Professional Documents
Culture Documents
Protocols,
Manual of Procedures &
Data Collection
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Protocol vs Manual of Operations Analogy
Protocol is general “blueprint” for
investigators + institutional review boards
sponsor
regulatory agencies
Manual of Procedures is detailed “construction document”
clinic staff
data management staff
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Desirable Protocol Characteristics
Clear
Consistent
Complete
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Scale Implications
“Simple”
One investigator, one patient, one encounter
“Harder”
Multiple investigators, multiple patients, multiple visits,
multiple cultures, multiple languages
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Considerations During Protocol
Development
For example
Randomization assignment and outcome ascertainment
how is potential bias minimized?
Treatment implementation
maximize compliance while minimizing variation
within and between investigators and clinic staff
patient and their support system
over study follow-up and calendar time
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Protocol (1)
Should include:
2. Statement of Objectives
What is the hypothesis that is being tested,
What endpoints or measurements & observations will be made to evaluate this therapy
e.g. BHAT
To determine whether chronic administration of proprandol to pts with at least one MI will
reduce mortality due to all causes significantly over a 2 yr. follow up period.
There may be more than one objective,
some primary
some secondary
subgroups.
3. Sample Size
Assumptions used, sources of data used & methods used to make the calculations
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Protocol (2)
4. Study Design
a. Recruitment
Entry Criteria - who are eligible
Exclusion Criteria - among those who are eligible, who should not be further considered
for various reasons
Statement of Informed Consent - patient must agree to all aspects of trial, particularly to
those things which will directly involve him
b. Randomization Process
Description of the mechanics of how the patient is to be randomized and
when (preferably as late as possible to avoid problems)
c. Baseline Evaluation
Clinical evaluation, history, & physical
Laboratory evaluation (e.g. EKG, X-ray, etc.)
Should describe what measurements are to be made
d. Treatment Description
Describe exactly how the two treatments are to be administered to the assigned patients,
how often, dosage, etc.
e. Follow Up Schedule & Evaluation
How often are patients to be seen, by whom & what measurements
are to be taken at each visit.
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Protocol (3)
5. Data Monitoring
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Protocol (4)
6. Analysis Plans
State at least what hypotheses will be tested and how in principle what
statistical methods will be used to answer these questions.
Primary question
Secondary questions
Subgroup questions
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Protocol (5)
7. Organizational Structure
Useful because it is then clear to everyone who is in charge of what, lines of
authority and what are the governing rules
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Contents (DCCT) [1]
SUMMARY ii
SECTION page
1. INTRODUCTION 1.1
Scope and Impact of Diabetes 1.1
Background 1.3
Historical Perspective 1.4
Future Directions 1.7
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Contents (DCCT) [2]
4. PATIENT SELECTION AND RECRUITMENT 4.1
Introduction 4.1
Eligibility Criteria 4.1
Eligibility Criteria Applicable to Both Categories of Subject 4.1
For Patients Without Retinopathy 4.2
For Patients With Minimal Background Retinopathy 4.3
Exclusion Criteria 4.4
Exclusion Criteria Applicable to Both Categories of Subject 4.4
Exclusion Criteria for Patients Without Retinopathy 4.10
Additional Exclusion Criteria for Patients With Minimal
Background Retinopathy 4.10
Recruitment
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Contents (DCCT) [3]
6.0 PRE-RANDOMIZATION EVALUATION 6.1
General Principles 6.1
Laboratory 6.1
Ophthalmologic 6.2
Renal 6.2
Neurologic 6.3
Cardiovascular 6.3
Psychological 6.4
Compliance/Adherence 6.5
Dietary 6.6
Examination Results 6.6
Quality Control 6.6
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Contents (DCCT) [4]
8.0 METABOLIC CONTROL
Intervention Strategy in the Standard Group 8.1
Intervention Strategy 8.1
Insulin 8.3
Diet 8.4
Exercise 8.5
Urine Tests 8.5
Self Blood Glucose Monitoring 8.5
Clinic Visits 8.6
Educational Program 8.6
Protection of Subjects 8.6
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Contents (DCCT) [6]
10. MONITORING PERFORMACE 10.1
General Principles 10.1
Central Biochemistry Laboratory & Hemoglobin Alc Laboratory 10.1
Central Ophthalmologic Reading Unit 10.2
Other Central Units 10.3
Local Procedures 10.3
Clinical Centers 10.3
Coordinating Center 10.3
Correction of Deficiencies 10.4
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Contents (DCCT) [7]
12. DEVIATIONS FROM ASSIGNED TREATMENT 12.1
Introduction 12.1
Deviations for Experimental Treatment 12.1
Mandatory Situations 12.1
Allowable Situations 12.2
Treatment Policy 12.3
Deviations from the Standard Treatment 12.4
Mandatory Situations 12.4
Allowable Situations 12.4
Treatment Policy 12.4
Transfer to Inactive Status (both treatment groups) 12.5
Procedures for Deviation or Transfer to Inactive Status 12.6
Appendix page
A. …………………………………………………………………………… A.1
B. …………………………………………………………………………… B.1
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Trial Organization
Components
sponsor
clinical centers
central resource units
Administration
Steering Committee
Independent Data Monitoring Committee
responsibilities
composition and independence
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NIH Model
Steering
Committee NIH
Policy Board
Data Monitoring
Committee
Central Units
Coordinating Center
(Labs, …)
Institutional
Clinical Centers
Review Board
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Industry-Modified NIH Model
Steering Pharmaceutical Regulatory
Committee Industry Sponsor Agencies
Independent
Data Monitoring
Committee (IDMC)
Institutional
Clinical Centers
Review Board
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Manual of Operations/Procedures
Multiple may be needed
investigators
central resource units
laboratory
Events Classification Committee ...
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Trial Data Collection
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Database Size (1)
Number of subjects
screened
enrolled
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Database Size (2)
Number of forms/patient
Central adjudication
clinical events
cause of death
severity of bleeding, ...
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Database Requirements
Integration of multiple data sources
clinic based
central resources
process
Audit trails
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Data Collection
Also See Meinert Reference!
Data collection must cover key questions or aspects
1. Recruitment Process/Eligibility Screen
2. Baseline Covariates
– Who was studied? (Eligibility)
– Trt Balance? (Comparability)
3. Compliance
– How did design get implemented?
4. Toxicity
5. Primary and Secondary Outcomes
6. Ancillary
Recruitment Goals
Need to establish recruitment goals and have contingency plans
Good planning and interim monitoring
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Data Collection
Eligibility
Modify Criteria
Changing entry criteria doesn't usually improve recruitment
that dramatically!
Big Net
Need to screen "10 to 20" patients for every one randomized |
Big net required
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Baseline Variables
(On Study Information)
All baseline data should be measured prior to randomization and start of
therapy.
Uses
1. Eligibility (Based on a subset)
2. Group comparability
3. Stratified randomization
4. Subgroup analysis
5. Establish prognostic variables
6. Evaluate changes from baseline for outcome or toxicity
7. Comparing centers & different studies
Timing
Should be measured as close to start of therapy as possible
May not be able to ascertain some variables
e.g. MILIS "infarct size" not possible at baseline
May need 2 visits to confirm eligibility
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Data Collection
Primary-Secondary Outcome
Clear definitions
Complete Ascertainment
Possible Adjudication
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Data Collection
Adverse Effects
Many possible adverse effects may be monitored.
A Multiple Comparisons Problem
Not always as well defined (too many perhaps)
Anticipated + Unexpected
Natural history effects
BHAT 66% placebo patients shortness of breath
only 6% at baseline had history
Need control group
Ascertainment
Eliciting vs. volunteer response
Length of follow-up
Frequency of patient contact
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Data Collection
Subject Compliance
Perfect Compliance Unusual
1. Patients will not absolutely adhere to planned protocol
Recruit "good" compliers
2. Try not to enter patients who would not be able to comply (Hard to
predict!)
3. Once entered, try to minimize compliance problems
4. Patients can't be dropped from analysis because of non-compliance
5. Patient adherence must be carefully monitored
a.visits
b. pill count, amount of therapy consumed
c.physiologic measurements
d. tracers
6. Off treatment does not mean off study!
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Data Collection-
Quality Control (1)
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Data Collection-
Quality Control (2)
Training/Certification
a. Sites b. Items
- Clinics - Protocol
- Central labs - Data forms
- Data center - Procedures
- Information flow
Manual of operations
-Clear definitions & instructions
QC Procedures
- Correct problems ASAP
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Data Form Construction
1. Need standard forms, either paper or electronic
2. Safeguards in construction
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Data Item Construction
1. Every item should force a response
Minimize free text
2. Terminology
• Keep it simple
• Provide key definitions on form
• If answer requires judgement or rating, provide basis
• Use "yes" to indicate "presence of" (No double negative)
• Indicate time frame
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Data Item Construction (2)
3. Use of Existing Forms
• Don't reinvent the wheel if already used elsewhere
• Don't use an entire form just because it exists
• Get permission
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Quality Assurance
Timely Review
Until recently, S.O.P. for industry was to collect data until trial was finished, then try
to clean it up or do it in batches as CRAs visited sites
Now QC can be an ongoing process
QC Procedures
5. Data edit queries back to clinic 10. Minimize lag time patient visit data entry
11. Audits
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Data Editing
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Audits/Data Integrity Check
1. Comparison of data on computer file to data form (within data
center)
Electronic data capture largely eliminates this problem
Procedures completed
Timeliness of forms
Clinic v data center
Data center v data file
Split/duplicate sample
Audits
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Typical Case Report Form
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Data Collection
Data submitted on case report forms
Clinical Sites Coordinating Center
Primary Method
Fax
DataFax
Alternatives Data Collection
E-Mail and Management
Oracle
Study Specific
Database
US Mail
Web
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ONCORE: A Web Based System
Secure, fast web based system
Manages portfolio of cancer oriented protocols
Many functionalities
Review & approval
Subject registration
Data collection
Analysis
Started at UWCCC, now in 15 Centers
Local software company, Percipenz
www.oncore.org
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Conclusion
Data collection personnel -- no matter how well-trained,
careful, and proficient -- should not be expected to resolve
all errors before their data are transmitted to a central
database management site
Centrally, someone must have big picture and also the little
details
Not paying attention to this can be the downfall of any trial
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