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

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