*Incorporates new chapters on Managing Conflicts of Interest in Human Subjects Research, Clinical Research from the Patient's Perspective, The Clinical Researcher and the Media, Data Management in Clinical Research, Evaluation of a Protocol Budget, Clinical Research from the Industry Perspective, and Genetics in Clinical Research
*Addresses the vast opportunities for translation of basic science observations to the bedside through clinical research
*Delves into data management and addresses how to collect data and use it for discovery
*Contains valuable, up-to-date information on how to obtain funding from the federal government
The second edition of this innovative work again provides a unique perspective on the clinical discovery process by providing input from experts within the NIH on the principles and practice of clinical research. Molecular medicine, genomics, and proteomics have opened vast opportunities for translation of basic science observations to the bedside through clinical research. As an introductory reference it gives clinical investigators in all fields an awareness of the tools required to ensure research protocols are well designed and comply with the rigorous regulatory requirements necessary to maximize the safety of research subjects. Complete with sections on the history of clinical research and ethics, copious figures and charts, and sample documents it serves as an excellent companion text for any course on clinical research and as a must-have reference for seasoned researchers.*Incorporates new chapters on Managing Conflicts of Interest in Human Subjects Research, Clinical Research from the Patient's Perspective, The Clinical Researcher and the Media, Data Management in Clinical Research, Evaluation of a Protocol Budget, Clinical Research from the Industry Perspective, and Genetics in Clinical Research *Addresses the vast opportunities for translation of basic science observations to the bedside through clinical research*Delves into data management and addresses how to collect data and use it for discovery*Contains valuable, up-to-date information on how to obtain funding from the federal government
Front cover 1
Principles and Practice of Clinical Research 4
Copyright page 5
Table of contents 6
Preface 12
Acknowledgements 14
Contributors 16
Chapter 1: A Historical Perspective on Clinical Research 18
1. THE EARLIEST CLINICAL RESEARCH 18
2. THE GREEK AND ROMAN INFLUENCE 19
3. MIDDLE AGES AND RENAISSANCE 19
4. SEVENTEENTH CENTURY 20
5. EIGHTEENTH CENTURY 21
6. NINETEENTH CENTURY 23
7. TWENTIETH CENTURY AND BEYOND 27
Acknowledgment 29
References and Notes 29
PART I: ETHICAL, REGULATORY, AND LEGAL ISSUES 32
Chapter 2: Ethical Principles in Clinical Research 32
1. DISTINGUISHING CLINICAL RESEARCHFROM CLINICAL PRACTICE 32
2. WHAT DOES ETHICS HAVE TO DOWITH CLINICAL RESEARCH? 32
3. HISTORY OF ETHICAL ATTENTION TOCLINICAL RESEARCH 33
4. CODES OF RESEARCH ETHICSAND REGULATIONS 34
5. ETHICAL FRAMEWORK FORCLINICAL RESEARCH 35
6. ETHICAL CONSIDERATIONS IN RANDOMIZED CLINICAL TRIALS 40
7. CONCLUSION 42
References 42
Chapter 3: Researching a Bioethical Question 44
1. TYPES OF BIOETHICAL ISSUES 44
2. TYPES OF BIOETHICAL RESEARCH METHODOLOGIES 44
3. EXAMPLES OF IMPORTANT BIOETHICAL RESEARCH 45
4. SPECIAL CONSIDERATIONS INBIOETHICAL RESEARCH 52
References and Notes 54
Chapter 4: Integrity in Research: Individual and Institutional Responsibility 56
1. GUIDELINES FOR THE CONDUCTOF RESEARCH 56
2. SCIENTIFIC INTEGRITY AND MISCONDUCT 57
3. MENTOR–TRAINEE RELATIONSHIPS 58
4. DATA ACQUISITION, MANAGEMENT, SHARING, AND OWNERSHIP 58
5. RESEARCH INVOLVING HUMAN AND ANIMAL SUBJECTS 59
6. COLLABORATIVE SCIENCE 59
7. CONFLICT OF INTEREST AND COMMITMENT 60
8. PEER REVIEW 61
9. PUBLICATION PRACTICES AND RESPONSIBLE AUTHORSHIP 61
Acknowledgment 63
References 63
Chapter 5: Institutional Review Boards 64
1. HISTORICAL, ETHICAL, ANDREGULATORY FOUNDATIONSOF CURRENT REQUIREMENTSFOR RESEARCH INVOLVINGHUMAN SUBJECTS 64
2. INSTITUTIONAL REVIEW BOARDS 67
3. CLINICAL RESEARCHERSAND IRBs 73
4. THE CURRENT IRB SYSTEM UNDER EVALUATION 73
5. CONCLUSION 74
References and Notes 75
Chapter 6: Data and Safety Monitoring Boards 76
1. DESCRIPTION OF THE DATA ANDSAFETY MONITORING BOARD 76
2. DATA AND SAFETY MONITORINGBOARD FUNCTIONS 77
3. DATA AND SAFETY MONITORINGBOARD DECISION MAKING 78
4. EXAMPLES 79
5. CONCLUSIONS 81
References 81
Chapter 7: Data Management in Clinical Trials 84
1. THE RESEARCH TEAM 84
2. PLANNING THE TRIAL 86
3. WHERE ARE DATA? 86
4. WHO CAN COLLECT DATA? 86
5. SITE INITIATION VISIT 87
6. INFORMED CONSENT 87
7. ELIGIBILITY 87
8. REGISTRATION 88
9. WHAT DATA DO YOU COLLECT? 88
10. TREATMENT PLAN 89
11. CONCURRENT THERAPY 89
12. ADVERSE EVENT MONITORING 91
13. ROUTINE MONITORING VISITS 91
14. AUDIT TRAIL 92
15. ELECTRONIC DATABASE 92
16. SUMMARY 92
References 92
Chapter 8: Unanticipated Risk in Clinical Research 94
1. THE REASONS 95
2. THE DRUG 96
3. THE TARGET 98
4. THE TRIALS 98
5. CASSANDRA REVEALED 99
6. EXTENDED STUDIES 100
7. FIAU TOXICITY 100
8. REASSESSING THEPRECLINICAL STUDIES 101
9. RESEARCH OVERSIGHT 102
10. THE INVESTIGATIONS BEGIN 103
11. SCIENTIFIC MISCONDUCT 103
12. THE FDA 104
13. THE NATIONAL INSTITUTES OF HEALTH 105
14. THE INSTITUTE OF MEDICINE 105
15. THE MEDIA 106
16. THE CONGRESS 107
17. THE LAW 107
18. EPILOGUE 108
Acknowledgments 110
References 110
Chapter 9: The Regulation of Drugs and Biological Products by the Food and Drug Administration 114
1. INTRODUCTION 114
2. BACKGROUND 114
3. MISSION, ORGANIZATION,AND TERMINOLOGY 115
4. DRUG AND BIOLOGIC LIFE CYCLE 117
5. Summary 124
Chapter 10: Legal Issues 126
1. LEGAL ISSUES RELATED TOINFORMED CONSENT FOR CLINICAL ANDRESEARCH CARE 126
2. ADVANCE DIRECTIVES/SUBSTITUTE CONSENT 127
3. CHILDREN IN RESEARCH 129
4. MEDICAL/RESEARCH RECORDS 130
5. CONFIDENTIALITY 130
6. LEGAL LIABILITY 131
7. CONFLICT OF INTEREST 132
8. AUTHORSHIP/RIGHTS IN DATA 133
References and Notes 134
Further Reading 134
Appendix: NIH Advance Directive for Health Careand Medical Research Participation 135
Chapter 11: Rules to Prevent Conflict of Interest for Clinical Investigators Conducting Human Subjects Research 138
1. PREVENTING CONFLICT OF INTERESTIN CLINICAL RESEARCH IN THE NIHINTRAMURAL RESEARCH PROGRAM 139
2. PREVENTING CONFLICT OF INTEREST BY MEMBERS OF INSTITUTIONAL REVIEW BOARDS 140
References 140
Appendix: A Guide to Preventing Financial and Non-financial Conflicts of Interest in Human Subjects Research at NIH 141
I. WHAT ARE A CLINICALINVESTIGATOR’S POTENTIALCONFLICTS OF INTEREST? 141
II. TO WHOM DOES THE GUIDE APPLY? 141
III. EXAMPLES OF INVESTIGATOR ANDIRB AND DSMB MEMBER FINANCIALCONFLICTS OF INTEREST 141
IV. EXAMPLES OF NON-FINANCIAL REAL OR APPARENT CONFLICTS OF INTEREST FOR IRB AND DSMB MEMBERS 142
V. NIH’S SYSTEM TO ASSIST INIDENTIFYING AND PREVENTINGFINANCIAL CONFLICTS FORINVESTIGATORS IN CLINICALRESEARCH 142
VI. IRB AND DSMB CLEARANCEFOR COI 143
VII. NIH INTELLECTUAL PROPERTYAND ROYALTIES 143
Chapter 12: National Institutes of Health Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research 146
1. NIH POLICY 147
2. FOCUS ON SCIENTIFICCONSIDERATIONS 149
3. ROLE OF THE NIH OFFICE OFRESEARCH ON WOMEN’S HEALTH 149
4. ROLE OF PEER REVIEW 150
5. ROLE OF THE INSTITUTIONALREVIEW BOARD 151
6. ROLE OF VOLUNTEERS ANDTHEIR COMMUNITIES 151
7. DEMOGRAPHIC DATA ONSUBJECT ENROLLMENT 153
8. WOMEN OF CHILDBEARINGPOTENTIAL, PREGNANT WOMEN,AND CHILDREN 154
9. FUTURE QUESTIONS 155
10. CONCLUSIONS 156
Acknowledgments 157
References and Notes 157
Chapter 13: Clinical Research: A Patient Perspective 160
1. THE PATIENT–SCIENTISTPARTNERSHIP 160
2. WALKING AWAY: WHY PATIENTSREFUSE TO PARTICIPATE INCLINICAL TRIALS 162
3. THE TRIAL BEGINS: UNDERSTANDING THE PATIENT EXPERIENCE 164
4. UNDERSTANDING THE CAREGIVER 166
5. THE ROLE OF PALLIATIVE CARE 166
6. MANAGING DIFFICULT NEWS 167
7. EFFECTIVE PATIENTCOMMUNICATIONS:RECOMMENDATIONS ANDCONSIDERATIONS 168
8. THE ASSERTIVE PATIENT: ALLY INSCIENTIFIC RESEARCH 169
9. CONCLUSION 170
Further Reading 170
Chapter 14: The Clinical Researcher and the Media 172
1. WHAT MAKES NEWS IN SCIENCEAND MEDICINE? 173
2. WHY TALK TO REPORTERS? 174
3. WHY REPORTERS WANT TO TALK TO YOU 174
4. WHY YOU SHOULD TALK TO REPORTERS 175
5. ENGAGING THE MEDIA:THE PROCESS 175
6. A WORD ABOUT E-MAIL ANDTHE INTERNET 176
7. THE INTERVIEW 176
8. WHAT IF YOU ARE MISQUOTED? 178
9. WHAT THE PUBLIC DOES NOT KNOWABOUT SCIENCE 178
10. UNEXPECTED QUESTIONS 178
11. WHEN THE NEWS IS NOT GOOD 178
12. A WORD ABOUTINVESTIGATIVE REPORTERS 179
13. THE FREEDOM OFINFORMATION ACT 179
14. EMBARGOES 179
15. THE INGELFINGER RULE 180
16. CLINICAL ALERTS 180
17. WHEN TO CONTACT YOURCOMMUNICATIONS OFFICE 180
18. CONCLUSION 180
PART II: BIOSTATISTICS AND EPIDEMIOLOGY 182
Chapter 15: An Introduction to Biostatistics: Randomization, Hypothesis Testing, and Sample Size Estimation 182
1. INTRODUCTION 182
2. ISSUES IN RANDOMIZATION 184
3. OVERVIEW OF HYPOTHESIS TESTING 191
4. SAMPLE SIZE AND POWER 203
5. SPECIAL CONSIDERATIONS 209
6. CONCLUSION 212
References 212
Chapter 16: Design and Conduct of Observational Studies and Clinical Trials 214
1. TYPES OF EPIDEMIOLOGICSTUDY DESIGNS 214
2. ECOLOGICAL (CORRELATIONAL)STUDIES 215
3. CASE REPORTS AND CASE SERIES 216
4. PREVALENCE SURVEYS ORCROSS-SECTIONAL STUDIES 216
5. CASE–CONTROL STUDIES 218
6. PROSPECTIVE OR LONGITUDINALCOHORT STUDIES 222
7. CAUSAL INFERENCE INOBSERVATIONAL STUDIES 224
8. CLINICAL TRIALS 224
9. CONDUCT OF EPIDEMIOLOGICSTUDIES: THE STUDY PROTOCOL 227
References 233
Chapter 17: Small Clinical Trials 236
1. INTRODUCTION 236
2. WHERE WE ARE IN THE SHORTHISTORY OF CONTROLLEDCLINICAL TRIALS 236
3. EXPLANATORY VERSUS PRAGMATICORIENTATION IN CLINICAL TRIALS:IMPLICATIONS FOR STUDY DESIGN 237
4. ISSUES IN SMALL CLINICAL TRIALSTHAT EXAMINE BOTH DISEASEMECHANISM AND TREATMENT EFFICACY 238
5. PLACEBO RESPONSES IN CLINICAL TRIALS 245
6. CONCLUSION 250
References 250
Chapter 18: Large Clinical Trials and Registries—Clinical Research Institutes 254
1. INTRODUCTION 254
2. HISTORY 254
3. PHASES OF EVALUATION OF THERAPIES 255
4. CRITICAL GENERAL CONCEPTS 255
5. EXPRESSING CLINICALTRIAL RESULTS 256
6. CONCEPTS UNDERLYING TRIAL DESIGN 259
7. GENERAL DESIGN CONSIDERATIONS 261
8. LEGAL AND ETHICAL ISSUES 262
9. HYPOTHESIS FORMULATION 266
10. PUBLICATION BIAS 267
11. STATISTICAL CONSIDERATIONS 267
12. META-ANALYSIS AND SYSTEMATIC OVERVIEWS 269
13. UNDERSTANDING COVARIATES AND SUBGROUPS 270
14. THERAPEUTIC TRUISMS 271
15. STUDY ORGANIZATION 272
16. INTEGRATION INTO PRACTICE 275
17. CONTROVERSIES ANDPERSONAL PERSPECTIVE 275
18. THE FUTURE 278
References 278
Chapter 19: Using Secondary Data in Statistical Analysis 282
1. TECHNIQUES OF META-ANALYSIS 282
2. META-ANALYSIS OF CLINICAL TRIALSOF ANTI-INFLAMMATORY AGENTSIN SEPSIS 284
3. CONCLUSIONS 285
References 287
Chapter 20: An Introduction to Survival Analysis 290
1. FEATURES OF SURVIVAL DATA 290
2. SURVIVAL FUNCTION 291
3. SPECIAL CONSIDERATIONS 297
4. CONCLUSION 298
References 298
Chapter 21: Measures of Function and Health-Related Quality of Life 300
1. INTRODUCTION TO FUNCTION ANDQUALITY OF LIFE 300
2. DEFINITION OF QUALITY OF LIFE 301
3. HEALTH-RELATED QUALITY OFLIFE MEASURES 302
4. OTHER INSTRUMENTS TO CONSIDER 305
5. IMPORTANCE OF QUALITY OF LIFEMEASURES FOR HEALTH CARE 305
References 306
PART III: TECHNOLOGY TRANSFER, PROTOCOL DEVELOPMENT, FUNDING AND OTHER ISSUES 308
Chapter 22: Overview of Technology Development 308
1. INTRODUCTION 308
2. SCENARIO: DISASTERS WAITING TO HAPPEN 309
3. THE FIRST AND BIGGEST MISTAKE:SIGNING THE AGREEMENTS 310
4. AGREEMENTS NOT TO DISCLOSE:TRADE SECRETS ANDTHE CONFIDENTIALDISCLOSURE AGREEMENT 312
5. AGREEMENTS TOTRANSFER MATERIALS 315
6. COLLABORATION AND INVENTIONS:THE COOPERATIVE RESEARCH ANDDEVELOPMENT AGREEMENT 320
7. PROPRIETARY MATERIALS: THEMATERIALS CRADA 325
8. TRADEMARKS AND COPYRIGHTS FORTHE GOVERNMENT SCIENTIST 326
9. CONCLUSION 328
References and Notes 329
Chapter 23: Technology Transfer 332
1. WHAT IS TECHNOLOGY TRANSFER? 332
2. PATENTS AS INTELLECTUAL PROPERTY 332
3. RATIONALE FOR USING PATENTS 333
4. HISTORICAL BEGINNINGS OF PATENTS 335
5. 35 U.S.C. 101: CONCEPTS OF NEWAND USEFUL 336
6. 35 U.S.C 102: CONCEPT OF NOVELTY 338
7. 35 USC 103: CONCEPT OF OBVIOUSNESS 342
8. MORE IS NEEDED TO ESTABLISH THEQUID PRO QUO 343
9. 35 U.S.C. 112 AND THE NEED TO KNOW 343
10. PROCEDURES FOR PROSECUTING APATENT APPLICATION AT THE USPTO 345
11. OBTAINING FOREIGN PATENTS 346
12. THE NIH PATH TO FILINGPATENT APPLICATIONS 347
13. THE NIH LICENSING PROCESS 349
14. OTHER OTT FUNCTIONS 350
15. CONCLUSION: THE MEASURE OF NIH TECHNOLOGY TRANSFER IS ITS SUCCESS 350
Acknowledgments 351
References 351
Chapter 24: Writing a Protocol 352
1. TYPES OF PROTOCOLS 352
2. WRITING A PROTOCOL 352
3. WHAT HAPPENS TO YOUR PROTOCOL? 353
4. ESSENTIAL ELEMENTS TO THE PROTOCOL 353
References 356
Chapter 25: Evaluating a Protocol Budget 358
1. INTRODUCTION 358
2. REQUIREMENTS 358
3. ESTABLISHING A PROTOCOL BUDGET 363
4. Summary 365
Chapter 26: Data Management in Clinical Research: General Principles and a Guide to Sources 368
1. INTRODUCTION 368
2. THE DIMENSIONS OF DATA 368
3. KINDS OF DATA 369
4. GENERAL CONSIDERATIONS 370
5. DOCUMENTS THAT GOVERN DATA MANAGEMENT 370
6. SUMMARY 374
References 375
Chapter 27: Getting the Funding You Need to Support Your Research: Navigating the National Institutes of Health Peer Review Process 376
1. OVERVIEW OF NIH 377
2. THE NIH PEER REVIEW PROCESSFOR GRANTS 382
3. HINTS FOR PREPARING BETTERGRANT APPLICATIONS 390
4. NIH AWARD MECHANISMSFOR SUPPORT OF CLINICALRESEARCHERS AT VARIOUS STAGES INTHEIR CAREERS 400
5. OTHER NIH PROGRAMS FORCLINICAL RESEARCHERS 403
6. NEW DIRECTIONS AND INITIATIVES AT NIH 405
7. HOW TO STAY INFORMED ABOUT THE NIH PEER REVIEW SYSTEM 407
Chapter 28: Clinical Research from the Industry Perspective 408
1. COMPONENTS OF THEPHARMACEUTICAL INDUSTRY 408
2. ISSUES IMPACTING INDUSTRYCLINICAL RESEARCH 413
3. INDUSTRY OUTLOOK 418
4. SUMMARY 419
References 419
Chapter 29: Human Genome Project, Genomics, and Clinical Research 422
1. OVERVIEW 422
2. GENETIC MODELS 423
3. COMPLEX TRAIT DISSECTION 424
4. SAMPLE COLLECTION ANDINFORMED CONSENT 425
5. APPROACH TO GENOTYPING 427
6. LINKAGE ANALYSIS (PARAMETRIC) 428
7. NONPARAMETRIC ANALYSIS 430
8. ASSOCIATION AND LINKAGEDISEQUILIBRIUM 431
9. GENE IDENTIFICATION 434
10. INTEGRATION OF GENETICS INTOMEDICAL PRACTICE 435
11. SUMMARY 436
Further Reading 436
References 436
Index 438
CHAPTER 1 A Historical Perspective on
Clinical Research
JOHN I. GALLIN,
National Institutes of Health Clinical Center, Bethesda, Maryland
If I have seen a little further it is by standing on the shoulders of giants.
—Sir Isaac Newton, 1676
The successful translation of a basic or clinical observation into a new treatment of disease is rare in an investigator’s professional life, but when it occurs, the personal thrill is exhilarating and the impact on society may be substantial. The following historical highlights provide a perspective of the continuum of the clinical research endeavor. These events also emphasize the contribution that clinical research has made to advances in medicine and public health.
In this chapter, and throughout this book, a broad definition of clinical research of the Association of American Medical Colleges Task Force on Clinical Research is used.1 That task force defined clinical research as
a component of medical and health research intended to produce knowledge essential for understanding human disease, preventing and treating illness, and promoting health. Clinical research embraces a continuum of studies involving interaction with patients, diagnostic clinical materials or data, or populations, in any of these categories: disease mechanisms; translational research; clinical knowledge; detection; diagnosis and natural history of disease; therapeutic interventions including clinical trials; prevention and health promotion; behavioral research; health services research; epidemiology; and community-based and managed care-based research.
1. THE EARLIEST CLINICAL RESEARCH
Medical practice and clinical research are grounded in the beginnings of civilization. Egyptian medicine was dominant from approximately 2850 bc to 525 bc. The Egyptian Imhotep, whose name means “he who gives contentment,” lived slightly after 3000 bc and was the first physician figure to rise out of antiquity.2 Imhotep was a known scribe, priest, architect, astronomer, and magician (medicine and magic were used together), and he performed surgery, practiced some dentistry,1 extracted medicine from plants, and knew the position and function of the vital organs.
There is also evidence that ancient Chinese medicine included clinical studies. For example, in 2737 bc Shen Nung, the putative father of Chinese medicine, experimented with poisons and classified medical plants,3 and I. Yin (1176-1123 bc), a famous prime minister of the Shang dynasty, described the extraction of medicines from boiling plants.4
Documents from early Judeo-Christian and Eastern civilizations provide examples of a scientific approach to medicine and the origin of clinical research. In the Old Testament, written from the 15th century bc to approximately the 4th century bc,5 a passage in the first chapter of the Book of Daniel describes a comparative “protocol” of diet and health. Daniel demonstrated the preferred diet of legumes and water made for healthier youths than the king’s rich food and wine:
Then Daniel said to the steward …
“Test your servants for ten days; let us be given vegetables to eat and water to drink. Then let your appearance and the appearance of the youths who eat the king’s rich food be observed by you, and according to what you see deal with your servants:
So he harkened to them in this matter; and tested them for ten days.
At the end of ten days it was seen that they were better in appearance and fatter in flesh than all the youths who ate the king’s rich food. So the steward took away their rich food and the wine they were to drink, and gave them vegetables.”
Daniel 1:11-16
The ancient Hindus also excelled in early medicine, especially in surgery, and there is evidence of Indian hospitals in Ceylon in 437 and 137 bc.4
2. THE GREEK AND ROMAN INFLUENCE
Although early examples of clinical research predate the Greeks, Hippocrates (460-370 bc) is considered the father of modern medicine, and he exhibited the strict discipline required of a clinical investigator.
His emphasis on the art of clinical inspection, observation, and documentation established the science of medicine. In addition, as graduating physicians are reminded when they take the Hippocratic oath, he provided physicians with high moral standards. Hippocrates’ meticulous clinical records were maintained in 42 case records representing the first known recorded clinical observations of disease.6 These case studies describe, among other maladies, malarial fevers, diarrhea, dysentery, melancholia, mania, and pulmonary edema with remarkable clinical acumen.
On pulmonary edema, he wrote the following:
Water accumulates; the patient has fever and cough; the respiration is fast; the feet become edematous; the nails appear curved and the patient suffers as if he has pus inside, only less severe and more protracted. One can recognize that it is not pus but water … if you put your ear against the chest you can hear it seethe inside like sour wine.7
Hippocrates also described the importance of cleanliness in the management of wounds. He wrote, “If water was used for irrigation, it had to be very pure or boiled, and the hands and nails of the operator were to be cleansed.”8 Hippocrates’ teachings remained dominant and unchallenged until Galen of Pergamum (ca. 130-200 ad), the physician to the Roman Emperor Marcus Aurelius.9 Galen was one of the first individuals to utilize animal studies to understand human disease. By experimenting on animals, he was able to describe the effects of transection of the spinal cord at different levels. According to Galen, health and disease were the balance of four humors (blood, phlegm, black bile, and yellow bile), and veins contained blood and the humors, together with some spirit.9
3. MIDDLE AGES AND RENAISSANCE
In the Middle Ages, improvements in medicine became evident, and the infrastructure for clinical research began to develop. Hospitals and nursing, with origins in the teachings of Christ,10 became defined institutions (although the forerunner of hospitals can be traced to the ancient Babylonian custom of bringing the sick into the marketplace for consultation, and the Greeks and Romans had military hospitals). 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. The influences of Arabic pharmacy and the contact of the Crusaders with their Moslem foes spread the knowledge of Arabic pharmaceuticals and greatly enhanced the value of drugs from the Far East. The records of the customhouse at the port of Acre (1191-1291) show a lively traffic in aloes, benzoin, camphor, nutmegs, and opium.11
Documentation through case records is an essential 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 the practice of well-known physicians.12 Hippocrates’ approach of case studies developed 1700 years earlier was reborn, particularly in the Bolognese and Paduan regions of Italy. Universities became important places of medicine in Paris, Bologna, and Padua.
Clinical research remained mostly descriptive, resembling today’s natural history and disease pathogenesis protocols. In 1348, Gentile da Foligno, a Paduan professor, described gallstones.12 Bartolommeo Montagnana (1470), an anatomist, described strangulated hernia, operated on lachrymal fistula, and extracted decayed teeth.12 There was also evidence of the beginning of a statistical approach to medical issues during this period. For example, a 14th-century letter from Petrach to Boccaccio states that
I once heard a physician of great renown among us express himself in the following terms: … I solemnly affirm and believe, if a hundred or a thousand of men of the same age, same temperament and habits, together with the same surroundings, were attacked at the same time by the same disease, that if the one half followed the prescriptions of the doctors of the variety of those practicing at the present day, and that the other half took no medicine but relied on Nature’s instincts, I have no doubt as to which half would escape.13
The Renaissance (1453-1600) represented the revival of learning and transition from medieval to modern conditions; many great clinicians and scientists prospered. At this time, many of the ancient Greek dictums of medicine, such as Galen’s four humors, were discarded. Perhaps the most important anatomist of this period was Leonardo da Vinci (1453-1519) (Fig. 1-1).14 Da Vinci created more than 750 detailed anatomic drawings (Fig. 1-2).
FIGURE 1-1 Leonardo da Vinci self-portrait (red chalk); Turin, Royal Library. From reference 14, Figure 1.
FIGURE 1-2 Example of anatomic drawing by Leonardo da Vinci. Trunk of female human body, with internal organs seen as though ventral side were transparent. From reference 14, p....
| Erscheint lt. Verlag | 28.4.2011 |
|---|---|
| Sprache | englisch |
| Themenwelt | Medizin / Pharmazie ► Allgemeines / Lexika |
| Medizin / Pharmazie ► Medizinische Fachgebiete | |
| Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie | |
| Technik | |
| ISBN-10 | 0-08-048956-7 / 0080489567 |
| ISBN-13 | 978-0-08-048956-8 / 9780080489568 |
| Haben Sie eine Frage zum Produkt? |
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