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

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.

"With this book in hand, people who manage the people who manage clinical trials can intelligently supervise their staff." (Journal of Clinical Research Best Practices, November 2007) "…a useful tool for understanding the entire clinical trial process." (Journal of Biopharmaceutical Statistics, Vol. 17, Issue 3, 2007)

• 1 Cut Costs and Increase Profits 1No Excuse for the Wastage 1Front-Loaded Solution 2Downsizing 3Think Transnational 3A Final Word 42 Guidelines 7Start with Your Reports 7The Wrong Way 9Keep it in the Computer 9Don’t Push the River 10KISS 11Plug the Holes as They Arise 12Pay for Results, Not Intentions 13Plan, Do, Then Check 13Part I Plan 153 Prescription for Success 17Plan 17A. Predesign Phase 17B. Design the Trials 17Do 19C. Obtain Regulatory Agency Approval for the Trials 19D. Form the Implementation Team 19E. Line Up Your Panel of Physicians 19F. Develop the Data Entry Software 19G. Test the Software 20H. Train 20I. Recruit Patients 20J. Set Up External Review Committees 20K. Conduct the Trials 20L. Develop Suite of Programs for Use in Data Analysis 20M. Analyze and Interpret the Data 21Check 21N. Complete the Submission 214 Staffing for Success 23The People You Need 23Design Team 23Obtain Regulatory Approval for the Trials 25Track Progress 25Implementation Team 26Develop Data Entry Software 26Test the Software 27Line Up Your Panel of Physicians 28External Laboratories 28Site Coordinators 28External Review Committees 29Recruit and Enroll Patients 29Transnational Trials 30Conduct the Trials 30Programs for Data Analysis 30Analyze and Interpret the Data 31The People You Don’t Need 31For Further Information 335 Design Decisions 35Should the Study Be Performed? 36Should the Trials Be Transnational? 37Study Objectives 37End Points 38Secondary End Points 39Should We Proceed with a Full-Scale Trial? 41Tertiary End Points 41Baseline Data 41Who Will Collect the Data? 41Quality Control 42Study Population 44Timing 45Closure 46Planned Closure 46Unplanned Closure 46Be Defensive. Review, Rewrite, Review Again 49Checklist for Design 50Budgets and Expenditures 50For Further Information 516 Trial Design 55Baseline Measurements 56Controlled Randomized Clinical Trials 57Randomized Trials 58Blocked Randomization 59Stratified Randomization 60Single- vs. Double-Blind Studies 60Allocation Concealment 62Exceptions to the Rule 62Sample Size 63Which Formula? 64Precision of Estimates 64Bounding Type I and Type II Errors 66Equivalence 68Software 68Subsamples 69Loss Adjustment 69Number of Treatment Sites 70Alternate Designs 70Taking Cost into Consideration 72For Further Information 737 Exception Handling 75Patient Related 75Missed Doses 75Missed Appointments 75Noncompliance 76Adverse Reactions 76Reporting Adverse Events 76When Do You Crack the Code? 77Investigator Related 77Lagging Recruitment 77Protocol Deviations 78Site-Specific Problems 78Closure 79Intent to Treat 80Is Your Planning Complete? 80Part II Do 818 Documentation 83Guidelines 84Common Technical Document 84Reporting Adverse Events 86Initial Submission to the Regulatory Agency 87Sponsor Data 88Justifying the Study 88Objectives 89Patient Selection 89Treatment Plan 90Outcome Measures and Evaluation 90Procedures 90Clinical Follow-Up 90Adverse Events 91Data Management, Monitoring, Quality Control 91Statistical Analysis 91Investigator Responsibilities 92Ethical and Regulatory Considerations 93Study Committees 93Appendixes 94Sample Informed Consent Form 94Procedures Manuals 95Physician’s Procedures Manual 96Laboratory Guidelines 97Interim Reports 97Enrollment Report 98Data in Hand 98Adverse Event Report 99Annotated Abstract 99Final Reports(s) 102Regulatory Agency Submissions 102e-Subs 104Journal Articles 104For Further Information 1059 Recruiting and Retaining Patients and Physicians 107Selecting Your Clinical Sites 107Recruiting Physicians 108Teaching Hospitals 109Clinical Resource Centers 109Look to Motivations 110Physician Retention 111Get the Trials in Motion 111Patient Recruitment 112Factors in Recruitment 112Importance of Planning 113Ethical Considerations 114Mass Recruiting 114Patient Retention 115Ongoing Efforts 116Run-In Period 117Budgets and Expenditures 118For Further Information 11810 Computer-Assisted Data Entry 123Pre-Data Screen Development Checklist 124Develop the Data Entry Software 124Avoid Predefined Groupings in Responses 126Screen Development 126Radio Button 128Pull-Down Menus 129Type and Verify 129When the Entries are Completed 130Audit Trail 132Electronic Data Capture 132Data Storage: CDISC Guidelines 133Testing 136Formal Testing 137Stress Testing 138Training 139Reminder 139Support 140Budgets and Expenditures 141For Further Information 14111 Data Management 143Options 143Flat Files 143Hierarchical Databases 145Network Database Model 146Relational Database Model 146Which Database Model? 149Object-Oriented Databases 150Clients and Servers 150One Size Does Not Fit All 151Combining Multiple Databases 151A Recipe for Disaster 152Transferring Data 154Quality Assurance and Security 155Maintaining Patient Confidentiality 155Access to Files 155Maintaining an Audit Trail 157Security 157For Further Information 15812 Are You Ready? 161Pharmaceuticals/Devices 161Software 162Hardware 162Documentation 162Investigators 162External Laboratories 163Review Committees 163Patients 163Regulatory Agency 163Test Phase 16313 Monitoring the Trials 165Roles of the Monitors 165Before the Trials Begin 167Kick-Off Meetings 168Duties During Trial 169Site Visits 169Between Visits 170Other Duties 173Maintaining Physician Interest in Lengthy Trials 17314 Managing the Trials 175Recruitment 176Supplies 176Late and Incomplete Forms 176Dropouts and Withdrawals 178Protocol Violations 178Adverse Events 179Quality Control 179Visualize the Data 180Roles of the Committees 183Termination and Extension 184Extending the Trials 186Budgets and Expenditures 186For Further Information 18715 Data Analysis 189Report Coverage 189Understanding Data 190Categories 190Metric Data 192Statistical Analysis 194Categorical Data 196Ordinal Data 197Metric Data 198An Example 199Time-to-Event Data 200Step By Step 203The Study Population 203Reporting Primary End Points 204Exceptions 204Adverse Events 207Analytical Alternatives 207When Statisticians Can’t Agree 208Testing for Equivalence 209Simpson’s Paradox 210Estimating Precision 211Bad Statistics 213Using the Wrong Method 213Deming Regression 213Choosing the Most Favorable Statistic 214Making Repeated Tests on the Same Data 214Ad Hoc, Post Hoc Hypotheses 215Interpretation 217Documentation 218For Further Information 219A Practical Guide to Statistical Terminology 222Part III Check 22516 Check 227Closure 227Patient Care 227Data 228Spreading the News 228Postmarket Surveillance 228Budget 228Controlling Expenditures 229Process Review Committee 229Trial Review Committee 230Investigatory Drug or Device 230Interactions 232Adverse Events 232Collateral Studies 233Future Studies 234For Further Information 234Appendix Software 237Choices 237All in One 237Almost All in One 238Project Management 238Data Entry 239Handheld Devices 239Touch Screen 239Speech Recognition 239e-CRFs 240Do it Yourself 240Data Collection Via the Web 240Preparing the Common Technical Document 241Data Management 241Data Entry and Data Management 242Small-Scale Clinical Studies 242Clinical Database Managers 242Data Analysis 243Utilities 244Sample Size Determination 244Screen Capture 245Data Conversion 245Author Index 247Subject Index 251