Clinical sas training overview

E-mail: contact@sasonlinetrainings.com
Contact Person : Balu
India : +91-9966956770
+91-9966946199
USA: +1 (551) 226-6061

Clinical Trial Process
Overview
By
Naidu
sasonlinetrainings.com
Contact : Balu India : +91-9966956770 +91-9966946199 USA: +1 (551) 226-6061
www.sasonlinetrainings.com E-mail : contact@sasonlinetrainings.com

What Is SAS?
 SAS-Statistical analysis software/System
 Developed in the early 1970s at North Carolina
State University.
Originally intended for management and analysis of
agricultural field experiments.
 Now the most widely used statistical software
CEO-Jim Gudnight (Founder of SAS institute)

What Is a Clinical Trial?
 Effectiveness of intervention to treat a
disease
 Safety of a new drug or device
 Defining dose administration
 Testing drug formulation
 Exploring combination therapies
 Evaluating effect of therapies on quality of
life

Clinical Research Process
Approved protocol Investigator selection Approval Process
Patient
Recruitment
Data Entry & ValidationData
Analysis
Presentation to Steering committee Submission for FDA/DCGI

Types of Clinical Trials
 Treatment
– Test new approaches to treat a disease
 Prevention
– What approaches can prevent disease
 Early-detection/screening
– What are new ways to find hidden disease
 Diagnostic
– How can new tests or procedures ID disease

Clinical Trails – Overview
Chemistry
Synthesis Purification
Formulation
Animal
Pharmacology
Animal Toxicity
Asses Safety &
Biological activity in
Animals
PHASE – I
Determine
Safety &
Dosage
PHASE – II
Evaluate
Efficacy, look
for side
effects
PHASE- III
Compare new
agent with
standard
treatment
Safety
FDA /
DCGI
PHASE IV
Additional
post
marketing
testing
required by
FDA
Pre-clinical Development Clinical Trails
Accelerated Development / Review
IND
5000 compounds
evaluated
5 enter trails 1 approved – SUCCESS RATE
File IND at
FDA / DCGI
File NDA at
FDA / DCGI
3-4 YEARS 6 YEARS 2 YEARS

Phases of Drug Development
Phase 1 Phase 2 Phase 3 Phase 4
No. of
Participants
15-30 100-300 100 to
thousands
Several
hundreds to
several
thousands
Purpose First in
humans
safe dose
POC
1/3 fail
Determine
efficacy
Safety
50% fail
Compare
new agent
with standard
treatment
Safety
1/3 fail
Post –market
Long-term
safety and
efficacy

Who are the Players?
 Human Subject Volunteers
 Physician Investigators & Staff
 NIH – National Institutes for Health
 Manufacturing companies (Sponsor)
 OHRP - Office for Human Research Protections
 FDA – Food & Drug Administration (CDER, CBER, CDRH)
 Settings: Academic, Private Practice, Professional

Why is Human Research Highly
Regulated?
 Past transgressions lead to the need for laws
that protect the rights and welfare of human
subjects.
– Nuremberg Doctors Trial of 1946 (Nuremberg Code)
– Thalidomide Tragedy (Kefauver-Harris Amendment)
– Tuskegee Experiments (Belmont Report)
– Human Radiation Experiments
– Gene Transfer Experiment

Evolution of Regulations
 1938 – Food, Drug & Cosmetic ACT
 1962 – Kefauver-Harris Amendment
 1968 – Drug Efficacy Study Implementation
 1981 – IRB Review Required
 1983 – Orphan Drug Act
 1997 – ICH-E6 Good Clinical Practice (GCP)
 1998 – Pediatric Rule
 2000 – NIH launches www.clinicaltrials.gov

Declaration of Helsinki
 World Medical Association June 1964
(Helsinki, Finland)
 Forms the basis of ICH-GCP
 Covers all “medical research”
 Most recent amendment October 2000

Human Research is Highly
Regulated
 Code of Federal Regulations (CFR)
– Title 21- Food and Drugs
» Part 50 Informed Consent
» Part 56 IRB
» Part 312 IND
» Part 314 NDA
» Part 600, 6001 Biologics
» Part 812, 813, 814 Medical Devices
– Title 45- Public Welfare
» Part 46 (subparts B, C, D) DHHS, Protection of Human subjects

What About International
Regulation?
ICH definition – GCP
 “A standard for the design, conduct, performance,
monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides assurance
that the data and reported results are credible and
accurate, and that the rights, integrity, and
confidentiality of trial subjects are protected”

ICH-GCP
 ICH is the International Conference on
Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for
Human Use
 ICH-GCP is Good Clinical Practice
guidelines agreed at the conference

The Objectives of ICH GCP
Guidelines
 Developed with consideration of the current good clinical
practices of the European Union, Japan & USA, plus those of
Australia, Canada, the Nordic countries & World Health
Organisation.
 Provide a unified standard for the European Union, Japan &
USA to facilitate the mutual acceptance of clinical data by the
regulatory authorities in these jurisdictions.

Good Clinical Practice - GCP
 What is GCP?
– Ethical and scientific quality standards for
designing, conducting, recording and reporting
trials that involve participation of human
subjects
 Why is it needed?
– To ensure that the RIGHTS, SAFETY and
WELLBEING of the trial subjects are protected
– Ensure the CREDIBILITY of clinical trial data

ICH GCP Guidelines cover…
Investigator’s
Brochure
Investigator

Research Protocol: Roadmap
 Detailed Research Plan that Includes:
– Objectives
– Background and Rationale
– Subject Selection Criteria
– Treatment Plan
– Study Procedures
– Response Evaluation Criteria
– Statistical Section

Protocols
 A Phase I, Double-blind, Placebo-
controlled, Dose-escalation Study of the
Safety and Pharmacokinetics of Drug A31
in Subjects with Type 2 Diabetes Mellitus
 A randomized, double-blind, placebo-
controlled study assessing the effect of
(study drug) Controlled-Release Tablet on
hypoglycemia in type 1 diabetic subjects
intensively treated with insulin

Protocol Mouthful
 A PHASE 1, RANDOMIZED, PLACEBO-
CONTROLLED, SEQUENTIAL PARALLEL
GROUP, MULTIPLE DOSE ESCALATION
TRIAL TO EVALUATE THE SAFETY,
TOLERABILITY, PHARMACOKINETICS,
AND PHARMACODYNAMICS OF 28 DAYS
OF ADMINISTRATION OF ND- 00254
TABLETS TO SUBJECTS WITH TYPE 2
DIABETES MELLITUS

Institutional Review Board
(IRB)
 All clinical trials must be approved and
monitored by an IRB.
 IRB is an independent committee of
physicians, nurses, statisticians, community
advocates and others.
 The function of the IRB is to ensure that a
clinical trial is ethical and the rights welfare
of study participants are protected.

What is Informed Consent?
"Informed consent is a process by which a subject
voluntarily confirms his or her willingness to
participate in a particular clinical trial, after having
been informed of all aspects of the trial that are
relevant to the subject's decision to participate”

Informed Consent
 Learning the key facts about a trial before
deciding whether to participate.
– Research study purpose
– Risks/Benefits
– Alternative treatments
– Confidentiality of records
– Medical treatment available if injury occurs
– Whom to contact for answers to questions
– Statement that participation is voluntary

Patient Recruitment Challenge
 Poor patient recruitment is the number one
reason that trials fail.
 Only 3 to 5 percent of newly diagnosed
adult cancer patients participate in a clinical
trial.
 Reasons for this relatively low number are
many.

Recruitment Strategies
 Physician trust and contact
 Study staff contact
 Speaking to community groups
 Newspaper and radio Ads
 Internet websites
 Physician referrals

Safety Data collected in Clinical
Trials
 Adverse Events
 Serious Adverse Events
 Adverse Reactions
 Suspected Unexpected Serious Adverse
Reaction
 Pregnancy
 Lab data
 Vital Signs
 Project specific data

Safety Data collected in Clinical
Trials
 Data is collected on case report forms
(CRF)
 Much of clinical data is taken from the
subjects medical record (source documents)
 Pharmaceutical and device trials, data is
verified by multiple players

Done in excel using a blank CRF template provided by
Openclinica
Designing CRFs

The excel sheet is then uploaded onto OpenClinica
Uploading CRFs

Event Definition

Data Entry

Data Extraction

 Backups implemented via a scheduled command
running as a batch file that writes out the data and
metadata for each of the studies databases adding
Timestamp information to the filename.
Pg Dump utility Creates a backup file on
the secondary HDD on the main server.
File automatically copied to NAS1
NAS1
DatabaseDatabase
server
The Back Up Setting

Clinical Data Management
Protocol CRF Design DB Design
DB
Validation
DatabaseReport Data Analysis

Data Analysis
Database Extraction SAS Tables

An Adverse Event (AE) is…
 Any untoward medical occurrence
 Not necessarily causal relationship with
treatment
 Unfavourable /unintended sign

A Serious Adverse Event (SAE) is an AE that…
 Results in death
 Is life threatening
 Requires hospitalisation or prolongation of
stay
 Results in persistent or significant
disability/incapacity

SAE definitions
 Results in death
– Record the event that lead to death as the SAE
– “Death” is the outcome
 Life threatening
– “The patient was, in the view of the
investigator, at immediate risk of death from
the event as it occurred. It does not include an
event that, had it occurred in a more serious
form, might have caused death”

SAE definitions
 Prolonged hospitalisation
- Record diagnosis NOT procedure
- Hospitalisation means in-patient
admission
- Not out-patient appointments or ED
visits
 Disabling or incapacitating
- Event which is disabling or

SAE definitions
 Prolonged hospitalisation
– Record diagnosis NOT procedure
– Hospitalisation means in-patient admission
– Not out-patient appointments or ED visits
 Disabling or incapacitating
– Event which is disabling or incapacitating or
causes a disruption of one’s ability to carry out
normal life functions or daily activitiesContact : Balu India : +91-9966956770 +91-9966946199 USA: +1 (551) 226-6061

SAE definitions
 Congenital anomaly
– Diagnosed in the offspring of a subject who
received study drug
 Other
– Additional option given by some
pharmaceutical companies
– Event not covered by SAE categories but in the
investigator’s opinion, should be considered
serious

A Suspected Adverse Reaction (SAR)
is…
 Untoward or unintended response to the
medicinal product under investigation

A Suspected Unexpected Serious Adverse Reaction
(SUSAR) is…
 A serious adverse reaction
 Unexpected-not consistent with information
already available in the protocol and the
Investigators Brochure

Adverse event reporting
 Will depend upon the trial and be defined in the
protocol
 Generally any AE or SAR should be recorded in the
patient notes and Case Report Form and reported to
the Principal Investigator (PI) at the study site
 The PI determines whether the AE or SAR is serious
 The PI informs the Chief Investigator (multicentre
studies) of any SAE or SUSAR
 The Chief Investigator will report any SAE or SUSAR
to the Trial Sponsor, Data Monitoring Committee,
MHRA and/or Ethics Committee, as specified in the
protocol

Introduction to MedDRA
(Medical Dictionary
for Regulatory Activities)

What is MedDRA?
Med = Medical
D = Dictionary for
R = Regulatory
A = Activities

Objectives for MedDRA Development
 An international multi-lingual terminology
 Standardized communication between
industry and regulators
 Support of electronic submissions
 Application through all phases of the
development cycle
To provide:

Objectives for MedDRA Development
(cont)
 Classification for a wide range of clinical
information
 Support for multiple medical product areas
 A terminology that saves time, resources,
and money
To provide (cont):

MedDRA Definition
MedDRA is a clinically-validated international
medical terminology used by regulatory
authorities and the regulated biopharmaceutical
industry. The terminology is used through the
entire regulatory process, from pre-marketing
to post-marketing, and for data entry, retrieval,
evaluation, and presentation.

MedDRA Hierarchy
System Organ Class (SOC)
High Level Group Term (HLGT)
High Level Term (HLT)
Preferred Term (PT)
Lowest Level Term (LLT)

System Organ Classes
• Blood and lymphatic system disorders
• Cardiac disorders
• Congenital, familial and genetic disorders
• Ear and labyrinth disorders
• Endocrine disorders
• Eye disorders
• Gastrointestinal disorders
• General disorders and administration site
conditions
• Hepatobiliary disorders
• Immune system disorders
• Infections and infestations
• Injury, poisoning and procedural
complications
• Investigations
• Metabolism and nutrition disorders
• Musculoskeletal and connective tissue
disorders
• Neoplasms benign, malignant and unspecified
(incl cysts and polyps)
• Nervous system disorders
• Pregnancy, puerperium and perinatal
conditions
• Psychiatric disorders
• Renal and urinary disorders
• Reproductive system and breast disorders
• Respiratory, thoracic and mediastinal disorders
• Skin and subcutaneous tissue disorders
• Social circumstances
• Surgical and medical procedures
• Vascular disorders

 Each MedDRA term assigned an 8-digit
numeric code
 The code is non-expressive
 Codes can fulfill a data field in various
electronic submission types (e.g., E2b)
 Initially assigned alphabetically by term
starting with 10000001
– New terms are assigned sequentially
 Supplemental terms are assigned codes
MedDRA Codes

 Terms are being renamed
– When terms are renamed, the code number is
reused for the renamed term
– Renaming has been done for spelling errors,
hyphenation, and parenthesis changes
 When HLT or HLGT terms are removed from
the terminology, they are deleted – NOT
moved to the LLT level and made non-current
MedDRA Codes (cont)

Non-Current Terms
 Non-current terms are flagged at the LLT
level within MedDRA
 Not recommended for continued use
 Retained within the terminology to preserve
historical data for retrieval and analysis
 Terms very vague, ambiguous, out-dated,
truncated, or misspelled
 Terms derived from other terminologies that
do not fit MedDRA rules

A Multi-Axial Terminology
Multi-axial = the representation of a medical
concept in multiple SOCs
 Allows terms to be grouped by different
classifications
 Allows retrieval and presentation via
different data sets
 Allows an automatic assignment of
predefined term groupings

SOC = Respiratory, thoracic and
mediastinal disorders
HLGT = Respiratory tract
infections
HLT =Viral upper respiratory
tract infections
HLT = Influenza viral
infections
HLGT = Viral infectious
disorders
SOC = Infections and
infestations
PT = Influenza
(cont)

PT = Diabetes mellitus
HLT = Diabetes mellitus (incl subtypes)
HLGT = Glucose metabolism disorders (incl diabetes mellitus)
(cont)
SOC = Metabolism and
nutrition disorders
SOC = Endocrine
disorders

What’s New for MedDRA
Version 15.1
 MedDRA Version 15.1 was made available
to subscribers on 1 September 2012

Clinical Trial End Product
 Ideal: Unambiguous conclusion regarding
the clinical outcome of the test
treatment/device.
 Always strive for the ideal, but in most
cases have to settle for the best comprise.

Thank You ….
Any Questions ?

Today’s Assignment
Visit www.sas.com to know more about SAS

Please Visit……
www.sasonlinetrainings.com
Address :
SAS onlineTraining Center
Near Cyber Towers, Hitech City
Hyderabad. Pin -500081
Andhra Pradesh, India.
E mail : contact@sasonlinetrainings.com
India : +91-9966956770
+91-9966946199
USA: +1 (551) 226-6061
Skype : appalanaidu412

Clinical sas training overview

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