Massachusetts Biotechnology Council Basics of Clinical Research Workshop

Clinical Data Management & Biostatistics

Global ViceVice-President, Clinical Affairs Surgical Devices Covidien

Xavier P. Lefebvre, Ph.D.

Today Todays Learning Objectives

To get an introduction to Clinical Data Management, and Biostatistics To get a basic understanding of the Roles, Responsibilities, and Key processes used by these two critical Clinical functions

Clinical Data Management

Clinical Data Management

What is it? A professional discipline that combines elements of
computer science, biostatistics, and clinical trial science

to process clinical data. It must use optimized and efficient principles and processes for rapid, and quality-driven processing of the data. It is extremely complex, and often not understood outside of the field. It is a critical part of the Clinical Trial.

Role of Clinical Data Manager

What is it? The CDM Organizes trial data to ensure complete and timely traceability. Organizes clinical data into a computerized database that completely and accurately reflects the findings and events of the trials. Ensures that the clinical data is of high enough quality to ensure valid statistical analysis of the study findings. Ensures that the clinical data is managed in a timely basis.
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Overview of CDM Responsibilities

During Study Set-Up Phase Protocol Design and Review CRF Development Systems Set-Up During Study Conduct Phase Data Management Process Management Quality Assurance

Study SetSet-Up Activities

Study SetSet-Up Activities:

Protocol Design and Review Protocol Overview Contains procedures & methods providing guidelines as to how the study is to be conducted. Submitted to FDA for approval prior to study start. Logistical Aspects of the Trial CRF completion time Database lock time Need for interim analyses Need for summary/annual reports Data Collection Issues Adverse event reporting Visit schedule Patient self-administrated Quality of Life surveys Study Timeline Aggressive, yet realistic
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Study SetSet-Up Activities:

CRF Development CRF Design/Review Best design practices
Maximize ease of data collection Maximize ease of data processing Minimize completion errors Does not limit/compromise accuracy of clinical information

Based on final (or draft) protocol Use company standard library of pre-designed modules Maintain consistency across project protocols CRF Completion Guidelines Proper and standardized CRF completion instructions Provide guidelines for
Investigators Study Coordinators CRAs
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Study SetSet-Up Activities:

Systems SetSet-Up (1/4) Data Entry Screen Design Similarity with actual paper CRF format
Ease of data entry Ease of QC and testing

Maintain consistency across project protocols

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Study SetSet-Up Activities:

Systems SetSet-Up (2/4) Database Design Structured to meet:
Data fields requirements Statistical analysis requirements

Annotated CRFs as blueprint for database

Database naming conventions: Date of Birth = DOB Database coding conventions: Yes=1, No=0

Connectivity with other data analysis/collection tools

Data Coding Lab data import IVRS data import

Maintain consistency across project protocols

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Study SetSet-Up Activities:

Systems SetSet-Up (3/4) Automated Data Validation System Design Three main types of checks
Logical consistency Validity range Cross-checks across multiple CRFs

Specifications established before start of trial Validation plans developed before start of trial Checks run against clinical database at regular intervals Ensure thorough, systematic, fast validation Streamline manual review

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Study SetSet-Up Activities:

Systems SetSet-Up (4/4) Manual Review/Validation Guidelines What can be automated vs. what must be done manually Medical judgements must be reviewed manually The 3 Cs of data review:
Complete Correct Consistent

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Study Management Activities

Study Management Activities:

Data management (1/5) Receipt of CRFs Batch vs. singly Regular vs. sporadic frequency Tracking system Each piece of paper is critical and tracked individually Tracking status:
Receipt Entry Validation Lock

Storage/Handling of 3-part NCR forms Original in secure FDA-auditable files

Fire-proof Restricted access

Copy #1 for data management Copy #2 remains at investigational site

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Study Management Activities:

Data management (2/5) Entry of CRF Data into Database Two Primary Methods
Single data entry with 100% verification Double data entry
Blind data entry with delayed comparison Active entry with verifier override; immediate comparison

Standard Software Packages

Clintrial Oracle Clinical SAS

Incorporation of Data from Other Sources Typical Sources

Labs IVRS Patient Diaries Previous/other Studies

Handled Like CRF data

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Study Management Activities:

Data management (3/5) Review and Validation of CRF Data Pre-Entry Review
Self-evident corrections
Legibility, spelling, abbreviations Header information, signatures

May or may not result in generation of query to sites Very dangerous since done outside of audit trail

After Data Entry

Automated validation
As per checks setup for study Conducted on a regular basis

Manual review validation

For completeness For all checks not programmed into automated validation plan

Results in generation of queries to sites

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Study Management Activities:

Data management (4/5) Query Generation Generated by automated and manual data review Logistics very important
Clarity of the question asked Supporting documentation Sent to the appropriate party

Requires careful coordination with monitoring staff Query Resolution Answers from sites reviewed by CDM/CRA staff Database updated to match new information (and CRF) Changes fully documented in audit trail Hot Spots tracked for future improvement Query Tracking Query state logged in Tracking System
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Study Management Activities:

Data management (5/5) Medical Coding of CRF Data Medical Coding
Categorization of data reported To permit statistical analysis

Which Data Get Coded

Adverse events Medications Diagnoses

Coding Dictionaries
MEDDRA COSTART WHO-DRUG, WHO-MED Home-grown

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Study Management Activities:

Quality Assurance Database Auditing Rigorous Methodology
Percentage of records to be audited Predefined acceptability levels Approved audit plan Signed-off audit reports

Necessary to ensure that Output = Input Conducted in Two Stages

Sample audit first Complete audit if error rate above pre-defined level
Less than 0.5% for non-critical data 0% for critical data

Key to Database Lock

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Impact of WebWeb-Based System on Clinical Data Management Processes

PaperPaper-Based Clinical Trials Trials

Source Document CRFs CRFs DB1 CRC

Primary Investigator

Master Clinical Data DB Double Data Entry Query Report Form DB2

Source Document Verification

CRA CDM

Edit checks Generate Queries Print Query Report

Site
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Sponsor

Query Report Form

Query System DB

WebWeb-Based Clinical Trials Trials

Web Hosting Site
Firewall

Web Clinical Trial Application Server

Trial DB

Internet

Source CRA Document Verification

Firewall

LAN

Medical Monitor

Source Document CRA CRC Project Mngr CDM

Primary Investigator

Site

Sponsor

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Potential webCRF Environment

Visit Schedule CRF Tabs

Query

Status Icons
Comment Query Audit Trail

Missing Data

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System Data Accuracy

Paper

Sample-Audit Source to CRF Verification SDV Only Source CRF Database Doc

Web-Based System

Source Doc

End-to-End SDV (replaces CRF to DB audit)

Database

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Workflow Implications for CDMs

Real-time information on clinical site activities Automatic and manual queries dealt with immediately Real-time information on screening, enrollment, CRF completion, query backlog, monitoring status Online clinical data mining capability permits easy and timely review of safety findings Online clinical data mining capability permits easy and timely interim analyses Field level query log and audit trail with date/time stamp available at all time Online device accountability log No storage of paper CRFs
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Conclusion
The Clinical Data Manager Organizes clinical trial data into a computerized database that completely and accurately reflects the findings and events of the trials. Ensures that the clinical data is of high enough quality to ensure valid statistical analysis of the study findings. Ensures that the clinical data is managed in a timely basis. This is an extremely complex task, critical to the Clinical Trial process.

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Biostatistics

Biostatistics
What is it? The CDM makes sure that what happened to the patient was accurately put down on the CRF and entered in the study database. The Biostatistician analyzes the data to show the study findings that are reported to the FDA. The Biostatistician must do so while minimizing bias. It is extremely complex. It is a critical part of the Clinical Trial.

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Role of Biostatisticians
Clinical Biostatisticians Clinical development strategy & work
Based on the proposed indication for use, what must be done to show that the drug is generally recognized as safe and effective.

Design of clinical trial and analysis plan

Most Important Role of Biostatistician Document what to do, then do it to minimize BIAS

Statistical analysis of study results Preparation of study reports, including FDA submissions.

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Role of Biostatisticians
Non-Clinical Biostatisticians Pre-clinical biology:
How many samples must be tested in animals & test tubes to prove the hypothesis?

Drug manufacturing stability:

What must be done to ensure that the drug manufactured is pure and stable?

Medical device manufacture:

How many millions of times should the device be stressed to prove that it will work as stated?

Etc

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Formal Statistical Hypothesis Testing

Formal procedure often employed in scientific research to test theories or models:
Bet that results of experiment will agree with theory and cannot be accounted for by chance If results cannot be explained by chance variation involved in drawing the sample, then theory is confirmed. NULL HYPOTHESIS assumes results are due to chance alone (Null hypothesis is opposite of what investigation really wants to conclude) ALTERNATIVE HYPOTHESIS is the opposite - the theory that will be confirmed if the null hypothesis is rejected.

H0: 1 = 2 where: H0 = the null hypothesis H1: 1 2 H1 = the alternative hypothesis

1 = the mean of population 1 2 = the mean of population 2 Experiment is successful when Null Hypothesis can be rejected, and alternative hypothesis is accepted
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Definition of Type I Error

Probability of meeting the study success criteria when the test device should not be approved (Risk of False Positive - Society Societys Risk)

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Definition of Type II Error

Probability of failing to pass the study success criteria when the test device should be approved (Risk of False Negative - Sponsor Sponsors Risk)

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Research Hypothesis
If the research hypothesis is is
TRUE True Positive: NOT TRUE False Positive:

And The Study Results are are NEGATIVE

(Fail to Reject Ho)

POSITIVE (Reject Ho)

Study is correct
1- (Confidence Level) False Negative:

Study is incorrect
(type I error) Society Societys Risk (Not Tolerated)

Study is incorrect
(type II error) Sponsor Sponsors Risk (Accepted)

Study is correct
1- (Power)

True Negative:

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Research Hypothesis Example

Study to test if Drug A superior to Drug B
H0: Drug A Drug B H1: Drug A > Drug B

If The Research Hypothesis is is

TRUE (Drug A > Drug B) True Positive: Study Indicates that Study is correct A is superior to B, and this is true 1- (Confidence Level)
Study Indicates that False Negative: AStudy is not is superior to B, incorrect but this is in fact not true

NOT TRUE (Drug A Drug B)

Study Indicates that False Positive: A is superior to B, Study is incorrect but this is in fact not true

POSITIVE (Reject Ho)

And > Drug B The Study Results NEGATIVE (Fail to are are
Reject Ho) Drug A Drug B
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Drug A

(type I error) Society Societys Risk (Not Tolerated)

True Negative: Study Indicates that is correct A Study is not superior to B, and this is true 1- (Power)

(type II error) Sponsor Sponsors Risk (Accepted)

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Sample Size (1/2)

Number of patients required to test study hypothesis Typical Assumptions:
Confidence Level (1- ) = 95% Power (1-) = 80%

Is Higher when Data population has high spread Difference to be detected very small Trying to show no difference Must also take into consideration FDA expectations Feasibility Program vs Breakthrough Technology

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Sample Size (2/2)

Must take into consideration Study design
Cross-overs

Study analysis plan

Interim analysis Intention-to-treat analysis Per-Protocol analysis

Study attrition
Consent withdrawals Lost to follow-up Test non compliance Technical problems

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Statistical Tests
Tests selected based on the data to be analyzed Some Popular Tests Student t-test
Used for continuous variables Example: Age, height, weight

Fishers Exact test

Used for categorical variables when expected frequency is less than 5 Example: Occurrence of adverse events

Chi-Square test
Used for other categorical variables Example: Gender comparison

Kaplan-Meier test
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Used for incidence of events over time Example: Mortality rate

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Statistical Methods
Statistical analysis plan must describe how everything will be handled during the study Patient disposition (100% accountability expected) Study visit assignments Unblinding Efficacy hypothesis testing
Primary endpoint Secondary endpoints

Safety analysis
Impact on primary endpoint (interim analyses)

Interim analyses
Impact on primary endpoint

Changes in statistical methods (post-hoc analyses) Missing, unused, spurious data

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Conclusion
The Biostatistician Participates to the clinical trial design and prepares the analysis plan Checks that the clinical data is of high enough quality to ensure valid statistical analysis of the study findings. Analyzes the data to show the study findings that are reported to the FDA. Does so in a timely basis. Does so while minimizing bias. This is an extremely complex tasks, critical to the Clinical Trial process.
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