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PRINCIPLES AND
PRACTICE OF
CLINICAL
RESEARCH
FOURTH EDITION
Edited by

JOHN I. GALLIN
FREDERICK P. OGNIBENE
LAURA LEE JOHNSON
Academic Press is an imprint of Elsevier
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may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
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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, Maryrose Franko Health Research Alliance, Research
United States Triangle Park, NC, United States
Elizabeth A. Bartrum National Institutes of Health, Bradley D. Freeman Washington University School of
Bethesda, MD, United States Medicine, St. Louis, MO, United States
Karen E. Berliner National Institutes of Health, Bethesda, Elaine K. Gallin QE Philanthropic Advisors, Potomac, MD,
MD, United States United States
Juliana Blome National Institutes of Health, Bethesda, MD, John I. Gallin National Institutes of Health, Bethesda, MD,
United States United States
Enriqueta Bond QE Philanthropic Advisors, Warrenton, VA, Naomi L. Gerber George Mason University, Fairfax, VA,
United States United States; Inova Health System, Falls Church, VA,
Valerie H. Bonham National Institutes of Health, Bethesda, United States
MD, United States Bruce Goldstein a National Institutes of Health, Rockville,
Craig B. Borkowf Centers for Disease Control and MD, United States
Prevention, Atlanta, GA, United States Marjorie J. Good National Cancer Institute, National
John T. Burklow National Institutes of Health, Bethesda, Institutes of Health, Rockville, MD, United States
MD, United States Michael M. Gottesman National Institutes of Health,
Robert M. Califf Duke University School of Medicine, Bethesda, MD, United States
Durham, NC, United States; Verily Life Sciences (Alphabet), Christine Grady National Institutes of Health, Bethesda,
South San Francisco, CA, United States; Stanford University MD, United States
Department of Medicine, Stanford, CA, United States David K. Henderson National Institutes of Health,
Leighton Chan National Institutes of Health, Bethesda, MD, Bethesda, MD, United States
United States Nicholas C. Ide National Institutes of Health, Bethesda, MD,
Sue Cheng Bayer HealthCare Pharmaceuticals, Inc., United States
Whippany, NJ, United States Jonathan P. Jarow U.S. Food and Drug Administration,
James J. Cimino University of Alabama School of Medicine, Silver Spring, MD, United States
Birmingham, AL, United States Laura Lee Johnson U.S. Food and Drug Administration,
Janine Clayton National Institutes of Health, Bethesda, MD, Silver Spring, MD, United States
United States Barbara I. Karp National Institutes of Health, Bethesda, MD,
Patricia S. Coffey National Institutes of Health, Bethesda, United States
MD, United States Phyllis Klein Washington University, St. Louis, MO, United
Melissa C. Colbert National Institutes of Health, Bethesda, States
MD, United States Laura M. Lee National Institutes of Health, Bethesda, MD,
Josh A. Duberman National Institutes of Health, Bethesda, United States
MD, United States Juan J.L. Lertora Duke University School of Medicine,
Michelle Feige Association for the Accreditation of Human Durham, NC, United States
Research Protection Programs, Inc., Washington, DC, Diane M. Maloney U.S. Food and Drug Administration,
United States Silver Spring, MD, United States
Cheryl A. Fisher National Institutes of Health, Bethesda, Patrick McGarey National Institutes of Health, Bethesda,
MD, United States MD, United States
Molly M. Flannery U.S. Food and Drug Administration, Amy E. McKee U.S. Food and Drug Administration, Silver
Silver Spring, MD, United States 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
xiv LIST OF CONTRIBUTORS

Jon W. McKeeby National Institutes of Health, Bethesda, Amy P.N. Skubitz University of Minnesota, Minneapolis,
MD, United States MN, United States
Theresa Mullin U.S. Food and Drug Administration, Silver Jean R. Slutsky Patient-Centered Outcomes Research
Spring, MD, United States Institute (PCORI), Washington, DC, United States
Charles Natanson National Institutes of Health, Bethesda, Julia Slutsman National Institutes of Health, Washington,
MD, United States DC, United States
Lynnette Nieman National Institutes of Health, Bethesda, Diane C. St Germain National Cancer Institute, National
MD, United States Institutes of Health, Rockville, MD, United States
Robert B. Nussenblatt y National Institutes of Health, Catherine M. Stoney National Institutes of Health,
Bethesda, MD, United States Bethesda, MD, United States
Frederick P. Ognibene National Institutes of Health, Stephen E. Straus y National Institutes of Health, Bethesda,
Bethesda, MD, United States MD, United States
Christopher O. Olopade The University of Chicago, Elyse I. Summers Association for the Accreditation of
Chicago, IL, United States Human Research Protection Programs, Inc., Washington,
Olufunmilayo I. Olopade The University of Chicago, DC, United States
Chicago, IL, United States Junfeng Sun National Institutes of Health, Bethesda, MD,
Valerie L. Prenger National Institutes of Health, Bethesda, United States
MD, United States Michelle Tagle The University of Chicago, Chicago, IL,
Jillian K. Price Inova Health System, Falls Church, VA, United States
United States Tony Tse National Institutes of Health, Bethesda, MD,
Michael A. Proschan National Institutes of Health, United States
Bethesda, MD, United States Konstantina M. Vanevski Bayer HealthCare
Jerry Sachs National Institutes of Health, Bethesda, MD, Pharmaceuticals, Inc., Basel, Switzerland
United States Paul G. Wakim National Institutes of Health, Bethesda, MD,
Joseph A. Sclafani National Institutes of Health, Bethesda, United States
MD, United States; Medstar Georgetown University/ Gwenyth R. Wallen National Institutes of Health, Bethesda,
National Rehabilitation Network, Washington, DC, United MD, United States
States Evelyn P. Whitlock Patient-Centered Outcomes Research
Joe V. Selby Patient-Centered Outcomes Research Institute Institute (PCORI), Washington, DC, United States
(PCORI), Washington, DC, United States Rebecca J. Williams National Institutes of Health, Bethesda,
Pamela A. Shaw University of Pennsylvania Perelman MD, United States
School of Medicine, Philadelphia, PA, United States Deborah A. Zarin National Institutes of Health, Bethesda,
Kelly S. Sherman Patient-Centered Outcomes Research MD, United States
Institute (PCORI), Washington, DC, United States
Pamela C. Sieving Sieving Information Solutions, Bethesda,
MD, United States

y
Deceased.
 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

1
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 1 Nineteenth Century 7

Greek and Roman Influence 2
Twentieth Century and Beyond 11
Middle Ages and Renaissance 2
Summary Questions 14
Seventeenth Century 3
Eighteenth Century 4 References 14

If I have seen a little further it is by standing on the shoulders health services research; epidemiology; and community-based
of giants. Sir Isaac Newton (1676). and managed care-based research.

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 EARLIEST CLINICAL RESEARCH
the personal thrill is exhilarating, and the impact on
society may be substantial. The following historical Medical practice and clinical research are grounded
highlights provide a perspective of the continuum of in the beginnings of civilization. Egyptian medicine
the clinical research endeavor. These events also was dominant from approximately 2850 BC to 525 BC.
emphasize the contributions that clinical research has The Egyptian Imhotep, whose name means “he who
made to advances in medicine and public health. gives contentment,” lived slightly after 3000 BC and
In this chapter, and throughout the book, a broad was the first physician figure to rise out of antiquity.2
definition of clinical research from the Association of Imhotep was a known scribe, priest, architect, astron-
AmericanMedicalCollegesTaskForceonClinicalResearch omer, and magician (medicine and magic were used
is used.1 This task force defined clinical research as together); he performed surgery, practiced some
dentistry, extracted medicine from plants, and knew
a component of medical and health research intended to the position and function of the vital organs. Imhotep
produce knowledge essential for understanding human disease, likely provided the first description of cancer in one of
preventing and treating illness, and promoting health. Clinical his 48 clinical case reports. In case 45, he reported, “If
research embraces a continuum of studies involving interaction you examine (a case) having bulging masses on (the
with patients, diagnostic clinical materials or data, or populations,
in any of these categories: disease mechanisms; translational
breast) and you find that they have spread over his
research; clinical knowledge; detection; diagnosis and natural breast; if you place your hand upon (the) breast (and)
history of disease; therapeutic interventions including clinical find them to be cool, there being no fever at all therein
trials; prevention and health promotion; behavioral research; when your hand feels him; they have no granulations,

Principles and Practice of Clinical Research

http://dx.doi.org/10.1016/B978-0-12-849905-4.00001-0 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 medicine. In addition, as graduating physicians are
they feel protuberant to your touch you say concerning reminded when they take the Hippocratic oath, he pro-
him: ‘This is a case of bulging masses I have to contend vided physicians with high moral standards. Hippocrates’
with.’ Bulging tumors of the breast mean the existence meticulous clinical records were maintained in 42 case re-
of swellings on the breast, large, spreading, and cords.8 These case studies describe, among other maladies,
hard; touching them is like touching a ball of wrap- malarial fevers, diarrhea, dysentery, melancholia, mania,
pings, or they may be compared with unripe hemat and pulmonary edema with remarkable clinical acumen.
fruit, which is hard and cool to the touch.”3 On pulmonary edema, he wrote the following:
Evidence also shows that ancient Chinese medicine
included clinical studies. For example, in 2737 BC, Water accumulates; the patient has fever and cough; the
Shen Nung, the putative father of Chinese medicine, respiration is fast; the feet become edematous; the nails appear
curved and the patient suffers as if he has pus inside, only less
experimented with poisons and classified medical severe and more protracted. One can recognize that it is not pus
plants,4 and I. Yin (1176e1123 BC), a famous prime min- but water.if you put your ear against the chest you can hear it
ister of the Shang dynasty, described the extraction of seethe inside like sour wine.9
medicines from boiling plants.5
Documents from early Judeo-Christian and Eastern Hippocrates also described the importance of cleanli-
civilizations provide examples of a scientific approach ness in the management of wounds. He wrote, “If water
to medicine and the origin of clinical research. In the was used for irrigation, it had to be very pure or boiled,
Old Testament, written from the 15th century BC to and the hands and nails of the operator were to be
approximately the 4th century BC,6 a passage in the first cleansed.”10
chapter of the Book of Daniel describes a comparative Hippocrates used the Greek word for “crab,” karkinos,
“protocol” of diet and health. In the setting of Babylon to describe cancer. The tumor, with its clutch of swollen
where Israelites defiled the sin of eating rich food, blood vessels around it, reminded Hippocrates of a crab
Daniel described the preferred diet of legumes and dug in the sand with its legs spread in a circle.11
water made for healthier youths compared with the Hippocrates’ teachings remained dominant and
king’s rich food and wine: unchallenged until the time of Claudius Galen of Perga-
mum (c.130e200 AD), the physician to the Roman
Then Daniel said to the steward. Emperor Marcus Aurelius.12 Galen was one of the first in-
“Test your servants for ten days; let us be given vegetables to dividuals to utilize animal studies to understand human
eat and water to drink. Then let your appearance and the
appearance of the youths who eat the king’s rich food be disease. By experimenting on animals, he was able to
observed by you, and according to what you see deal with describe the effects of transection of the spinal cord at
your servants. different levels. According to Galen, health and disease
So he harkened to them in this matter; and tested them for reflected the balance of four humors (blood, phlegm,
ten days. black bile, and yellow bile), and veins contained blood
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 and the humors, together with some spirit.12 Inflamma-
king’s rich food. So the steward took away their rich food and tion, described by Galen as a red, hot, and painful
the wine they were to drink, and gave them vegetables.” Daniel distention, was attributed to excessive blood. Tubercles,
1:11e16 pustules, catarrh, and nodules of lymph, all cool, boggy
and white, were attributed to excesses of lymph. Jaundice
The ancient Hindus excelled in early medicine, espe- was an overflow of yellow bile. Cancer was attributed to
cially in surgery. Sushruta, the father of Indian surgery, black bile as was melancholia, the medieval term for
resided in the court of the Gupta kings in about 600 depression. Thus cancer and depression were closely
BC and wrote medical texts about surgery, the most intertwined.13
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 MIDDLE AGES AND RENAISSANCE

GREEK AND ROMAN INFLUENCE In the Middle Ages, improvements in medicine

became evident, and the infrastructure for clinical
Although early examples of clinical research predate research began to develop. Hospitals and nursing,
the Greeks, Hippocrates (460e370 BC) is considered the with origins in the teachings of Christ,14 became defined
father of modern medicine, and he exhibited the strict institutions (although the beginnings of hospitals can be
discipline required of a clinical investigator. traced to the ancient Babylonian custom of bringing the
His emphasis on the art of clinical inspection, observa- sick into the marketplace for consultation, and the
tion, and documentation established the science of Greeks and Romans had military hospitals).

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

 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 1.3 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
FIGURE 1.2 Example of anatomic drawing by Leonardo da Vinci. Made Upon the Bills of Mortality.30 In this book of compar-
Trunk of female human body, with internal organs seen as though ative statistics, population and mortality statistics were
ventral side were transparent. From Da Vinci L. Copyright in Italy by compared for different countries, ages, and sexes in
the Institute Geografic DeAgostini S.p.A. e Novara. New York: Reymal rural and urban areas. Use of data on mortality among
& Company; 1956. p. 369 [Wikipedia].
groups would have major importance in future clinical
studies.
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 EIGHTEENTH CENTURY
multiple cellular and humoral elements, so to some
extent Galen was correct.) The famous architect Sir The 18th century brought extraordinary advances in
Christopher Wren (1632e1723), originally known as an the biological sciences and medicine. At the end of the
astronomer and anatomist (Fig. 1.3), in 1656 assembled 17th century, Antony van Leeuwenhoek of Delft
quills and silver tubes as cannulas and used animal (1632e1723) invented the microscope. Although he is
bladders to inject opium into the veins of dogs.25 The best known for using his microscope to provide the first
first well-documented transfusions of blood were done descriptions of protozoa and bacteria, Leeuwenhoek
in animals (dogs) in 1667 by Richard Lower and also provided the first description of striated voluntary
Edmund King in London26 and were mentioned in muscle, the crystalline structure of the lens, red blood
Pepys’ diary.27 The first transfusions into humans are cells, and spermatozoa (Figs. 1.4 and 1.5).31
attributed to the French physician Jean-Baptiste Denys Modern clinical trials can be recognized in the 1700s.
who in June 1667 transfused sheep blood into a 15- Scurvy was a major health problem for the British Navy.
year-old boy who survived. James Blundell performed William Harvey earlier had recommended lemons to
the first modern transfusions in humans in 1818, some treat scurvy but argued that the therapeutic effect was
of whom survived.28 Transfusions did not become an a result of the acid in the fruit. James Lind (Fig. 1.6), a
accepted approach until Landsteiner discovered the native of Scotland and a Royal Navy surgeon, conducted
major A, B, AB, and O blood groups in 1900 and 1901.29 a clinical trial in 1747 to assess this hypothesis by

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

 EIGHTEENTH CENTURY 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 1.4 Antony van Leeuwenhoek. From Dobell C. Antony FIGURE 1.5 Title page from Leeuwenhoek’s paper, “Microscopical
van leeuwenhoek and his little animals. New York, Dover: A Collection of Observations.” From Dobell C. Antony van leeuwenhoek and his little
Writings by the Father of Protozoology and Bacteriology; 1960 [Original work animals. New York, Dover: A Collection of Writings by the Father of
published in 1932]. Protozoology and Bacteriology; 1960 [Original work published in 1932].

comparing three therapies for scurvy (Table 1.1).32 diseases of the vascular system.33 Hunter’s student
Twelve sailors with classic scurvy were divided into Edward Jenner (1749e1823)33 introduced vaccination
six groups of two each, all given identical diets; the as a tool to prevent infectious diseases (Fig. 1.7).34 Jenner
various groups were supplemented with vinegar, dilute was aware that dairymaids who had contracted cowpox
sulfuric acid, cider, seawater, and a nutmeg, garlic, and through milking did not get smallpox. In 1798, Jenner
horseradish mixture, along with two oranges and one conceived of applying this observation on a grand scale
lemon daily. to prevent smallpox.35
Sulfuric acid, vinegar, seawater, cider, and the physi- Jenner was not the first to conceive of the idea of inoc-
cian’s remedy had no benefit. Two sailors receiving ulation for smallpox. The Chinese had thought of this
citrus fruit avoided scurvy. Although not significant earlier, and Sir Hans Sloane had done small studies in
because of sample size, this early clinical study formed 1717 using variolation (inoculating healthy people
the basis for successful avoidance of scurvy with citrus with pus from blisters obtained from patients with
fruit. Studies with sulfuric acid, vinegar, and cider smallpox).36 In 1718, after providing variolation vaccina-
excluded acid as a likely explanation for the beneficial tion of her 3-year-old son in Turkey and, 3 years later,
effect of citrus fruit. her 5-year-old daughter in England, Lady Mary Worley
The 18th century saw great progress in the area of Montagu introduced the Ottoman practice of variolation
surgery. A remarkable succession of teachers and their to the West.36 In addition, James Jurin published several
students led these studies. Percival Pott of St. Bartholo- articles between 1723 and 1727 comparing death from
mew’s Hospital described tuberculosis of the spine, or natural smallpox in people who had not been inoculated
Pott’s disease.33 John Hunter, Pott’s pupil, was the versus those who had been inoculated. Jurin showed
founder of experimental and surgical pathology and that death occurred in 5 of 6 subjects in the first group
was a pioneer in comparative physiology and experi- compared with 1 in 60 in the latter,37 providing one of
mental morphology. Hunter described shock, phlebitis, the first studies using mortality as a critical clinical
pyremia, and intussusception and reported major find- end point. In 1734, Voltaire wrote, “The Cirassians [a
ings of inflammation, gunshot wounds, and surgical Middle Eastern people] perceived that of a thousand

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

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

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

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
FIGURE 1.9 Ignaz Philipp Semmelweis. From Garrison FH. His- the 19th century.49 The discovery of anesthesia led
tory of medicine. Philadelphia: Saunders; 1917. p. 436. Reprinted 1963. to the dissociation of pain from surgery, allowing sur-
geons to perform prolonged operations. Oliver Wendell
Semmelweis, a Hungarian pupil, became an assistant in Holmes is credited with proposing the words anesthetic
the first obstetric ward of the Allgemeines Krankenhaus and anesthesia.49 Recognition of the importance of hand
in Vienna in 1846. Semmelweis was troubled by the washing and the discovery of anesthetics were essential
death rate associated with puerperal or “childbed” findings of the 19th century that were critical in the
fever. From 1841 to 1846, the maternal death rate from development of modern surgery. In 1865, a Scottish sur-
puerperal sepsis averaged approximately 10%, and in geon named Joseph Lister recognized the importance of
some periods was as high as 50%, in the First Maternity keeping surgical wounds clean and wrote “.that the
Division of the Vienna General Hospital. In contrast, the decomposition in the injured part might be avoided.by
rate was only 2% or 3% in the Second Division, which applying as a dressing some material capable of destroy-
was attended by midwives rather than physicians. The ing the life of the floating particles.” Based on the obser-
public knew the disparity, and women feared being vation that carbolic acid cleansed raw storage, Lister
assigned to the First Division. Semmelweis became frus- began to apply carbolic acid to wounds with great
trated by this mystery and began to study cadavers of success, establishing the importance of antisepsis in
fever victims. In 1847, his friend and fellow physician the operating room.50
Jakob Kolletschka died after receiving a small cut on The work of Holmes and Semmelweis on the impor-
the finger during an autopsy. The risk of minor cuts tance of hand washing opened the door for Pasteur’s
during autopsies was well known, but Semmelweis work on the germ basis of infectious diseases. Louis
made the further observation that Kolletschka’s death Pasteur (1822e95) was perhaps the most outstanding
was characteristic of death from puerperal fever. clinical investigator of the 19th century (Fig. 1.10). He
He reasoned that puerperal fever was “caused by was trained in chemistry. His fundamental work in

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

 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 cellular components of host defense
importance of informed consent in clinical research, against infection.53 Paul Ehrlich (1854e1915) discovered
removed Hansen from his position as director of Lepro- the complement system and asserted the importance of
sarium No. 1, where the experiments had taken place. the humoral components of host defense. In 1908,
However, Hansen retained his position as chief medical Metchnikoff and Ehrlich shared the Nobel Prize
officer for leprosy52 and later in his life received world- (Figs. 1.13 and 1.14).
wide recognition for his life’s work on leprosy. At the end of the 19th century, studies of yellow fever
In the same era, Emil von Behring (1854e1917) increased awareness of the importance of the informed
demonstrated in 1890 that inoculation with attenuated consent process in clinical research. In 1897, Italian
diphtheria toxins in one animal resulted in production bacteriologist Giuseppe Sanarelli announced that he
of a therapeutic serum factor (antitoxin) that could be had discovered the bacillus for yellow fever by injecting
delivered to another, thus discovering antibodies the organism into five people. William Osler was present
and establishing a role for passive immunization. On at an 1898 meeting at which the work by Sanarelli was
Christmas Eve of 1891, the first successful clinical use discussed, and Osler said, “To deliberately inject a
of diphtheria antitoxin occurred.51 By 1894, diphtheria poison of known high degree of virulency into a human
antiserum became commercially available as a result of being, unless you obtain that man’s sanction.is crim-
Paul Ehrlich’s work establishing methods of producing inal.”54 This commentary by Osler had substantial influ-
high-titer antisera. Behring’s discovery of antitoxin ence on Walter Reed, who demonstrated in human
was the beginning of humoral immunity, and in 1901 volunteers that the mosquito is the vector for yellow
Behring received the first Nobel Prize. Koch received fever. Reed adopted written agreements (contracts)
the Prize in 1905 (Fig. 1.12). with all his yellow fever subjects. In addition to obtain-
The Russian scientist Elie Metchnikoff (1845e1916) ing signed permission from all his volunteers, Reed
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 FIGURE 1.13 Elie Metchnikoff in his 40s. From Tauber AI, Chernyak
in host defense mechanisms: vol. 1. Phagocytic cells. New York: Raven L. Metchnikoff and the origins of immunology. New York: Oxford
Press; 1982. p. 7. University Press; 1991, Fig. 5 [Wikipedia].

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

 TWENTIETH CENTURY AND BEYOND 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
FIGURE 1.14 Paul Ehrlich. From Hirsch JG. Host resistance to parasites). Ehrlich, in 1910, working with his assistant
infectious diseases: a centennial. In: Gallin JI, Fauci AS, editors. Advances Sahachiro Hata, developed Salvarsan (arsphenamine),
in host defense mechanisms: vol. 1. Phagocytic cells. New York: Raven
Press; 1982. p. 9.
a trivalent arsenic-based chemotherapeutic to cure syph-
ilis. Salvarsan and later Neosalvarsan were commercial-
made certain that all published reports of yellow fever ized by Hoechst AG as one of the first pharmaceuticals
cases included the phrase “with his full consent.”54 (antibiotics). Sir Alexander Fleming’s discovery of peni-
On November 8, 1895, Wilhelm Röntgen (1845e1923), cillin in 1928 in Scotland spawned expansion of the
a German physicist, produced and detected electromag- pharmaceutical industry through the development of
netic radiation, and on December 22, 1895, he took the antibiotics, antiviral agents, and new vaccines. The
first X-ray of his wife’s hand. For this achievement, Canadian physician Frederick Banting and medical
Röntgen won the first Nobel Prize in Physics in 1901 student Charles Best’s discovery of insulin in 1921 was
(Fig. 1.15A and B). followed by their collaboration with the Canadian
Toward the end of the 19th century, women began to chemist James B. Collip who assisted with purification
play important roles in clinical research. Marie Curie of insulin from cows for use in humans and then
(1867e1934) and her husband Pierre won the Nobel the Scottish physiologist J.J.R. Macleod’s confirmatory
Prize in Physics in 1903 for their work on spontaneous studies on use of insulin in humans provided life-
radiation; in 1911 Marie Curie won a second Nobel Prize saving long-standing management of diabetes for which
(in chemistry) for her studies on the separation of Banting and Macleod won the Noble Prize in Physiology
radium and description of its therapeutic properties. and Medicine in 1923. The discovery of insulin was fol-
Marie Curie and her daughter Irene Joliot-Curie (who lowed by the discovery of multiple hormones to save
won a Nobel Prize in Chemistry in 1935 for her work lives.
synthesizing new radioactive elements leading to the In the 1920s and 1930s, Sir Ronald Aylmer Fisher
discovery of uranium fission) promoted the therapeutic (1890e1962), from the United Kingdom, introduced
use of radium during World War I (Fig. 1.16).55 the application of statistics and experimental design.58
Florence Nightingale (1820e1910), in addition to her Fisher worked with farming and plant fertility to intro-
famous work in nursing, was an accomplished mathe- duce the concepts of randomization and analysis of
matician who applied her mathematical expertise to variancedprocedures used today throughout the world.
dramatize the needless deaths caused by unsanitary In 1930, Torald Sollmann emphasized the importance to
conditions in hospitals and the need for reform a study of controlled experiments with placebo and
(Fig. 1.17).56 blind limbsda rebirth of the “blinded” or “masked”

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

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 13
studies originated by Benjamin Franklin in 1784. the Declaration of Helsinki, stressing the importance of
Sollmann wrote, “Apparent results must be checked assessing risks and determining that risks are out-
by the ‘blind test,’ i.e., another remedy or a placebo, weighed by potential benefits of research. In 1966, Henry
without the knowledge of the observer, if possible” Beecher pointed out major ethical issues in clinical
(Fig. 1.18). He said “Observations without adequate research.60 During the same year, the US Surgeon Gen-
controls and checks are practically useless.”59 Through eral issued a memo to the heads of institutions con-
these approaches, many new drugs for treatment of ducting research with Public Health Service grants
hypertension, cardiovascular disease, manic depression, requiring prior review of all clinical research. The
and epilepsy, to name a few, were developed. purposes of this review were to ensure protection of
The spectacular advances of the 20th century were research subjects, to assess the appropriateness of
associated with troubling events in clinical research methods employed, to obtain informed consent, and to
that heightened public attention and formalized the field review risks and benefits of the research; thus institu-
of clinical bioethics. Nazi human experimentation led to tional review boards were established. In 1967, the U.S.
the Nuremberg Code in 1947, which was designed to pro- Food and Drug Administration added the requirement
tect human subjects by ensuring voluntary consent of that all new drug sponsors must obtain informed con-
the human subject and by asserting that the anticipated sent for use of investigational drugs in humans.
result of research must justify its performance. The Tus- Over the past 50 years, clinical research has become
kegee syphilis experiments initiated in the 1930s and big business. The pharmaceutical and biotechnology
continued until 1972 in African American men and the industries have engaged university-based clinical inves-
Willowbrook hepatitis studies of the mid-1950s in chil- tigators in the business of clinical research. For example,
dren with Down syndrome highlighted the need to in the United States interaction between federal investi-
establish strict rules to protect research patients. gators and industry, encouraged by the US Congress
In 1953 the US National Institutes of Health (NIH) when it passed the Federal Technology Transfer Act in
issued “Guiding Principles in Medical Research 1986, has successfully increased the translation of basic
Involving Humans,” which required prior review by a research to the bedside by US government scientists.
medical committee of all human research to be conduct- At the same time, however, the relationship between
ed at the newly opened NIH Clinical Center. In 1962, the industry and academia has grown closer, and new
Kefauver-Harris amendment to the 1938 US Federal ethical, legal, and social issues have evolved worldwide.
Food, Drug, and Cosmetics Act stipulated that subjects Clinical investigators have become increasingly associ-
must be told whether a drug is being used for investiga- ated with real and perceived conflicts. Examples of these
tional purposes and that subject consent must be issues include promoting an investigator’s financial or
obtained. In 1964, the World Medical Assembly adopted 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
FIGURE 1.18 Testing puddings and gelatins at Consumers Union.
century that are greater than ever. A new urgency to
Copyright 1945 by Consumers Union of U.S., Inc., Yonkers, NY. Reprinted move clinical research findings from the laboratory
with permission from the April 1945 issue of Consumer Reports. to the patient and into the community has prioritized

I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

14 1. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

translational research globally. Today, understanding References

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I. A HISTORICAL PERSPECTIVE ON CLINICAL RESEARCH

 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 hypotheses and permits generalizable conclusions use-
for society, yet continues to pose profound ethical ques- ful in understanding human health and illness,
tions. This chapter briefly describes: five overlapping improving medical care or the public health, and devel-
but distinct eras reflecting the history of clinical research oping safe and effective interventions to prevent, diag-
ethics; codes of research ethics; and seven ethical nose, and treat disease. As such, research serves the
principles that guide clinical research ethics and partic- common or collective good; the individual subject
ular ethical challenges in randomized controlled trials participating in clinical research may or may not benefit
(RCTs). from participation.
Clinical research is distinct from clinical practice in
that each has different, yet not mutually exclusive, pur-
DISTINGUISHING CLINICAL RESEARCH poses, goals, and methods.1 Clinical practice involves
FROM CLINICAL PRACTICE diagnosis, prevention, treatment, and care for a partic-
ular individual or group of individuals with the goal
Clinical research involves the study of human beings of meeting the health needs of and benefiting that indi-
in a systematic investigation of health and illness, vidual(s). Clinical practice is based on evidence or expe-
designed to develop or contribute to generalizable rience, is designed to enhance the patient’s well-being,
knowledge. The goal of clinical research is to gather and has a reasonable expectation of success. Usual
knowledge through a set of activities that tests 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 others, including future persons and society. Ethical re-
interventions or procedures employed in clinical prac- quirements aim to minimize the possibility of exploit-
tice are justified by the prospect of therapeutic benefit ing research participants by ensuring that they are
to the individual. In contrast, clinical research aims to treated with respect while contributing to the genera-
generate useful knowledge and is not designed to tion of knowledge, and their rights and welfare are
meet the health needs of, nor necessarily to benefit, indi- protected throughout the process of research.
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 HISTORY OF ETHICAL ATTENTION TO
much research does not directly benefit individual par- CLINICAL RESEARCH
ticipants. Further, frequently used research methodolo-
gies, such as randomization, blinding, dose escalation, Throughout history, perception and acceptance of the
placebo controls, and others are rarely found and might methods, goals, and scope of clinical research have
be considered unacceptable, in clinical practice. In clin- evolved significantly, as have attention to and apprecia-
ical research, some risk is justified by the importance tion of what respecting and protecting research partici-
of the knowledge to be gained rather than benefit to pants entails. A brief detour through the history of
the individual participant. clinical research illustrates these changing perspectives.5

Benefit to the Individual

ETHICS AND CLINICAL RESEARCH
Historically and for hundreds of years, there was little
Two fundamental ethical questions regarding clinical basis for a distinction between experimentation and
research are important to consider: (1) why should we therapy because most therapy was experimental, and
do research with human beings and (2) how should it systematic evidence of the effectiveness of medical inter-
ethically be done? Two competing considerations frame ventions was rare. Experimental therapies were used in
these questions: clinical research is valuable in generating the hopes of benefiting ill patients, but such “therapy”
practical knowledge useful for advancing or improving frequently contributed to or caused morbidity or mortal-
medical care and health, yet respect for the rights, ity. Systematic research was sporadic. Most researchers
welfare, dignity, and freedom of choice of individual were medical practitioners, motivated to do what they
humans is indispensable. Research with human beings thought best for their patients, and trusted to do the
is essential to advancing or improving medical care right thing. Fraud and abuse were minimized to some
and/or the public health and providing health profes- extent through peer censorship because no specific
sionals with the knowledge and evidence necessary to codes of ethics, laws, or regulations governed the
appropriately and safely care for patients. The pursuit conduct of research. Early regulations, such as the
of knowledge through research should be rigorous to Pure Food and Drug Act of 1906 in the United States,
inform effective and safe clinical practice, and progress prohibited unsubstantiated claims on medicine labels.
would not be possible without rigorous clinical research. Yet, research began to grow as an enterprise only after
Conducting clinical research designed to enhance the the development of early antibiotics like penicillin and
understanding of human health and illness may be the passage of the Food, Drug, and Cosmetic Act in
more than a social good; arguably it is a social impera- 1938, which required evidence of safety before a product
tive.2 Although progress in medical care and health is a was marketed.6
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
Benefit to Society
in medical care or health through clinical research is an Around the time of World War II, there was a
option or an imperative, limits are necessary. Human dramatic shift in clinical research with tremendous
research participants are the means to securing practical growth in the research enterprise. Pharmaceutical
knowledge, but because people should not be treated companies were established; large amounts of both
“merely [as] means to an end, but always as ends in public and private money were devoted to research;
themselves,”4 the need to respect and protect human and research became increasingly centralized, coordi-
research participants is paramount. nated, standardized in method, and valued. Human
The primary ethical tension in clinical research, subjects research entered what has since been described
therefore, is that a few individuals are asked to accept as an “unashamedly utilitarian phase.”7 Individuals
some research burden, risk, or inconvenience to benefit often were included in research because they were

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

 HISTORY OF ETHICAL ATTENTION TO CLINICAL RESEARCH 21
available, captive, and marginalized, and they were Services (DHHS) regulations became the currently oper-
seen as making a contribution to society. The federal ative Common Rule,12 which governs the conduct of hu-
government and the pharmaceutical industry sup- man subjects research funded by 17 US federal agencies.
ported intensive research efforts to develop vaccines The major thrust of these federal regulations and of
and antibiotics for infectious diseases to help soldiers, many existing codes of research ethics continues to be
as infectious diseases were a significant problem for protection of subjects from the burdens and harms of
the armed services. research.
During this era, research was commonly conducted in
prisons, orphanages, and homes for the emotionally or
developmentally disturbed, as well as with other institu-
Research as a Benefit
tionalized groups. The distinction between research and Events in the late 1980s and 1990s altered some public
therapy was fairly clear; subjects not necessarily in need perspectives on clinical research. Certain articulate and
of therapy were accepting a personal burden to make a vocal activists asserted that research participation can
contribution to society. A utilitarian justification served offer an advantage that individuals want access to, rather
as the basis of claims that some individuals could be than simply harm to be protected from.13 According to
used for the greater common good. Revelations of Nazi this perspective, as espoused by human immunodefi-
medical experiments and war crimes, and the Nurem- ciency virus (HIV) and breast cancer activists and others,
berg trial of Nazi doctors, raised public and professional participation in research is a benefit, protectionism is
concerns about the justification and scope of research discrimination, and exclusion from research can be un-
with human subjects.8 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-
Protection of Research Subjects
tive changes in the way research is done and drugs are
In the late 1960s and early 1970s in the United States, approved.
shock and horror at stories of abuse of human subjects In addition to the possible benefits of participation for
led to intense scientific and public scrutiny and reflec- individuals, it was claimed that certain traditionally
tion, and debate about the scope and limitations of underrepresented groups were being denied the bene-
research involving human subjects. A renowned fits of the application of knowledge gained through
Harvard anesthesiologist, Henry Beecher, published a research.16 Since 1994, the US National Institutes of
landmark article in the New England Journal of Medicine Health (NIH) has required that those who receive
in 19669 highlighting ethical problems in 22 research research funding must include previously underrepre-
studies conducted in reputable US institutions. sented women and ethnic minorities.17 Since 1998,
Exposition of studies such as the hepatitis B studies at NIH guidelines have required the inclusion of children
Willowbrook, the U.S. Public Health Service Tuskegee in research or justification for their exclusion.18
syphilis studies, and others generated intense public
attention and concern. Congressional hearings and
Community Involvement in Research
action led to passage of the 1974 National Research
Act (PL 93e348) and establishment of the US National In subsequent years, the growth of genetics
Commission for the Protection of Human Subjects of research, research with stored biospecimens and
Biomedical and Behavioral Research.10 This extremely data, and international collaborative research, in
influential body authored multiple reports and recom- particular, have highlighted the value of greater
mendations about clinical research, including reports public and community involvement in research. Clin-
on research with children and on institutional review ical research does not occur in a vacuum but is a
boards (IRBs). Included in its legacy is the Belmont collaborative social activity that requires the support
Report, in which ethical principles underlying the and investment of involved communities; and it also
conduct of human subject research and their application comes with inherent risks and potential benefits for
are explained.11 The Commission’s work emphasized communities and groups. As such, involvement of
the need to protect individuals participating in research the community (1) in helping to set research prior-
from potential exploitation and harm, and provided the ities, (2) in planning and approving research, (3) in
basis for subsequent federal regulations codified in 1981 evaluating risks and benefits during and after a trial,
in Title 45, US Code of Federal Regulations (USCFR), and (4) in influencing particular aspects of recruit-
Part 46 (45CFR46), titled “Protection of Human ment, informed consent, and the realization of com-
Subjects,” and similar FDA regulations (21 CFR.50 and munity benefits demonstrates respect for the
56). In 1991, the Department of Health and Human community and can facilitate successful research.

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

22 2. ETHICAL PRINCIPLES

CODES OF RESEARCH ETHICS AND and is considered a living document. Certain provi-
REGULATIONS sions of the Helsinki Declaration, such as posttrial
obligations and the use of placebo controls, have
Throughout this history, several influential docu- been topics of continued debate among international
ments have helped to shape our sense of the contours researchers.
of ethical research (Table 2.1). Most were written in The Belmont Report, published by the US National
response to specific crises or historical events, yet all Commission for the Protection of Human Subjects of
have accepted an underlying assumption that research Biomedical and Behavioral Research, describes three
as a means to progress in medical care or health is a so- broad ethical principles that guide the conduct of
cial good. The Nuremberg Code, a 10-point code on the research and form the “basis on which specific rules
ethics of human experimentation, was written as the could be formulated, criticized, and interpreted.”11
concluding part of the judgment at the Nuremberg Trials These three principles are respect for persons, benefi-
(1949).19 Established in response to Nazi experimenta- cence, and justice. Respect for persons requires respect
tion, the Nuremberg Code recognized the potential value for the autonomous decision-making of capable individ-
of research knowledge to society but emphasized the ab- uals as applied in the process of informed consent and
solute necessity of voluntary consent of the subject. The also calls for protection of those with diminished auton-
Nuremberg Code established that ethical research must omy. Beneficence requires protecting individuals from
prioritize the rights and welfare of the subject. Most sub- deliberate and unnecessary harm, as well as maximizing
sequent codes and guidelines for the ethical conduct of benefits and minimizing harms, and is applied to clin-
research have maintained this emphasis and all have ical research through careful risk/benefit evaluation.
incorporated requirements for informed consent. The Justice demands a fair distribution of the benefits and
Declaration of Helsinki was developed by the World Med- burdens of research and is applied in the Belmont Report
ical Assembly (WMA) in 1964 as a guide to the world’s to fairness in the processes and outcomes of selecting
physicians involved in human subject research.20 The research subjects.
Declaration of Helsinki recognizes that some, but not all, In 1982, the Council of International Organizations of
medical research is combined with clinical care and em- Medical Sciences (CIOMS), in conjunction with the
phasizes that patients’ participation in research should World Health Organization (WHO), issued International
not put them at a disadvantage with respect to medical Ethical Guidelines for Biomedical Research Involving Human
care. The Declaration of Helsinki also recognizes legiti- Subjects, which were revised in 1993, 2002, and 2015.21
mate research with people who cannot give their own The CIOMS guidelines acknowledge that background
informed consent, such as children and the cognitively circumstances sometimes differ between low- and
impaired, but for whom informed permission could be middle-income and high-income countries, and there
obtained from a legal guardian. The Declaration of Hel- may be differences in the primacy of focus on the indi-
sinki has had considerable influence on the formulation vidual and individual rights. CIOMS set out to apply
of international, regional, and national legislation and the Helsinki principles to the “special circumstances of
regulations governing clinical research. The Declaration many technologically developing countries.” CIOMS
of Helsinki has been revised multiple times by the adopted the three ethical principles spelled out in the
WMA (1975, 1983, 1989, 1996, 2000, 2008, and 2013) US National Commission’s Belmont Report and main-
tains most of the tenets of Nuremberg and Helsinki
but has provided additional and valuable guidance
TABLE 2.1 Selected Codes and US Regulations Guiding Clinical and commentary on externally sponsored research and
Research
research with vulnerable populations. The 2015 revision
• The Nuremberg Code (1949) restructures and expands many previously existing
guidelines and adds new guidelines on compensation
• The World Medical Association Declaration of Helsinki (1964, 1975,
1983, 1989, 1996, 2000, 2008, and 2013) for research-related injury, research with stored bio-
specimens and data, and implementation science,
• The National Commission’s Belmont Report (1979)
among others.21
• CIOMS International Ethical Guidelines for Biomedical Research Federal regulations found in Title 45, USCFR, Part 46
Involving Human Subjects (1982, 2002, 2015) (45CFR46),12 were promulgated in 1981 for research
• International Conference on Harmonization Guidelines for Good funded by DHHS (formerly the Department of Health,
Clinical Practice (1996) Education, and Welfare), and at Title 21 USCFR, Part
• Title 45, USCFR, Part 46, “The Common Rule” 50 and 56 for the U.S. Food and Drug Administration
(FDA).22 FDA regulations are similar, but not identical,
• Title 21, USCFR, Part 50 (“Protection of Human subjects”) and 56
to those found in the Common Rule.23 Compliance
(“Institutional Review Boards”)
with these and other FDA regulations is required for

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

 ETHICAL FRAMEWORK FOR CLINICAL RESEARCH 23
research investigating FDA-regulated products, such as example, bioethics research on voluntariness, an essen-
drugs, biologics, and medical devices. tial part of informed consent, could better our under-
DHHS regulations were extended in 1991 as the Fed- standing of what voluntariness means and how to
eral Common Rule, applicable to research funded by maximize it in the process of informed consent. Such
17 US federal agencies (not including the FDA). Based research might include an analysis of the concept.
on recommendations of the National Commission, the Recognizing that all decisions and actions can be influ-
Common Rule stipulates both the membership and the enced by one’s understanding, previous experiences,
function of IRBs, and the criteria that an IRB should religion and culture, and the influences of respected
apply when reviewing a research protocol to determine others, distinguishing what makes a choice sufficiently
whether to approve it. The Common Rule also delin- voluntary from a choice that is controlled is important.
eates the information that should be included in an Conceptual bioethics research also might examine the
informed consent document, how consent should be concepts of coercion, undue influence, and manipula-
documented, and criteria for waiver or alteration of tion, which are different possible controlling influ-
informed consent. Subparts B, C, and D of 45CFR46 ences.28 Empirical research might seek to elucidate
describe additional protections for DHHS-funded how people actually choose research participation,
research with fetuses and pregnant women, prisoners, what sources of influence and pressure they identify,
and children, respectively. In 2017, a final revision to whether they perceive they could say no to participation
the Common Rule was published in the Federal Register, and under what circumstances, experiences of manipu-
with the most extensive changes to the Common Rule lation or undue influence, and other phenomena. Re-
since 1991.24 quirements for rigorous and ethical research on topics
The International Conference on Harmonization in bioethics are similar to those for ethical clinical
(ICH) sought to harmonize regulatory guidelines for research.
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 ETHICAL FRAMEWORK FOR CLINICAL
guidance promoting the ethical conduct of research RESEARCH
and reporting of accurate and reliable data.25 The World
Health Organization produced good clinical research A systematic framework of principles for ethical clin-
guidelines that incorporated ICH-GCP and also ical research was derived from guidance provided in
included types of clinical research beyond drug- various ethical codes, guidelines, literature, and
registration trials.26 Good clinical practice guidelines bioethics research. This proposed framework of princi-
are being adopted by countries around the world to ples is meant to apply sequentially and universally to
guide the conduct of research. clinical research.29 According to this framework, ethical
clinical research should satisfy the following require-
ments: social or scientific value, scientific validity, fair
RESEARCH ON BIOETHICAL QUESTIONS subject selection, favorable risk/benefit ratio, indepen-
dent review, informed consent, and respect for enrolled
The historical evolution of clinical research ethics and subjects30 (Table 2.2). Each will be described briefly.
the development of guidelines and regulations was
largely in response to particular events or scandals.
The Nuremberg Code, for example, was a response to
Value and Validity
atrocities performed by Nazi research doctors during
World War II; the formation of the National Commission The first requirement of ethical research is that the
for the Protection of Human Subjects of Biomedical and research question must be worth askingdthat is, have
Behavioral Research was in response to revelations of potential social, scientific, or clinical value. The antici-
the U.S. Public Health Service syphilis studies in Tuske- pated usefulness of knowledge to be gained in under-
gee. Our systems for protection of human subjects, the standing or improving health or health care is the crux
focus of the ethics of clinical research, and the existing of determining valuednot whether study results are
regulations grew out of these efforts. Another essential positive or negative. A study should have sufficient so-
way to inform our thinking about the ethics of clinical cial value to justify asking individuals to assume risk or
research, and one that has gained traction in recent de- inconvenience in research and to justify the expenditure
cades, is research on bioethical questions. Bioethics of resources.31 A valuable research question then ethi-
research is usually conducted using one or more of the cally requires validity and rigor in research design and
following methodologies: historical inquiry, conceptual implementation to produce valid, reliable, interpretable,
analysis, empirical studies, or policy analysis.27 For and generalizable results. Poorly designed researchdfor

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

24 2. ETHICAL PRINCIPLES

TABLE 2.2 Ethical Framework for Clinical Research procedures means that investigators should identify
groups or individuals who would be appropriate for sci-
Principles of Ethical Clinical
entific reasonsdthat is, for reasons related to the prob-
Research Description
lem being studied and justified by the design and the
Value Research poses a clinically, particular questions being askeddnot because of their
scientifically, or socially valuable easy availability or manipulability, or because subjects
question that will contribute to
generalizable knowledge about
are favored or disfavored.11 Extra care should be taken
health or will be useful in to justify the inclusion of vulnerable subjects, as well
improving health. Research is as to justify excluding those who stand to benefit from
responsive to health needs and participation. Exclusion without adequate justification
priorities. can be unfair; therefore, eligibility criteria should be as
Validity The study has an appropriate and broad as possible, consistent with the scientific objec-
feasible design and end points, tives and the anticipated risks of the research. Distribu-
rigorous methods, and a feasible tive justice is concerned with a fair distribution of
strategy to ensure valid and
interpretable data.
benefits and burdens, thus expected benefit and burden
in a particular study is an important consideration for
Fair subject selection The process and outcomes of subject selection. Scientifically appropriate individuals
subject and site selection are fair
and are based on scientific
or groups may be fairly selected consistent with atten-
appropriateness, minimization of tion to equitably distributing benefits and burdens, as
vulnerability and risk, and well as minimizing risks and maximizing benefits.
maximization of benefit. Persons are considered vulnerable when their ability
Favorable risk/benefit ratio Study risks are justified by to protect or promote their own interests is compro-
potential benefits and the value of mised, often because of an impaired capacity to provide
the knowledge. Risks are informed consent. Although disagreement remains
minimized and benefits are about the meaning of vulnerability in research and
enhanced to the extent possible.
who is actually vulnerable,32 there is support for the
Independent review Independent evaluation of idea that among scientifically appropriate subjects, the
adherence to ethical guidelines in less vulnerable should be selected first. For example,
the design, conduct, and analysis
of research.
an early drug safety study should be conducted with
adults before children, and with consenting adults
Informed consent Clear processes for providing before including those who cannot consent.
adequate information to and
promoting the voluntary
Certain groups, such as pregnant women, fetuses,
enrollment of subjects. prisoners, and children, are further protected by specific
regulations requiring additional safeguards in research.
Respect for enrolled participants Study shows respects for the
rights and welfare of participants
According to US regulations, determination of the
both during and at the conclusion permissibility of research with children depends on the
of research. 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-
example, with an inappropriate design, inadequate po- mal risk must be counterbalanced by a prospect of direct
wer, insufficient or sloppy data, or inappropriate or un- therapeutic benefit for the children in the study, (3) for
feasible methodsdis harmful because human and research with small amounts of additional risk (minor
material resources are wasted and individuals are increment over minimal), but without the prospect of
exposed to risk for no benefit.30 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
Fair Subject Selection prospect of benefit that poses greater than minimal risk
Fair subject selection requires that subjects be chosen to participating children can only be conducted if
for participation in clinical research based first on the approved by a special panel convened by the US Secre-
scientific question, balanced by considerations of risk, tary of the DHHS.33 Enrolling children in research also
benefit, and vulnerability. As described in the Belmont requires permission from their parents or legal guard-
Report, fairness in both the processes and the outcomes ians, along with the child’s assent whenever possible.
of subject selection prevents exploitation of vulnerable Fair subject selection also requires considering the
individuals and populations and promotes equitable outcomes of subject selection. For example, if women,
distribution of research burdens and benefits. Fair minorities, or children are not included in studies of a

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

 ETHICAL FRAMEWORK FOR CLINICAL RESEARCH 25
particular intervention, then study results may be diffi- justified by the expected value of the information and
cult to apply to these groups in practice, and interven- any possible benefit to the participants. Studies should
tions could actually be harmful. Therefore, study be designed so that risks to participants are minimized
populations recruited for research should be representa- and benefits are enhanced. When reviewing a study,
tive of the populations likely to use the strategies tested an IRB identifies possible risks and benefits and deter-
in the research.34 mines whether the relationship of risks to benefits is
Similarly, it has been argued that justice requires sub- favorable enough that the proposed study should go for-
jects to be among the beneficiaries of research. This ward or instead be modified or rejected. When review-
means that subjects should be selected as participants ing studies with little or no expected benefit for
in research from which they or others like them can individual subjects, the IRB determines whether the
benefit and should not be asked to bear the burdens of anticipated risks or burdens to study subjects are justi-
research from which they can reap no benefits. This un- fied only by the potential value of the knowledge to be
derstanding of justice has raised important and chal- gained, a particularly challenging risk/benefit assess-
lenging questions in the conduct of collaborative ment. Prospective subjects make their own risk/benefit
international research. Some have argued that if an assessment of whether the risks of participating in a
experimental drug or vaccine is found effective in a given study are acceptable to them and are worth their
certain tested population, there should be prior assur- participation.
ance that population will have access to the drug or vac- A risk/benefit assessment can include consideration
cine.35 Alternatively, subjects or communities should be of many types of risks and benefits, including physical,
assured of and involved in negotiation about fair bene- psychological, social, economic, and legal. For example,
fits derived from research that are not necessarily in a genetics study, physical risks may be limited to a
limited to the benefits of available products of blood draw or a buccal swab, so assessment of potential
research.36 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.
Favorable Risk/Benefit Ratio For example, IRBs consider only health-related benefits
The ratio of risks to benefits in research is favorable of the research in justifying risks, whereas subjects are
when risks are justified by benefits to participants or to likely to consider access to care and financial compensa-
society, and when research is designed in a way that tion as important benefits that may tip the balance in
minimizes risk and enhances benefit for participating favor of participation. Acknowledging that risk/benefit
subjects. The ethical principle of beneficence obliges assessment is not a straightforward or easy process does
that we (1) protect people from deliberate or unneces- not in any way diminish its importance. An important
sary harm and (2) maximize possible benefits and mini- step in evaluating the ethics of clinical research involves
mize possible harms. A widely accepted principle states not only careful attention to potential benefits to individ-
that one should not deliberately harm another individ- uals or society of a particular study in relation to its
ual regardless of the benefits that might be made avail- risks, but also consideration of the risks of not con-
able to others as a result. However, as the Belmont ducting the research.
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
Independent Review
exposed to the risk of harm. To a great extent, clinical
research is an activity designed to learn about the bene- Independent review is a process that allows evalua-
fits and harms of unproven methods of diagnosing, pre- tion of the research for adherence to established ethical
venting, treating, and caring for human beings. The guidelines by individuals with varied expertise and no
challenge for clinical investigators and review/over- personal or business interests in the research. For most
sight groups is to decide in advance when it is justifiable clinical research, this independent review is carried
to seek certain benefits despite the research risks, what out by an IRB or research ethics committee (REC). Using
level of risk is acceptable, whether risks have been mini- criteria detailed in US federal regulations,12,22 IRBs eval-
mized to the extent possible, and when it is better to uate the value of doing the study, the risks involved, the
forego the possible benefits because of the risks. This is fairness of subject selection, whether the risks have been
called a risk/benefit assessment. sufficiently minimized and are justified, and the plans
The calculation and weighing of risks and benefits in for obtaining informed consent; they then decide
research can be complicated. When designing a study, whether to approve a study, with or without modifica-
investigators consider whether the inherent risks are tions, to table a proposal for major revisions or more

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

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

I. ETHICAL, REGULATORY, AND LEGAL ISSUES

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

Exploring the Variety of Random
Documents with Different Content
nukahti paikoilleen — alotettiin ennen päivänkoittoa ja lopetettiin
vasta sitten kun ei enää nähnyt työskennellä. Kokkikin pantiin
hankoamaan ja Harvey vaihdettiin suolanantajaksi, Danin siirtyessä
auttamaan perkkauksessa. Onneksi muuan "Parry Normanin"
miehistä nyrjähdytti nilkkansa pudotessaan alas kanssin portailta, ja
"Täällä Ollaan" pääsi siten etunenään. Harvey ei voinut käsittää
miten ainoatakaan kalaa enää saataisiin mahtumaan kuunariin,
mutta Disko ja Tom Platt ahtoivat ja ahtoivat ja pusersivat kalakasaa
alemmaksi lankuilla, joitten päällä oli painolastista otettuja suuria
kiviä, ja aina vain oli tilaa "vielä yhden päivän työlle". Disko ei
sanonut heille milloin kaikki suola oli kosteana. Hän meni vain
kajuutan perällä olevaan lasarettiin ja alkoi hilata ulos suurta
isoapurjetta. Tämä tapahtui kello kymmenen aamulla. Puolenpäivän
aikana oli pieni isonmaston purje otettu alas ja varsinainen isopurje
ja huippupurje nostettu sen sijalle, ja veneitä souti kuunarin sivulle
tuoden kirjeitä kotiin vietäväksi ja kadehtien heidän hyvää onneaan.
Vihdoin puhdistettiin kannet, kohotettiin lippu — kuten ensimäiseksi
matalikoilta palaamaan lähtevällä aluksella on oikeus tehdä —,
nostettiin ankkuri ja lähdettiin liikkeelle. Disko sanoi haluavansa
vähentää vaivaa niiltä, jotka eivät vielä olleet lähettäneet hänelle
kirjeitään, ja tällä tekosyyllä ohjaili kuunariaan taitavasti toisten
alusten välitse. Itse asiassa tämä oli hänen pieni riemukulkunsa, ja
samoin kuin jo viitenä edellisenä vuotena peräkkäin, se osotti kuinka
pystyvä merimies hän oli. Danin hanuri ja Tom Plattin viulu soittivat
sen taikavoimaisen värsyn säveltä, jota ei pidä laulaa ennenkuin
kaikki suola on kostutettu:

Hei! Hei! Hoi! Hoi! Tuokaa kirjeenne! Kastettu on suola, ja

nyt ankkurin nostamme! Isopurje mastoon, jo paluun aika on,
ja viistoista sataa sentneriä, niin, viistoista sataa sentneriä,
toista sataa kukkura-sentneriä meillä saaliinamme on.
 Viimeiset kirjeet putoilivat kannelle hiilipalan ympärille käärittyinä
ja Gloucesterin miehet huutelivat terveisiä vaimoilleen ja
naisväelleen ja isännilleen, silläaikaa kun "Täällä Ollaan" suoritti
soiton säestämää kulkuaan laivaston läpi, keulapurjeitten
lieputtaessa kuin ihmisen käsi jäähyväisiä viittoessaan.

Harvey tuli hyvin pian huomaamaan, että ankkuripurjeineen

pyyntipaikasta toiseen kuljeksiva "Täällä Ollaan" ja täysin purjein
lounasta kohti laskettava "Täällä Ollaan" olivat kaksi aivan eri alusta.
Ruoriratas kiskoi ja tempoi "poikasen ilmallakin", hän saattoi tuntea
kuinka ruumassa oleva lasti painollaan työnsi kuunarin
hyökylaineitten halki, ja laivan sivulla kiitävien porejonojen
katseleminen sai hänen silmänsä huikenemaan.

Disko piti heidät työssä purjeita hoidellessa; ja kun ne veltostuivat

kuin kilpapurjehtijalla, oli Danin huolehdittava, isosta latvapurjeesta,
joka oli käännettävä käsin joka kerta kun alus kävi tuulen yli.
Väliaikoina he pumppusivat, sillä tiukkaan ahdetusta kalasta tihkui
suolavettä, joka ei ole lastille hyväksi. Mutta kun ei ollut
pyyntihommaa, oli Harveylla aikaa katsella merta toiselta
näkökannalta. Matalarunkoinen kuunari oli tietysti mitä
läheisimmissä suhteissa ympäristöönsä. Taivaanrantaa ei juuri
näkynyt muulloin kuin sen ollessa vyöryaallon harjalla; ja tavallisesti
se työntyi, pujottelehti ja soljui eteenpäin pitkin harmaita,
harmaansinisiä tai mustia, vaahtoviirujen risteilemiä aallonlaaksoja,
tai hivuutui hyväillen jonkun isomman vesikummun kuvetta myöten.
Se näytti ikäänkuin sanovan: "Ethän tee minulle pahaa? Minä olen
vain pikkuinen 'Täällä Ollaan'." Sitten se liukui pois nauraa hihittäen
hiljaa itsekseen, kunnes jokin uusi este veti puoleensa sen huomion.
Tylsinkään ihminen ei voi katsella tällaista tunti tunnilta
kiinnittämättä siihen huomiotaan; ja Harvey, joka oli kaikkea muuta
kuin tylsä, alkoi pian tajuta ja nautinnolla seurata aallonharjojen
korutonta kuoroa niitten käpertyessä vaahtoreunaisiksi
katkeamatonta repeämistä muistuttavalla äänellä, tuulten touhua
niitten rientäessä poikki aavojen ilmojen ja paimentaessa
purppuransinisiä pilvenlonkia, punaisen päivänkoiton loistokasta
nousua, aamusumujen kääriytymistä ja poissiirtymistä valli vallin
jälkeen yli valkoisten lakeuksien, keskipäivän suolaista, huikaisevaa
päivänpaistetta, sateen kosteaa suutelua sen vihmoessa yli
tuhansien aavojen, lakeiden neliöpeninkulmien, näköpiirin viileätä
tummenemista päivän päättyessä ja kuunvaloisen meren miljoonia
väreitä, kun halkaisijapuomi viittasi juhlallisesti alataivaan tähtiin ja
Harvey meni alas pyytääkseen kokilta voitorttuja.

Mutta hauskinta oli silloin kun pojat pantiin yhdessä ruorirattaan

ääreen, Tom Plattin ollessa äänen kuulumilla, ja kuunari lyyhisti
suojanpuoleisen reilinkinsä alas hyrskivään vedenpintaan ja laittoi
pienen omatekoisen sateenkaaren katkeamattomana kaartumaan
vintturinsa yläpuolitse. Sitten puomien hangot vingahtivat mastoa
vastaan, nuorat narahtivat ja purjeet alkoivat humista; ja liukuessa
aallon syvennykseen se tuuskahti eteenpäin kuin silkkihameensa
helmuksiin kompastuva nainen ja nousi ylös halkaisija puolitiehen
märkänä, kurkistellen ja tähystellen Thatcher-saaren suurta kaksois-
majakkaa.

He jättivät taakseen matalikkomeren kylmän harmauden, näkivät

St. Lawrence-salmen kautta Quebec'iin matkalla olevat
puutavaralaivat sekä Espanjasta ja Sisiliasta palaavat Jerseyn
suolaprikit; osuivat Artimon-matalikon kohdalla ystävälliseen
koillistuuleen, joka kiidätti heidät Sable Islandin itäisen majakan
näkyville — näky, jota Disko ei pysähtynyt ihailemaan — ja seurasi
heitä ohi Westernin ja Le Haven, Georgesin pohjoisreunamille
saakka. Siinä he saapuivat syvemmälle vedelle ja antoivat aluksensa
viilettää hilpeästi.

"Hattie vetää nuorasta", uskoi Dan Harveylle. "Hattie ja äiti. Ensi

sunnuntaina saat palkata pojan viskaamaan vettä akkunoihin, jotta
voisit nukkua. Sinä jäät kai meille siksi kunnes vanhempasi tulevat.
Tiedätkö mikä on parasta päästäessä taas maalle?"

"Lämmin kylpy", sanoi Harvey. Hänen kulmakarvansa olivat aivan

valkoisina kuivaneista pärskeistä.

"Se on kyllä hyvä, mutta yöpaita on vielä parempi. Olen nähnyt

unta yöpaidoista siitä saakka kun nostimme isonpurjeen. Silloin
kelpaa kyyhöttää. Äidillä on varmaankin odottamassa ihan uusi,
pehmeäksi pesty. Me tulemme kotiin, Harve, kotiin! Sen tuntee ihan
ilmasta. Me kuljemme nyt lämpimän aallon liepeen poikki, ja minä
tunnen laakerimarjan hajua. Mahdammeko päästä perille illalliseksi.
Käännä hiukan vasemmalle."

Purjeet lepattivat epäröiden ja painautuivat toiselle puolelle

raskaassa ilmassa, meren levitessä sinisin, öljymäisin mainingein
heidän ympärillään. Heidän toivotellessaan tuulta tuli vain sade
lukemattomin ohuin, suorin raipoin, kuplien ja ropisten, ja sateen
takana jyrähteli oikea elokuun ukkonen välkähtelevine salamoineen.
Miehet makasivat kannella paljain jaloin ja käsivarsin, kertoen
toisilleen mitä kukin tilaisi ensimäiseksi ateriakseen maalla; sillä maa
oli nyt selvästi näkyvissä. Gloucesterilainen miekkakala-alus ajautui
ohitse, ja sen kokkapuulla olevassa aitiomaisessa kojussa istuva mies
heilutti harppuunaansa, paljas pää märkänä sateesta. "Kaikki hyvin!"
hoilasi hän iloisesti, kuin olisi ollut pitämässä vartiota suurella
höyrylaivalla. "Wouverman odottaa sinua, Disko. Mitä kuuluu
laivastolle?"
 Disko huusi hänelle vastauksen ja ajautui edelleen, rajun
loppukesän myrskyn jymistessä yläpuolella ja salamain välkkyessä
niemekkeiden kohdalla neljältä taholta yhtaikaa. Ne näyttivät
Gloucesterin satamaa ympäröivän matalan kukkulakehän,
Kymmenennaulansaaren, kalamakasiinit, talonkattojen murtoviivan
ja jokaisen riu'un ja poijun vedenpinnalla häikäisevinä
silmänräpäyskuvina, joita välähti kymmenkunta minuutissa, kun
"Täällä Ollaan" liukui satamaan nousuveden kuljettamana ja
vihellyspoiju vaikeroi ja huokaili sen takapuolella. Sitten myrsky
vaimeni pitkiksi, erillisiksi, lieskamaisiksi sinisen valkoisiksi
leimahduksiksi, jota seurasi kertautumaton, mörssäripatteria
muistuttava jyrähdys, ja järkytetty ilma humisi tähdittyvän taivaan
alla, pimeyden ja hiljaisuuden laskeutuessa sen ylle.

"Lippu, lippu", sanoi Disko äkkiä, viitaten ylöspäin.

"Mikä on?" sanoi Pitkä Jack.

"Otto! Puolimastoon. Rannalta voivat jo nähdä meidät."

"Olin kokonaan unhottanut. Eihän hänellä ole omaisia

Gloucesterissa, vai kuinka?"

"Tyttö, jonka kanssa hänen piti mennä naimisiin tänä syksynä."

"Neitsyt olkoon hänelle armollinen!" sanoi Pitkä Jack ja laski

pienen lipun puolimastoon Oton takia, joka oli huuhtoutunut yli
laidan myrskyssä Le Havelia kolme kuukautta aikaisemmin.

Disko pyyhkäisi kosteuden silmästään ja ohjasi Wouvermanin

telakkaa kohti, jaellen määräyksiään kuiskaten, kuunarin
kaarratellessa ankkurissa olevien hinaaja-aluksien ympäri ja
yövahtien huudellessa sille sysimustien laiturien päistä. Tuon
pimeyden ja kulkueen salaperäisyyden ohella Harvey saattoi tuntea
jälleen ympärillään maan, tuhansine uneen vaipuneine ihmisineen,
mullan tuoksuessa tuoreelta sateen jälkeen ja vaihdeveturin
röhkiessä tuttua röhkinäänsä jossakin ratapihalla; ja kaikki tämä sai
hänen sydämensä sykkimään ja kurkun tuntumaan karhealta hänen
seisoessaan keulapurjeen vieressä. He kuulivat ankkurivahdin
kuorsaavan jollakin hinaaja-aluksella, työntyivät pimeään perukkaan,
jonka kummallakin puolella tuikotti lyhty; joku heräsi murahtaen,
viskasi heille köyden, ja he kiinnittivät aluksensa äänettömään
laituriin, jota reunustivat lämmintä tyhjyyttä huokuvat, avarat,
rautakattoiset vajat, ja jäivät siihen odottamaan hiiskumatta.

Silloin Harvey istui ruorirattaan viereen ja nyyhkytti, nyyhkytti kuin

olisi sydämensä ollut särkymäisillään, ja eräs kookas nainen, joka oli
istunut vaakalaivalla laiturin vieressä, laskeutui kuunariin ja suuteli
Dania kerran poskelle; hän oli Danin äiti ja hän oli nähnyt kuunarin
tulon salamain valossa. Hän ei kiinnittänyt huomiotaan Harveyhin
ennenkuin tämä oli vähän tointunut ja Disko oli kertonut hänelle
hänen tarinansa. Sitten he menivät Diskon kotiin yhdessä aamun
kajastaessa; ja siihen saakka kun sähkösanomatoimisto avattiin ja
Harvey saattoi sähköttää vanhemmilleen, oli hän ehkä yksinäisin
poika koko Amerikassa. Mutta omituista oli se, etteivät Disko ja Dan
näyttäneet lainkaan pitävän pahana sitä että hän itki.

Wouverman ei ollut halukas hyväksymään Diskon määräämää

hintaa ennenkuin Disko oli antanut hänelle muutamia päiviä aikaa
sen sulattamiseksi; Disko saattoi tehdä sen turvallisesti, sillä hän tiesi
tulleensa ainakin viikkoa aikaisemmin kuin yksikään muu
Gloucesterin aluksista; niin ollen saivat kaikki miehet kuljeksia
kaduilla, ja Pitkä Jack pysäytti ahkeraan Rocky Neckin raitiovaunua,
periaatteen vuoksi, hän sanoi, kunnes kuljettaja antoi hänen ajaa
ilmaiseksi. Mutta Dan kuljeskeli pisamainen nenänsä pystyssä,
äärettömän salaperäisenä ja hyvin kopeana kotiväelleen.

"Dan, minun täytyy ottaa sinut käsiini, jos sinä jatkat tähän
tapaan", sanoi Troop totisena. "Sinä olet tämän viimeisen kotiintulon
jälkeen ollut aivan liian nenäkäs."

"Minä ottaisin hänet käsiini heti, jos hän olisi minun poikani", sanoi
Salters-setä äreästi. Hän ja Penn asuivat Troopilla.

"Ohoo!" sanoi Dan, kierrellen hanurineen takapihalla, valmiina

hyppäämään aidan yli vihollisen lähestyessä. "Isä, sinä saat kernaasti
pitää omat mielipiteesi, mutta muista että minä olen sinua
varottanut. Sinun oma lihasi ja veresi on varottanut sinua! Ei ole
minun syyni, jos sinä erehdyt, mutta minä aion olla saapuvilla
katsomassa. Ja mitä sinuun tulee, Salters-setä, niin faaraon
ylimmäinen juomanlaskija ei ole mitään sinun rinnallasi! Odota niin
saat nähdä. Sinut kynnetään maahan niinkuin sinun oma siunattu
apilasi; mutta minä — Dan Troop — minä kukoistan kuin viheriä
laakeripuu, sentähden että minä en pitänyt niin itsepäisesti kiinni
mielipiteistäni."

Disko poltteli tupakkaa täydessä maa-arvokkuudessaan, jaloissa

koreat huopatohvelit. "Sinä alat tulla yhtä hulluksi kuin Harvey-rukka.
Te tirskutte ja iskette silmää ja potkitte toisianne pöydän alitse, niin
ettei enää ole rauhaa talossa", sanoi hän.

"Vielä vähemmän sitä on jonkun ajan perästä — joillakin ihmisillä",

vastasi Dan. "Odotahan vain."
 Dan ja Harvey ajoivat raitiovaunulla East Gloucesteriin, jossa he
samosivat laakeripensaitten läpi majakalle ja panivat maata suurille
punaisille mukulakiville ja nauroivat itsensä nälkäisiksi. Harvey oli
näyttänyt Danille sähkösanoman, ja he lupasivat toisilleen olla
hiiskumatta kunnes pommi räjähtäisi.

"Harveyn sukulaisetko?" sanoi Dan levollisin naamoin illallisen

jälkeen. "Minä luulen että heistä ei ole paljon laitaa, muuten kai
olisimme jo heistä jotain kuulleet. Hänen isänsä pitää jonkinlaista
kauppaa Lännessä. Ehkä hän antaa sinulle viitisen dollaria, isä."

"Enkös minä sitä sanonut?" sanoi Salters. "Älä pyrski ruokiisi,

Dan."
IX.

Mitä yksityisiä suruja monimiljoonikolla lieneekin, täytyy hänen,

niinkuin jokaisen muunkin työtätekevän miehen, pitää huolta
asioistaan. Harvey Cheyne vanhempi oli lopulla kesäkuuta
matkustanut itään ottamaan vastaan murtunutta, puolittain järkensä
menettänyttä vaimoaan, joka päivät ja yöt kuvitteli näkevänsä
poikansa hukkumassa harmaisiin aaltoihin. Cheyne oli ympäröinyt
hänet lääkäreillä, sairaanhoitajattarilla, sairasvoimistelijoilla, vieläpä
uskolla-parantajain lahkokuntalaisillakin, mutta niistä ei ollut apua.
Rouva Cheyne makasi hervottomana ja vaikeroi taikka puhui
pojastaan tunnittain jokaiselle joka vain oli halukas kuuntelemaan.
Toivoa ei hänellä ollut, ja kukapa saattoi antaa sitä hänelle? Hän
tahtoi vain vakuutusta siitä, että hukkuminen ei ollut tuskallista, ja
hänen miehensä vartioi tarkoin ettei hän pääsisi itse sitä
koettamaan. Omasta surustaan Cheyne ei paljon puhunut — hän
tuskin tajusikaan sen syvyyttä, ennenkuin tapasi itsensä kysymästä
kirjotuspöytänsä almanakalta: "Mitä hyödyttää jatkaa enää?"

Jossain päänsä sopukassa oli hänellä aina ollut sellainen

mielihyvää synnyttävä ajatus, että kerran, hänen saatuaan kaikki
asiansa hyvälle tolalle ja pojan lopetettua opiskelunsa, hän ottaisi
poikansa huostaansa ja perehdyttäisi hänet asioihinsa. Silloin tuosta
pojasta — niin hän päätteli, kuten toimeliaat isät tekevät — tulisi heti
hänen seuralaisensa, liikekumppaninsa ja liittolaisensa, ja sitten
seuraisi ihania aikoja, jolloin he yhdessä suorittaisivat suuria töitä —
vanhemman älyn tukiessa nuoremman intoa. Nyt oli hänen poikansa
kuollut — hukkunut mereen aivan samoin kuin saattoi tehdä joku
tavallinen merimies Cheynen suurilla teelaivoilla; vaimo oli lähellä
kuolemaa, jollei vielä pahempaa; häntä itseään ahdisti lakkaamatta
hoitajanaisten ja lääkärien ja kamarineitien ja seuralaisten parvi; hän
oli miltei sietämättömiin kiusaantunut vaimo-parkansa levottomista
päähänpistoista, toivoton ja vailla tarmoa käydä monilukuisia
vihollisiaan vastaan.

Hän oli tuonut vaimonsa äsken valmistuneeseen palatsiinsa San

Diegoon, jossa hänellä ja hänen hoitajajoukollaan oli hallussaan
kokonainen kallisarvoinen kylkirakennus, Cheynen itsensä istuessa
verantahuoneessa sihteerin ja konekirjottajan seurassa, joista
jälkimäinen samalla oli sähköttäjä, ja työskennellessä väsyneesti
päivästä toiseen. Neljän läntisen rautatielinjan välillä oli käymässä
rahtitariffisota, johon hänellä katsottiin olevan osaa; tuhoisa lakko oli
puhjennut hänen metsänhakkuumaillaan Oregonissa, ja Kalifornian
valtion lainsäädäntölaitos, jolla ei ole helliä tunteita valtion luojia
kohtaan, valmistautui ilmisotaan häntä vastaan.

Tavallisissa oloissa hän olisi ottanut vastaan taisteluvaatimuksen

ennenkuin sitä olisi ehditty kunnolla esittääkään, ja antautunut
nautinnolla häikäilemättömään kamppailuun. Mutta nyt hän istui
velttona tuolissaan, pehmeä musta hattu vedettynä alas nenälle,
kookas ruumiinsa kutistuneena väljissä vaatteissaan, tuijottaen
kenkiensä kärkiin tai lahdella kelluviin kiinalaisiin dshonkkeihin ja
vastaillen hajamielisesti sihteerin kysymyksiin tämän avatessa
lauantai-postia.
 Cheyne aprikoi, kuinka paljon tulisi maksamaan, jos heittäisi kaikki
pois ja siirtyisi rauhalliseen yksityiselämään. Hän oli vakuutuksessa
suurenmoisista summista, hän olisi voinut lunastaa itselleen
ruhtinaalliset elinkorot, ja viettämällä aikaansa osaksi jollakin
Coloradossa olevista tiloistaan, osaksi seuraelämässä vaikkapa
Washingtonissa (se tekisi hänen vaimolleen hyvää) ja osaksi Etelä-
Carolinan saaristossa hän ehkä saattaisi unhottaa kaikki tyhjiin
rauenneet suunnitelmansa. Toiselta puolen taas…

Kirjotuskoneen nakutus pysähtyi; tyttö katsoi sihteeriin, joka oli

valahtanut kalpeaksi.

Sihteeri ojensi Cheynelle San Fransiskosta toistetun

sähkösanoman:

"Pelastettu kalastajakuunariin Täällä Ollaan pudottuani

laivasta aika kulunut hauskasti Matalikoilla kalastamassa
kaikki hyvin odotan rahaa tai määräyksiä Gloucesterissa Mass.
Disko Troopin luona sähköttäkää mitä teen ja kuinka äiti voi
Harvey N Cheyne."

Isä päästi sähkösanoman putoamaan, laski päänsä

kirjotuspulpettinsa suljettua kantta vasten ja hengitti raskaasti.
Sihteeri juoksi hakemaan rouva Cheynen lääkäriä, joka tapasi
Cheynen astelemassa edestakaisin lattialla.

"Mitä — mitä arvelette siitä? Onko se mahdollista? Onko sillä

mitään merkitystä? Minä en voi oikein käsittää sitä", huudahti hän.

"Minä voin kyllä", sanoi tohtori. "Minä menetän

seitsemäntuhannen dollarin vuosipalkan — siinä kaikki." Hän ajatteli
newyorkilaisen lääkärin vaivalloista ammatinharjotusta, jonka hän oli
jättänyt Cheynen pakottavista pyynnöistä, ja ojensi sähkösanoman
takaisin huokaisten.

"Arveletteko että sen voisi ilmottaa vaimolleni? Se voi olla

petosta."

"Missä tarkotuksessa?" sanoi tohtori levollisesti. "Ilmitulo on liian

varma. Kyllä se on oikea poika."

Sisään astui ranskalainen kamarineiti, rohkeasti kuten ainakin

sellainen, joka saadaan pysymään edelleen palveluksessa ainoastaan
suurella palkalla.

"Rouva Cheyne sanoo että teidän pitää tulla heti. Hän luulee että
te olette sairas."

Kolmenkymmenen miljoonan haltija taivutti nöyrästi päätään ja

seurasi Suzannea; ja leveitten, suorakulmaisten, valkopuisten
portaitten yläpäästä huusi hento, kimeä ääni: "Mikä siellä on? Mitä
on tapahtunut?"

Eivät mitkään ovet voineet pidättää sitä kirkaisua, joka kajahti läpi
talon muutamia hetkiä myöhemmin, kun Cheyne ilman esipuheita
ilmotti uutisen vaimolleen.

"Ei ole vaarallista", sanoi tohtori tyvenesti konekirjottajalle.

"Jokseenkin ainoa romaaneissa tavattava lääketieteellinen lausunto,
jossa on jotain totta, on se, että ilo ei tapa, neiti Kinzey."

"Tiedän sen; mutta meillä on paljon työtä." Neiti Kinzey oli kotoisin
Milwaukeesta ja jokseenkin suorasukainen puheissaan, ja kun hän oli
hiukan mielistynyt sihteeriin, arvasi hän että työtä oli tulossa.
Sihteeri tähysti innokkaasti seinälle levitettyä Amerikan rullakarttaa.
 "Milsom, me matkustamme heti. Yksityisvaunu — suoraan poikki
mantereen — Bostoniin. Järjestäkää yhdynnät", huusi Cheyne
ylhäältä portailta.

"Sitä arvelinkin."

Sihteeri kääntyi konekirjottajaan päin ja heidän katseensa yhtyivät

(siitä punoutui tarina, joka ei kuitenkaan kuulu tähän
kertomukseen). Tyttö katseli sihteeriin kysyvästi, epäillen kykenikö
tämä täyttämään määräystä. Sihteeri viittasi häntä päännyökäyksellä
siirtymään sähkölennättimen ääreen, aivan kuten kenraali
johtaessaan joukkojaan tuleen. Sitten hän haraisi kädellään
tukkaansa musiikkimiehen tapaan, katsahti kattoon ja ryhtyi
sanelemaan, neiti Kinzeyn valkoisten sormien manatessa koko
Amerikan mantereen kääntämään huomionsa heihin.

"K. H. Wade, Los Angeles — 'Constance'han on Los Angelesissa,

eikö niin, neiti Kinzey?"

"On." Neiti Kinzey nyökkäsi nakutusten välillä sihteerin katsoessa

kelloonsa.

"Onko valmis? Lähettäkää yksityisvaunu 'Constance' tänne ja

järjestäkää ylimääräinen lähtemään täältä sunnuntaina ajoissa
liittyäkseen Newyorkin pikajunaan Sixteenth Street'in asemalla
Chicagossa ensi tiistaina."

Nak-nak-nak! "Ettekö voisi parantaa nopeutta?"

"Ei sellaisilla nousuilla. He saavat aikaa kuusikymmentä tuntia

täältä Chicagoon. He eivät voittaisi mitään ottamalla ylimääräistä
siitä eteenpäin. Onko valmis? — Järjestäkää myös että
Järvenrannikko- ja Etelä-Michigan-rautatie vie 'Constancen'
Newyorkin pikajunalla Buffaloon ja New York Central & Hudson River
edelleen Buffalosta Albanyyn ja Boston & Albany samoin Albanysta
Bostoniin. Välttämätöntä minulle saapua Bostoniin keskiviikko-iltana.
Pitäkää huoli ettei mikään tule estämään. Olen myös sähköttänyt
Canniffille, Touceylle ja Barnesille. — Cheyne."

Neiti Kinzey nyökkäsi, ja sihteeri jatkoi.

"No niin, nyt sitten Canniffille, Touceylle ja Barnesille. Onko

valmis? — Canniff, Chicago. Pyydän ottamaan Santa Fé-radalta
tulevan yksityisvaununi 'Constancen' Sixteenth Streetin asemalta ensi
tiistaina i.p. Newyorkin pikajunalla Buffaloon ja jättämään N.Y.C:lle
lähetettäväksi edelleen Albanyyn. — Oletteko koskaan käynyt
Newyorkissa, neiti Kinzey? Meidän pitää mennä sinne joskus. —
Onko valmis? — Pyydän ottamaan yksityisvaununi 'Constancen'
Buffalosta Albanyyn pikajunalla tiistaina i.p. — Tämä oli Touceylle."

"En ole käynyt Newyorkissa, mutta sen verran kuitenkin

ymmärrän!" vastasi neiti Kinzey päätään keikauttaen.

"Pyydän anteeksi. Sitten Boston & Albanyn johtajalle Barnesille

samat ohjeet Albanystä Bostoniin. Lähtee kello kolme ja viisi i. p.
(sitä ei tarvitse sähköttää); saapuu yhdeksän ja viisi keskiviikko-
iltana. Siinä on Wadelle tekemistä täysin määrin, mutta noita johtajia
sietää toisinaan ravistella vähän eloon."

"Suurenmoista", virkkoi neiti Kinzey luoden häneen ihailevan

katseen.
Sellaista miestä hän osasi ymmärtää ja pitää arvossa.
 "Ei huonoimmastikaan", sanoi Milsom vaatimattomasti. "Joku muu
kuin minä olisi kuluttanut vähintään vuorokauden
matkasuunnitelman sommittelemiseen, sen sijaan että olisi
yksinkertaisesti jättänyt Santa Fé-radan asiaksi järjestää koko
matkan Chicagoon saakka."

"Mutta mitenkähän on sen Newyorkin pikajunan laita. Ei itse

Chauncey Depew [amerikkalainen valtiomies ja puhuja] saanut
yhdistetyksi vaunuaan siihen", huomautti neiti Kinzey tullen jälleen
entiselleen.

"Ei kyllä, mutta Chauncey ei olekaan Cheyne. Kun Cheyne sitä

haluaa, niin se menee että vilahtaa."

"Niinköhän? Mutta eikö olisi sähkötettävä pojalle? Sen olette

kuitenkin unohtanut."

"Minä kysyn."

Kun hän palasi saatuaan Cheyneltä määräyksen pyytää Harveyta

olemaan heitä vastassa Bostonissa määrätyllä hetkellä, tapasi hän
neiti Kinzeyn nauramassa näppäimistönsä yli kumartuneena. Sitten
Milsomkin rupesi nauramaan, sillä Los Angelesista naputettiin hurjaa
vauhtia: "Me tahdomme tietää miksi — miksi — miksi? Yleinen
levottomuus syntynyt ja on leviämässä."

Kymmenen minuutin kuluttua Chicago kääntyi neiti Kinzeyn

puoleen näillä sanoilla: "Jos vuosisatojen rikos on tekeillä, olkaa hyvä
ja varottakaa ystäviä ajoissa. Me etsimme täällä kaikki
turvapaikkoja."
 Tästäkin vei voiton Topekasta lähetetty sanoma (ja mitä syytä
Topekalla oli levottomuuteen, ei edes Milsom voinut arvata): "Älkää
ampuko, eversti. Me antaudumme."

Cheyne hymyili jurosti vihamiestensä hätäännykselle, kun

sähkösanomat esitettiin hänelle. "He luulevat meidän olevan
sotapolulla. Sanokaa heille ettemme ole sotaisalla päällä tällä erää,
Milsom. Ilmottakaa heille matkamme tarkotus. On ehkä parasta että
te ja neiti Kinzey tulette mukaan, vaikka on tuskin luultavaa että
minä suoritan mitään liikeasioita tällä matkalla. Sanokaa heille totuus
— tämän kerran."

Ja niin sanottiin totuus. Neiti Kinzey nakutti lauseen

sähkölennättimeen, sihteerin lisätessä siihen nämä muistettavat
sanat. "Vallitkoon rauha!" ja johtokuntain huoneissa
kahdentuhannen peninkulman päässä kuuteenkymmeneenkolmeen
miljoonaan dollariin nousevien rautatieosuuksien edustajat
hengittivät keveämmin. Cheyne riensi tapaamaan ainoaa poikaansa,
jonka hän niin ihmeellisellä tavalla oli saanut takaisin. Karhu oli
menossa pentuaan hakemaan, ei karjaa raatelemaan. Päättäväiset
miehet, jotka olivat paljastaneet puukkonsa taistellakseen
taloudellisen olemassaolonsa puolesta, laskivat aseensa syrjään ja
toivottivat hänelle onnea matkalle, samalla kuin puolikymmentä
säikähtynyttä pikkurautatietä pöyhisteli rintojaan, puhuen niistä
merkillisistä asioista, joita he olisivat tehneet, jollei Cheyne olisi
haudannut sotakirvestään.

Sähkölennättimille tuli kiireinen viikonloppu, sillä kun ihmiset ja

kaupungit olivat päässeet levottomuudestaan, riensivät he
saattamaan asioita vaadittuun järjestykseen. Los Angeles antoi
tiedon San Diegoon ja Barstowiin, että Etelä-Kalifornian radan
junankuljettajat tietäisivät olla valmiina syrjäisissä vahtituvissaan;
Barstow lähetti sanoman Atlantic & Pacific-linjalle, ja Albuquerque
lennätti sen pitkin koko Atchison, Topeka & Santa Fé-rataa ja aina
Chicagoon asti. Veturi, yhdysvaunu miehistöineen sekä suuri,
kultakoristeinen yksityisvaunu "Constance" olivat lähetettävät tuon
kahdentuhannen kolmensadan viidenkymmenen mailin matkan
poikki. Junan oli sivuutettava sataseitsemänkymmentäseitsemän
vastaantulevaa tai samaan suuntaan kulkevaa junaa, ja jokaisen
lähettäjälle ja miehistölle oli siitä annettava tieto. Kuusitoista veturia,
kuusitoista kuljettajaa ja kuusitoista lämmittäjää oli varustettava
määräpaikkoihinsa — kaikki parhaita mitä oli saatavissa. Kaksi ja
puoli minuuttia oli sallittu käyttää veturien vaihtamiseen, kolme
vedenottoon ja kaksi hiilien ottoon. "Antakaa tieto miehille ja
varustakaa vesisäiliöt ja hiilivarastot asianmukaiseen kuntoon, sillä
Harvey Cheynellä on kiire — kiire — kiire!" lauloivat sähkölangat.
"Neljänkymmenen mailin tuntinopeus vaaditaan, ja piiripäälliköt
seuraavat tätä ylimääräistä junaa kukin piiriinsä kuuluvan matkan.
San Diegosta Sixteenth Streetille Chicagoon levitettäköön
taikamatto! Joutuun, oi joutuun!"

"Tulee kuuma ilma", sanoi Cheyne, kun juna lähti vierimään San
Diegosta varhain sunnuntai-aamuna. "Me teemme kyllä matkaa niin
joutuun kuin voimme, äiti, mutta en tosiaankaan luule olevan
tarpeen sinun vielä panna hattua päähäsi ja hansikkaita käsiisi. Olisi
parempi jos panisit maata ja ottaisit lääkettäsi. Pelaisin kanssasi
vähän dominoa, mutta nyt on sunnuntai."

"Minä tahdon olla kärsivällinen. Oi, minä tahdon olla kärsivällinen.

Mutta — jos otan pois hatun, niin minusta tuntuu siltä kuin emme
ikinä pääsisi perille."
 "Koeta nukkua vähän, äiti, niin olemme Chicagossa ennenkuin
huomaatkaan."

"Mutta meidänhän on mentävä Bostoniin asti. Käske heidän

kiiruhtaa."

Kuuden jalan korkuiset käyttöpyörät jyskyttivät eteenpäin San

Bernardinoa ja Mohaven erämaata kohti, mutta radan nousu ei
sallinut suurta nopeutta. Se oli tuleva myöhemmin. Erämaan
kuumuus seurasi vuoriston kuumuutta, kun he kääntyivät itäänpäin
Needlesiä ja Colorado-jokea kohti. Vaunu rasahteli tavattomassa
kuivuudessa ja helteessä, rikkisurvottua jäätä pantiin rouva Cheynen
takaraivon alle, ja juna ponnisteli eteenpäin pitkän pitkiä nousuja
myöten, Ash Forkin ohitse kohti Flagstaffia, missä metsät ja
kivilouhimot ovat, korkealla kaartuvan pilvettömän taivaan alla.
Vauhdinosottajan viisari värähteli ja liikkui edestakaisin; hiilituhkan
sirut rapisivat katolla ja tomupilvi pyöri kiitävien pyörien kintereillä.
Yhdysvaunun miehistö istui paitahihasillaan läähättäen lavereillaan,
ja Cheyne oli usein heidän luonaan huutaen junan kolinan yli
vanhoja rautatietarinoita, jotka ovat jokaiselle junamiehelle tuttuja.
Hän kertoi heille pojastaan, jonka meri oli antanut takaisin, kun
häntä jo kauan oli surtu kuolleena, ja miehet nyökyttivät päitään ja
syljeksivät ja iloitsivat hänen kanssaan; kysyivät kuinka rouva siellä
toisessa vaunussa voi ja sietäisikö hän jos kuljettaja "löysäisi vielä
vähän", ja Cheyne arveli hänen sietävän. Niinpä annettiin tulihepojen
ravata hillitsemättä Flagstaffista Winslowiin, kunnes eräs
piiripäällikkö pani vastalauseen.

Mutta rouva Cheyne, joka makasi upeassa budoaari-osastossaan,

missä ranskalainen kamarineiti kauhusta kalpeana piteli kiinni
hopeaisesta ovenrivasta, ainoastaan vaikeroi hiljaa ja pyysi että
hänen miehensä käskisi heitä kiiruhtamaan. Ja niin he jättivät
taaksensa Arizonan kuivat hietikot ja omituisen muotoiset kalliot ja
huohottivat edelleen, kunnes kytkyitten kalina ja jarruletkun sihinä
ilmottivat heille että he olivat saapuneet Coolidgeen Kalliovuorten
juurelle.

Kolme urheaa ja kokenutta miestä — tyyninä, luottavaisina ja

kuivina alottaessaan, kalpeina, vapisevina ja märkinä lopettaessaan
ajovuoronsa — kiidätti junan pitkää rinnettä ylöspäin Albuquerquesta
Gloriettaan ja toiselle puolelle Springerin, aina yhä ylemmäksi
Ratonin tunnelille saakka, mistä he laskeutuivat heilahdellen La
Juntaan, näkivät Arkansas-joen ja syöksyivät pitkää myötämaata
Dodge Cityyn, missä Cheyne sai lohduttautua kääntämällä taas
kelloaan tunnin eteenpäin.

Vaunussa ei paljoa puhuttu. Sihteeri ja konekirjottaja istuivat

nahkapäällyksisillä sohvilla suurien peililasisten havaintoikkunoitten
ääressä vaunun perässä, katsellen taakse kiitävien ratapölkkyjen
aaltomaista kutistumista ja, kuten otaksutaan, tehden
maisemahuomioita. Cheyne kulki hermostuneesti edestakaisin oman
loisteliaan ylellisyytensä ja yhdysvaunun alastoman
yksinkertaisuuden väliä, sytyttämätön sikaari suussa, kunnes
sääliväinen miehistö unhotti että hän oli heidän perivihollisensa ja
teki parhaansa saadakseen hänen aikansa kulumaan.

Yöllä valaisivat kimppuihin järjestetyt sähkölamput tuota surullista

ylellisyyspalatsia, ja he porhalsivat korskeasti eteenpäin läpi
autioitten maisemain tyhjyyden. Heidän korviinsa kuului milloin
vesisäiliön kohina ja kiinalaisen terävä kurkkuääni, vasarain kalahtelu
niiden koetellessa kruppinteräksisten pyöräin eheyttä ja jonkun
maankulkijan kiroilu, kun hänet ajettiin pois perimmäiseltä
vaunusiltamalta, milloin tenderiin syöksyvän kivihiilen kumea kohina,
milloin taas äkkiä vaimeneva äänten humina heidän kiitäessään
odottavan junan ohitse. Milloin he näkivät vieressään syviä kuiluja,
hirsisillan jyristessä heidän allaan, milloin korkeita kallioita, jotka
peittivät heidän näkyvistään puolet tähdistä. Sitten jyrkänteet ja
rotkot vaihtuivat ja etenivät näköpiirin reunalla kuvastuviksi
rosoharjaisiksi vuorenselänteiksi, vaipuen yhä matalammiksi
kukkuloiksi, kunnes viimein oltiin varsinaisilla tasangoilla.

Dodge Cityssä joku tuntematon viskasi vaunuun erään Kansasin

sanomalehden numeron, jossa oli jonkunlainen Bostonista
sähköteitse saapunut haastattelu Harveysta, joka nähtävästi oli
osunut tapaamaan jonkun toimeliaan sanomalehti-reportterin.
Tuosta ilahuttavasta uutisesta kävi selväksi, että kysymyksessä oli
todellakin ilman epäilystä heidän poikansa, ja se rauhoitti rouva
Cheyneä joksikin ajaksi. Hänen ainoan sanansa: "kiiruhtakaa!"
ilmottivat junamiehet kuljettajille Nickersonissa, Topekassa ja
Marcelinessa, missä nousut ovat loivat, ja he pyyhälsivät manteretta
taakseen. Kaupunkeja ja kyliä oli nyt tiheämmässä, ja saattoi tuntea
liikkuvansa ihmisten joukossa.

"En voi nähdä mittaria, ja minun silmiäni särkee niin kovin. Kuinka
joutuun me menemme?"

"Niin joutuun kuin voimme, äiti. Ei ole mitään järkeä siinä, että
ehättäydymme Chicagoon ennen pikajunan aikaa. Saisimme vain
odottaa."

"En välitä siitä. Minä haluan tuntea olevamme liikkeessä. Istu

tänne ja sano minulle peninkulmat."
 Cheyne istui ja luki hänelle nopeusmittarin osottamia
peninkulmamääriä (muutamat peninkulmaennätykset ovat
voittamattomina vielä tänäkin päivänä), eikä seitsemänkymmenen
jalan pituinen vaunu kertaakaan hiljentänyt höyrylaivan tapaista
vaarumistaan kiitäessään halki pimeyden jättiläismehiläistä
muistuttavaa surinaa pitäen. Kuitenkaan ei kulku ollut kyllin nopeaa
rouva Cheynen mielestä; kuumuus, säälimätön elokuun helle,
pyörrytti hänen päätään; kellon viisarit eivät liikkuneet, ja milloin, oi,
milloin he pääsisivät Chicagoon?

Ei ole totta, että Fort Madisonissa koneita vaihdettaessa Cheyne

olisi lahjottanut Veturinkuljettajien Liitolle niin suuren rahasumman,
että he olisivat sen avulla kyenneet vastedes tasavoimaiseen
taisteluun häntä ja hänen vertaisiaan vastaan. Hän maksoi
veturinkuljettajille ja lämmittäjille sen mukaan kuin hän katsoi heidän
ansainneen, ja ainoastaan hänen pankkinsa tietää, mitä hän antoi
junamiehille, jotka olivat osottaneet häntä kohtaan
myötätuntoisuutta. On jäänyt tiedoksi, että viimeinen junamiehistö
otti kokonaan huolekseen vaihtotoimet Sixteenth Streetin asemalla,
koska "rouva" oli vihdoinkin vaipunut unenhorrokseen ja paha peri
sen, joka tölmäisi häntä.

Se korkeapalkkainen ammattimies, joka kuljettaa Järvenrannikko-

ja Etelä-Michigan-radan pikajunaa Chicagosta Elkhartiin, on
jommoinenkin mahtimies, eikä hän suvaitse että hänelle neuvotaan
millä tavoin hänen on peräytettävä juna vaunuun kiinni. Kuitenkin
kaikitenkin hän käsitteli "Constancea" kuin olisi se ollut lastattu
dynamiitilla, ja kun toiset moittivat häntä, niin he tekivät sen
kuiskauksin ja äänettömin elein.
 "Pyh!" sanoivat Atchison, Topeka & Santa Fé-linjan miehet
myöhemmin, puhellessaan muinaisista. "Me emme koettaneet ajaa
ennätystä. Harvey Cheynen eukko oli sairaana vaunussa, emmekä
me tahtoneet paiskia häntä. Mutta kun sen nyt muistan, niin voin
mainita että koko aikamme San Diegosta Chicagoon oli 57 tuntia 54
minuuttia. Voitte sanoa sen niille idän puolen junille. Kun koetamme
ajaa ennätystä, niin ilmotamme siitä erikseen."

Lännen miehen mielestä Chicago ja Boston ovat lähinaapuruksia,

ja jotkut rautatiet yllyttävät tuota harhaluuloa. Pikajuna kiidätti
"Constancen" Buffaloon ja jätti sen New York Central & Hudson
River-rautatien huostaan (suuria mahtimiehiä valkoisine
poskipartoineen ja kultakellukkeisine kellonvitjoineen astui siellä
vaunuun puhelemaan hieman liikeasioista Cheynen kanssa);
viimeksimainittu rautatie solautti sen sievästi Albanyyn, mistä Boston
& Albanyn rata suoritti loppuun matkan valtamerestä valtamereen —
yhteenlasketun ajan ollessa kahdeksankymmentäseitsemän tuntia
kolmekymmentäviisi minuuttia, eli kolme vuorokautta ja viisitoista ja
puoli tuntia. Harvey oli siellä heitä odottamassa.

Voimakkaitten mielenliikutusten jälkeen tuntevat useimmat ihmiset

ja ainakin kaikki pojat ravinnon tarvetta. He kestitsivät palannutta
tuhlaajapoikaa alasvedettyjen uutimien takana, erillään muusta
maailmasta suuressa onnessaan, tulevien ja menevien junien
kohistessa heidän ympärillään. Harvey söi ja joi ja kertoili
seikkailuistaan samaan hengenvetoon, ja milloin hänen kätensä oli
joutilaana, hyväili hänen äitinsä sitä. Hänen äänensä oli tullut
syvemmäksi suolaisessa meri-ilmassa oleskelusta; hänen
kämmenensä olivat karheat ja kovat, ranteensa kirjavana
kalanrasvahaavojen arpia; ja voimakas turskantuoksu lemahti hänen
kautsusaappaistaan ja sinisestä villamekostaan.
 Isä, joka oli hyvin tottunut arvostelemaan ihmisiä, katseli häntä
tutkivasti. Hän ei ainakaan nähnyt että pojalle olisi mitään
parantumatonta haittaa koitunut. Tosin hän tuli nyt ajatelleeksi, että
hän oli yleensä sangen vähän tietänyt mitään pojastaan; mutta hän
muisti selvästi tyytymättömän, kellertävänaamaisen pojannulikan,
joka huvitteli käskettämällä isäänsä ja itkettämällä äitiään. Mutta
tämä suoraryhtinen kalastajanuorukainen ei luikerrellut eikä
kujehtinut, vaan katsoi häneen avoimin, kirkkain ja rohkein silmin ja
puhutteli häntä huomattavan, jopa hämmästyttävän kunnioittavasti.
Hänen äänessään oli lisäksi sellainen sointi, joka tuntui lupaavan,
että muutos oli pysyväinen, että uusi Harvey tulisi jäämään.

"Joku on pitänyt häntä kurissa", ajatteli Cheyne. "Sitä ei Constance

olisi koskaan sallinut. Tuskinpa Eurooppa olisi tehnyt sen
terveellisempää vaikutusta."

"Mutta miksi et sanonut tuolle miehelle, Troopille, kuka sinä olit?"

toisti äiti, kun Harvey oli jutellut tarinansa ainakin kahdesti.

"Disko Troop, äiti kulta. Hän on paras mies mitä koskaan on

kävellyt laivan kannella."

"Miksi et sanonut hänelle, että hän olisi vienyt sinut maihin? Tiesit
kai että isä olisi korvannut sen hänelle kymmenkertaisesti."

"Tiesin kyllä; mutta hän luuli minua hulluksi. Minä pelkään

nimittäneeni häntä varkaaksi, kun en löytänyt seteleitä taskustani."

"Eräs laivamies löysi ne lipputangon luota sinä — sinä iltana",

nyyhkytti rouva Cheyne.
 "No, se selittää asian. Minä en moiti ollenkaan Troopia. Minä väitin
etten tahtonut tehdä työtä — kaikkein vähimmin kalastaja-aluksella
— ja hän luonnollisesti löi minua vasten nenää; ja ooh! siitä tuli verta
kuin härän kurkusta."

"Lapsi raukkani! He lienevät rääkänneet sinua hirveästi."

"Tuskin vain. Ja sen jälkeen minä pääsin vähän järkiini."

Cheyne löi kämmentään polveensa ja nauroi hiljaista naurua.

Tässä näytti olevan muodostumassa poika juuri sellainen, jota hänen
sydämensä halasi. Hän ei ollut koskaan ennen nähnyt juuri tuollaista
välkähdystä Harveyn silmissä.

"Ja Troop antoi minulle palkkaa kymmenen ja puoli dollaria

kuussa; hän on nyt maksanut siitä puolet; ja minä otin Danin
oppaakseni ja kävin heti työhön käsiksi. Minä en pysty vielä
tekemään miehen työtä. Mutta minä voin käsitellä venettä melkein
yhtä hyvin kuin Dankin, enkä minä joudu sekaannuksiin sumussa —
kovin paljoa; ja minä voin pitää perää sievillä tuulilla, ja minä voin
panna syötit pitkäänsiimaan melkein omin päin; ja minä tiedän
luonnollisesti kaikki köydet laivassa; ja minä voin hangota kaloja aina
pimeään asti, ja minä osaan mainiosti vanhaa Josefusta, ja minä
voin näyttää teille kuinka kahvi selvitetään kalannahkapalasella ja —
saisinko vielä kupin lisää? Teillä ei ole aavistustakaan, kuinka paljon
työtä sisältyy kymmenen ja puolen dollarin kuukausipalkkaan!"

"Minä alotin kahdeksalla ja puolella, poikaseni", sanoi Cheyne.

"Niinkö? Sitä et ole koskaan sanonut minulle."

 "Sinä et ole koskaan kysynyt, Harve. Voin kertoa siitä joskus
sinulle, jos viitsit kuunnella. Etkö halua maistaa täytettyä oliivia?"

"Troop sanoo, että kaikkein mieltäkiinnittävintä maailmassa on

saada selville, miten kukin ansaitsee elatuksensa. On mainiota istua
taas oikein valikoidulla aterialla. Ei sillä ettei meillä olisi ollut hyvä
ruoka. Paras keittiö koko matalikoilla. Disko piti ensiluokkaisen
ruuan. Hän on mainio mies. Ja Dan — hän on Diskon poika — Dan
on minun toverini. Ja sitten siellä on Salters-setä lannotusaineineen,
hän lukee Josefusta. Hän uskoo vielä vahvasti, että minä olen hullu.
Ja sitten siellä on pieni Penn-raukka, ja hän on hullu. Hänelle ei pidä
puhua Johnstownista, koska… Ja teidän täytyy tulla tuntemaan Tom
Platt ja Pitkä Jack ja Manuel. Manuel pelasti minun henkeni. On
ikävä että hän on portugalilainen. Hän ei osaa puhua paljon, mutta
hän on mainio soittoniekka. Hän tapasi minut laivasta pudonneena
veden varassa ja korjasi minut veneeseensä."

"Minua ihmetyttää ettei sinun hermostosi oli aivan pilalla", sanoi

rouva Cheyne.

"Miksikä se olisi, äiti? Minä tein työtä kuin hevonen ja söin kuin
susi ja nukuin kuin kuollut."

Tämä oli liikaa rouva Cheynelle, jonka mieleen muistuivat hänen

kuvittelunsa aalloilla ajelehtivasta ruumiista. Hän nousi ja poistui
omaan huoneeseensa, ja Harvey kyyristyi isänsä viereen selittäen
hänelle kiitollisuudenvelkaansa.

"Voit luottaa siihen, että teen kaiken voitavani miehistön hyväksi,

Harve. He tuntuvat olevan kelpo miehiä sinun kuvauksestasi
päättäen."
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