Introduction to Clinical Trials

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:

1. Literature Review (Brief)

Describe the "state of the art" and motivate rationale for this clinical trial

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

a. Toxicity: look for possible harmful effects; what variables will

be considered

b. Early Stopping: what mechanism, what endpoint will be

watched to assess whether a large early benefit has been detected, what
statistical procedures

c. Quality Control: statement of procedures to insure data

obtained is of highest quality, usually involves laboratory
results mainly

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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

Avoids criticism of "data dredging”

Useful in pointing out potential problems in the analysis

A more detailed analysis plan can be included in an appendix or in a separate document –

Statistical Analysis Plan (SAP)

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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

8. List of Participating Centers and Principle Investigators

"good public relations"

9. Data Monitoring & Committee Membership

10. Publication Policy

 who is acknowledged
 who does the work
 what is editorial process
 what is study material and what belongs to each PI
 time schedule of publications

"Area most sensitive to young PI's"

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 Protocol Example Outline
Diabetes Control & Complications
Trial (DCCT)

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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

2. OBJECTIVES AND DESIGN 2.1

Objectives 2.1
Design 2.2

3. SAMPLE SIZE 3.1

Introduction 3.1
Basis of Sample Size Calculations 3.2

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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

5. INFORMED CONSENT 5.1

General Principles 5.1
Sequence of Procedures 5.3

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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

7.0 RANDOMIZATION 7.1

Phase II Randomization 7.1
Considerations for Phase III 7.3
Ineligible Patients Who Are Randomized 7.4

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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

Intervention Strategy in the Experimental Group 8.7

General Guidelines 8.7
Diet 8.10
Exercise 8.10
Urine Tests 8.10
Self Blood Glucose Monitoring 8.11
Clinic Visits 8.11

General Procedures to Maximize Adherence to Protocol 8.12

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Contents (DCCT) [5]

9. FOLLOW-UP PROCEDURES FOR ENDPOINT VISITS 9.1

General Principles 9.1
Blood Glucose Control 9.1
Ophthalmologic 9.2
Renal 9.3
Neurologic 9.3
Cardiovascular 9.4
Psychological 9.4
Compliance/Adherence 9.5
Dietary 9.6
Examination Results 9.6
Missed Visits 9.6
Transfer 9.6

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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

11. MANAGEMENT OF INTERCURENT EVENTS 11.1

General Principles 11.1
Guidelines 11.2

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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

13. RESULTS AND STATISTICAL ANALYSIS 13.1

General Principles 13.1
Baseline Results and Analyses 13.1
Outcome Variables 13.2
Analysis Plan 13.3
Interim Analyses 13.5
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Contents (DCCT) [8]
14. PUBLICATIONS AND PRESENTATIONS 14.1
Introduction 14.1
Duties of the Publications and Presentations Committee 14.1
Implementation 14.3

15. ANCIALLARY STUDIES 15.1

Introduction 15.1
Definition of an Ancillary Study 15.1
Reason for Requirement Approval 15.2
Levels of Approval Required for Ancillary Studies 15.2
Funding of Ancillary Study Results 15.3
Publication of Ancillary Study Results 15.3
Implementation 15.4

16. PROTOCOL CHANGES 16.1

Introduction 16.1
Policy 16.1
Procedures 16.1
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Contents (DCCT) [9]
17. ADMINISTRATIVE STRUCTURE 17.1
Introduction 17.1
Structure 17.1

18. DISPOSITION OF DOCUMENTS, DATA, AND MATERIALS 18.1

Documents 18.1
Data Forms 18.1
Tapes of Data and Analysis Files 18.2
Laboratory Specimens 18.2
Photographs and Other Materials 18.3

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)

Statistical Analysis Data Management Central Units

Center (SAC) Center (Sponsor or (Labs, …)
Contract Research
Organization)

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 ...

Purpose - standardization of procedures

laboratory - quality of reagent, equipment replacement,
temporal drift, ...

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Trial Data Collection

Data collection forms or Case Report Forms

(CRFs)
Data Completeness
Data Integrity

Important Note: Off Treatment does not mean

Off Study

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Database Size (1)
 Number of subjects
 screened
 enrolled

 Length of follow-up/ number of subject

visits

 Number central resource items

 Central blood measurements
 Central pathology

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Database Size (2)
Number of forms/patient

Amount of coding of free text

adverse events
concomitant medications
logs, journals, recalls, ….

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

Unique identification of patient

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

 Two points in time

- At or before randomization
- Sometime after randomization

 Most trials collect too much data!

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 Data Collection
Recruitment
 Over optimism
 Investigators usually overestimate number of patients they can recruit

 Recruitment Goals
 Need to establish recruitment goals and have contingency plans
 Good planning and interim monitoring

 Review Patient Admissions

 Ask investigators to show patient admissions which meet entry criteria, if
possible
 Poor Recruitment Center
 Usual reason is not enough patients screened
 If a center can't recruit effectively, it may have to be dropped from further
efforts BUT don't throw out enrolled patients

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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

 Can't "catch up”

Patient exposure to treatment lost due to lagging recruitment

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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
[Link]
b. pill count, amount of therapy consumed
[Link] measurements
d. tracers
6. Off treatment does not mean off study!

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Data Collection-
Quality Control (1)

No study is better than quality of its data

Focus energy on selected key variables
Strategies
Proper data collection forms
Data editing
a. Missing data
b. Range checks
c. Visual inspection
d. Consistency

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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

 Allow time for developing & testing

 Solicit content advice
 Review other RCT forms in similar trials
 Pre-test before using
 Research record  medical record
 Link each item with stated objective
 Require adequate review before adding new items

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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

4. Avoid open form - Use closed form

• Use response checklist
• Specify units of measurement (lbs. or kg.)
• Enough boxes to specify adequate precision __._
• Minimize calculations - obtain raw data

5. Use STOP & SKIP instructions

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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

1. Visual check at clinic 6. Periodic QA reports v feedback

2. Visual check at data center 7. Submission of duplicate records

3. Double data entry 8. Comparison of clinics

4. Computer edit for admissible values 9. Re-certification of clinic personnel

5. Data edit queries back to clinic 10. Minimize lag time patient visit  data entry

11. Audits

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 Data Editing

1. Patient Identification & Record Linkage

- Need internal check
2. Legibility
3. Form admissibility
- Correct form, correct time window
4. Missing Information
5. Consistency
- Consistent answers from form to form
- Within one form/section to section
6. Ranges and Code Check
- Codes legal
- Responses within "acceptable" or "reasonable" range

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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

2. Comparison of computer file to original medical record(at

clinical center)

3. Often 10% random sample used (military audit)

-Do not disclose which 10% ahead of time

4. Data center integrity

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Trial QC Report
 Patient visits on schedule

 Procedures completed

 Timeliness of forms
Clinic v data center
Data center v data file

 Edit messages (by form)

Completeness
Legibility
Errors

 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
 [Link]

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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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