed to answer specific questions about drugs, treatments, devices
or new ways of using known interventions, generating safety and
efficacy data.
Clinical Research is a study that tests how well an intervention
works in a group of people, Tests for new methods of screening,
prevention, diagnosis, or therapy. During a trial, additional information
is learned about an intervention, its Risks, and its effectiveness.
Clinical Research Process

Pre-clinical testing
Investigational New Drug Application (IND)
Phase I (assess safety)
Phase II (test for effectiveness)
Phase III (large-scale testing)
Licensing (approval to use)
Approval (available for prescription)
Post-marketing studies (special studies and long-term effectiveness/
use)
Pre-Clinical Testing
Pre-clinical testing is required before testing humans. Pre-clinical
testing is often conducted on animals many pre-clinical studies use a
review Committee to determine if the use of animals is warranted. The
review Committee also checks to see if the research can be improved
by reducing or replacing animals. Laboratory and animal studies
are conducted to find out if there is a potential benefit of the drug,
vaccine, or other product and to explore general safety concerns. If a
vaccine, Drug has a potential benefit, it is prepared for human testing.
Pre-clinical testing takes approximately three to four years.
4 SAS Clinical Programming
Investigational New Drug Application (IND):
For studies that involve a new vaccine, drug, after completing Preclinical testing, an investigational new drug application (IND) must
be filed describing the results of pre-clinical testing and how future
studies will be conducted. The U.S. Food and Drug Administration
(FDA) have 30 days to review the IND. If the FDA approves the IND
within 30 days, the test drug can precede to a phase I trial.
Phase I (Assess Drug Safety):
The Phase I clinical trial is the first experiment in which a drug is tested
on the human body. The primary aim of the trial is to assess the safety
of the new drug. Phase I trials are usually conducted with open label,
i.e. the subjects are aware of the drugs that they are being given. For
the first time, the Test drug is introduced to humans. Testing occurs in
a small number of healthy volunteers (20 to 100). This initial phase of
testing usually lasts several months to 1 year.
The goals of phase I clinical trials are Assess safety for humans as
well as select the dose to be used in future studies. During phase I, the
study is designed to determine how the human body reacts and what
side effects occur as dosage levels is increased.
Open-label Study: A trial in which subjects and investigators
know which product each subject is receiving.
Phase II (Test for Safety and Effectiveness):A phase II study provides comparative information about relative safety
and effectiveness and efficacy.
Most phase II studies are randomized trials. This means One group
receives the experimental Test Drug other Control group receives the
current standard treatment or Placebo.
Some phase II studies are blinded, This means participants and
researchers do not know who receives the experimental test drug, this
testing may last from several months to 2 years it may involve from
100-300 participants.
Phase III (Large-Scale Testing):The objective of Phase III is to confirm the efficacy of the drug in a
large patient group. This trial is normally conducted in several hospitals
Y Lakshmi Prasad 5
in different demographic locations, to determine the influence of ethnic
responses, so this trial is also known as a multicentre trial. This largescale testing (1,000-3,000 participants/volunteers) provides a better
understanding of efficacy.
Most phase III studies are randomized and blinded trials with
specific entry criteria. Phase III studies typically last several years.
After a phase III study is successfully completed, a company can
request NDA from the FDA.
Randomization: The Process of assigning trial subjects to treatment
or control groups using an element of chance to determine the
assignments in order to reduce bias.
Blinded study: A study in which the subject, the investigator, or anyone
assessing the outcome is unaware of the treatment assignment(s).
Control group: The group of subjects in a controlled study that
receives no treatment, a standard treatment or a placebo.
Placebo: A pharmaceutical preparation that does not contain the
investigational agent.
Multicenter trial: Clinical trial conducted according to a single
protocol but at more than one site and therefore, carried out by more
than one investigator.
Food and Drug Administration (FDA): The United States regulatory
authority charged with, among other responsibilities, granting IND
and NDA approvals.
New Drug Application (NDA): An application to FDA for a license
to market a new drug in the United States.
Licensing (Approval to Use):
After all three clinical trial phases are complete and, if the research
demonstrates that the test drug is safe and effective, a New Drug
Application (NDA)/ Biologics License Application (BLA) is filed
with the FDA. This NDA/BLA must contain all scientific information
compiled over the course of the trials. The FDA is allowed at least
6 months to review the NDA/BLA. However, this review Process
can sometimes take up to 2 years, depending on specific country
requirements.
6 SAS Clinical Programming
Approval (Available for Prescription):
Health care providers are able to prescribe. Even after approval, reviews
continue to ensure safety over time. For example, all cases of adverse
events must be reported, and quality control standards must be met
(Sometimes studies to evaluate long-term effects are also required).
The accelerated approval Process for serious diseases is designed to
help development of treatments and to fill an unmet medical need to get
important new treatments to patients faster.
Post-Marketing Studies:
Post-marketing studies (special studies and long-term effectiveness/
use) are also called Phase IV studies. These studies are often
performed in special populations not previously studied (for example,
children or the elderly) the studies are designed to monitor Long-term
effectiveness and/or efficacy and the impact on a person’s quality of
life. Some studies help determine the cost -effectiveness of a therapy
compared to other traditional and new therapies.
Industry Regulations and Standards for Clinical Trials
Every trial has to be approved and carried out under regulatory
compliance to comply with GCP requirements. Different countries
have different requirements for clinical trials. Two organizations that
carry significant regulatory weight are the combined forces of the US
Food and Drug Administration (FDA) and International Conference
on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH).
It is the role of public regulatory authorities to ensure that
pharmaceutical companies comply with regulations. There is legislation
that requires drugs to be developed, tested, trialed and manufactured in
accordance to guidelines so that they are safe and patient’s well being
is protected.
Regulatory authorities perform the watchdog role to ensure that
animal studies comply with Good Laboratory Practice (GLP), clinical
trials are performed in accordance with Good Clinical Practice (GCP)
and drugs are manufactured under current Good Manufacturing
Practice (cGMP) conditions.
ICH stands for “International Conference on Harmonization
of Technical Requirements for Registration of Pharmaceuticals for
Y Lakshmi Prasad 7
Human Use”. ICH is a joint initiative involving both regulators and
research-based industry representatives of the EU, Japan and the US in
scientific and technical discussions of the testing Procedures required
to assess and ensure the safety, quality and efficacy of medicines.
The objective of ICH is to increase international harmonization of
technical requirements to ensure that safe, effective and high quality
medicines are developed and registered in the most efficient and cost
effective manner.
The ICH Topics are divided into four major categories:
Quality (Q): Those relating to chemical and pharmaceutical Quality
Assurance.
Safety (S): Those relating to in vitro and in vivo pre clinical studies.
Efficacy (E): Those relating to clinical studies in human subject.
Multidisciplinary topics (M): Topics which do not fit uniquely into
one of the above categories.
Efficacy Topics:
E3: Structure and Content of Clinical Study Reports
E4: Dose-Response Information to Support Drug Registration
E6: Good Clinical Practice: Consolidated Guideline
E8: General Considerations for Clinical Trials
E9: Statistical Principles for Clinical Trials
E10: Choice of Control Group and Related Issues in Clinical Trials
ICH’s mission is to make recommendations towards achieving
greater harmonization in the interpretation and application of technical
Guidelines and requirements for pharmaceutical product registration.
The ICH Steering Committee and its sub-committee are comprised
of representatives from six parties that represent the regulatory bodies
and research-based industry in the European Union, Japan and the
USA.
8 SAS Clinical Programming
Region Japan
Europe
USA
Regulatory Body
MHLW - Ministry of
Health, Labour and
Welfare
EU - European
Union
FDA - Food and
Drug Administration
Research Based Industry
JPMA-Japan Pharmaceutical
Manufacturers Association
EFPIA - European Federation
of Pharmaceutical Industries
and Associations
PhRMA - Pharmaceutical
Research and Manufacturers of
America
U.S.FDA: Branch of the United States Department of Health and
Human Services and regulates all aspects of pharmaceutical industry.
21 CFR Part 11 Compliance: In your research the computer systems
used to collect and analyze data must be validated to meet the FDA
requirements for electronic records and signatures.
Title 21 of the Code of Federal Regulations (CFR):
Parts applicable to clinical research:
Part 11 - Electronic Records and Signatures
Part 50 - Protection of Human Subjects
Part 54 - Financial Disclosure by Clinical Investigators
Part 56 - Institutional Review Boards
Part 312 - Investigational New Drug Application
Part 314 - Applications for FDA Approval to Market a New Drug
or an Antibiotic Drug
Part 600 - Biological Products
Part 812 - Medical Devices
Departments and Roles in a CRO
Contract Research Organization: CRO is an organization that provides
support to the Pharmaceutical, biotechnology, and medical device
industries in the form of research services outsourced on a contract basis.
A CRO may provide such services as Pre Clinical Research, Clinical
Research, Clinical Trials Management, Clinical Data Management, Bio
statistics and SAS Programming.
Y Lakshmi Prasad 9
A Typical Clinical Research Organization may contain the
following departments:
Clinical Operations
Data Management
Medical writing
Pharmacovigilance
Biostatistics/ SAS Programming
Regulatory affairs
Key Functions in Clinical Operations:
 Managing and coordination of study conduct
Monitoring and tracking of project milestones to ensure that the
project runs within timelines.
Participation as appropriate to expedite the feasibility and conduct
of global trials
Ensuring that the regulatory submission are of acceptable quality
Support Investigator as and when required (e.g. Finalization of
Investigator agreements and contracts, Finalization of Protocol
and CRF)
Key Functions in Data Management:
 Data Entry
Database creation, Updating, Validation and Database lock
 Data Quality Check
Data Clarification Form generation
 Coordination with Operations team to resolve queries
10 SAS Clinical Programming
Protocol: Clinical research is conducted according to a plan (a
protocol) or action plan. The plan describes what will be done in the
study, how it will be conducted, and why each part of the study is
necessary. The protocol or plan is carefully designed to safeguard the
participant’s health and answer specific research questions.
Case Report Form (CRF). A printed, optical, or electronic document
designed to record all of the protocol-required information to be
reported to the sponsor for each trial subject.
Key Functions in Quality Assurance:
Facilitate audits which are conducted by clients locally within the
country
Ensure that all staff within the country has a complete and current
training record
Facilitate the auditing of suppliers and vendors used by company
within the country
Ensure that all GCP compliance issues with sites or elsewhere are
raised to the Director of Quality Assurance and the Director of
Medical Affairs
Maintaining version control of SOPs to ensure that all staff are
following the correct and up to date SOPs
Key Functions in Pharmacovigilance:
Collect, follow-up, transmit all local adverse events, and pregnancy
cases, to Global Pharmacovigilance.
Process
cases in accordance
Pharmacovigilance Procedures.
with
Global
and
Local
Answer ADR and ADR case processing questions from local
Regulatory Authorities and Health Care Professionals.
Submit the report able ADRs, to the local Regulatory Authorities
according to the national regulations and answer any subsequent
questions in collaboration with the Global Pharmacovigilance.
Y Lakshmi Prasad 11
Key Functions in Medical Writing:
Clinical Study Protocol Writing
Documentation for Regulatory Submission
Technical Documentation for Clinical Trials
Writing Medical Cases
Managing SAEs during clinical trials
Closely associated with regulatory department in preparing
narratives for submission
Standard Operating Procedure (SOP): Detailed, written instructions
to achieve uniformity of the performance of a specific function.
Adverse Drug Reaction (ADR): Any noxious and unintended
response associated with the use of a drug in humans.
Serious Adverse Event (SAE ): Any untoward medical occurrence
that at any dose: results in death, is life threatening, requires inpatient
hospitalization or prolongation of existing hospitalization, results
in persistent or significant disability/incapacity, or is a congenital
anomaly / birth defect.
12 SAS Clinical Programming
Process Flow in a Typical Clinical Trial
Protocol Development
Blank CRF
SITE
CLINICAL
OPERATIONS
CRF designing
Database Designing
Filled CRF
DCF
Edit check Programming
Data Entry
Discrepancy
DATA MANAGEMENT
Data Validation
Database Lock
Data Extract
CDISC Conversion
BIO STATISTICS
ADS Creation
TLF Creation
Study Submission
Process Flow in a Typical Clinical Trial:
Every clinical investigation begins with the development of a clinical
protocol. The protocol is a document that describes how a clinical
trial will be conducted and ensures the safety of the trial subjects and
integrity of the data collected.
After preparing the protocol we go with CRF designing, The
Case Report Form is a data-reporting document used in a clinical
study. CRF Collects relevant data in a specific format in accordance
with the protocol and compliance with regulatory requirements which
SAS Clinical Programming
In 18 Easy Steps
FOR M.Pharm / M.Sc (Life Sciences) /M.sc (Stats)/
M.C.A/M.Tech / B.Pharm /Bio-Tech/B.Tech.