A Manager's Guide to the Design and Conduct of Clinical Trials / Edition 2

by Phillip I. Good

Overview

This newly updated edition of the benchmark guide to computer-assisted clinical trials provides a comprehensive primer for prospective managers. It covers every critical issue of the design and conduct of clinical trials, including study design, organization, regulatory agency liaison, data collection and analysis, as well as recruitment, software, monitoring, and reporting.

Keeping the same user-friendly format as the original, this Second Edition features new examples and the latest developments in regulatory guidelines, such as e-submission procedures and computerized direct data acquisition. The new edition also reflects the increasing globalization of clinical trial activities, and includes new information about international standards and procedures, including the Common Technical Document and CDISC standards.

This step-by-step guide is supported by handy checklists and extracts from submitted protocols. Experienced author and consultant Phillip Good incorporateshumorous yet instructive anecdotes to illustrate common pitfalls. Based on the proven industrial formula of planning, implementing, and finally performing essential checks, the book's three sections-"Plan," "Do," and "Check"-includethe following material:
* Should the trials be conducted?
* Put it in the computer and keep it there
* Staffing for success
* Designing trials and determining sample size
* Budgeting
* Recruiting and retaining patients and physicians
* Data management
* Monitoring the trials
* Data analysis
* After action review
* Exception handling

Executive and managerial professionals involved in the design and analysis of clinical experiments, along with clinical research associates, biostatisticians, and students in public health will find A Manager's Guide an indispensable resource.

Praise for the First Edition:

". . . readable, informative and at times witty . . . never stops being concise and well written . . . a book worth a read . . ."
-Statistics in Medicine

"The book is very prescriptive and full of lists and tables with which to guide managers in making effective decisions in using computer-assisted clinical trials in pharmaceutical studies." -Technometrics

"This book is must-have reading for anyone in the business . . ."
-Clinical Chemistry

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

Phillip Good, Ph.D., a graduate of UC Berkeley's statistics program, is the author of sixteen published books. He has 23 years of experience in the pharmaceutical and medical device industries, first with Upjohn, and then as an independent consultant. He has taught anatomy and biology, and has also served as Calloway Professor of Computer Science at the University of Georgia at Fort Valley. Dr. Good has lectured extensively throughout the world, including an appointment as traveling lecturer for the American Statistical Association.

Read an Excerpt

A Manager's Guide to the Design and Conduct of Clinical Trials

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By Phillip I. Good

John Wiley & Sons

ISBN: 0-471-22615-7

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Chapter One

Design Decisions

From 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...

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Excerpted from A Manager's Guide to the Design and Conduct of Clinical Trials by Phillip I. Good Excerpted by permission.
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Table of Contents

1 Cut Costs and Increase Profits 1

No 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

Editorial Reviews

"With this book in hand, people who manage the people who manageclinical trials can intelligently supervise their staff."(Journal of Clinical Research Best Practices, November 2007)

"…a useful tool for understanding the entire clinicaltrial process." (Journal of Biopharmaceutical Statistics,Vol. 17, Issue 3, 2007)

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