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PRINCIPLES AND
PRACTICE OF
CLINICAL
RESEARCH
FOURTH EDITION
Edited by

JOHN I. GALLIN
FREDERICK P. OGNIBENE
LAURA LEE JOHNSON
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 Contents

List of Contributors xiii 3. Integrity in Research:

Acknowledgments xv Principles for the Conduct of
Preface xvii Research
MELISSA C. COLBERT, ROBERT B. NUSSENBLATT,
MICHAEL M. GOTTESMAN

1. A Historical Perspective on Clinical Guidelines and Principles for the Conduct of

Research Research 33
JOHN I. GALLIN Scientific Integrity and Research Misconduct 34
Responsibilities of Research Supervisors and
The Earliest Clinical Research 1 Trainees 36
Greek and Roman Influence 2 Data Management, Archiving, and Sharing 36
Middle Ages and Renaissance 2 Research Involving Human and Animal Subjects 38
Seventeenth Century 3 Collaborative and Team Science 39
Eighteenth Century 4 Conflict of Interest and Commitment 40
Nineteenth Century 7 Peer Review 41
Twentieth Century and Beyond 11 Publication Practices, Responsible Authorship,
Summary Questions 14 and Results Reproducibility 42
References 14 Study Questions 45
Acknowledgments 45
References 45
I Further Reading 46

ETHICAL, REGULATORY 4. Institutional Review Boards

AND LEGAL ISSUES JULIA SLUTSMAN, LYNNETTE NIEMAN

Historical, Ethical, and Regulatory

2. Ethical Principles in Clinical Foundations of Current Requirements
Research for Research Involving Human
CHRISTINE GRADY Subjects 47
Institutional Review Boards 50
Distinguishing Clinical Research From Clinical Researchers and Institutional Review
Clinical Practice 19 Boards 57
Ethics and Clinical Research 20 Evaluation and Evolution of the Current
History of Ethical Attention to Clinical System of Research Oversight and
Research 20 Institutional Review Boards 57
Codes of Research Ethics and Conclusion 59
Regulations 22 Summary Questions 59
Research on Bioethical Questions 23 References 59
Ethical Framework for Clinical
Research 23 5. Accreditation of Human Research
Ethical Considerations in Randomized Protection Programs
Controlled Trials 27 ELYSE I. SUMMERS, MICHELLE FEIGE
Conclusion 29
Summary Questions 29 A Brief History 63
References 30 Principles of Accreditation 64

v
vi CONTENTS

Human Research Protection Programs: Registering Clinical Trials at ClinicalTrials.gov 116

The Shift to Shared Responsibility 65 Reporting Results to ClinicalTrials.gov 118
The Accreditation Standards 66 Using ClinicalTrials.gov Data 120
Steps to Accreditation 70 Looking Forward 121
Value of Accreditation 70 Conclusion 123
Summary Questions 72 Summary/Discussion Questions 123
References 72 References 123

6. The Regulation of Drugs and Biological 10. Data and Safety Monitoring
Products by the Food and Drug PAUL G. WAKIM, PAMELA A. SHAW
Administration
MOLLY M. FLANNERY, AMY E. McKEE, Why Monitor? 127
DIANE M. MALONEY, JONATHAN P. JAROW Who Monitors? 128
What to Monitor? 130
Background 73 When and How Often to Monitor? 136
Mission and Terminology 74 Special Topics 137
Drug and Biological Product Life Cycle 76 Summary 138
Compliance 84 Summary Questions 139
Summary 84 Acknowledgments 139
Summary Questions 84 References 139

7. International Regulation of Drugs

11. Unanticipated Risk in Clinical
and Biological Products
Research
THERESA MULLIN
STEPHEN E. STRAUS
Introduction 87
Background 88 The Reasons 143
The Drug 144
Overview of the International Council on
The Target 145
Harmonisation Technical Harmonization
The Trials 145
Process 93
Cassandra Revealed 147
International Council on Harmonisation
Extended Studies 147
Guidelines Most Relevant to Clinical
Fialuridine Toxicity 147
Research 95
Reassessing the Preclinical Studies 149
Future Work in Regulatory Harmonization 98
References 98 Research Oversight 149
The Investigations Begin 150
8. Clinical Research in International Scientific Misconduct 150
The Food and Drug Administration 151
Settings: Opportunities, Challenges,
The National Institutes of Health 152
and Recommendations The Institute of Medicine 152
CHRISTOPHER O. OLOPADE, MICHELLE TAGLE, The Media 153
OLUFUNMILAYO I. OLOPADE
The Congress 154
Introduction 99 The Law 154
Challenges 100 Epilogue 155
Recommendations 103 Acknowledgments 157
Conclusion 106 References 157
Summary Questions 106 Further Reading 158
References 107
12. Legal Issues in Clinical Research 161
9. The Role and Importance of Clinical VALERIE H. BONHAM
Trial Registries and Results Databases
Introduction 161
DEBORAH A. ZARIN, REBECCA J. WILLIAMS,
TONY TSE, NICHOLAS C. IDE Protecting Individual Participant Interests 162
Special Protections for Fetal Tissue,
Introduction 111 Human Embryos, and Human Embryonic
Background 112 Stem Cells 166
Current Policies 115 Conflict of Interest and Financial Disclosure 167
 CONTENTS vii
Public Transparency: Registration and Development and Importance of a Study
Results Reporting 168 Protocol 204
Recordkeeping and Privacy Protection 168 Equipoise 213
Data Sharing and Individual Consent 171 Manual of Operating Procedures 213
Conclusion 173 Reporting the Results 216
Summary/Discussion Questions 173 Conclusions 217
References 173 Summary Questions 217
Acknowledgments 217
13. National Institutes of Health Policy Disclosures 217
on the Inclusion of Women and References 217
Minorities as Subjects in Clinical Research
JANINE CLAYTON, JULIANA BLOME
16. Writing a Protocol
ELIZABETH A. BARTRUM, BARBARA I. KARP
National Institutes of Health Policy 177
Scientific Considerations and Peer Review 179 Introduction 219
Role of the Institutional Review Board 180 Regulatory Oversight 219
Challenges to Enrolling Volunteers 181 Writing a Protocol 220
Women of Childbearing Potential, Pregnant Elements of a Protocol 220
Women, and Children 182 Summary 229
Demographic Trends in Clinical Trial Acknowledgments 229
Participation 183 References 229
What Have We Learned? 184
Conclusion 186
17. Design of Observational Studies
Summary Questions 186 LAURA LEE JOHNSON
References 186
Introduction 231
Further Reading 187
Ecological (Correlational) Studies 233
14. Clinical Research: A Patient Perspective Case Reports and Case Series 233
Single Time Point Studies: Cross-sectional
JERRY SACHS
Studies, Prevalence Surveys, and
The PatienteScientist Partnership 190 Incidence Studies 234
Walking Away: Why Patients Case-Control Studies 236
Refuse to Participate in Clinical Trials 191 Cohort Studies: Retrospective, Prospective,
The Trial Begins: Understanding the Patient and Studies Nested Within a Cohort 239
Experience 193 Odds Ratios, Risk Ratios, Relative Risks,
Understanding the Caregiver 195 and Attributable Risk 242
The Role of the Patient Representative 195 Mistakes, Misconceptions, and
The Role of Palliative Care 196 Misinterpretations 243
Managing Difficult News 196 Conclusions 247
Effective Patient Communications: Questions 247
Recommendations and Considerations 197 Acknowledgments 247
The Assertive Patient: Ally in Scientific Disclosures 247
Research 198 References 247
Conclusion 199
Further Reading 199
18. Design of Clinical Trials and
Studies
II CATHERINE M. STONEY, LAURA LEE JOHNSON

STUDY DESIGN AND BIOSTATISTICS Design of Clinical Trials 250

The Purpose of Clinical Trials and Clinical
15. Development and Conduct of Studies 250
Studies Understanding the Spectrum of the Research
CATHERINE M. STONEY, LAURA LEE JOHNSON Continuum 251
Clinical Trial Designs 255
Development and Conduct of Studies 203 Critical Issues in Clinical Study Design 258
How to Choose a Study Design 204 Control Groups 258
viii CONTENTS

Placebo Responses 261 21. Measures of Function and

Mistakes and Misconceptions 262 Health-Related Quality of Life
Conclusions 266 NAOMI L. GERBER, JILLIAN K. PRICE
Summary Questions 266
Acknowledgments 266 Introduction to Patient-Reported Outcomes,
Disclosures 266 Measures of Function, and Health-Related
References 266 Quality of Life 303
Further Reading 268 Systematic Reviews 305
Outcomes: Functional Measures and Patient-
19. The Role of Comparative Reported Outcomes 306
Effectiveness Research Summary Questions 313
JOE V. SELBY, EVELYN P. WHITLOCK, References 313
KELLY S. SHERMAN, JEAN R. SLUTSKY Further Reading 315
Introduction 269 22. Meta-analysis of Clinical Trials
A History of Comparative Clinical
JUNFENG SUN, BRADLEY D. FREEMAN,
Effectiveness Research 270 CHARLES NATANSON
The Patient-Centered Outcomes Research
Institute 271 Techniques of Meta-analysis 318
The Role of Comparative Clinical Meta-analysis of Clinical Trials of
Effectiveness Research in the Nation’s Antiinflammatory Agents in Sepsis 321
Medical Research Enterprise 273 Conclusions 323
The Methods of Comparative Clinical Summary Questions 323
Effectiveness Research 275 References 324
Study Designs for CER Studies 278
Evidence Synthesis in CER 285 23. Issues in Randomization
Building a National Infrastructure for the PAMELA A. SHAW, LAURA LEE JOHNSON,
Conduct of Comparative Effectiveness CRAIG B. BORKOWF
Research 287
Conclusions 290 What Is Randomization? 329
References 290 Importance of Randomization 330
History of the Randomized Trial 330
Randomization Methods 331
20. Using Large Data Sets for Issues in Implementation 333
Population-Based Health Research Special Considerations 335
LEIGHTON CHAN, PATRICK McGAREY, Conclusion 337
JOSEPH A. SCLAFANI Summary Questions 338
Acknowledgments 338
Introduction 293 Disclosures 338
What Are the Original Sources for References 338
These Data? 294
Uses of Secondary Data in Health 24. Hypothesis Testing
Research 294
LAURA LEE JOHNSON, CRAIG B. BORKOWF,
Strengths 296 PAMELA A. SHAW
Limitations (and Solutions) 297
Surveys 298 Introduction 342
Linking Data Sets 298 Basic Concepts in Hypothesis Testing 343
Ethical Considerations 299 Formulation of Statistical Hypotheses
Future Directions and Conclusions 300 in the Motivating Examples 345
Summary Questions 300 One-Sample Hypothesis Tests With
References 300 Applications to Clinical Research 346
 CONTENTS ix
Two-Sample Hypothesis Tests With Missing Data 403
Applications to Clinical Research 349 Causal Inference in Observational Studies 405
Hypothesis Tests for the Motivating Examples 351 Concluding Remarks 406
Common Mistakes in Hypothesis Testing 353 Summary Questions 406
Misstatements and Misconceptions 353 Acknowledgments 407
Special Considerations 354 Disclaimers 407
Conclusion 356 References 407
Summary Questions 356
Acknowledgments 357 28. Large Clinical Trials and
Disclaimers 357 RegistriesdClinical Research Institutes
References 357 ROBERT M. CALIFF

25. Power and Sample Size Calculations Introduction 412

CRAIG B. BORKOWF, LAURA LEE JOHNSON, History 412
PAUL S. ALBERT Phases of Evaluation of Therapies 413
Critical General Concepts 414
Introduction 359 Expressing Clinical Trial Results 415
Sample Size Calculations for Precision in Concepts Underlying Trial Design 417
Confidence Interval Construction 361 General Design Considerations 420
Sample Size Calculations for Hypothesis Legal and Ethical Issues 422
Tests: One Sample of Data 362 Hypothesis Formulation 427
Sample Size Calculations for Hypothesis Publication Bias 427
Tests: Paired Data 364 Statistical Considerations 428
Sample Size Calculations for Hypothesis Meta-analysis and Systematic Reviews 430
Tests: Two Independent Samples 366 Understanding Covariates and Subgroups 431
Advanced Methods and Other Topics 368 Therapeutic Truisms 432
Conclusion 369 Operational Organization for Large-Scale
Exercises 370 Clinical Research 433
Acknowledgments 371 Integration Into Practice 437
Disclaimers 371 Controversies and Personal Perspective 437
References 371 The Future 439
Summary Questions 440
26. An Introduction to Survival Analysis References 440
LAURA LEE JOHNSON

Introduction 373
III
Features of Survival Data 374 TECHNOLOGY TRANSFER,
Survival Function 375 DATA MANAGEMENT, AND
Common Mistakes 380 SOURCES OF FUNDING SUPPORT
Conclusion 380
FOR RESEARCH
Questions 381
Acknowledgments 381
Disclaimers 381 29. Intellectual Property and Technology
References 381 Transfer
BRUCE GOLDSTEIN
27. Intermediate Topics in Biostatistics
PAMELA A. SHAW, LAURA LEE JOHNSON, Introduction 448
MICHAEL A. PROSCHAN Part One: Intellectual Property Generally 448
Part Two: Patents and Technology Transfer 487
Special Topics in Trial Design 384 Part Three: Technology Transfer Agreements 503
Special Considerations in Data Analysis 392 Conclusion 518
Regression to the Mean 394 Brief Glossary of Critical Terms in Patenting 519
Diagnostic Testing 396 Review Questions 519
Special Considerations in Survival Analysis 400 References 520
x CONTENTS

30. Data Management in Clinical Trials 33. Evaluating a Protocol Budget

DIANE C. ST GERMAIN, MARJORIE J. GOOD PHYLLIS KLEIN

The Research Team 531 Overview 571

Data Management 533 Institutional Review Board Fees 572
Auditing 538 Overhead or Indirect Cost 572
Unanticipated Problems and Adverse Event Determining the Hourly Rate 572
Monitoring and Reporting 540 The “Per Patient” Budget 573
Legal and Regulatory Issues Related to Data Start-Up Cost and Invoiced Items 577
Reporting 542 Submitting Your Budget to
Follow-Up and Analysis 543 the Sponsor for Approval 582
Record Retention 543 Areas of Concern 585
Conclusion 544 Walking Away 586
Summary Questions 544 Wrapping Up 586
References 544
34. Getting the Funding You Need to
31. Clinical Research Data: Characteristics, Support Your Research: Navigating the
Representation, Storage, and Retrieval National Institutes of Health Peer
JAMES J. CIMINO Review Process
VALERIE L. PRENGER
Introduction 547
Data as Surrogates 547 Overview of National Institutes of Health 590
Types of Data 550 The National Institutes of Health Peer
Data Standards 550 Review Process for Grants 594
Data Capture, Storage, and Retrieval 551 Hints for Preparing Better Grant
Responsible Stewardship of Data 553 Applications 600
Cooperative Sharing Efforts 555 Recent Changes to Application
Summary 556 Procedures for National Institutes
Summary Questions 556 of HealtheFunded Clinical Trialsd
References 557 More to Come 605
Revising Unsuccessful Applications 605
32. Management of Patient Samples National Institutes of Health
Grant Programs for Clinical
KAREN E. BERLINER, AMY P.N. SKUBITZ
Researchers at Various Stages
Introduction 559 in Their Careers 607
Successful Research Rests on a Foundation How to Stay Informed About National
of Careful Planning 560 Institutes of Health Peer Review 609
The Role of Pre-analytic Variables in Research
Using Patient Specimens 560 35. Philanthropy’s Role in Advancing
Training and Accreditation 561 Biomedical Research
The Importance of Good Record Keeping 562 ELAINE K. GALLIN, MARYROSE FRANKO,
Specimen Tracking 562 ENRIQUETA BOND
Specimen Collection 563
Specimen Handling 565 Introduction 611
Organization of the Philanthropic
Specimen Transit 565
Sector and Terminology 613
Specimen Storage 566
History of the Philanthropic Sector 615
Access to Patient Samples 567
Areas of Contribution 617
Specimen Culling, Transfer of Collections,
Conclusions and Future Directions 628
and Repository Closings 567
Summary Questions 629
Summary Questions 567
References 629
References 568
 CONTENTS xi

IV Additional Educational Approaches and

Support for Training 668
CLINICAL RESEARCH Conclusions 669
INFRASTRUCTURE Summary/Discussion Questions 669
References 669
36. Identifying, Understanding, and
Managing Patient Safety and Clinical 39. Clinical Research Nursing: A New
Risks in the Clinical Research Environment Domain of Practice
GWENYTH R. WALLEN, CHERYL A. FISHER
LAURA M. LEE, DAVID K. HENDERSON

Identifying and Managing Clinical Risk Introduction 671

in the Clinical Research Environment 633 Clinical Research Nursing: An Evolving
Building a Road map to Safe and High-Quality Practice Specialty 672
Care and Research Support: Applying the Defining and Documenting the Specialty
Principles of High Reliability in the Clinical of Clinical Research Nursing 674
Research Environment 635 Legal Scope of Practice Issues 679
Leveraging Patient Safety and Quality Tools to Assist a Principal Investigator in
Improvement Techniques in the Staffing a Study 680
Conduct of Clinical Research 635 Future Considerations 682
Proactively Assessing Clinical and Operational Summary/Discussion Questions 684
Risk 638 Acknowledgments 684
Electronic Surveillance for Errors and System References 684
Failures 641
Patient Safety and Clinical Quality 40. The Importance and Use of
Measures 641 Electronic Health Records in Clinical
Assessing Clinical Research Participants’ Research
Perceptions of the Clinical Research JON W. McKEEBY, PATRICIA S. COFFEY
Experience 642
Conclusion 642 Electronic Medical Record 687
Summary Questions 643 Electronic Health Record 688
References 643 Electronic Health Record Architecture 688
Clinical Research Information Systems 688
37. Clinical Pharmacology and Its Using an Electronic Health Record in
Role in Pharmaceutical Development Clinical Research 692
SUE CHENG, KONSTANTINA M. VANEVSKI, Secondary Use of the Electronic Health
JUAN J.L. LERTORA Record for Clinical Research 698
Legislation and the Electronic Health Record 698
Clinical Pharmacology as a Translational Summary 699
Discipline 645 Summary Questions 699
Overview of Drug Development 646 Terms 701
Current State of Affairs in Drug Development 647 References 701
Contribution of Clinical Pharmacology 649 Further Reading 702
The Role of the Regulatory Agency 654
Summary Questions 656
41. The Clinical Researcher and the
References 656
Media
JOHN T. BURKLOW
38. Career Paths in Clinical Research
FREDERICK P. OGNIBENE What Makes News in Science and Medicine? 704
Published SciencedThe Media’s Bread and
Background 661 Butter 704
Student and Resident Training in Clinical Novelty 704
Research 662 The Unexpected 705
PhysicianeScientist Workforce 664 Celebrity 705
Clinical Research Curriculum and Training 665 Controversy 705
NIH Clinical Center Core Curriculum 666 Impact 706
xii CONTENTS

Why Talk to Reporters? 706 Content and Structure 715

Why Reporters Want to Talk to You 706 Search Capabilities 717
Why You Should Talk to Reporters 706 Citation Searching 721
Social Media: What to Keep in Mind 707 Access and Business Models 721
Engaging the MediadThe Process 707 Familiarity and Currency 723
A Word About Email, the Web, and Social Biomedical Databases 724
Media 707 Bioinformatics Resources 744
The Interview 708 Data Management 746
What if You Are Misquoted? 710 Data Integration and Precision Medicine 746
What the Public Does Not Know About Bibliometrics 747
Science 710 Bibliographic Managers 748
Unexpected Questions 710 Resource Selection and Search Strategy 748
When the News Is Not Good 710 Educational Resources 749
A Word About Investigative Reporters 710 Final Notes 749
The Freedom of Information Act 711 Acknowledgments 750
Embargoes 711 Disclosure 750
When to Contact Your Communications References 750
Office 712
Conclusion 712 Appendix 1: Answer Key to Summary
Summary Questions 712 Questions 753
Appendix 2: Acronyms 761
42. Information Resources for the
Index 775
Clinical Researcher
JOSH A. DUBERMAN, PAMELA C. SIEVING

Introduction 714
Organization and Features of Information
Resources 714
Origin 715
 List of Contributors
Paul S. Albert National Institutes of Health, Rockville, MD,
United States
Elizabeth A. Bartrum National Institutes of Health,
Bethesda, MD, United States
Karen E. Berliner National Institutes of Health, Bethesda,
MD, United States
Juliana Blome National Institutes of Health, Bethesda, MD,
United States
Enriqueta Bond QE Philanthropic Advisors, Warrenton, VA,
United States
Valerie H. Bonham National Institutes of Health, Bethesda,
MD, United States
Craig B. Borkowf Centers for Disease Control and
Prevention, Atlanta, GA, United States
John T. Burklow National Institutes of Health, Bethesda,
MD, United States
Robert M. Califf Duke University School of Medicine,
Durham, NC, United States; Verily Life Sciences (Alphabet),
South San Francisco, CA, United States; Stanford University
Department of Medicine, Stanford, CA, United States
Leighton Chan National Institutes of Health, Bethesda, MD,
United States
Sue Cheng Bayer HealthCare Pharmaceuticals, Inc.,
Whippany, NJ, United States
James J. Cimino University of Alabama School of Medicine,
Birmingham, AL, United States
Janine Clayton National Institutes of Health, Bethesda, MD,
United States
Patricia S. Coffey National Institutes of Health, Bethesda,
MD, United States
Melissa C. Colbert National Institutes of Health, Bethesda,
MD, United States
Josh A. Duberman National Institutes of Health, Bethesda,
MD, United States
Michelle Feige Association for the Accreditation of Human
Research Protection Programs, Inc., Washington, DC,
United States
Cheryl A. Fisher National Institutes of Health, Bethesda,
MD, United States
Molly M. Flannery U.S. Food and Drug Administration,
Silver Spring, MD, United States
a
Mr. Goldstein is a patent attorney serving as the Assistant Director for Monitoring & Enforcement Unit in the NIH Office of
Technology Transfer. This chapter reflects the personal views of Mr. Goldstein, not of his employer. No official support or endorsement
by the National Institutes of Health or the United States Government is intended or should be inferred.
xiii
Maryrose Franko Health Research Alliance, Research
Triangle Park, NC, United States
Bradley D. Freeman Washington University School of
Medicine, St. Louis, MO, United States
Elaine K. Gallin QE Philanthropic Advisors, Potomac, MD,
United States
John I. Gallin National Institutes of Health, Bethesda, MD,
United States
Naomi L. Gerber George Mason University, Fairfax, VA,
United States; Inova Health System, Falls Church, VA,
United States
Bruce Goldstein a National Institutes of Health, Rockville,
MD, United States
Marjorie J. Good National Cancer Institute, National
Institutes of Health, Rockville, MD, United States
Michael M. Gottesman National Institutes of Health,
Bethesda, MD, United States
Christine Grady National Institutes of Health, Bethesda,
MD, United States
David K. Henderson National Institutes of Health,
Bethesda, MD, United States
Nicholas C. Ide National Institutes of Health, Bethesda, MD,
United States
Jonathan P. Jarow U.S. Food and Drug Administration,
Silver Spring, MD, United States
Laura Lee Johnson U.S. Food and Drug Administration,
Silver Spring, MD, United States
Barbara I. Karp National Institutes of Health, Bethesda, MD,
United States
Phyllis Klein Washington University, St. Louis, MO, United
States
Laura M. Lee National Institutes of Health, Bethesda, MD,
United States
Juan J.L. Lertora Duke University School of Medicine,
Durham, NC, United States
Diane M. Maloney U.S. Food and Drug Administration,
Silver Spring, MD, United States
Patrick McGarey National Institutes of Health, Bethesda,
MD, United States
Amy E. McKee U.S. Food and Drug Administration, Silver
Spring, MD, United States
xiv LIST OF CONTRIBUTORS
Jon W. McKeeby National Institutes of Health, Bethesda,
MD, United States
Theresa Mullin U.S. Food and Drug Administration, Silver
Spring, MD, United States
Charles Natanson National Institutes of Health, Bethesda,
MD, United States
Lynnette Nieman National Institutes of Health, Bethesda,
MD, United States
Robert B. Nussenblatt y National Institutes of Health,
Bethesda, MD, United States
Frederick P. Ognibene National Institutes of Health,
Bethesda, MD, United States
Christopher O. Olopade The University of Chicago,
Chicago, IL, United States
Olufunmilayo I. Olopade The University of Chicago,
Chicago, IL, United States
Valerie L. Prenger National Institutes of Health, Bethesda,
MD, United States
Jillian K. Price Inova Health System, Falls Church, VA,
United States
Michael A. Proschan National Institutes of Health,
Bethesda, MD, United States
Jerry Sachs National Institutes of Health, Bethesda, MD,
United States
Joseph A. Sclafani National Institutes of Health, Bethesda,
MD, United States; Medstar Georgetown University/
National Rehabilitation Network, Washington, DC, United
States
Joe V. Selby Patient-Centered Outcomes Research Institute
(PCORI), Washington, DC, United States
Pamela A. Shaw University of Pennsylvania Perelman
School of Medicine, Philadelphia, PA, United States
Kelly S. Sherman Patient-Centered Outcomes Research
Institute (PCORI), Washington, DC, United States
Pamela C. Sieving Sieving Information Solutions, Bethesda,
MD, United States
y
Deceased.
Amy P.N. Skubitz University of Minnesota, Minneapolis,
MN, United States
Jean R. Slutsky Patient-Centered Outcomes Research
Institute (PCORI), Washington, DC, United States
Julia Slutsman National Institutes of Health, Washington,
DC, United States
Diane C. St Germain National Cancer Institute, National
Institutes of Health, Rockville, MD, United States
Catherine M. Stoney National Institutes of Health,
Bethesda, MD, United States
Stephen E. Straus y National Institutes of Health, Bethesda,
MD, United States
Elyse I. Summers Association for the Accreditation of
Human Research Protection Programs, Inc., Washington,
DC, United States
Junfeng Sun National Institutes of Health, Bethesda, MD,
United States
Michelle Tagle The University of Chicago, Chicago, IL,
United States
Tony Tse National Institutes of Health, Bethesda, MD,
United States
Konstantina M. Vanevski Bayer HealthCare
Pharmaceuticals, Inc., Basel, Switzerland
Paul G. Wakim National Institutes of Health, Bethesda, MD,
United States
Gwenyth R. Wallen National Institutes of Health, Bethesda,
MD, United States
Evelyn P. Whitlock Patient-Centered Outcomes Research
Institute (PCORI), Washington, DC, United States
Rebecca J. Williams National Institutes of Health, Bethesda,
MD, United States
Deborah A. Zarin National Institutes of Health, Bethesda,
MD, United States
 Acknowledgments

The editors extend special thanks to Ms. Jennifer Simmons for her energetic administrative support in coor-
dinating the many activities associated with the development of the fourth edition of this textbook, Ms. Rona
Buchbinder for her dedicated and excellent editorial assistance, and Ms. Kristine Jones, Ms. Molly McLaughlin, and
Mr. Fenton Coulthurst at Elsevier for their patience and perseverance in bringing this huge undertaking to fruition.
Very special thanks to all of the authors who contributed outstanding, up-to-date chapters to this fourth edition and
the numerous patients, study participants, and course participants over the years who inspired them.

xv
 Preface

The positive reactions and feedback to the first three editions of Principles and Practice of Clinical Research have been
appreciated and reinforced the importance of this textbook to the discipline of clinical research. In each edition the
content of the textbook has been updated and new information added. The textbook nearly doubled in size from the
second to the third editions as an expanded and comprehensive section on biostatistics was included. The critical
importance of study design and biostatistics, coupled with enhanced research regulatory requirements prompted the
addition of a new editor, Laura Lee Johnson, PhD. Dr. Johnson has been a colleague for years, having been a faculty
member and currently codirector of the National Institutes of Health (NIH) Clinical Center’s “Introduction to the
Principles and Practice of Clinical Research” (IPPCR) course. After many years at the NIH, she is now Acting Director
of the Division of Biometrics III in the Center for Drug Evaluation and Research at the U.S. Food and Drug
Administration (FDA). She is an extremely welcome addition as the third editor of this textbook.
IPPCR started at the NIH Clinical Center in 1995 and was the impetus for the first edition of this textbook. Currently
IPPCR is a web-based course using recorded lectures by many of the textbook’s authors, online bulletin boards for
each lecture, and local study groups hosted by volunteer institutions around the world. In the 2016e17 academic year
we had over 8,800 registrants at 270 sites around the world. Since its inception the course has had nearly 38,000
participants formally enroll and an even wider audience informally taking the course or watching lectures via YouTube.
In addition, the textbook has been translated into Chinese, Japanese, and Russian and has been used for live intensive
IPPCR courses taught in China, Nigeria, Russia, India, Brazil, and South Africa.
Based on broad international needs and interest in enhancing clinical research infrastructure around the world, this
fourth edition includes an expanded chapter on clinical research in international settings as well as a new chapter
focusing on international regulation of drugs and biologics. It also includes updated content on large clinical trials and
registries as well as a new chapter focusing on the emergence of the important role of comparative effectiveness
research. Since clinical research has become more complex and thus, potentially, more risky, there is a new chapter
devoted to identifying clinical risks and managing patient safety in a clinical research setting. There also is new content
on the use of electronic health records in clinical research and a very detailed presentation of the broad utility and
application of informational resources in clinical research. With the growth of the clinical research enterprise and the
need to ensure that the highest standards are maintained, chapters about accreditation of human research protection
programs, regulatory sciences, and research integrity have been enhanced.
We hope that this book provides its audience with a deeper understanding of the broadening scope of the global
clinical research enterprise. The textbook provides not only details about clinical research mechanics and practical
information but also introduces the reader to the complexities and intricacies of ensuring safe, ethically sound, and
scientifically rigorous clinical research. All clinical investigators must consider the safety of research subjects enrolled
in their investigational protocols while navigating the research pathways from the bedside to the bench and back. We
are proud of this book on so many levels and hope that the passion, expertise, and dynamic quality of our contributors
and their content are appreciated by you, the readers.

John I. Gallin, MD
Frederick P. Ognibene, MD
Laura Lee Johnson, PhD

xvii
 C H A P T E R
A Historical Perspective on Clinical Research
John I. Gallin
National Institutes of Health, Bethesda, MD, United States
O U T L I N E
The Earliest Clinical Research
Greek and Roman Influence
Middle Ages and Renaissance
Seventeenth Century
Eighteenth Century
If I have seen a little further it is by standing on the shoulders
of giants. Sir Isaac Newton (1676).
The successful translation of a basic or clinical
observation into a new treatment of disease is rare in
an investigator’s professional life, but when it occurs,
the personal thrill is exhilarating, and the impact on
society may be substantial. The following historical
highlights provide a perspective of the continuum of
the clinical research endeavor. These events also
emphasize the contributions that clinical research has
made to advances in medicine and public health.
In this chapter, and throughout the book, a broad
definition of clinical research from the Association of
AmericanMedicalCollegesTaskForceonClinicalResearch
is used.1 This task force defined clinical research as
a component of medical and health research intended to
produce knowledge essential for understanding human disease,
preventing and treating illness, and promoting health. Clinical
research embraces a continuum of studies involving interaction
with patients, diagnostic clinical materials or data, or populations,
in any of these categories: disease mechanisms; translational
research; clinical knowledge; detection; diagnosis and natural
history of disease; therapeutic interventions including clinical
trials; prevention and health promotion; behavioral research;
Principles and Practice of Clinical Research
http://dx.doi.org/10.1016/B978-0-12-849905-4.00001-0
1
1 Nineteenth Century 7
2
Twentieth Century and Beyond 11
2
Summary Questions 14
3
4 References 14
health services research; epidemiology; and community-based
and managed care-based research.
THE EARLIEST CLINICAL RESEARCH
Medical practice and clinical research are grounded
in the beginnings of civilization. Egyptian medicine
was dominant from approximately 2850 BC to 525 BC.
The Egyptian Imhotep, whose name means “he who
gives contentment,” lived slightly after 3000 BC and
was the first physician figure to rise out of antiquity.2
Imhotep was a known scribe, priest, architect, astron-
omer, and magician (medicine and magic were used
together); he performed surgery, practiced some
dentistry, extracted medicine from plants, and knew
the position and function of the vital organs. Imhotep
likely provided the first description of cancer in one of
his 48 clinical case reports. In case 45, he reported, “If
you examine (a case) having bulging masses on (the
breast) and you find that they have spread over his
breast; if you place your hand upon (the) breast (and)
find them to be cool, there being no fever at all therein
when your hand feels him; they have no granulations,
1 Copyright © 2018. Published by Elsevier Inc.
2 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
contain no fluid, give rise to no liquid discharge, yet
they feel protuberant to your touch you say concerning
him: ‘This is a case of bulging masses I have to contend
with.’ Bulging tumors of the breast mean the existence
of swellings on the breast, large, spreading, and
hard; touching them is like touching a ball of wrap-
pings, or they may be compared with unripe hemat
fruit, which is hard and cool to the touch.”3
Evidence also shows that ancient Chinese medicine
included clinical studies. For example, in 2737 BC,
Shen Nung, the putative father of Chinese medicine,
experimented with poisons and classified medical
plants,4 and I. Yin (1176e1123 BC), a famous prime min-
ister of the Shang dynasty, described the extraction of
medicines from boiling plants.5
Documents from early Judeo-Christian and Eastern
civilizations provide examples of a scientific approach
to medicine and the origin of clinical research. In the
Old Testament, written from the 15th century BC to
approximately the 4th century BC,6 a passage in the first
chapter of the Book of Daniel describes a comparative
“protocol” of diet and health. In the setting of Babylon
where Israelites defiled the sin of eating rich food,
Daniel described the preferred diet of legumes and
water made for healthier youths compared with the
king’s rich food and wine:
Then Daniel said to the steward.
“Test your servants for ten days; let us be given vegetables to
eat and water to drink. Then let your appearance and the
appearance of the youths who eat the king’s rich food be
observed by you, and according to what you see deal with
your servants.
So he harkened to them in this matter; and tested them for
ten days.
At the end of ten days it was seen that they were better in
appearance and fatter in flesh than all the youths who ate the
king’s rich food. So the steward took away their rich food and
the wine they were to drink, and gave them vegetables.” Daniel
1:11e16
The ancient Hindus excelled in early medicine, espe-
cially in surgery. Sushruta, the father of Indian surgery,
resided in the court of the Gupta kings in about 600
BC and wrote medical texts about surgery, the most
famous being Sushruta Samhita, an encyclopedia of med-
ical learning. In addition, there is evidence of Indian
hospitals in Ceylon in 437 BC and 137 BC.7
GREEK AND ROMAN INFLUENCE
Although early examples of clinical research predate
the Greeks, Hippocrates (460e370 BC) is considered the
father of modern medicine, and he exhibited the strict
discipline required of a clinical investigator.
His emphasis on the art of clinical inspection, observa-
tion, and documentation established the science of
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
medicine. In addition, as graduating physicians are
reminded when they take the Hippocratic oath, he pro-
vided physicians with high moral standards. Hippocrates’
meticulous clinical records were maintained in 42 case re-
cords.8 These case studies describe, among other maladies,
malarial fevers, diarrhea, dysentery, melancholia, mania,
and pulmonary edema with remarkable clinical acumen.
On pulmonary edema, he wrote the following:
Water accumulates; the patient has fever and cough; the
respiration is fast; the feet become edematous; the nails appear
curved and the patient suffers as if he has pus inside, only less
severe and more protracted. One can recognize that it is not pus
but water.if you put your ear against the chest you can hear it
seethe inside like sour wine.9
Hippocrates also described the importance of cleanli-
ness in the management of wounds. He wrote, “If water
was used for irrigation, it had to be very pure or boiled,
and the hands and nails of the operator were to be
cleansed.”10
Hippocrates used the Greek word for “crab,” karkinos,
to describe cancer. The tumor, with its clutch of swollen
blood vessels around it, reminded Hippocrates of a crab
dug in the sand with its legs spread in a circle.11
Hippocrates’ teachings remained dominant and
unchallenged until the time of Claudius Galen of Perga-
mum (c.130e200 AD), the physician to the Roman
Emperor Marcus Aurelius.12 Galen was one of the first in-
dividuals to utilize animal studies to understand human
disease. By experimenting on animals, he was able to
describe the effects of transection of the spinal cord at
different levels. According to Galen, health and disease
reflected the balance of four humors (blood, phlegm,
black bile, and yellow bile), and veins contained blood
and the humors, together with some spirit.12 Inflamma-
tion, described by Galen as a red, hot, and painful
distention, was attributed to excessive blood. Tubercles,
pustules, catarrh, and nodules of lymph, all cool, boggy
and white, were attributed to excesses of lymph. Jaundice
was an overflow of yellow bile. Cancer was attributed to
black bile as was melancholia, the medieval term for
depression. Thus cancer and depression were closely
intertwined.13
MIDDLE AGES AND RENAISSANCE
In the Middle Ages, improvements in medicine
became evident, and the infrastructure for clinical
research began to develop. Hospitals and nursing,
with origins in the teachings of Christ,14 became defined
institutions (although the beginnings of hospitals can be
traced to the ancient Babylonian custom of bringing the
sick into the marketplace for consultation, and the
Greeks and Romans had military hospitals).
 SEVENTEENTH CENTURY 3
The Persian al-Razi (865e925) discovered the use of
alcohol as an antiseptic and wrote the first treatise on
pediatrics, as well as more than 180 books and articles.15
Persian scientists emphasized the importance of meth-
odology, and Ibn al-Haytham (Alhazen) wrote his Book
of Optics, for which he is regarded as the father of
optics.16 The surgical needle was invented and
described by Abu al-Qasim al-Zahrawi in his Al-Tasrif
in the year 1000.17 The Iraqi surgeon Ammar ibn Ali
al-Mawsili invented the first injection syringe in the
9th century using a hollow glass tube and suction to
extract and remove cataracts from patients’ eyes.18 By
the 1100s and 1200s, hospitals were being built in
England, Scotland, France, and Germany.
Early progress in pharmacology can be linked to the
Crusades and the development of commerce. Drug trade
became enormously profitable during the Middle Ages.
Drugs were recognized as the lightest, most compact,
and most lucrative of all cargoes. Records of the custom-
house at the port of Acre (1191e1291) show a lively traffic
in aloes, benzoin, camphor, nutmegs, and opium.19 Influ-
ences of Arabic pharmacy and contact of the Crusaders
with their Muslim foes spread the knowledge of Arabic
pharmaceuticals and greatly enhanced the value of
drugs from the Far East. The Persian Ibn Sina-Avicenna
(980e1037), a leader in pharmacy, philosophy, medicine,
and pharmacology, wrote The Canon of Medicine, which
describes seven conditions for “the recognition of the
strengths of the characteristics of medicines through
experimentation”: ensuring the use of pure drugs, testing
the drug for only one disease, use of control groups, use
of dose escalation, requirement of long-term observation,
requirement of reproducible results, and requirement of FIGURE 1.1 Leonardo da Vinci self-portrait (red chalk); Turin,
human over animal testing.20 Royal Library. From Da Vinci L. Copyright in Italy by the Institute
Geografic DeAgostini S.p.A. e Novara. New York: Reymal & Company;
Documentation through case records is an essential 1956, Fig. 1 [Wikipedia].
feature of clinical research. Pre-Renaissance medicine
of the 14th and 15th centuries saw the birth of “Consilia”
or medical case books, consisting of clinical records from this period was Leonardo da Vinci (1453e1519)
the practice of well-known physicians.21 Hippocrates’ (Fig. 1.1).22 Da Vinci created more than 750 detailed
approach of case studies developed 1700 years earlier anatomic drawings (Fig. 1.2). In 1533, Andreas Vesalius,
was reborn, particularly in the Bolognese and Paduan at age 19, was beginning his incredible career as an anat-
regions of Italy. Universities became important places omist. His dissections and recordings of the human
of medicine in Paris, Bologna, and Padua. anatomy recorded in detailed plates and drawings of
Clinical research remained mostly descriptive, resem- patients with cancer failed to note black bile in any
bling today’s natural history and disease pathogenesis cancer, regardless of the organ involved, and provided
protocols. In 1348, Gentile da Foligno, a Paduan profes- the basis for dismissing Galen’s theory of the role of
sor, described gallstones.21 Bartolomeo Montagna black bile in cancer.23
(1470), an anatomist, described strangulated hernia, oper-
ated on lachrymal fistula, and extracted decayed teeth.21
The Renaissance (1453e1600) represented the revival SEVENTEENTH CENTURY
of learning and the transition from medieval to modern
conditions; many great clinicians and scientists pros- Studies of blood began in the 17th century. William
pered. At this time, many of the ancient Greek dictums Harvey (1578e1657) convincingly described the circula-
of medicine, such as Galen’s four humors, were tion of blood from the heart through the lungs and back
discarded. Perhaps the most important anatomist of to the heart and then into the arteries and back through

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

4 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
FIGURE 1.2 Example of anatomic drawing by Leonardo da Vinci.
Trunk of female human body, with internal organs seen as though
ventral side were transparent. From Da Vinci L. Copyright in Italy by
the Institute Geografic DeAgostini S.p.A. e Novara. New York: Reymal
& Company; 1956. p. 369 [Wikipedia].
the veins.24 Harvey emphasized that the arteries and
veins carried only one substance, the blood, ending
Galen’s proposal that veins carried a blend of multiple
humors. (Of course, today we know that blood contains
multiple cellular and humoral elements, so to some
extent Galen was correct.) The famous architect Sir
Christopher Wren (1632e1723), originally known as an
astronomer and anatomist (Fig. 1.3), in 1656 assembled
quills and silver tubes as cannulas and used animal
bladders to inject opium into the veins of dogs.25 The
first well-documented transfusions of blood were done
in animals (dogs) in 1667 by Richard Lower and
Edmund King in London26 and were mentioned in
Pepys’ diary.27 The first transfusions into humans are
attributed to the French physician Jean-Baptiste Denys
who in June 1667 transfused sheep blood into a 15-
year-old boy who survived. James Blundell performed
the first modern transfusions in humans in 1818, some
of whom survived.28 Transfusions did not become an
accepted approach until Landsteiner discovered the
major A, B, AB, and O blood groups in 1900 and 1901.29
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
FIGURE 1.3 Christopher Wren’s drawing of the brain shows blood
vessels discovered by Thomas Willis. From Knoeff R. Book review of soul
made flash: discovery of the brain and how it changed the world by C.
Zimmer. Nature 2004;427:585.
The 17th century also brought the first vital statistics,
which were presented in Graunt’s book Natural and
Political Observations Mentioned in a Following Index, and
Made Upon the Bills of Mortality.30 In this book of compar-
ative statistics, population and mortality statistics were
compared for different countries, ages, and sexes in
rural and urban areas. Use of data on mortality among
groups would have major importance in future clinical
studies.
EIGHTEENTH CENTURY
The 18th century brought extraordinary advances in
the biological sciences and medicine. At the end of the
17th century, Antony van Leeuwenhoek of Delft
(1632e1723) invented the microscope. Although he is
best known for using his microscope to provide the first
descriptions of protozoa and bacteria, Leeuwenhoek
also provided the first description of striated voluntary
muscle, the crystalline structure of the lens, red blood
cells, and spermatozoa (Figs. 1.4 and 1.5).31
Modern clinical trials can be recognized in the 1700s.
Scurvy was a major health problem for the British Navy.
William Harvey earlier had recommended lemons to
treat scurvy but argued that the therapeutic effect was
a result of the acid in the fruit. James Lind (Fig. 1.6), a
native of Scotland and a Royal Navy surgeon, conducted
a clinical trial in 1747 to assess this hypothesis by
 EIGHTEENTH CENTURY
FIGURE 1.4 Antony van Leeuwenhoek. From Dobell C. Antony
van leeuwenhoek and his little animals. New York, Dover: A Collection of
Writings by the Father of Protozoology and Bacteriology; 1960 [Original work
published in 1932].
comparing three therapies for scurvy (Table 1.1).32
Twelve sailors with classic scurvy were divided into
six groups of two each, all given identical diets; the
various groups were supplemented with vinegar, dilute
sulfuric acid, cider, seawater, and a nutmeg, garlic, and
horseradish mixture, along with two oranges and one
lemon daily.
Sulfuric acid, vinegar, seawater, cider, and the physi-
cian’s remedy had no benefit. Two sailors receiving
citrus fruit avoided scurvy. Although not significant
because of sample size, this early clinical study formed
the basis for successful avoidance of scurvy with citrus
fruit. Studies with sulfuric acid, vinegar, and cider
excluded acid as a likely explanation for the beneficial
effect of citrus fruit.
The 18th century saw great progress in the area of
surgery. A remarkable succession of teachers and their
students led these studies. Percival Pott of St. Bartholo-
mew’s Hospital described tuberculosis of the spine, or
Pott’s disease.33 John Hunter, Pott’s pupil, was the
founder of experimental and surgical pathology and
was a pioneer in comparative physiology and experi-
mental morphology. Hunter described shock, phlebitis,
pyremia, and intussusception and reported major find-
ings of inflammation, gunshot wounds, and surgical
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
5
0*0
PHILOSOPHICAL
TRANSACTIONS.
For the Months of Jng*Ji and Stftemttr.
Stftemt. 21. 1674,
The CONTENTS.
llxnfatictl Qtftrtfttutt firna «#r. Leeuwcnboeck, «fotf
Blood, Milk, Bones, tkt Brain, Spitle, Coticula, Sweat,
Fact, Teares 5 ummtmutei t» t** Letttrs to the PaUfitr.
An AtuHit tf* ntttkU Ctfe if* Dropfy, mfoktn fir Grt-
vibtk* at+yt**g W*mt* ^ imftrttAh* Lttnttd Ptyfoi*
MI* Holland. jfa4tt*at,f three E»hr LDE SE-
CRET IQKE JN-IM.ALI Ctgtutt, 4»tb. Gall.
Co'e, At D. IF. Ertfmi BtrthiM SELECT A
GEO eX£ fR \CA. III. LOG ICJ, fat An
CritoUi; f * Gtllit* i» iMnnu* Strmutem vtrfc SUM
A*t*u&o*rfait *p* tke Latin Verfon, mult by C. S. of the
Pbil.TranUflions*/' J. 1665.1666.1667.
l OtftnnttoKfr** e^C Leeowrahoeck, u#tr»-
*7 Blood, Milk, Bones, /fc Bnio,SpitIe,36^ Cuticula,^.
MmmmtiUAk tkt JUt Obfervtr i» tin fMjbtr in *
Letttr, lUteljUK r. 1674,
Sir,
Ours of 14* of Mrit\a& was my welcome to roe j
Y Wheocelnnd«ftoodwitfj great cooteotfneot, that my
Microfcopical Cooxnookatiom badnot been nnaocepoble co
yoaaod yoor Philofophkal Frkndr; wUcb hath encouraged
R **
FIGURE 1.5 Title page from Leeuwenhoek’s paper, “Microscopical
Observations.” From Dobell C. Antony van leeuwenhoek and his little
animals. New York, Dover: A Collection of Writings by the Father of
Protozoology and Bacteriology; 1960 [Original work published in 1932].
diseases of the vascular system.33 Hunter’s student
Edward Jenner (1749e1823)33 introduced vaccination
as a tool to prevent infectious diseases (Fig. 1.7).34 Jenner
was aware that dairymaids who had contracted cowpox
through milking did not get smallpox. In 1798, Jenner
conceived of applying this observation on a grand scale
to prevent smallpox.35
Jenner was not the first to conceive of the idea of inoc-
ulation for smallpox. The Chinese had thought of this
earlier, and Sir Hans Sloane had done small studies in
1717 using variolation (inoculating healthy people
with pus from blisters obtained from patients with
smallpox).36 In 1718, after providing variolation vaccina-
tion of her 3-year-old son in Turkey and, 3 years later,
her 5-year-old daughter in England, Lady Mary Worley
Montagu introduced the Ottoman practice of variolation
to the West.36 In addition, James Jurin published several
articles between 1723 and 1727 comparing death from
natural smallpox in people who had not been inoculated
versus those who had been inoculated. Jurin showed
that death occurred in 5 of 6 subjects in the first group
compared with 1 in 60 in the latter,37 providing one of
the first studies using mortality as a critical clinical
end point. In 1734, Voltaire wrote, “The Cirassians [a
Middle Eastern people] perceived that of a thousand
6 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

FIGURE 1.6 James Lind. FIGURE 1.7 Edward Jenner (painting by Sir Thomas Lawrence).
From Garrison FH. History of medicine. Philadelphia: Saunders; 1917.
Reprinted 1963.
TABLE 1.1 Treatment of Scurvy by James Lind
Continental Armydthe first massive immunization of
Treatment Arm Cured p-valuea a military group.40 In 1774 Benjamin Jesty, a cattle
Sulfuric acid 0/2 >0.05 breeder in Dorset, England, inoculated his wife and
two sons with cowpox to protect them during an
Vinegar 0/2 >0.05
outbreak of smallpox. Jenner, based on his clinical obser-
Seawater 0/2 >0.05 vation that persons who had cowpox were protected
Cider 0/2 >0.05 from smallpox and his subsequent work showing that
people inoculated with cowpox were protected when
Physicians 0/2 >0.05
challenged with smallpox, was the first to try vaccina-
Citrus fruit 2/2 >0.05 tion on a large scale using scabs from cowpox to protect
a
against human smallpox. Jenner was the first to use
Compared to patients in the five areas of the trial; no placebo group.
experimental approaches to establish the scientific basis
for vaccination and he transformed a local country tradi-
persons hardly one was attacked twice by full blown tion into a viable prophylactic principle. Jenner’s
smallpox; that in truth one sees three or four mild cases vaccine was adopted quickly in Germany and then in
but never two that are serious and dangerous; that in a Holland, Denmark, the rest of Europe, and the United
word one never truly has that illness twice in life.”38 States.
Thus, Voltaire recognized natural immunity to small- The 1700s were also the time when the first known
pox, which was an important concept for future vacci- blinded clinical studies were performed. In 1784 a
nology. In 1721, Cotton Mather demonstrated that commission of inquiry was appointed by King Louis
variolation protected citizens of the American colonies XVI of France to investigate medical claims of “animal
in Massachusetts,39 and, in 1777, George Washington magnetism” or “mesmerism.” The commission, headed
used variolation against smallpox to inoculate the by Benjamin Franklin and consisting of such

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

 NINETEENTH CENTURY
distinguished members as Antoine Lavoisier, Jean-
Sylvain Bailly, and Joseph-Ignace Guillotin, had as a
goal to assess whether reported effects of this new heal-
ing method were due to “real” force or to “illness of the
mind.” Among the many tests performed, blindfolded
people were told that they were either receiving or not
receiving magnetism when in fact, at times, the reverse
was happening. Results showed that study subjects felt
effects of magnetism only when they were told that they
received magnetism and felt no effects when they were
not told this, whether or not they were receiving treat-
ment.41 This was the beginning of the use of blinded
studies in clinical research. In addition to the first
blinded or masked studies, Franklin, for the first time,
also pointed out the importance of the placebo effect.
The 18th century provided the first legal example that
physicians must obtain informed consent from patients
before performing a procedure. In an English lawsuit,
Slater vs. Baker & Stapleton, two surgeons were found
liable for disuniting a partially healed fracture without
the patient’s consent.42 This case set an important prece-
dent described by the court: “Indeed it is reasonable that
a patient should be told what is about to be done to him
that he may take courage and put himself in such a sit-
uation as to enable him to undergo the operation.”
7
of the great Justice Holmes, read his article, “On the
Contagiousness of Puerperal Fever,”46 to the Boston
Society for Medical Improvement (Fig. 1.8). Holmes
stated that women in childbed should never be attended
by physicians who have been conducting postmortem
sections on cases of puerperal fever; that the disease
may be conveyed in this manner from patient to patient,
even from a case of erysipelas; and that washing the
hands in calcium chloride and changing the clothes after
leaving a puerperal fever case was likely to be a preven-
tive measure. Holmes’ essay stirred up violent opposi-
tion by obstetricians. However, he continued to
reiterate his views, and in 1855 in a monograph, Puer-
peral Fever as a Private Pestilence, Holmes noted that
Semmelweis, working in Vienna and Budapest, had less-
ened the mortality of puerperal fever by disinfecting the
hands with chloride of lime and the nail brush.47
Ignaz Philipp Semmelweis (1818e65) performed the
most sophisticated preventive clinical trial of the 19th
century, which established the importance of hand
washing to prevent the spread of infection (Fig. 1.9).48

NINETEENTH CENTURY

In the first days of the 19th century, Benjamin Water-

house, a Harvard professor of medicine, brought Jen-
ner’s vaccine to the United States, and by 1802 the first
vaccine institute was established by James Smith in
Baltimore, Maryland. In 1813 this led to the establish-
ment of a national vaccine agency by the Congress of
the United States under the direction of James Smith.43
Jenner’s vaccination for smallpox was followed by
other historic studies in the pathogenesis of infectious
diseases. In the mid-1800s, John Snow (1813e58), an
anesthesiologist by training, performed the classic
studies that determined how cholera was spread in
contaminated water. Snow’s studies, which included
the first use of statistical mapping, identified contami-
nated water as the source of cholera. For his work,
John Snow is widely considered to be the father of mod-
ern epidemiology.44
The French physician Pierre Charles Alexandre Louis
(1787e1872) realized that clinical observations on large
numbers of patients were essential for meaningful clin-
ical research. He published classical studies on typhoid
fever and tuberculosis, and his research in 1835 on the
effects of bloodletting demonstrated that the benefits
claimed for this popular mode of treatment were unsub-
stantiated.45 On February 13, 1843, one of Louis’ FIGURE 1.8 Oliver Wendell Holmes. From Garrison FH. History of
students, Oliver Wendell Holmes (1809e94), the father medicine. Philadelphia: Saunders; 1917. p. 435. Reprinted 1963.

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

8 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
FIGURE 1.9 Ignaz Philipp Semmelweis. From Garrison FH. His-
tory of medicine. Philadelphia: Saunders; 1917. p. 436. Reprinted 1963.
Semmelweis, a Hungarian pupil, became an assistant in
the first obstetric ward of the Allgemeines Krankenhaus
in Vienna in 1846. Semmelweis was troubled by the
death rate associated with puerperal or “childbed”
fever. From 1841 to 1846, the maternal death rate from
puerperal sepsis averaged approximately 10%, and in
some periods was as high as 50%, in the First Maternity
Division of the Vienna General Hospital. In contrast, the
rate was only 2% or 3% in the Second Division, which
was attended by midwives rather than physicians. The
public knew the disparity, and women feared being
assigned to the First Division. Semmelweis became frus-
trated by this mystery and began to study cadavers of
fever victims. In 1847, his friend and fellow physician
Jakob Kolletschka died after receiving a small cut on
the finger during an autopsy. The risk of minor cuts
during autopsies was well known, but Semmelweis
made the further observation that Kolletschka’s death
was characteristic of death from puerperal fever.
He reasoned that puerperal fever was “caused by
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
conveyance to the pregnant women of putrid particles
derived from living organisms, through the agency of
the examining fingers.” In particular, he identified
cadaveric matter from the autopsy room, with which
midwives had no contact, as the source of the infection.
In 1847 Semmelweis insisted that all students and
physicians scrub their hands with chlorinated lime
before entering the maternity ward, and during 1848,
the mortality rate on his division dropped from 9.92%
to 1.27%. Despite his convincing data, colleagues
rejected Semmelweis’ findings and accused him of
insubordination. The dominant medical thinking at the
time was that high mortality in the charity hospital
was related to the poor health of impoverished women,
despite the differences between control (no chlorinated
lime hand washing) and experimental (washing with
chlorinated lime) divisions. Without any opportunity
for advancement in Vienna, Semmelweis returned to
his home in Budapest and repeated his studies with
the same results. In 1861, he finally published The Etiol-
ogy, Concept, and Prophylaxis of Childhood Fever.48
Although Holmes’ work antedated Semmelweis by
5 years, the superiority of Semmelweis’ observation
lies not only in his experimental data but also in his
recognition that puerperal fever was a blood poisoning.
The observations of Holmes and Semmelweis represent
a critical step for medicine and surgery.
In addition to the discovery of the importance of hand
washing, the first well-documented use of ether for sur-
gery (1846) by William Thomas Green Morton, a Boston
dentist, with Dr. John Collins Warren as the surgeon at
the Massachusetts General Hospital, occurred during
the 19th century.49 The discovery of anesthesia led
to the dissociation of pain from surgery, allowing sur-
geons to perform prolonged operations. Oliver Wendell
Holmes is credited with proposing the words anesthetic
and anesthesia.49 Recognition of the importance of hand
washing and the discovery of anesthetics were essential
findings of the 19th century that were critical in the
development of modern surgery. In 1865, a Scottish sur-
geon named Joseph Lister recognized the importance of
keeping surgical wounds clean and wrote “.that the
decomposition in the injured part might be avoided.by
applying as a dressing some material capable of destroy-
ing the life of the floating particles.” Based on the obser-
vation that carbolic acid cleansed raw storage, Lister
began to apply carbolic acid to wounds with great
success, establishing the importance of antisepsis in
the operating room.50
The work of Holmes and Semmelweis on the impor-
tance of hand washing opened the door for Pasteur’s
work on the germ basis of infectious diseases. Louis
Pasteur (1822e95) was perhaps the most outstanding
clinical investigator of the 19th century (Fig. 1.10). He
was trained in chemistry. His fundamental work in
 NINETEENTH CENTURY 9
bacterial culture and identification easy and widely
available. Koch cultured the tubercle bacillus and iden-
tified the causative agent for anthrax, which was later
used by Pasteur to develop a vaccine, and he established
Koch’s postulates to prove that an infectious agent
causes disease (Fig. 1.11).51
The studies of Pasteur and Koch were performed
during the same period as the work of the Norwegian
Gerhard Armauer Hansen (1841e1912). In 1874, based
on epidemiologic studies in Norway, Hansen concluded
that Mycobacterium leprae was the microorganism
responsible for leprosy. Hansen’s claim was not well
received, and in 1880, in an attempt to prove his point,
he inoculated live leprosy bacilli into humans, including
nurses and patients, without first obtaining permission.
One of the patients brought legal action against Hansen.

FIGURE 1.10 Louis Pasteur. One of the remarkable facts about

Pasteur was his triumph over a great physical handicap. In 1868 at age
46, just after completing his studies on wine, he had a cerebral hem-
orrhage. Although his mind was not affected, he was left with partial
paralysis of his left side, which persisted for the remainder of his life.
This photograph, taken after he was awarded the Grand Cross of the
Legion of Honor in 1881, gives no hint of his infirmity. From Haagensen
CD, Lloyd EB. A hundred years of medicine. New York: Sheridan House;
1943. p. 116.

chemistry led to the discovery of levo and dextro

isomers. He then studied the ferments of microorgan-
isms, which eventually led him to study the detrimental
causes of three major industries in France: wine, silk,
and wool. Pasteur discovered the germ basis of fermen-
tation, which formed the basis of the germ theory of
disease.51 He discovered Staphylococcus pyogenes as a
cause of boils and the role of Streptococcus pyogenes in
puerperal septicemia. In other studies, he carried for-
ward Jenner’s work on vaccination and developed
approaches to vaccine development using attenuation
of a virus for hydrophobia (rabies) and inactivation of FIGURE 1.11 Robert Koch. His career in research began in 1872,
a bacterium for anthrax. when his wife gave him a microscope as a birthday present. He was
The work of Pasteur was complemented by the then 28 years old, performing general practice in a small town in
studies of Robert Koch (1843e1910), who made critical Silesia. This was an agricultural region where anthrax was common
among sheep and cattle, and it was in the microscopic study of this
technical advances in bacteriology. Koch was the first disease in rabbits that Koch made his first great discovery of the role of
to use agar as a culture medium, and he introduced anthrax bacilli in disease. From Haagensen CD, Lloyd EB. A hundred
the Petri dish, pour plates, and blood agar to make years of medicine. New York: Sheridan House; 1943. p. 132.

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

10 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
The court, in one of the early cases demonstrating the
importance of informed consent in clinical research,
removed Hansen from his position as director of Lepro-
sarium No. 1, where the experiments had taken place.
However, Hansen retained his position as chief medical
officer for leprosy52 and later in his life received world-
wide recognition for his life’s work on leprosy.
In the same era, Emil von Behring (1854e1917)
demonstrated in 1890 that inoculation with attenuated
diphtheria toxins in one animal resulted in production
of a therapeutic serum factor (antitoxin) that could be
delivered to another, thus discovering antibodies
and establishing a role for passive immunization. On
Christmas Eve of 1891, the first successful clinical use
of diphtheria antitoxin occurred.51 By 1894, diphtheria
antiserum became commercially available as a result of
Paul Ehrlich’s work establishing methods of producing
high-titer antisera. Behring’s discovery of antitoxin
was the beginning of humoral immunity, and in 1901
Behring received the first Nobel Prize. Koch received
the Prize in 1905 (Fig. 1.12).
The Russian scientist Elie Metchnikoff (1845e1916)
discovered the importance of phagocytosis in host-
defense against infection and emphasized the
FIGURE 1.12 Emil von Behring. From Hirsch JG. Host resistance to
infectious diseases: a centennial. In: Gallin JI, Fauci AS, editors. Advances
in host defense mechanisms: vol. 1. Phagocytic cells. New York: Raven
Press; 1982. p. 7.
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
importance of cellular components of host defense
against infection.53 Paul Ehrlich (1854e1915) discovered
the complement system and asserted the importance of
the humoral components of host defense. In 1908,
Metchnikoff and Ehrlich shared the Nobel Prize
(Figs. 1.13 and 1.14).
At the end of the 19th century, studies of yellow fever
increased awareness of the importance of the informed
consent process in clinical research. In 1897, Italian
bacteriologist Giuseppe Sanarelli announced that he
had discovered the bacillus for yellow fever by injecting
the organism into five people. William Osler was present
at an 1898 meeting at which the work by Sanarelli was
discussed, and Osler said, “To deliberately inject a
poison of known high degree of virulency into a human
being, unless you obtain that man’s sanction.is crim-
inal.”54 This commentary by Osler had substantial influ-
ence on Walter Reed, who demonstrated in human
volunteers that the mosquito is the vector for yellow
fever. Reed adopted written agreements (contracts)
with all his yellow fever subjects. In addition to obtain-
ing signed permission from all his volunteers, Reed
FIGURE 1.13 Elie Metchnikoff in his 40s. From Tauber AI, Chernyak
L. Metchnikoff and the origins of immunology. New York: Oxford
University Press; 1991, Fig. 5 [Wikipedia].
 TWENTIETH CENTURY AND BEYOND
FIGURE 1.14 Paul Ehrlich. From Hirsch JG. Host resistance to
infectious diseases: a centennial. In: Gallin JI, Fauci AS, editors. Advances
in host defense mechanisms: vol. 1. Phagocytic cells. New York: Raven
Press; 1982. p. 9.
made certain that all published reports of yellow fever
cases included the phrase “with his full consent.”54
On November 8, 1895, Wilhelm Röntgen (1845e1923),
a German physicist, produced and detected electromag-
netic radiation, and on December 22, 1895, he took the
first X-ray of his wife’s hand. For this achievement,
Röntgen won the first Nobel Prize in Physics in 1901
(Fig. 1.15A and B).
Toward the end of the 19th century, women began to
play important roles in clinical research. Marie Curie
(1867e1934) and her husband Pierre won the Nobel
Prize in Physics in 1903 for their work on spontaneous
radiation; in 1911 Marie Curie won a second Nobel Prize
(in chemistry) for her studies on the separation of
radium and description of its therapeutic properties.
Marie Curie and her daughter Irene Joliot-Curie (who
won a Nobel Prize in Chemistry in 1935 for her work
synthesizing new radioactive elements leading to the
discovery of uranium fission) promoted the therapeutic
use of radium during World War I (Fig. 1.16).55
Florence Nightingale (1820e1910), in addition to her
famous work in nursing, was an accomplished mathe-
matician who applied her mathematical expertise to
dramatize the needless deaths caused by unsanitary
conditions in hospitals and the need for reform
(Fig. 1.17).56
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
11
TWENTIETH CENTURY AND BEYOND
The spectacular advances in medicine that occurred
during the 20th century would never have happened
without centuries of earlier progress. In the 20th century,
medical colleges became well established in Europe and
the United States. The great contributions of the United
States to medicine in the 20th century are linked to an
early commitment to strong medical education. The
importance of clinical research as a component of
the teaching of medicine was recognized in 1925 by
the American medical educator Abraham Flexner, who
wrote, “Research can no more be divorced from medical
education than can medical education be divorced from
research.”57
Two other dominant drivers of progress in medicine
through clinical research were government investment
in biomedical research and private investment in the
pharmaceutical industry. These investments, closely
linked with academia, resulted in enhanced translation
of basic observations to the bedside. Paul Ehrlich coined
the term “chemotherapy” and popularized the concept
of a “magic bullet” (chemicals injected into the blood
to fight various diseases, particularly those caused by
parasites). Ehrlich, in 1910, working with his assistant
Sahachiro Hata, developed Salvarsan (arsphenamine),
a trivalent arsenic-based chemotherapeutic to cure syph-
ilis. Salvarsan and later Neosalvarsan were commercial-
ized by Hoechst AG as one of the first pharmaceuticals
(antibiotics). Sir Alexander Fleming’s discovery of peni-
cillin in 1928 in Scotland spawned expansion of the
pharmaceutical industry through the development of
antibiotics, antiviral agents, and new vaccines. The
Canadian physician Frederick Banting and medical
student Charles Best’s discovery of insulin in 1921 was
followed by their collaboration with the Canadian
chemist James B. Collip who assisted with purification
of insulin from cows for use in humans and then
the Scottish physiologist J.J.R. Macleod’s confirmatory
studies on use of insulin in humans provided life-
saving long-standing management of diabetes for which
Banting and Macleod won the Noble Prize in Physiology
and Medicine in 1923. The discovery of insulin was fol-
lowed by the discovery of multiple hormones to save
lives.
In the 1920s and 1930s, Sir Ronald Aylmer Fisher
(1890e1962), from the United Kingdom, introduced
the application of statistics and experimental design.58
Fisher worked with farming and plant fertility to intro-
duce the concepts of randomization and analysis of
variancedprocedures used today throughout the world.
In 1930, Torald Sollmann emphasized the importance to
a study of controlled experiments with placebo and
blind limbsda rebirth of the “blinded” or “masked”
12 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

FIGURE 1.15 (A) Wilhelm Conrad Röntgen. (B) Print of Wilhelm Röntgen’s first X-ray of his wife’s hand.

FIGURE 1.16 Marie Curie (1867e1934). FIGURE 1.17 Florence Nightingale (1820e1910).

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

 TWENTIETH CENTURY AND BEYOND
studies originated by Benjamin Franklin in 1784.
Sollmann wrote, “Apparent results must be checked
by the ‘blind test,’ i.e., another remedy or a placebo,
without the knowledge of the observer, if possible”
(Fig. 1.18). He said “Observations without adequate
controls and checks are practically useless.”59 Through
these approaches, many new drugs for treatment of
hypertension, cardiovascular disease, manic depression,
and epilepsy, to name a few, were developed.
The spectacular advances of the 20th century were
associated with troubling events in clinical research
that heightened public attention and formalized the field
of clinical bioethics. Nazi human experimentation led to
the Nuremberg Code in 1947, which was designed to pro-
tect human subjects by ensuring voluntary consent of
the human subject and by asserting that the anticipated
result of research must justify its performance. The Tus-
kegee syphilis experiments initiated in the 1930s and
continued until 1972 in African American men and the
Willowbrook hepatitis studies of the mid-1950s in chil-
dren with Down syndrome highlighted the need to
establish strict rules to protect research patients.
In 1953 the US National Institutes of Health (NIH)
issued “Guiding Principles in Medical Research
Involving Humans,” which required prior review by a
medical committee of all human research to be conduct-
ed at the newly opened NIH Clinical Center. In 1962, the
Kefauver-Harris amendment to the 1938 US Federal
Food, Drug, and Cosmetics Act stipulated that subjects
must be told whether a drug is being used for investiga-
tional purposes and that subject consent must be
obtained. In 1964, the World Medical Assembly adopted
FIGURE 1.18 Testing puddings and gelatins at Consumers Union.
Copyright 1945 by Consumers Union of U.S., Inc., Yonkers, NY. Reprinted
with permission from the April 1945 issue of Consumer Reports.
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
13
the Declaration of Helsinki, stressing the importance of
assessing risks and determining that risks are out-
weighed by potential benefits of research. In 1966, Henry
Beecher pointed out major ethical issues in clinical
research.60 During the same year, the US Surgeon Gen-
eral issued a memo to the heads of institutions con-
ducting research with Public Health Service grants
requiring prior review of all clinical research. The
purposes of this review were to ensure protection of
research subjects, to assess the appropriateness of
methods employed, to obtain informed consent, and to
review risks and benefits of the research; thus institu-
tional review boards were established. In 1967, the U.S.
Food and Drug Administration added the requirement
that all new drug sponsors must obtain informed con-
sent for use of investigational drugs in humans.
Over the past 50 years, clinical research has become
big business. The pharmaceutical and biotechnology
industries have engaged university-based clinical inves-
tigators in the business of clinical research. For example,
in the United States interaction between federal investi-
gators and industry, encouraged by the US Congress
when it passed the Federal Technology Transfer Act in
1986, has successfully increased the translation of basic
research to the bedside by US government scientists.
At the same time, however, the relationship between
industry and academia has grown closer, and new
ethical, legal, and social issues have evolved worldwide.
Clinical investigators have become increasingly associ-
ated with real and perceived conflicts. Examples of these
issues include promoting an investigator’s financial or
career goals while protecting the patient, protecting
“unborn children” while pursuing the potential use of
embryonic stem cells to rebuild damaged organs, and
protecting patient confidentiality as a result of gene
sequencing. As a consequence of these issues, the public
has engaged in debate about the well-being of current
and future generations of patients who volunteer to
partner with a clinical investigator on protocols.
The 20th century saw incredible advances in geno-
mics, including the Nobel prizes to Watson and Crick
for the description of the double helix model of DNA61
and to Barbara McClintock for her work in the 1940s
for studies of corn indicating an organism’s genome is
not a stationary entity, but rather is subject to alteration
and rearrangement through transposable elements or
jumping genes.62 In the 1970s Janet Rowley discovered
that translocation between chromosome 8 and 21 caused
acute myelogenous leukemia and between chromosome
15 and 17 caused promyelocytic leukemia.63 These and
other genomic and molecular discoveries have provided
opportunities for conducting clinical research in the 21st
century that are greater than ever. A new urgency to
move clinical research findings from the laboratory
to the patient and into the community has prioritized
14 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
translational research globally. Today, understanding
and meeting public concerns is as important for the clin-
ical investigator as performing the clinical study. Princi-
ples for conducting clinical research have evolved from
centuries of experience. As the science moves forward,
ethical, legal, and social issues pose special challenges
for the clinical investigator. These challenges are the
focus of the following chapters of this book.
SUMMARY QUESTIONS
1. The definition of clinical research embraces a
continuum of studies in which of these following
categories? (More than one item can be selected.)
a. Behavioral research
b. Health services research
c. Epidemiology
d. Disease mechanisms
e. Translational research
f. Diagnosis and natural history of disease
g. Therapeutic interventions including clinical
trials
h. Prevention and health promotion
i. Community-based and managed care-based
research
j. All of the above
2. True or False: Although early examples of clinical
research predate the Greeks, Galen (AD 129 216) is
considered the father of modern medicine, and he
exhibited the strict discipline required of a clinical
investigator.
3. Ignaz Semmelweis performed the most sophisticated
preventive clinical trial of the 19th century, which
established the importance of hand washing. Circle
all of the following statements related to Semmelweis’
work that are true: (More than one item can be selected.)
a. Semmelweis started his career as a student on an
obstetric ward
b. The death rate from puerperal sepsis reached 90%
in select maternity divisions
c. The second division used midwives and the death
rate was only 2%e3%
d. Semmelweis started his work by studying
cadavers
e. Semmelweis introduced hand washing with
chlorinated lime to decrease mortality rates
f. Despite convincing data, Semmelweis’ work was
condemned by colleagues
4. The first blinded clinical study was done by which of
the following?
a. Hippocrates
b. Galen
c. James Lind
d. Benjamin Franklin
e. Louis Pasteur
I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH
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27. Nicolson MH. Pepys’ diary and the new science. Charlottesville: Uni-
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 P A R T I

ETHICAL, REGULATORY AND

LEGAL ISSUES
 C H A P T E R

2
Ethical Principles in Clinical Research
Christine Grady
National Institutes of Health, Bethesda, MD, United States

O U T L I N E

Distinguishing Clinical Research From Clinical Value and Validity 23

Practice 19 Fair Subject Selection 24
Ethics and Clinical Research 20 Favorable Risk/Benefit Ratio 25
Independent Review 25
History of Ethical Attention to Clinical Research 20
Benefit to the Individual 20 Informed Consent 26
Benefit to Society 20 Respect for Enrolled Subjects 27
Protection of Research Subjects 21
Ethical Considerations in Randomized Controlled
Research as a Benefit 21
Trials 27
Community Involvement in Research 21
Codes of Research Ethics and Regulations 22 Conclusion 29

Research on Bioethical Questions 23 Summary Questions 29

Ethical Framework for Clinical Research 23 References 30

Clinical research has resulted in significant benefits
for society, yet continues to pose profound ethical ques-
tions. This chapter briefly describes: five overlapping
but distinct eras reflecting the history of clinical research
ethics; codes of research ethics; and seven ethical
principles that guide clinical research ethics and partic-
ular ethical challenges in randomized controlled trials
(RCTs).
DISTINGUISHING CLINICAL RESEARCH
FROM CLINICAL PRACTICE
Clinical research involves the study of human beings
in a systematic investigation of health and illness,
designed to develop or contribute to generalizable
knowledge. The goal of clinical research is to gather
knowledge through a set of activities that tests
hypotheses and permits generalizable conclusions use-
ful in understanding human health and illness,
improving medical care or the public health, and devel-
oping safe and effective interventions to prevent, diag-
nose, and treat disease. As such, research serves the
common or collective good; the individual subject
participating in clinical research may or may not benefit
from participation.
Clinical research is distinct from clinical practice in
that each has different, yet not mutually exclusive, pur-
poses, goals, and methods.1 Clinical practice involves
diagnosis, prevention, treatment, and care for a partic-
ular individual or group of individuals with the goal
of meeting the health needs of and benefiting that indi-
vidual(s). Clinical practice is based on evidence or expe-
rience, is designed to enhance the patient’s well-being,
and has a reasonable expectation of success. Usual
methods in clinical practice are evidence-based and

Principles and Practice of Clinical Research

http://dx.doi.org/10.1016/B978-0-12-849905-4.00002-2 19 Copyright © 2018. Published by Elsevier Inc.
20 2. ETHICAL PRINCIPLES
guided by standard practice and experience. The risks of
interventions or procedures employed in clinical prac-
tice are justified by the prospect of therapeutic benefit
to the individual. In contrast, clinical research aims to
generate useful knowledge and is not designed to
meet the health needs of, nor necessarily to benefit, indi-
vidual patient participants. Although an individual may
receive quality patient care and treatment when partici-
pating in research, this is not the goal of research, and
much research does not directly benefit individual par-
ticipants. Further, frequently used research methodolo-
gies, such as randomization, blinding, dose escalation,
placebo controls, and others are rarely found and might
be considered unacceptable, in clinical practice. In clin-
ical research, some risk is justified by the importance
of the knowledge to be gained rather than benefit to
the individual participant.
ETHICS AND CLINICAL RESEARCH
Two fundamental ethical questions regarding clinical
research are important to consider: (1) why should we
do research with human beings and (2) how should it
ethically be done? Two competing considerations frame
these questions: clinical research is valuable in generating
practical knowledge useful for advancing or improving
medical care and health, yet respect for the rights,
welfare, dignity, and freedom of choice of individual
humans is indispensable. Research with human beings
is essential to advancing or improving medical care
and/or the public health and providing health profes-
sionals with the knowledge and evidence necessary to
appropriately and safely care for patients. The pursuit
of knowledge through research should be rigorous to
inform effective and safe clinical practice, and progress
would not be possible without rigorous clinical research.
Conducting clinical research designed to enhance the
understanding of human health and illness may be
more than a social good; arguably it is a social impera-
tive.2 Although progress in medical care and health is a
societal good, some contend it is an optional good,3 and
that other considerations, such as the primacy of the indi-
vidual, should take precedence. Whether improvement
in medical care or health through clinical research is an
option or an imperative, limits are necessary. Human
research participants are the means to securing practical
knowledge, but because people should not be treated
“merely [as] means to an end, but always as ends in
themselves,”4 the need to respect and protect human
research participants is paramount.
The primary ethical tension in clinical research,
therefore, is that a few individuals are asked to accept
some research burden, risk, or inconvenience to benefit
I. ETHICAL, REGULATORY, AND LEGAL ISSUES
others, including future persons and society. Ethical re-
quirements aim to minimize the possibility of exploit-
ing research participants by ensuring that they are
treated with respect while contributing to the genera-
tion of knowledge, and their rights and welfare are
protected throughout the process of research.
HISTORY OF ETHICAL ATTENTION TO
CLINICAL RESEARCH
Throughout history, perception and acceptance of the
methods, goals, and scope of clinical research have
evolved significantly, as have attention to and apprecia-
tion of what respecting and protecting research partici-
pants entails. A brief detour through the history of
clinical research illustrates these changing perspectives.5
Benefit to the Individual
Historically and for hundreds of years, there was little
basis for a distinction between experimentation and
therapy because most therapy was experimental, and
systematic evidence of the effectiveness of medical inter-
ventions was rare. Experimental therapies were used in
the hopes of benefiting ill patients, but such “therapy”
frequently contributed to or caused morbidity or mortal-
ity. Systematic research was sporadic. Most researchers
were medical practitioners, motivated to do what they
thought best for their patients, and trusted to do the
right thing. Fraud and abuse were minimized to some
extent through peer censorship because no specific
codes of ethics, laws, or regulations governed the
conduct of research. Early regulations, such as the
Pure Food and Drug Act of 1906 in the United States,
prohibited unsubstantiated claims on medicine labels.
Yet, research began to grow as an enterprise only after
the development of early antibiotics like penicillin and
the passage of the Food, Drug, and Cosmetic Act in
1938, which required evidence of safety before a product
was marketed.6
Benefit to Society
Around the time of World War II, there was a
dramatic shift in clinical research with tremendous
growth in the research enterprise. Pharmaceutical
companies were established; large amounts of both
public and private money were devoted to research;
and research became increasingly centralized, coordi-
nated, standardized in method, and valued. Human
subjects research entered what has since been described
as an “unashamedly utilitarian phase.”7 Individuals
often were included in research because they were
 HISTORY OF ETHICAL ATTENTION TO CLINICAL RESEARCH
available, captive, and marginalized, and they were
seen as making a contribution to society. The federal
government and the pharmaceutical industry sup-
ported intensive research efforts to develop vaccines
and antibiotics for infectious diseases to help soldiers,
as infectious diseases were a significant problem for
the armed services.
During this era, research was commonly conducted in
prisons, orphanages, and homes for the emotionally or
developmentally disturbed, as well as with other institu-
tionalized groups. The distinction between research and
therapy was fairly clear; subjects not necessarily in need
of therapy were accepting a personal burden to make a
contribution to society. A utilitarian justification served
as the basis of claims that some individuals could be
used for the greater common good. Revelations of Nazi
medical experiments and war crimes, and the Nurem-
berg trial of Nazi doctors, raised public and professional
concerns about the justification and scope of research
with human subjects.8
Protection of Research Subjects
In the late 1960s and early 1970s in the United States,
shock and horror at stories of abuse of human subjects
led to intense scientific and public scrutiny and reflec-
tion, and debate about the scope and limitations of
research involving human subjects. A renowned
Harvard anesthesiologist, Henry Beecher, published a
landmark article in the New England Journal of Medicine
in 19669 highlighting ethical problems in 22 research
studies conducted in reputable US institutions.
Exposition of studies such as the hepatitis B studies at
Willowbrook, the U.S. Public Health Service Tuskegee
syphilis studies, and others generated intense public
attention and concern. Congressional hearings and
action led to passage of the 1974 National Research
Act (PL 93e348) and establishment of the US National
Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research.10 This extremely
influential body authored multiple reports and recom-
mendations about clinical research, including reports
on research with children and on institutional review
boards (IRBs). Included in its legacy is the Belmont
Report, in which ethical principles underlying the
conduct of human subject research and their application
are explained.11 The Commission’s work emphasized
the need to protect individuals participating in research
from potential exploitation and harm, and provided the
basis for subsequent federal regulations codified in 1981
in Title 45, US Code of Federal Regulations (USCFR),
Part 46 (45CFR46), titled “Protection of Human
Subjects,” and similar FDA regulations (21 CFR.50 and
56). In 1991, the Department of Health and Human
I. ETHICAL, REGULATORY, AND LEGAL ISSUES
21
Services (DHHS) regulations became the currently oper-
ative Common Rule,12 which governs the conduct of hu-
man subjects research funded by 17 US federal agencies.
The major thrust of these federal regulations and of
many existing codes of research ethics continues to be
protection of subjects from the burdens and harms of
research.
Research as a Benefit
Events in the late 1980s and 1990s altered some public
perspectives on clinical research. Certain articulate and
vocal activists asserted that research participation can
offer an advantage that individuals want access to, rather
than simply harm to be protected from.13 According to
this perspective, as espoused by human immunodefi-
ciency virus (HIV) and breast cancer activists and others,
participation in research is a benefit, protectionism is
discrimination, and exclusion from research can be un-
just. Empirical studies have demonstrated that oncology
patients, for example, who participate in clinical trials
benefit through improved survival.14,15 Activism and
changes in public attitudes about research led to substan-
tive changes in the way research is done and drugs are
approved.
In addition to the possible benefits of participation for
individuals, it was claimed that certain traditionally
underrepresented groups were being denied the bene-
fits of the application of knowledge gained through
research.16 Since 1994, the US National Institutes of
Health (NIH) has required that those who receive
research funding must include previously underrepre-
sented women and ethnic minorities.17 Since 1998,
NIH guidelines have required the inclusion of children
in research or justification for their exclusion.18
Community Involvement in Research
In subsequent years, the growth of genetics
research, research with stored biospecimens and
data, and international collaborative research, in
particular, have highlighted the value of greater
public and community involvement in research. Clin-
ical research does not occur in a vacuum but is a
collaborative social activity that requires the support
and investment of involved communities; and it also
comes with inherent risks and potential benefits for
communities and groups. As such, involvement of
the community (1) in helping to set research prior-
ities, (2) in planning and approving research, (3) in
evaluating risks and benefits during and after a trial,
and (4) in influencing particular aspects of recruit-
ment, informed consent, and the realization of com-
munity benefits demonstrates respect for the
community and can facilitate successful research.
22 2. ETHICAL PRINCIPLES
CODES OF RESEARCH ETHICS AND
REGULATIONS
Throughout this history, several influential docu-
ments have helped to shape our sense of the contours
of ethical research (Table 2.1). Most were written in
response to specific crises or historical events, yet all
have accepted an underlying assumption that research
as a means to progress in medical care or health is a so-
cial good. The Nuremberg Code, a 10-point code on the
ethics of human experimentation, was written as the
concluding part of the judgment at the Nuremberg Trials
(1949).19 Established in response to Nazi experimenta-
tion, the Nuremberg Code recognized the potential value
of research knowledge to society but emphasized the ab-
solute necessity of voluntary consent of the subject. The
Nuremberg Code established that ethical research must
prioritize the rights and welfare of the subject. Most sub-
sequent codes and guidelines for the ethical conduct of
research have maintained this emphasis and all have
incorporated requirements for informed consent. The
Declaration of Helsinki was developed by the World Med-
ical Assembly (WMA) in 1964 as a guide to the world’s
physicians involved in human subject research.20 The
Declaration of Helsinki recognizes that some, but not all,
medical research is combined with clinical care and em-
phasizes that patients’ participation in research should
not put them at a disadvantage with respect to medical
care. The Declaration of Helsinki also recognizes legiti-
mate research with people who cannot give their own
informed consent, such as children and the cognitively
impaired, but for whom informed permission could be
obtained from a legal guardian. The Declaration of Hel-
sinki has had considerable influence on the formulation
of international, regional, and national legislation and
regulations governing clinical research. The Declaration
of Helsinki has been revised multiple times by the
WMA (1975, 1983, 1989, 1996, 2000, 2008, and 2013)
TABLE 2.1 Selected Codes and US Regulations Guiding Clinical
Research
• The Nuremberg Code (1949)
• The World Medical Association Declaration of Helsinki (1964, 1975,
1983, 1989, 1996, 2000, 2008, and 2013)
• The National Commission’s Belmont Report (1979)
• CIOMS International Ethical Guidelines for Biomedical Research
Involving Human Subjects (1982, 2002, 2015)
• International Conference on Harmonization Guidelines for Good
Clinical Practice (1996)
• Title 45, USCFR, Part 46, “The Common Rule”
• Title 21, USCFR, Part 50 (“Protection of Human subjects”) and 56
(“Institutional Review Boards”)
I. ETHICAL, REGULATORY, AND LEGAL ISSUES
and is considered a living document. Certain provi-
sions of the Helsinki Declaration, such as posttrial
obligations and the use of placebo controls, have
been topics of continued debate among international
researchers.
The Belmont Report, published by the US National
Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research, describes three
broad ethical principles that guide the conduct of
research and form the “basis on which specific rules
could be formulated, criticized, and interpreted.”11
These three principles are respect for persons, benefi-
cence, and justice. Respect for persons requires respect
for the autonomous decision-making of capable individ-
uals as applied in the process of informed consent and
also calls for protection of those with diminished auton-
omy. Beneficence requires protecting individuals from
deliberate and unnecessary harm, as well as maximizing
benefits and minimizing harms, and is applied to clin-
ical research through careful risk/benefit evaluation.
Justice demands a fair distribution of the benefits and
burdens of research and is applied in the Belmont Report
to fairness in the processes and outcomes of selecting
research subjects.
In 1982, the Council of International Organizations of
Medical Sciences (CIOMS), in conjunction with the
World Health Organization (WHO), issued International
Ethical Guidelines for Biomedical Research Involving Human
Subjects, which were revised in 1993, 2002, and 2015.21
The CIOMS guidelines acknowledge that background
circumstances sometimes differ between low- and
middle-income and high-income countries, and there
may be differences in the primacy of focus on the indi-
vidual and individual rights. CIOMS set out to apply
the Helsinki principles to the “special circumstances of
many technologically developing countries.” CIOMS
adopted the three ethical principles spelled out in the
US National Commission’s Belmont Report and main-
tains most of the tenets of Nuremberg and Helsinki
but has provided additional and valuable guidance
and commentary on externally sponsored research and
research with vulnerable populations. The 2015 revision
restructures and expands many previously existing
guidelines and adds new guidelines on compensation
for research-related injury, research with stored bio-
specimens and data, and implementation science,
among others.21
Federal regulations found in Title 45, USCFR, Part 46
(45CFR46),12 were promulgated in 1981 for research
funded by DHHS (formerly the Department of Health,
Education, and Welfare), and at Title 21 USCFR, Part
50 and 56 for the U.S. Food and Drug Administration
(FDA).22 FDA regulations are similar, but not identical,
to those found in the Common Rule.23 Compliance
with these and other FDA regulations is required for
 ETHICAL FRAMEWORK FOR CLINICAL RESEARCH
research investigating FDA-regulated products, such as
drugs, biologics, and medical devices.
DHHS regulations were extended in 1991 as the Fed-
eral Common Rule, applicable to research funded by
17 US federal agencies (not including the FDA). Based
on recommendations of the National Commission, the
Common Rule stipulates both the membership and the
function of IRBs, and the criteria that an IRB should
apply when reviewing a research protocol to determine
whether to approve it. The Common Rule also delin-
eates the information that should be included in an
informed consent document, how consent should be
documented, and criteria for waiver or alteration of
informed consent. Subparts B, C, and D of 45CFR46
describe additional protections for DHHS-funded
research with fetuses and pregnant women, prisoners,
and children, respectively. In 2017, a final revision to
the Common Rule was published in the Federal Register,
with the most extensive changes to the Common Rule
since 1991.24
The International Conference on Harmonization
(ICH) sought to harmonize regulatory guidelines for
product registration trials for the United States, the Eu-
ropean Union, and Japan. The ICH Good Clinical Prac-
tice (GCP) (E-6) Guidelines provide widely accepted
guidance promoting the ethical conduct of research
and reporting of accurate and reliable data.25 The World
Health Organization produced good clinical research
guidelines that incorporated ICH-GCP and also
included types of clinical research beyond drug-
registration trials.26 Good clinical practice guidelines
are being adopted by countries around the world to
guide the conduct of research.
RESEARCH ON BIOETHICAL QUESTIONS
The historical evolution of clinical research ethics and
the development of guidelines and regulations was
largely in response to particular events or scandals.
The Nuremberg Code, for example, was a response to
atrocities performed by Nazi research doctors during
World War II; the formation of the National Commission
for the Protection of Human Subjects of Biomedical and
Behavioral Research was in response to revelations of
the U.S. Public Health Service syphilis studies in Tuske-
gee. Our systems for protection of human subjects, the
focus of the ethics of clinical research, and the existing
regulations grew out of these efforts. Another essential
way to inform our thinking about the ethics of clinical
research, and one that has gained traction in recent de-
cades, is research on bioethical questions. Bioethics
research is usually conducted using one or more of the
following methodologies: historical inquiry, conceptual
analysis, empirical studies, or policy analysis.27 For
I. ETHICAL, REGULATORY, AND LEGAL ISSUES
23
example, bioethics research on voluntariness, an essen-
tial part of informed consent, could better our under-
standing of what voluntariness means and how to
maximize it in the process of informed consent. Such
research might include an analysis of the concept.
Recognizing that all decisions and actions can be influ-
enced by one’s understanding, previous experiences,
religion and culture, and the influences of respected
others, distinguishing what makes a choice sufficiently
voluntary from a choice that is controlled is important.
Conceptual bioethics research also might examine the
concepts of coercion, undue influence, and manipula-
tion, which are different possible controlling influ-
ences.28 Empirical research might seek to elucidate
how people actually choose research participation,
what sources of influence and pressure they identify,
whether they perceive they could say no to participation
and under what circumstances, experiences of manipu-
lation or undue influence, and other phenomena. Re-
quirements for rigorous and ethical research on topics
in bioethics are similar to those for ethical clinical
research.
ETHICAL FRAMEWORK FOR CLINICAL
RESEARCH
A systematic framework of principles for ethical clin-
ical research was derived from guidance provided in
various ethical codes, guidelines, literature, and
bioethics research. This proposed framework of princi-
ples is meant to apply sequentially and universally to
clinical research.29 According to this framework, ethical
clinical research should satisfy the following require-
ments: social or scientific value, scientific validity, fair
subject selection, favorable risk/benefit ratio, indepen-
dent review, informed consent, and respect for enrolled
subjects30 (Table 2.2). Each will be described briefly.
Value and Validity
The first requirement of ethical research is that the
research question must be worth askingdthat is, have
potential social, scientific, or clinical value. The antici-
pated usefulness of knowledge to be gained in under-
standing or improving health or health care is the crux
of determining valuednot whether study results are
positive or negative. A study should have sufficient so-
cial value to justify asking individuals to assume risk or
inconvenience in research and to justify the expenditure
of resources.31 A valuable research question then ethi-
cally requires validity and rigor in research design and
implementation to produce valid, reliable, interpretable,
and generalizable results. Poorly designed researchdfor
24 2. ETHICAL PRINCIPLES
TABLE 2.2 Ethical Framework for Clinical Research
Principles of Ethical Clinical
Research Description
Value Research poses a clinically,
scientifically, or socially valuable
question that will contribute to
generalizable knowledge about
health or will be useful in
improving health. Research is
responsive to health needs and
priorities.
Validity The study has an appropriate and
feasible design and end points,
rigorous methods, and a feasible
strategy to ensure valid and
interpretable data.
Fair subject selection The process and outcomes of
subject and site selection are fair
and are based on scientific
appropriateness, minimization of
vulnerability and risk, and
maximization of benefit.
Favorable risk/benefit ratio Study risks are justified by
potential benefits and the value of
the knowledge. Risks are
minimized and benefits are
enhanced to the extent possible.
Independent review Independent evaluation of
adherence to ethical guidelines in
the design, conduct, and analysis
of research.
Informed consent Clear processes for providing
adequate information to and
promoting the voluntary
enrollment of subjects.
Respect for enrolled participants Study shows respects for the
rights and welfare of participants
both during and at the conclusion
of research.
example, with an inappropriate design, inadequate po-
wer, insufficient or sloppy data, or inappropriate or un-
feasible methodsdis harmful because human and
material resources are wasted and individuals are
exposed to risk for no benefit.30
Fair Subject Selection
Fair subject selection requires that subjects be chosen
for participation in clinical research based first on the
scientific question, balanced by considerations of risk,
benefit, and vulnerability. As described in the Belmont
Report, fairness in both the processes and the outcomes
of subject selection prevents exploitation of vulnerable
individuals and populations and promotes equitable
distribution of research burdens and benefits. Fair
I. ETHICAL, REGULATORY, AND LEGAL ISSUES
procedures means that investigators should identify
groups or individuals who would be appropriate for sci-
entific reasonsdthat is, for reasons related to the prob-
lem being studied and justified by the design and the
particular questions being askeddnot because of their
easy availability or manipulability, or because subjects
are favored or disfavored.11 Extra care should be taken
to justify the inclusion of vulnerable subjects, as well
as to justify excluding those who stand to benefit from
participation. Exclusion without adequate justification
can be unfair; therefore, eligibility criteria should be as
broad as possible, consistent with the scientific objec-
tives and the anticipated risks of the research. Distribu-
tive justice is concerned with a fair distribution of
benefits and burdens, thus expected benefit and burden
in a particular study is an important consideration for
subject selection. Scientifically appropriate individuals
or groups may be fairly selected consistent with atten-
tion to equitably distributing benefits and burdens, as
well as minimizing risks and maximizing benefits.
Persons are considered vulnerable when their ability
to protect or promote their own interests is compro-
mised, often because of an impaired capacity to provide
informed consent. Although disagreement remains
about the meaning of vulnerability in research and
who is actually vulnerable,32 there is support for the
idea that among scientifically appropriate subjects, the
less vulnerable should be selected first. For example,
an early drug safety study should be conducted with
adults before children, and with consenting adults
before including those who cannot consent.
Certain groups, such as pregnant women, fetuses,
prisoners, and children, are further protected by specific
regulations requiring additional safeguards in research.
According to US regulations, determination of the
permissibility of research with children depends on the
level of research risk and the anticipated benefits.
Accordingly, (1) research that poses minimal risk to
children is acceptable, (2) research with more than mini-
mal risk must be counterbalanced by a prospect of direct
therapeutic benefit for the children in the study, (3) for
research with small amounts of additional risk (minor
increment over minimal), but without the prospect of
direct therapeutic benefit for the children can sometimes
be justified by the importance of the question for children
with the disorder under study, or (4) research without a
prospect of benefit that poses greater than minimal risk
to participating children can only be conducted if
approved by a special panel convened by the US Secre-
tary of the DHHS.33 Enrolling children in research also
requires permission from their parents or legal guard-
ians, along with the child’s assent whenever possible.
Fair subject selection also requires considering the
outcomes of subject selection. For example, if women,
minorities, or children are not included in studies of a
 ETHICAL FRAMEWORK FOR CLINICAL RESEARCH
particular intervention, then study results may be diffi-
cult to apply to these groups in practice, and interven-
tions could actually be harmful. Therefore, study
populations recruited for research should be representa-
tive of the populations likely to use the strategies tested
in the research.34
Similarly, it has been argued that justice requires sub-
jects to be among the beneficiaries of research. This
means that subjects should be selected as participants
in research from which they or others like them can
benefit and should not be asked to bear the burdens of
research from which they can reap no benefits. This un-
derstanding of justice has raised important and chal-
lenging questions in the conduct of collaborative
international research. Some have argued that if an
experimental drug or vaccine is found effective in a
certain tested population, there should be prior assur-
ance that population will have access to the drug or vac-
cine.35 Alternatively, subjects or communities should be
assured of and involved in negotiation about fair bene-
fits derived from research that are not necessarily
limited to the benefits of available products of
research.36
Favorable Risk/Benefit Ratio
The ratio of risks to benefits in research is favorable
when risks are justified by benefits to participants or to
society, and when research is designed in a way that
minimizes risk and enhances benefit for participating
subjects. The ethical principle of beneficence obliges
that we (1) protect people from deliberate or unneces-
sary harm and (2) maximize possible benefits and mini-
mize possible harms. A widely accepted principle states
that one should not deliberately harm another individ-
ual regardless of the benefits that might be made avail-
able to others as a result. However, as the Belmont
Report reminds us, offering benefit to people and avoid-
ing harm requires learning what is of benefit and what is
harmful, even if in the process some people may be
exposed to the risk of harm. To a great extent, clinical
research is an activity designed to learn about the bene-
fits and harms of unproven methods of diagnosing, pre-
venting, treating, and caring for human beings. The
challenge for clinical investigators and review/over-
sight groups is to decide in advance when it is justifiable
to seek certain benefits despite the research risks, what
level of risk is acceptable, whether risks have been mini-
mized to the extent possible, and when it is better to
forego the possible benefits because of the risks. This is
called a risk/benefit assessment.
The calculation and weighing of risks and benefits in
research can be complicated. When designing a study,
investigators consider whether the inherent risks are
I. ETHICAL, REGULATORY, AND LEGAL ISSUES
25
justified by the expected value of the information and
any possible benefit to the participants. Studies should
be designed so that risks to participants are minimized
and benefits are enhanced. When reviewing a study,
an IRB identifies possible risks and benefits and deter-
mines whether the relationship of risks to benefits is
favorable enough that the proposed study should go for-
ward or instead be modified or rejected. When review-
ing studies with little or no expected benefit for
individual subjects, the IRB determines whether the
anticipated risks or burdens to study subjects are justi-
fied only by the potential value of the knowledge to be
gained, a particularly challenging risk/benefit assess-
ment. Prospective subjects make their own risk/benefit
assessment of whether the risks of participating in a
given study are acceptable to them and are worth their
participation.
A risk/benefit assessment can include consideration
of many types of risks and benefits, including physical,
psychological, social, economic, and legal. For example,
in a genetics study, physical risks may be limited to a
blood draw or a buccal swab, so assessment of potential
psychological and social risks is more important. Inves-
tigators, reviewers, and potential subjects may not only
have dissimilar perspectives about research but also are
likely to assign different weights to risks and benefits.
For example, IRBs consider only health-related benefits
of the research in justifying risks, whereas subjects are
likely to consider access to care and financial compensa-
tion as important benefits that may tip the balance in
favor of participation. Acknowledging that risk/benefit
assessment is not a straightforward or easy process does
not in any way diminish its importance. An important
step in evaluating the ethics of clinical research involves
not only careful attention to potential benefits to individ-
uals or society of a particular study in relation to its
risks, but also consideration of the risks of not con-
ducting the research.
Independent Review
Independent review is a process that allows evalua-
tion of the research for adherence to established ethical
guidelines by individuals with varied expertise and no
personal or business interests in the research. For most
clinical research, this independent review is carried
out by an IRB or research ethics committee (REC). Using
criteria detailed in US federal regulations,12,22 IRBs eval-
uate the value of doing the study, the risks involved, the
fairness of subject selection, whether the risks have been
sufficiently minimized and are justified, and the plans
for obtaining informed consent; they then decide
whether to approve a study, with or without modifica-
tions, to table a proposal for major revisions or more
26 2. ETHICAL PRINCIPLES

information, or to disapprove a study as unacceptable TABLE 2.3 The Process of Informed Consent
(See also Chapter 4).
Informed Consent Considerations and
Independent review of the risks of proposed research
Elements Description Challenges
by someone other than the investigator has been described
as a “central protection for research participants.”37 None- Disclosure of Information about There is a need to
theless, there is concern that the current IRB system in the information the study based on a balance the goal of being
“reasonable” person comprehensive with
United States is outdated given the current profile of clin- standard is disclosed attention to the amount
ical research, and also is bureaucratic, beset with con- to prospective and complexity of
flicts, and in need of reform.38 Both the 2017 revisions participants. information, to give
to the Common Rule and recent NIH policy require sin- Disclosure takes into participants the
gle IRB review for domestic multisite studies.24,39 account subjects’ information they need
language, education, and facilitate
familiarity with understanding.
research, and cultural
values. Both written
Informed Consent information
and discussion are
Once a proposal is deemed valuable, valid, with
usually provided.
acceptable risks in relation to benefits and fair subject se-
lection, individuals are recruited and are asked to give Understanding Knowledge of study Empirical data show
purpose, risks, that participants often
their informed consent. The process of informed consent
benefits, alternatives, do not have a good
shows respect for persons and their autonomy, giving and requirements. understanding of the
prospective subjects the opportunity to make autono- details of the research.
mous decisions about participating and remaining in
Voluntary decision- Free from coercion Many possible
research, and respecting their choices about participa- making and undue influence. influences affect
tion. We show lack of respect when we do not provide Subject is free to participants’ decisions
the necessary information to make a considered judg- choose not to enroll. about enrolling in
ment, pressure an individual to make a particular judg- research. Avoid
controlling influences.
ment or deny him or her the freedom to act on
judgments. The process of informed consent involves: Authorization Usually given by a For some individuals or
disclosure of study information, comprehension of the signature on a written communities, requiring
consent document. a signature reflects lack
information, voluntariness with respect to the decision,
of appreciation for their
and authorization40 (Table 2.3). Information provided culture or literacy level.
to subjects about a research study should be adequate,
according to a “reasonable volunteer” standard,
balanced, and presented in an understandable manner. and complex, and large amounts of information may
Information should be provided in the language of the actually hinder subject understanding. Scientific infor-
subject, at an appropriate level of complexity given the mation is often complex; research methods are unfamil-
subject’s age, educational level, and culture. US federal iar to many people; and subjects have varying levels of
regulations detail the types of information that should education, understanding of science, and knowledge
be included in informed consent12,22; this is essentially about their diseases and treatments, and are dissimilar
information that a reasonable person needs to know to in their willingness to enter into dialogue. Besides the
make an informed decision about initial or ongoing amount and detail of information, understanding may
research participation. Ideally, individuals receive the be influenced by who presents the information and the
necessary information, understand it, process it in the setting. In some cases, information may be more acces-
context of their own situation and life experiences, and sible to potential subjects if presented in group sessions
make a “voluntary” choice free from coercion or undue or through print, video, or other media presentations.
influence. The process of initial research informed con- Determining whether a subject has the capacity to
sent usually culminates with the signing of a consent consent and understands the particular study informa-
form. However, respect for persons requires that sub- tion is challenging. Capacity to provide consent is study
jects continue to be informed throughout a study and specific. Individuals who are challenged in some areas of
are free to modify or withdraw their consent at any time. decision-making may still be capable of consenting to a
Although widely accepted as central to the ethical particular research study. Similarly, individuals may
conduct of research, achieving informed consent is chal- not have the capacity to consent to a particular study,
lenging. Determining the appropriate amount and even if generally able to function in other areas of their
complexity of information for disclosure is not straight- lives. Assessing capacity might take into account an indi-
forward. Written consent documents have become long vidual’s educational level and familiarity with science

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

 ETHICAL CONSIDERATIONS IN RANDOMIZED CONTROLLED TRIALS
and research, as well as evidence of cognitive or
decisional impairment. In some but not all cases, mental
illness, depression, sickness, desperation, or pain may
interfere with a person’s capacity to understand or
process information. Empirical research on informed
consent shows that participants do not always have a
good understanding of the purpose or potential risks of
the research studies for which they gave their consent.41
Informed consent to participation in research should
be voluntary, and free of controlling influences, coercion
and undue influence.40 Terminal or chronic illness,
exhaustion of other treatment options, and lack of health
insurance may limit a participant’s options but do not
necessarily render decisions involuntary. Payment and
other incentives, trust in health care providers, depen-
dence on the care of clinicians, family pressures, and
other factors commonly influence decisions about
research participation. Most of the time, these are
acceptable influences, but some worry that under certain
circumstances, they can become controlling. Given these
multiple factors, it is important to ensure that prospec-
tive subjects have and perceive that they have the option
to say no to research participation and to do so with
impunity.
Research has demonstrated that active and ongoing
dialogue and discussion between the research team
and subjects, opportunities to have questions answered,
waiting periods between the presentation of information
and the actual decision to participate, the opportunity to
consult with family members and trusted others, a clear
understanding of alternatives, and other strategies can
serve to enhance the process of informed consent.42,43
Respect for Enrolled Subjects
Research participants deserve continued respect after
enrollment, throughout the duration of the study, and
when the study ends. Respect for subjects is demon-
strated through appropriate clinical monitoring and
attention to participants’ well-being throughout the
study. Adverse effects of research interventions and
any research-related injuries should be treated. Private
information collected about subjects should be handled
confidentially, and participants informed about the
limits of confidentiality. Research subjects should be
reminded of their right to withdraw from the research
at any time without penalty. A change in clinical status
or life circumstances, as well as new information from
the study or other studies, may be relevant to a person’s
willingness to continue participation. Investigators
should make plans regarding the end of the trial,
including participants’ continued access to successful
interventions when indicated and to study results after
the study is finished.
I. ETHICAL, REGULATORY, AND LEGAL ISSUES
27
In summary, ethical clinical research is conducted ac-
cording to the seven principles delineated in Table 2.2.
Application of these principles to specific cases will al-
ways involve judgment and specification on the part of
investigators, sponsors, review boards, and others
involved in clinical research.
ETHICAL CONSIDERATIONS IN
RANDOMIZED CONTROLLED TRIALS
RCTs remain the principal method and “gold stan-
dard” for demonstrating safety and efficacy in the devel-
opment of new drugs and biologics, and other
interventions. An RCT has several characteristic fea-
tures: RCTs are controlled, randomized, and usually
blinded, and the significance of the results is determined
statistically according to a predetermined algorithm. An
RCT typically involves comparison of two or more inter-
ventions (e.g., Drug A vs. Drug B) to demonstrate that
they are similar or that one is superior in the treatment,
diagnosis, or prevention of a specific disorder. RCTs pre-
sent a spectrum of unique ethical problems (Table 2.4).
“In considering the RCT, the average IRB member
must be baffled by its complexity and by the manifold
problems it represents.”44
The ethical justification to begin an RCT is usually
described as that of “an honest null hypothesis,” also
often referred to as equipoise or clinical equipoise.45 In an
RCT comparing interventions A and B, clinical equipoise
is satisfied if there is no convincing evidence about the
relative merits of A and B (e.g., evidence that A is
more effective than or less toxic than B). The goal of an
RCT is to provide credible evidence about the relative
value of each intervention. Equipoise rests on a thera-
peutic commitment that patients should not receive a
treatment known in advance to be inferior, nor should
they be denied effective treatment that is otherwise
available. Doubt based on lack of evidence about which
intervention is superior justifies giving subjects an equal
chance to get either one and makes it ethically acceptable
to assign half or some portion of subjects to different
treatments provided in an RCT. There remains some
disagreement about the meaning, justification, and
application of equipoise in clinical research. Some argue
that equipoise is based on a mistaken confluence of
research with therapy and therefore should be
abandoned.46
Another controversy in RCTs involves what should
count as “convincing” evidence. Some worry that the
common acceptance of statistical significance at the
P ¼ .05 level potentially discounts clinically significant
observations. Statisticians recently criticized overreli-
ance and misuse of the p-value, reiterating that it cannot
28 2. ETHICAL PRINCIPLES

TABLE 2.4 Selected Ethical Considerations in Randomized Another important scientific and ethical consider-
Controlled Trials (RCTs) ation in RCTs is the selection of outcome variables by
which the relative merits of an intervention will be
Features
of RCTs Description Considerations determined. Different conclusions may be reached
depending on whether the efficacy of an intervention
Equipoise No convincing How to factor in early is a measure of survival or of tumor shrinkage, symp-
evidence that one evidence? Does a
intervention is better requirement for
toms, surrogate end points, quality of life, or some com-
(i.e., more effective or equipoise conflate posite measure. The choice of end points in a clinical
less toxic) than research and therapy? trial is never simply a scientific decision.
another. In an RCT, subjects are assigned to treatment through
Choice of control Appropriate choice Choice of control is not a process of randomization, rather than on the basis of
of control is necessary simply a scientific individual needs and characteristics. The goal of
for scientific validity decision. Placebos as random assignment is to control for confounding vari-
and generalizability. controls require ethical ables by keeping two or more treatment arms similar
justification.
in relevant and otherwise uncontrollable aspects. Also,
Randomization Random assignment Random assignment RCTs are often single blind (subject does not know
decreases bias and does not allow for which intervention he or she is receiving) or double
controls for many autonomous
factors. preferences.
blind (both subject and investigator are blinded to the
intervention). Random assignment and blinding are
Blinding Single or double Research participants methods used in clinical trials to reduce bias and
blinding is often consent to temporarily
used to decreases suspend knowledge of
enhance study validity. Although compatible with the
bias. which intervention goals of an RCT, random assignment to treatment and
they are receiving. In blinding to treatment assignment may seem incompat-
rare cases, a blind may ible with the best interests or autonomy interests of the
need to be broken to patient-subject. In some placebo-controlled blinded
manage certain clinical
problems.
studies, both subjects and investigators can guess (often
because of side effects) whether they are receiving active
Sharing preliminary As evidence Study monitors, drug or placebo, potentially thwarting the goal of
information accumulates independent data and
information about safety monitoring
reducing bias.49 The necessity and adequacy of blinding
risks and benefits committees monitor and randomization should be assessed in the design and
may change, and data to help determine review of each proposed research protocol. When
equipoise may be when the study should randomization and blinding are deemed useful and
disturbed. be stopped or altered, appropriate for a particular protocol, two ethical con-
or information should
be shared with
cerns remain: (1) preferences for an intervention and in-
participants. formation about which intervention a subject is
receiving may be relevant to autonomous decisions
and (2) information about which intervention the subject
is receiving may be important in managing an adverse
event or a medical emergency. With respect to the first
tell you the probability that results are true or due to concern, subjects should be informed about the purpose
random chance, but only the probability of seeing re- of the research and should be asked to consent to
sults given a particular hypothetical explanation.47 Peo- random assignment and a temporary suspension of
ple also disagree about the extent to which preliminary knowledge about which intervention they are receiving.
data, data from previous studies, data from uncontrolled To balance the need for scientific objectivity with respect
studies and pilot studies, and historical data do or for a research subject’s need for information to make
should influence the balance of evidence. In some cases, autonomous decisions, investigators should provide
the existence of these other types of data may make equi- subjects with adequate information about the purpose
poise impossible. However, data from small, uncon- and methods of randomization and blinding. Subjects
trolled, or observational studies can lead to false or are asked to consent to a suspension of knowledge about
inconclusive impressions about safety or efficacy. RCTs their treatment assignment until completion of the pro-
are usually monitored by data and safety monitoring tocol or some other predetermined point, at which
committees who see data at specified time points during time they should be informed about which intervention
the trial and can recommend altering or stopping a trial they received in the clinical trial.
based on prespecified boundaries for safety, efficacy, or In some cases, knowledge of which medications a
futility.48 subject is receiving may be important in the treatment

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

Another random document with
no related content on Scribd:
glad of the people who come in. But, here we have all nations
and all kinds, and if they were to get burgher rights quickly
then that would be the end of our independence, and then they
could send us away where they liked. I would like His
Excellency to bear that in mind.

"His Excellency.—I do not see how the old burghers can have it
both ways. They cannot have a very large population streaming
in to develop the resources of the country, and giving it a
much higher position in the world than it would otherwise
have, and at the same time exclude these people from
participation in the Government of the country.

"President.—Your Excellency must bear this in mind. There is

no Gold Law in the world that is so liberal as that of the
Republic."

The President then recurred to the right which the Uitlanders

might obtain, of voting for the Second Volksraad after two
years, and becoming eligible to seats in it after four years,
and said that it was in the Second Volksraad that their own
interests were dealt with—not in the First. The High
Commissioner asked if the Second Raad could act without
consent of the First. The President acknowledged that the
latter could alter any law which "appears to be against the
general welfare," but contended that it had no wish to go into
gold field matters, though it has the power, and that it had
interfered with action of the Second Rand in but three or four
instances. The High Commissioner remarked that Uitlanders who
abandoned their own nationality to wait years for full
citizenship in the Republic might have the latter prospect
taken away from them at any moment by a single resolution of
the First Raad. The President replied: "They haven't done it
yet. The legislatures of all the world have the same power."
To which the High Commissioner made answer: "This power
existing, the new comers cannot be expected—I should not
recommend one of them—to give up his present citizenship for
 the mere chance of becoming a citizen of the new country."

{484}

"His Excellency.—If the President thinks we are asking too

much … I must report to Her Majesty's Government that the
President rejects our friendly suggestions.

"The President.—I would be misleading you if I should tell you

that I can give all the strangers the franchise in a very
short time. I would consider that our independence was
sacrificed thereby: but I say this, let His Excellency keep
impartially in view my points of difficulty, and let him make
his proposals and submit them to us, so that we can consider
them and judge about them. … I have already said that perhaps
means may be found to alter the form of oath. … I would now
like His Excellency to propose a scheme.

"His Excellency.— … What I suggest is this: That every

foreigner who can prove satisfactorily that he has been
resident in the country for five years, and that he desires to
make it his permanent place of residence, that he is prepared
to take the oath to obey the laws, to undertake all the
obligations of citizenship, and to defend the independence of
the country, should be allowed to become a citizen on taking
that oath. This should be confined to persons possessing a
certain amount of property, or a certain amount of yearly
wages, and who have good characters. In order to make that
proposal of any real use for the new citizens who mostly live
in one district in the Republic, and a district which only
returns one member in 28 to the First Raad, and one in 28 to
the Second Raad, I propose that there should be a certain
number of new constituencies created, the number of which is a
detail upon the discussion of which I will not now enter. But
what is vital from my point of view is that the number of
these districts should not be so small as to leave the
representatives of the new population in a contemptible
minority.

"President.—With us the majority of the enfranchised burghers

constitutes the ruling voice, and must be listened to in the
Volksraad. If the 60,000 came in immediately, they would swamp
the 30,000. … I mean this: that if they are all enfranchised then
they would at once form the majority of the whole population,
and the majority of enfranchised burghers, according to our
law, must be listened to by the Volksraad; since in a Republic
we cannot leave the sovereign voice out of account.

"His Excellency.—This is pure theory, that the Volksraad have

to do what the majority of the people desire. The Volksraad
does what it considers right in its own eyes; it is elected by
the people, and does what it thinks right, and the President has
made it quite clear during the last year or two that anything
the Volksraad does is law."

At an afternoon meeting on the same day, there was a long

discussion of the dynamite grievance of the Uitlanders, and
the President wished to bring up other points; but the High
Commissioner objected:

"His Excellency.—I think the discussion will be of

interminable length if we are to proceed in this way, and if
we cannot approach one another on the point on which I have
made my suggestions, and which lies outside all the pending
questions between the two Governments, these other
controversies may as well be allowed to go on in the usual
course. If the President to-morrow will give me an answer on
the first subject I raised, and then wishes to bring forward
his grievances, I will consider them to-morrow. I do not want
to go on with a long list of my own until I understand what is
the basis on which I stand in regard to what I consider the
most important question of all.

"President.—I think it would be as well if we returned in a

little while to discuss our points, but I would like to give
His Excellency some things to think over. The first point I
would like to mention is my wish that Swaziland should now be
handed over to me as a portion of my land. … Secondly, the
demand made with regard to the damages for the Jameson Raid,
Mr. Chamberlain said he was against paying the million, but he
is not against paying the expenses incurred. Thirdly, that
differences such as those now existing between us, should be
settled by arbitration, and then no war or quarrel could arise
between us. … These are some of the questions I wish His
Excellency to think about."

At the opening of the Conference on the third day, the

President sought to commit the High Commissioner to an
"understanding," that "if we came," he said, "to some
agreement on the franchise Her Majesty's Government then would
engage not in any way to concern itself with internal affairs in
the Republic any longer, and that in future questions that
then may arise, whether out of the Convention or otherwise,
Her Majesty would agree to have such questions referred to
arbitration." The High Commissioner declined to deal with the
subject of the franchise as a matter of "bargain." It was a
subject of grievances and discontent, dangerous to the
Republic and dangerous to the relations between the Republic
and Great Britain, which ought to be dealt with on its merits
alone. Nevertheless, after some controversy, he said:

"His Excellency.— … As far as the Jameson Indemnity is

concerned I know that a despatch is on the way to me at this
present moment, which forwards a statement from the British
South Africa Company examining the details of the claim which
has been sent in, and asking that the question of the amount
payable in respect of the Raid may be submitted to
arbitration. I have received a telegram that that despatch is
coming. The position is this—the British Government have
admitted in principle that the Company must pay what is fairly
due on account of that raid; but the question of the amount is
 still under discussion, and I hope that this proposal will lead
to a settlement. As to the question of arbitration, which I
think is the matter that interests the President most, I am in
so far entirely with him that I want if possible to have in
future as few questions to discuss with the Government of the
South African Republic, as I now have with the Government of
the Orange Free State. I feel that the President will need, if
he accepts my scheme of franchise, or any other similar
proposal, to have some assurance that there shall not be
perpetual controversies between him and England, and that if
there are controversies, some regular way of dealing with them
should be devised.
{485}
The President once proposed that some question, or a number of
questions, should be submitted to the President of the Swiss
Republic. The British Government refused that on the general
principle—from which I am sure they will not depart—that they
will not have any foreign Government, or any foreign
interference at all, between them and the South African
Republic. But if some other method can be devised of
submitting to an impartial tribunal questions that may in
future arise between us, and perhaps even some questions which
exist at present—but in any case to provide for the future—if
such a plan can be devised and suggested to me, I will lay it
before Her Majesty's Government and do what I can personally
to assist in a satisfactory solution of the matter. The
President must understand that I cannot pledge Her Majesty's
Government in any way on this subject. The question has taken
me by surprise; I didn't come here contemplating a discussion
on it, but I must say if it could be satisfactorily arranged
while excluding the interference of the foreigner, it would
seem to me to open a way out of many difficulties. But all the
same, I adhere firmly to my proposal that we should first try
and settle on the scheme which the President would accept as
regards the matter which I put forward."

At the close of the morning interview, both parties expressed

hopelessness of agreement. On meeting again in the afternoon,
the President submitted in writing the following proposals
concerning the franchise: "As the purpose I had in view at
this Conference principally consists in the removal of
existing grounds of disagreement and further to provide for
the friendly regulation of the way of settling future disputes
by means of arbitration, the following proposals with regard to
the franchise must be considered as conditional and dependent
on the satisfactory settlement of the first mentioned points,
and on the request that my request to incorporate Swaziland in
the South African Republic shall be submitted by the High
Commissioner to Her Majesty's Government. Subject to the
foregoing I undertake to submit without delay to the approval
of the Volksraad and the people the following proposals about
the franchise:

"I. Every person who fixes his residence in the South African
Republic has to get himself registered on the Field-cornets'
books within fourteen days after his arrival according to the
existing law; will be able after complying with the conditions
mentioned under 'A.,' and after the lapse of two years to get
himself naturalised; and will five years after naturalisation,
on complying with the conditions mentioned under 'B.,' obtain
the full franchise.

"A.—
1. Six months' notice of intention to apply for naturalisation;
2. Two years' continued registration;
3. Residence in the South African Republic during that period;
4. No dishonouring sentence;
5. Proof of obedience to the laws; no act against Government
or independence;
6. Proof of full State citizenship and franchise or title
thereto in former country;
7. Possession of unmortgaged fixed property to the value of
£150 approximately, or occupation of house to the rental of
£50 per annum, or yearly income of at least £200. Nothing,
however, shall prevent the Government from granting
naturalisation to persons who have not satisfied this
condition;
8. Taking of an oath similar to that of the Orange
Free State.

"B.—
1. Continuous registration five years after naturalisation;
2. Continuous residence during that period;
3. No dishonouring sentence;
4. Proof of obedience to the laws, &c.;
5. Proof that applicant still complies with the condition A(7).

"II. Furthermore, the full franchise shall be obtained in the

following manner:—
(a.)
Those who have fixed their residence in the South African
Republic before the taking effect of Act 4, 1890, and who get
themselves naturalised within six months after the taking
effect of this Act on complying with the conditions under 1A,
shall obtain the full franchise two years after such
naturalisation on proof of compliance with the conditions
mentioned under 1B (altering the five into two years). Those
who do not get themselves naturalised within six months under
Article 1,
(b.)
Those who have been resident in the South African Republic for
two years or more can get themselves immediately naturalised
on compliance with the conditions under 1A., and shall five
years after naturalisation obtain the full franchise on
compliance with the conditions under 1B.
(c.)
Those who have been already naturalised shall five years after
naturalisation obtain the full franchise on compliance with
the conditions under 1B."

At the meeting next day, the High Commissioner presented to

 the President a written memorandum in reply to the proposals
of the latter. He admitted that "the scheme proposed is a
considerable advance upon the existing provisions as to
franchise," but said that he could not recommend its
acceptance as adequate to the needs of the case. "Under this
plan," he continued, "no man who is not already naturalised,
even if he has been in the country 13 or 14 years, will get a
vote for the First Volksraad in less than 2½ years from the
passing of the new law. There will be no considerable number
of people obtaining that vote in less than five years, that is
if they come in and naturalise. But I fear the majority of
them will not come in, because the scheme retains that
unfortunate provision, first introduced in 1890, by which,
owing to the two stages—first, naturalisation with a partial
franchise, and then, after five years, full franchise—a man
has to abandon his old citizenship before he becomes a
full-fledged citizen of his new country. My plan avoided this.
My doctrine is that, however long a period of residence you
fix before a man becomes a citizen of your State, you should
admit him, once for all, to full rights on taking the oath of
allegiance. And this is especially important in the South
African Republic, because, owing to the facility and frequency
with which laws—even fundamental laws—are altered, the man who
takes the oath and thereby loses his old country will never
feel quite sure that something may not happen in the interval,
when he is only half a citizen, to prevent his becoming a whole
one. The vote for the First Volksraad is the essential point.
According to the present constitution of the Transvaal, the
First Volksraad and the President really are the State. But
under this scheme it will be a considerable time before any
number of Uitlanders worth mentioning can vote for the First
Volksraad, and even then they will only command one or two
seats. My point was to give them at once a few
representatives. They might be a minority, even a small
minority.
{486}
I have said over and over again I do not want to swamp the old
burghers. But as long as the representatives of the new comers
are entirely excluded from the supreme legislative council,
they will, as a body, remain an inferior caste. The
co-operation and gradual blending of the two sections of the
population will not take place. The old separation and
hostility will continue. I see no prospect here of that
concord to which I had looked both to bring about a more
progressive system of government, and to remove causes of
friction between the Government of the South African Republic
and Great Britain. For these reasons I regret to say the
scheme seems to me so inadequate that I think it would be
wasting the time of the Conference to discuss its details."

The President rejoined in another memorandum, which added one

more to his former proposals, namely this: "I am ready to
propose and to recommend to the First Volksraad to increase
the number of members of the First Volksraad, whereby the Gold
Fields will be represented by five, instead of as now by two,
members."

The response to this by the High Commissioner was a review, at

length, of all that had been proposed, leading to the
conclusion which he expressed as follows:

"If I am asked whether I think they will satisfy the Uitlander

community, and are calculated to relieve the British
Government from further solicitude on the score of its
Uitlander subjects, I cannot answer in the affirmative. Still
less can I encourage the idea that the British Government can
be asked to give something in exchange for such legislation
as the President proposes. My own proposal was put forward in
no bargaining spirit. I asked myself, in advancing it, what is
the smallest measure of reform that will really be of any use,
that is to say, which will allay the present unrest and enable
the Uitlanders to exercise within a reasonable time an
appreciable influence on the Government of the country. It was
in that spirit that I suggested the outline of a scheme,
 intentionally not working it out in detail (for I was ready to
listen as to details), but indicating a certain minimum from
which I am not prepared to depart. … When I came here I came
in the hope that I might be able to report to Her Majesty's
Government that measures were about to be adopted which would
lead to such an improvement in the situation as to relieve Her
Majesty's Government from pressing for the redress of
particular grievances on the ground that the most serious
causes of complaint would now gradually be removed from
within. I do not feel that what His Honour has seen his way to
propose in the matter of franchise or what he indicates as the
extreme length to which he might, at some future time, be
willing to go in the extension of local government is
sufficient to justify me in reporting in that sense."

The Conference was ended by a last memorandum from the

President, in which he said: "As it is my earnest wish that
this Conference should not be fruitless, I wish to make the
following proposal to His Excellency, viz.:—As according to
his own admission my proposal about franchise is an important
step in the right direction, I shall be prepared to lay my
proposal before the Volksraad and to recommend it, even though
His Excellency does not fully agree with it. From his side I
shall then expect that His Excellency will lay before and
recommend to Her Majesty's Government my request about
arbitration on future matters of difference under the
Convention. His Excellency will, however, readily understand
that if Her Majesty's Government should not meet me so far, so
as to grant my acknowledged fair request for arbitration, it
could be with difficulty expected that the people of the South
African Republic would approve of my comprehensive proposal
with regard to franchise."

Great Britain,
Papers by Command: 1899, C. 9404.

SOUTH AFRICA: The Transvaal: A. D. 1899 (May-August).

Advice to President Kruger from Cape Afrikanders, and
from Holland and Germany.

Several private letters written at the time of these

occurrences by Sir J. E. De Villiers, a leading Afrikander,
Chief Justice of Cape Colony, and one of the Commissioners who
negotiated the Convention of 1881, addressed to persons who
might have influence with President Kruger, were made public a
year later. In the first of these letters, written to
President Steyn of the Orange Free State, on the 21st of May,
1899, Justice De Villiers used strong expressions, as follows:
"On my recent visit to Pretoria I did not visit the President
as I considered it hopeless to think of making any impression
on him, but I saw Reitz, Smuts, and Schalk Burger, who, I
thought, would be amenable to argument, but I fear that either
my advice had no effect on them, or else their opinion had no
weight with the President. I urged upon them to advise the
President to open the Volksraad with promises of a liberal
franchise and drastic reforms. It would have been so much
better if these had come voluntarily from the Government
instead of being gradually forced from them. In the former
case they would rally the greater number of the malcontents
around them, in the latter case no gratitude will be felt to
the Republic for any concessions made by it. Besides, there
can be no doubt that as the alien population increases, as it
undoubtedly will, their demands will increase with their
discontent, and ultimately a great deal more will have to be
conceded than will now satisfy them. The franchise proposal
made by the President seems to be simply ridiculous. I am
quite certain that if in 1881 it had been known to my fellow
Commissioners that the President would adopt his retrogressive
policy, neither President Brand nor I would ever have induced
them to consent to sign the Convention. They would have
advised the Secretary of State to let matters revert to the
condition in which they were before peace was concluded; in
other words, to recommence the war. … If I had any influence
with the President I would advise him no longer to sit on the
 boiler to prevent it from bursting. Some safety-valves are
required for the activities of the new population. In their
irritation they abuse the Government, often unjustly, in the
press, and send petitions to the Queen; but that was only to
be expected. Let the Transvaal Legislature give them a liberal
franchise and allow them local self-government for their
towns, and some portion of the discontent will be allayed. The
enemies of the Transvaal will not be satisfied; on the
contrary, the worst service that can be done to them is the
redress of the grievance, but it is the friends of the country
who should be considered."

{487}

On the 31st of July, the Justice wrote still more urgently and
impatiently to a Mr. Fischer, who was in close relations with
the Transvaal President: "I do not think that President Kruger
and his friends realize the gravity of the situation. Even now
the State Secretary is doing things which would be almost
farcical if the times were not so serious. Some time ago I
begged of him to drop the censorship of telegrams because it
serves no useful purpose and only delays the publication of
lies by a few days. His answer was that the Government should
not disseminate lies by its own wires. He might as well have
said Government should not disseminate lies by its own
post-office. To crown all, I see that he has now gone so far
as to stop a private telegram (which had been paid for)
because it contained a lie. I really do not know where he is
going to stop or whether he intends to guarantee that all
telegrams allowed to pass contain the truth and nothing but
the truth. Could you not induce him to stop such childish
nonsense? The Transvaal will soon not have a single friend
left among the cultivated classes. Then there is the Franchise
Bill, which is so obscure that the State Attorney had to issue an
explanatory memorandum to remove the obscurities. But surely a
law should be clear enough to speak for itself, and no
Government or Court of Law will be bound by the State
Attorney's explanations. I do not know what those explanations
are, but the very fact that they are required condemns the
Bill. That Bill certainly does not seem quite to carry out the
promises made to you, Mr. Hofmeyr, and Mr. Herholdt. The time
really has come when the friends of the Transvaal must induce
President Kruger to become perfectly frank and take the
newcomers into his confidence. It may be a bitter pill to have
to swallow in yielding to further demands, but it is quite
clear to the world that he would not have done as much as he
has done if pressure had not been applied. What one fears is
that he will do things in such a way as to take away all grace
from his concessions. Try to induce him to meet Mr.
Chamberlain in a friendly manner and at once remove all the
causes of unrest which have disturbed this unhappy country for
so many years. As one who signed the Convention in 1881, I can
assure you that my fellow Commissioners would not have signed
it if they had not been led to believe that President Kruger's
policy towards the Uitlanders would have been very different
from what it has been."

Three confidential despatches sent to President Kruger, in the

same period, by the Minister for Foreign Affairs in the
Netherlands government were laid before the States General at
The Hague, October 25, 1900, and made public through Reuter's
press agency, as follows:

"In the first despatch, which is dated May 13, 1899, the
Minister states that news received from different capitals
leads him to believe in the imminence of the danger of a
violent solution of the problem in South Africa. As a faithful
friend he counsels Mr. Kruger in the true interests of the
Republic to show himself as conciliatory and moderate as
possible, and adds that he learns from a trustworthy source
that the German Government fully shares that opinion. Mr.
Kruger replied that he had always been conciliatory and did
not desire war, but that he could not sacrifice the
independence of the Republic. He was willing enough to grant
the suffrage, but he could not tolerate Englishmen remaining
subjects of the Queen while receiving at the same time the
right to vote in the Republic. In the second despatch, dated
August 4, 1899, the Netherlands Minister for Foreign Affairs
advised President Kruger, in the interests of the country, not
to refuse peremptorily the British proposal for an
international commission. Mr. Kruger replied that the
commission would not be international, but an Anglo-Transvaal
commission. He intended to ask for further information from
Great Britain as to the scope and composition of the
commission, and did not mean to give a decided refusal.
Finally, the Netherlands Minister, in a telegram dated August
15, 1899, stated that the German Government entirely shared
his opinion as to the inadvisability of declining the English
proposal, adding that the German Government, like himself, was
convinced that any request to one of the Great Powers at such
a critical moment would be barren of result and highly
dangerous to the Republic. To this Mr. Kruger replied that the
British proposal would result in very direct interference by
the English in the internal affairs of the Republic. He added
that he had no intention of appealing to a Great Power."

Speaking in the German Reichsrath, on the 10th of December,

1900, the Imperial Chancellor, Count von Bülow, referred to
the above publications by the Dutch government, and confirmed
them, saying that it was in accordance with the views of the
German Government that the Dutch Foreign Minister "strongly
advised Mr. Kruger to maintain a moderate attitude. In June,
1899, Mr. Kruger was advised by Germany through the Dutch
Government to invite mediation, but Dr. Leyds informed the
Dutch Minister in Paris that Mr. Kruger did not consider 'that
the moment had yet come for applying for the mediation of
America.' Some time afterwards Mr. Kruger made the attempt to
obtain arbitration, but 'feeling had become too heated,' and
in August Mr. Kruger complained to the Dutch Government that
arbitration could not be arranged. The answer to this
complaint is given in the Dutch Yellow-book under the date of
 August 15, 1899, and points out that the German Government
would at that date have regarded any appeal to a Great Power
as hopeless and as very dangerous for the Republics. The
German Government also shared the Dutch view that Mr. Kruger
ought not to reject the English proposal then before him."

SOUTH AFRICA: The Transvaal: A. D. 1899 (July-September)

Amendment of the Franchise Law.

After much discussion and many changes, an amended Franchise

Law was adopted by the First Volksraad of the Republic and
published on the 26th of July. It conceded to foreigners who
had already been resident in the Republic for seven years a
possibility of obtaining full burgher rights simultaneously
with the taking of the oath of allegiance, but subjected the
proceeding to conditions which would make it, in Uitlander
opinion, of service to very few. The judgment of Sir Alfred
Milner, the High Commissioner, as expressed to Secretary
Chamberlain, was to the effect that "the bill, as it stands,
leaves it practically in the hands of the Government of the
South African Republic to enfranchise or not enfranchise the
Uitlanders as it chooses. If worked in a liberal spirit, its
clumsy and unreasonable provisions may be got over.
{488}
But if it is to be enforced rigidly, there will be practically
unlimited opportunities of excluding persons whom the
Government may consider undesirable, nor does the tone of the
debate in the Raad leave much doubt as to the spirit in which
some at least of the authors of the Bill would like to see it
worked." His criticism applied especially to the certificate
required from every applicant. "The certificate," he said,
"which every applicant must obtain from three different
officials, as to (a) continuous registration and domicile, (b)
obedience to the laws, (c) committing no crime against the
independence of the country, is one which these officials,
even if well disposed, would be able in hardly any case to
give. None of them can have any such knowledge of the
Uitlander population as would enable them to give this
comprehensive certificate; it is acknowledged that some of the
Johannesburg lists have been lost; and the Field-cornet has, I
believe, held his present office for less than four years."
Moreover, a requirement of "continuous" registration "may
mean," said the High Commissioner, "(and I cannot understand
what else it could mean) registration for seven years in one
ward and district; so that a person having resided and been
registered in one district and subsequently removed to another
would forfeit the benefit of his first period of residence. Even
if this were not so, he would doubtless have to get a double
set of certificates."

Simultaneously with the publication of the new Franchise Law

it was announced that the Executive Council had decided to
give the Witwatersrand Gold Fields a representation of five
members (out of 31) in the First Volksraad, as well as
representation by the same number in the Second Volksraad. To
the British Agent at Pretoria, Mr. Conyngham Greene, this
seemed to be "so wholly inadequate as not to be worthy of
serious consideration."

In view of the complexities and uncertainties involved in the

new Franchise Law, the High Commissioner addressed the
following communication to the government of the South African
Republic, August 1:

"Her Majesty's Government authorize me to invite President

South African Republic to appoint delegates to discuss with
delegates to be appointed by me on behalf of Her Majesty's
Government, whether Uitlander population will be given
immediate and substantial representation by franchise law
recently passed by Volksraad, together with other measures
connected with it, such as increase of seats, and, if not,
what additions or alterations may be necessary to secure that
result. In this discussion it should be understood that the
delegates of Her Majesty's Government would be free to make
any suggestions calculated to improve measures in question and
secure their attaining the end desired."

The reply to this proposal was given by the Boer government to

the British Agent at Pretoria in two notes, the first, dated
August 19, as follows: "With reference to your proposal for a
joint enquiry contained in your despatches of the 2nd and 3rd
August, Government of South African Republic have the honour
to suggest the following alternative proposal for
consideration of Her Majesty's Government, which this
Government trusts may lead to a final settlement.

(1.) The Government are willing to recommend to the Volksraad

and the people a 5 years' retrospective franchise, as proposed
by His Excellency the High Commissioner on the 1st June, 1899.

(2.) The Government are further willing to recommend to the

Volksraad that 8 new seats in the First Volksraad, and, if
necessary, also in the Second Volksraad, be given to the
population of the Witwatersrand, thus with the 2 sitting
members for the Goldfields giving to the population thereof 10
representatives in a Raad of 36, and in future the
representation of the Goldfields of this Republic shall not
fall below the proportion of one-fourth of the total.

(3.) The new Burghers shall equally with the old Burghers be
entitled to vote at the election for State President and
Commandant-General.

(4.) This Government will always be prepared to take into

consideration such friendly suggestions regarding the details
of the Franchise Law as Her Majesty's Government, through the
British Agent, may wish to convey to it.

(5.) In putting forward the above proposals Government of

South African Republic assumes:
 (a) That Her Majesty's Government will agree that the
present intervention shall not form a precedent for future
similar action and that in the future no interference in
the internal affairs of the Republic will take place.

(b) That Her Majesty's Government will not further insist

on the assertion of the suzerainty, the controversy on the
subject being allowed tacitly to drop.

(c) That arbitration (from which foreign element other than

Orange Free State is to be excluded) will be conceded as
soon as the franchise scheme has become law.

(6.) Immediately on Her Majesty's Government accepting this

proposal for a settlement, the Government will ask the
Volksraad to adjourn for the purpose of consulting the people
about it, and the whole scheme might become law say within a
few weeks.

(7.) In the meantime the form and scope of the proposed

Tribunal are also to be discussed and provisionally agreed
upon, while the franchise scheme is being referred to the
people, so that no time may be lost in putting an end to the
present state of affairs. The Government trust that Her
Majesty's Government will clearly understand that in the
opinion of this Government the existing Franchise Law of this
Republic is both fair and liberal to the new population, and
that the consideration that induces them to go further, as
they do in the above proposals, is their strong desire to get
the controversies between the two Governments settled, and
further to put an end to present strained relations between
the two Governments and the incalculable harm and loss it has
already occasioned in South Africa, and to prevent a racial
war from the effects of which South Africa may not recover for
many generations, perhaps never at all, and therefore this
Government, having regard to all these circumstances would
highly appreciate it if Her Majesty's Government, seeing the
 necessity of preventing the present crisis from developing
still further and the urgency of an early termination of the
present state of affairs, would expedite the acceptance or
refusal of the settlement here offered.
(Signed) F. W. REITZ."

The second note, which followed on the 21st of August, was

in these terms:

{489}

"In continuation of my despatch of the 19th instant and with

reference to the communication to you of the State Attorney
this morning, I wish to forward to you the following in
explanation thereof, with the request that the same may be
telegraphed to His Excellency the High Commissioner for South
Africa, as forming part of the proposals of this Government
embodied in the above-named despatch.

(1.) The proposals of this Government regarding question of

franchise and representation contained in that despatch must
be regarded as expressly conditional on Her Majesty's
Government consenting to the points set forth in paragraph 5
of the despatch, viz.:
(a) In future not to interfere in internal affairs of the
South African Republic.
(b) Not to insist further on its assertion of existence of
suzerainty.
(c) To agree to arbitration.

(2.) Referring to paragraph 6 of the despatch, this Government

trusts that it is clear to Her Majesty's Government that this
Government has not consulted the Volksraad as to this question
and will only do so when an affirmative reply to its proposals
has been received from Her Majesty's Government.
(Signed) F. W. REITZ."
The above notes were repeated by cable, in full, to the
Colonial Secretary, at London, and, on the 28th of August, he
returned by the same medium his reply, as follows:

"Her Majesty's Government have considered the proposals which

the South African Republic Government in their notes to the
British Agent of 19th and 21st August have put forward as an
alternative to those contained in my telegram of 31st July.
Her Majesty's Government assume that the adoption in principle
of the franchise proposals made by you at Bloemfontein will
not be hampered by any conditions which would impair their
effect, and that by proposed increase of seats for the
Goldfields and by other provisions the South African Republic
Government intend to grant immediate and substantial
representation of the Uitlanders. That being so, Her Majesty's
Government are unable to appreciate the objections entertained
by the Government of the South African Republic to a Joint
Commission of Inquiry into the complicated details and
technical questions upon which the practical effect of the
proposals depends. Her Majesty's Government, however, will be
ready to agree that the British Agent, assisted by such other
persons as you may appoint, shall make the investigation
necessary to satisfy them that the result desired will be
achieved and, failing this, to enable them to make those
suggestions which the Government of the South African Republic
state that they will be prepared to take into consideration.
Her Majesty's Government assume that every facility will be
given to the British Agent by the Government of the South
African Republic, and they would point out that the inquiry
will be both easier and shorter if the Government of the South
African Republic will omit in any future Law the complicated
conditions of registration, qualification and behaviour which
accompanied previous proposals, and would have entirely
nullified their beneficial effect. Her Majesty's Government
hope that the Government of the South African Republic will
wait to receive their suggestions founded on the report of the
British Agent's investigation before submitting a new