A Manager's Guide to the Design and Conduct of Clinical Trials / Edition 2 available in Hardcover
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A Manager's Guide to the Design and Conduct of Clinical Trials / Edition 2
- ISBN-10:
- 0471788708
- ISBN-13:
- 9780471788706
- Pub. Date:
- 04/21/2006
- Publisher:
- Wiley
![A Manager's Guide to the Design and Conduct of Clinical Trials / Edition 2](http://img.images-bn.com/static/redesign/srcs/images/grey-box.png?v11.9.4)
A Manager's Guide to the Design and Conduct of Clinical Trials / Edition 2
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Overview
Product Details
ISBN-13: | 9780471788706 |
---|---|
Publisher: | Wiley |
Publication date: | 04/21/2006 |
Series: | Manager's Guide Series |
Edition description: | REV |
Pages: | 272 |
Product dimensions: | 6.50(w) x 9.60(h) x 0.82(d) |
About the Author
Read an Excerpt
A Manager's Guide to the Design and Conduct of Clinical Trials
By Phillip I. Good
John Wiley & Sons
ISBN: 0-471-22615-7Chapter One
Design DecisionsFrom the outset of the study, we are confronted with the need to make a large number of decisions, including, not least, "should the study be performed?" A clinical trial necessitates a large financial investment. Once we launch the trials, we can plan on tying up both our investment and the work product of several dozen individuals for at least the next two to six years. Planning pays.
Seven major design decisions that must and should be made before the trials begin are covered in the present chapter:
1. Should the study be performed?
2. What are the study's objectives?
3. What are the primary and secondary response variables?
4. How will the quality of the information be assured?
5. What types of subjects will be included in the study?
6. What is the time line of the study?
7. How will the study be terminated?
Five somewhat more technical design decisions are covered in the chapter following:
1. What experimental design will be utilized?
2. What baseline measurements will be made on each patient?
3. Will it be a single-blind or a double-blind study?
4. What sample size is necessary to detect the effect?
5. How many examination sites will we need?
We deal in Chapter 7 with the large number of minor details that must be thought through before we can concludeour preparations.
SHOULD THE STUDY BE PERFORMED?
We should always hesitate to undertake extensive trials when a surgical procedure is still in the experimental stages, or when the cross-effects with other commonly used drugs are not well understood. A cholesterol-lowering agent might well interfere with a beta blocker, for example.
If your study team is still uncertain about the intervention's mode of action, it may be advisable to defer full-scale trials till a year or so in the future and perform instead a trial of more limited scope with a smaller, more narrowly defined study population. For example, you might limit your trial to male nonsmokers between 20 and 40 who are not responding to current medications.
No full-scale long-term clinical trials of a drug should be attempted until you have first established both the maximum tolerable dose and the anticipated minimum effective dose. (In the United States, these are referred to as Phase I and Phase II clinical trials, respectively.) You should also have some ideas concerning the potential side effects.
STUDY OBJECTIVES
I'm constantly amazed by the number of studies that proceed well into the clinical phase without any clear-cut statement of objectives. The executive committee has decreed "the intervention be taken to market" and this decree is passed down the chain of command without a single middle manager bothering or daring to give the decree a precise written form.
Begin by stating your principal hypothesis such as:
An increase in efficacy with no increase in side effects
A decrease in side effects with no decline in efficacy
No worse than but less costly and/or less invasive
For Motrin(tm), for example, the principal hypothesis was that Motrin would provide the same anti-inflammatory effects as aspirin without the intestinal bleeding that so often accompanies continued aspirin use.
Keep the package insert in mind. For naproxen, another anti-inflammatory, the package insert reads: "In patients with osteoarthritus, the therapeutic action of naproxin has been shown by a reduction in join pain or tenderness, an increase in range of motion in knee joints, increased mobility as demonstrated by a reduction in walking time, and improvement in capacity to perform activities of daily living impaired by the disease.
"In clinical studies ... naproxin has been shown to be comparable to aspirin and indomethacin ... but the frequency and severity of the milder gastrointestinal adverse effects ... and nervous system adverse effects were less in naproxin treated patients than in those treated with aspirin and indomethacin."
The objectives of your study should be stated as precisely as possible. Consider the following: "The purpose of this trial is to demonstrate that X763 is as effective as aspirin in treating stress-induced headaches and has fewer side effects."
Not very precise, is it? Here is a somewhat more informative alternative: "The purpose of this trial is to demonstrate that in treating stress-induced headaches in adults a five-grain tablet of X763 is as effective as two five-grain tablets of aspirin and has fewer side effects." This is a marked improvement, though it is clear we still need to define what we mean by "effective."
A more general statement of objectives that may be used as template for your own studies takes the following form. "The purpose of this trial is to demonstrate that:
in treating conditions A, B, C
with subjects having characteristics D, E, F
an intervention of the form G
is equivalent to/ as effective as/ as or more effective than an intervention of the form H
and has fewer side effects."
Again, we still need to define what we mean by "effective" and to list some if not all of the side effects we hope to diminish or eliminate.
PRIMARY END POINTS
Our next task is to determine the primary end points that will be used to assess efficacy. Here are a few guidelines:
Objective criteria are always preferable to subjective.
True end points such as death or incidence of strokes should be employed rather than surrogate response variables such as tumor size or blood pressure. The latter is only appropriate (though not always avoidable) during the early stages of clinical investigation when trials are of short duration.
The fewer the end points the better. A single primary end point is always to be preferred as it eliminates the possibility that different end points will point in different directions. On the other hand, as we will see in Chapter 14 on data analysis, sometimes more effective use of the data can be made using a constellation of well-defined results.
The obvious exceptions are when (1) surrogate end points are employed and a change in a single factor would not be conclusive, (2) your marketing department hopes to make multiple claims, (3) competing products already make multiple claims.
The end point can be determined in two ways:
1. Duration of the symptom or disease.
2. Severity of the symptom or disease at some fixed point after the start of treatment. This latter can be expressed either in terms of (a) a mean value or (b) the proportion of individuals in the study population whose severity lies below some predetermined fixed value.
For a blood-pressure lowering agent such as metoprolol, the primary end point is diastolic blood pressure. For an anti-inflammatory such as Motrin, it might be either the duration or the extent of the inflammation. For a coronary-stenosis reducing surgical procedure or device, it might be the percentage of stenosis or the percentage of the population with less than 50% stenosis (termed "binary restenosis").
An exact quantitative definition should be provided for each end point. You also will need to specify how the determination will be made and who will make it. Subjective? Objective? By the treating physician? Or by an independent testing laboratory? Is the baseline measurement to be made before or after surgery?
In a study of several devices for maintaining flow through coronary arteries, the surgeon who performed the operation made the initial determination of stenosis. But it was decided that the more accurate and "official" reading would be made from an angiogram by an independent laboratory.
How much give in dates is permitted?-patients have been known not to appear as scheduled for follow-up exams. What if a patient dies during the study or requires a further remedial operation? How is the end point of such a patient to be defined?
Don't put these decisions off till some later date; make them now and make them in writing lest you risk not collecting the data you will ultimately need.
Secondary End Points
Secondary end points are used most often to appraise the safety of an intervention.
For a blood-pressure lowering agent like metoprolol these might include dizziness and diarrhea. But the systolic blood pressure would also be of interest.
For an anti-inflammatory, the most important are intestinal bleeding and ulcers. How does one detect and measure intestinal bleeding? Two ways, by self-evaluation and by measuring the amount of blood in the stool. Data relating to both must be collected.
For a coronary-stenosis reducing surgical procedure or device, the primary concern is with other procedure- and condition-related adverse events including death, myocardial infarctions, and restenosis severe enough to require further operations.
To ensure that you will collect all the data you need, a careful review of past clinical and pre-clinical experience with the present and related interventions is essential. For example, suppose that extremely high doses of your new agent had resulted in the presence of abnormal blood cells in mice. While such abnormal cells may be unlikely at the therapeutic dose you are using in the trials, to be on the safe side, blood tests should be incorporated in the trial's follow-up procedure.
During the trial and afterward, you will probably want to record the frequency of all adverse events, of specific adverse events, and of those events directly related to the intervention that exceed a certain level of severity.
You should also determine how the adverse event data are to be collected. By use of a checklist-"Since your last appointment, did you experience fever? nausea? dizziness?" Or a volunteered response-"Have you had any problems since your last visit?" Elicited responses tend to yield a higher frequency of complaints. To be on the safe side, use both methods. Of course, hospitalizations, emergency treatment, and phoned-in complaints between visits must always be recorded.
Some secondary end points may also concern efficacy. For example, in a study of sedatives, you might be interested in how rapidly the patient obtained relief.
Tertiary End Points. Tertiary end points such as costs may or may not be essential to your study. Don't collect data you don't need. When in doubt, let your marketing department be your guide.
BASELINE DATA
You will need to specify what baseline data should be gathered prior to the start of intervention and how it will be gathered-by interview, questionnaire, physical examination, specialized examinations (angiograms, ultrasound, MRI), and/or laboratory tests. Baseline data will be used both to determine eligibility and, as discussed in the next chapter, to stratify the patients into more homogeneous subgroups.
Be comprehensive. Unexpected differences in outcome (or lack thereof) may be the result of differences in baseline variables. What isn't measured can't be accounted for.
WHO WILL COLLECT THE DATA?
One further step involves grouping the questions in accordance with the individual who will be entering the data, for example, demographics and risk factors by the interview nurse with review by the physician, and laboratory results by the lab itself or by the individual who receives the report. These groupings will form the basis for programming the case report forms (see Chapter 10).
Finally, I would recommend you charge specific individuals with the responsibility of addressing each of the points raised in the preceding sections. The design committee can then function as a committee should in reviewing work that has already been performed.
QUALITY CONTROL
The secret of successful clinical trials lies in maintaining the quality of the data you collect. The most frequent sources of error are the following:
Protocol deviations that result when the intervention is not performed/administered as specified
Noncompliance of patients with the treatment regimen
Improperly labeled formulations
Improperly made observations
º Inaccurate measuring devices
º Inconsistent methods of observation, the result of
* Ambiguous directions
* Site-to-site variation
* Time-period to time-period variation
º Fraud (sometimes laziness, sometimes a misguided desire to please)
Improperly entered data
Improperly stored data
Among the more obvious preventive measures are the following:
1. Keep the intervention simple. I am currently serving as a statistician on a set of trials where, over my loudest protests, each patient will receive injections for three days, self-administer a drug for six months, and attend first semiweekly and then weekly counseling sessions over the same period. How likely are these patients to comply?
2. Keep the experimental design simple (see Chapter 6).
3. Keep the data collected to a minimum.
4. Pretest all questionnaires to detect ambiguities.
5. Use computer-assisted data entry to catch and correct data entry errors as they are made (see Chapter 10).
6. Ensure the integrity and security of the stored data (see Chapter 11).
7. Prepare a highly detailed procedures manual for the investigators and investigational laboratories to ensure uniformity in treatment and in measurement. Provide a training program for the investigators with the same end in mind.
This manual should include precise written instructions for measuring each primary and secondary end point. It should also specify how the data are to be collected. For example, are data on current symptoms to be recorded by a member of the investigator's staff, or by the self-administering patient?
8. Monitor the data and the data collection process. Perform frequent on-site audits.
Continues...
Excerpted from A Manager's Guide to the Design and Conduct of Clinical Trials by Phillip I. Good Excerpted by permission.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.
Table of Contents
1 Cut Costs and Increase Profits 1No Excuse for the Wastage 1
Front-Loaded Solution 2
Downsizing 3
Think Transnational 3
A Final Word 4
2 Guidelines 7
Start with Your Reports 7
The Wrong Way 9
Keep it in the Computer 9
Don’t Push the River 10
KISS 11
Plug the Holes as They Arise 12
Pay for Results, Not Intentions 13
Plan, Do, Then Check 13
Part I Plan 15
3 Prescription for Success 17
Plan 17
A. Predesign Phase 17
B. Design the Trials 17
Do 19
C. Obtain Regulatory Agency Approval for the Trials 19
D. Form the Implementation Team 19
E. Line Up Your Panel of Physicians 19
F. Develop the Data Entry Software 19
G. Test the Software 20
H. Train 20
I. Recruit Patients 20
J. Set Up External Review Committees 20
K. Conduct the Trials 20
L. Develop Suite of Programs for Use in Data Analysis 20
M. Analyze and Interpret the Data 21
Check 21
N. Complete the Submission 21
4 Staffing for Success 23
The People You Need 23
Design Team 23
Obtain Regulatory Approval for the Trials 25
Track Progress 25
Implementation Team 26
Develop Data Entry Software 26
Test the Software 27
Line Up Your Panel of Physicians 28
External Laboratories 28
Site Coordinators 28
External Review Committees 29
Recruit and Enroll Patients 29
Transnational Trials 30
Conduct the Trials 30
Programs for Data Analysis 30
Analyze and Interpret the Data 31
The People You Don’t Need 31
For Further Information 33
5 Design Decisions 35
Should the Study Be Performed? 36
Should the Trials Be Transnational? 37
Study Objectives 37
End Points 38
Secondary End Points 39
Should We Proceed with a Full-Scale Trial? 41
Tertiary End Points 41
Baseline Data 41
Who Will Collect the Data? 41
Quality Control 42
Study Population 44
Timing 45
Closure 46
Planned Closure 46
Unplanned Closure 46
Be Defensive. Review, Rewrite, Review Again 49
Checklist for Design 50
Budgets and Expenditures 50
For Further Information 51
6 Trial Design 55
Baseline Measurements 56
Controlled Randomized Clinical Trials 57
Randomized Trials 58
Blocked Randomization 59
Stratified Randomization 60
Single- vs. Double-Blind Studies 60
Allocation Concealment 62
Exceptions to the Rule 62
Sample Size 63
Which Formula? 64
Precision of Estimates 64
Bounding Type I and Type II Errors 66
Equivalence 68
Software 68
Subsamples 69
Loss Adjustment 69
Number of Treatment Sites 70
Alternate Designs 70
Taking Cost into Consideration 72
For Further Information 73
7 Exception Handling 75
Patient Related 75
Missed Doses 75
Missed Appointments 75
Noncompliance 76
Adverse Reactions 76
Reporting Adverse Events 76
When Do You Crack the Code? 77
Investigator Related 77
Lagging Recruitment 77
Protocol Deviations 78
Site-Specific Problems 78
Closure 79
Intent to Treat 80
Is Your Planning Complete? 80
Part II Do 81
8 Documentation 83
Guidelines 84
Common Technical Document 84
Reporting Adverse Events 86
Initial Submission to the Regulatory Agency 87
Sponsor Data 88
Justifying the Study 88
Objectives 89
Patient Selection 89
Treatment Plan 90
Outcome Measures and Evaluation 90
Procedures 90
Clinical Follow-Up 90
Adverse Events 91
Data Management, Monitoring, Quality Control 91
Statistical Analysis 91
Investigator Responsibilities 92
Ethical and Regulatory Considerations 93
Study Committees 93
Appendixes 94
Sample Informed Consent Form 94
Procedures Manuals 95
Physician’s Procedures Manual 96
Laboratory Guidelines 97
Interim Reports 97
Enrollment Report 98
Data in Hand 98
Adverse Event Report 99
Annotated Abstract 99
Final Reports(s) 102
Regulatory Agency Submissions 102
e-Subs 104
Journal Articles 104
For Further Information 105
9 Recruiting and Retaining Patients and Physicians 107
Selecting Your Clinical Sites 107
Recruiting Physicians 108
Teaching Hospitals 109
Clinical Resource Centers 109
Look to Motivations 110
Physician Retention 111
Get the Trials in Motion 111
Patient Recruitment 112
Factors in Recruitment 112
Importance of Planning 113
Ethical Considerations 114
Mass Recruiting 114
Patient Retention 115
Ongoing Efforts 116
Run-In Period 117
Budgets and Expenditures 118
For Further Information 118
10 Computer-Assisted Data Entry 123
Pre-Data Screen Development Checklist 124
Develop the Data Entry Software 124
Avoid Predefined Groupings in Responses 126
Screen Development 126
Radio Button 128
Pull-Down Menus 129
Type and Verify 129
When the Entries are Completed 130
Audit Trail 132
Electronic Data Capture 132
Data Storage: CDISC Guidelines 133
Testing 136
Formal Testing 137
Stress Testing 138
Training 139
Reminder 139
Support 140
Budgets and Expenditures 141
For Further Information 141
11 Data Management 143
Options 143
Flat Files 143
Hierarchical Databases 145
Network Database Model 146
Relational Database Model 146
Which Database Model? 149
Object-Oriented Databases 150
Clients and Servers 150
One Size Does Not Fit All 151
Combining Multiple Databases 151
A Recipe for Disaster 152
Transferring Data 154
Quality Assurance and Security 155
Maintaining Patient Confidentiality 155
Access to Files 155
Maintaining an Audit Trail 157
Security 157
For Further Information 158
12 Are You Ready? 161
Pharmaceuticals/Devices 161
Software 162
Hardware 162
Documentation 162
Investigators 162
External Laboratories 163
Review Committees 163
Patients 163
Regulatory Agency 163
Test Phase 163
13 Monitoring the Trials 165
Roles of the Monitors 165
Before the Trials Begin 167
Kick-Off Meetings 168
Duties During Trial 169
Site Visits 169
Between Visits 170
Other Duties 173
Maintaining Physician Interest in Lengthy Trials 173
14 Managing the Trials 175
Recruitment 176
Supplies 176
Late and Incomplete Forms 176
Dropouts and Withdrawals 178
Protocol Violations 178
Adverse Events 179
Quality Control 179
Visualize the Data 180
Roles of the Committees 183
Termination and Extension 184
Extending the Trials 186
Budgets and Expenditures 186
For Further Information 187
15 Data Analysis 189
Report Coverage 189
Understanding Data 190
Categories 190
Metric Data 192
Statistical Analysis 194
Categorical Data 196
Ordinal Data 197
Metric Data 198
An Example 199
Time-to-Event Data 200
Step By Step 203
The Study Population 203
Reporting Primary End Points 204
Exceptions 204
Adverse Events 207
Analytical Alternatives 207
When Statisticians Can’t Agree 208
Testing for Equivalence 209
Simpson’s Paradox 210
Estimating Precision 211
Bad Statistics 213
Using the Wrong Method 213
Deming Regression 213
Choosing the Most Favorable Statistic 214
Making Repeated Tests on the Same Data 214
Ad Hoc, Post Hoc Hypotheses 215
Interpretation 217
Documentation 218
For Further Information 219
A Practical Guide to Statistical Terminology 222
Part III Check 225
16 Check 227
Closure 227
Patient Care 227
Data 228
Spreading the News 228
Postmarket Surveillance 228
Budget 228
Controlling Expenditures 229
Process Review Committee 229
Trial Review Committee 230
Investigatory Drug or Device 230
Interactions 232
Adverse Events 232
Collateral Studies 233
Future Studies 234
For Further Information 234
Appendix Software 237
Choices 237
All in One 237
Almost All in One 238
Project Management 238
Data Entry 239
Handheld Devices 239
Touch Screen 239
Speech Recognition 239
e-CRFs 240
Do it Yourself 240
Data Collection Via the Web 240
Preparing the Common Technical Document 241
Data Management 241
Data Entry and Data Management 242
Small-Scale Clinical Studies 242
Clinical Database Managers 242
Data Analysis 243
Utilities 244
Sample Size Determination 244
Screen Capture 245
Data Conversion 245
Author Index 247
Subject Index 251