Principles and Practice of Clinical Research

John I. Gallin, Frederick P Ognibene

• Publisher: Academic Press
• Year: 2012
• ISBN:
  9780123821683
• Edition: 3
• Topic: Sciences biologiques
• Subtopic: Biologie moléculaire

The third 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

Part I

Ethical, Regulatory and Legal Issues

Chapter 1 A Historical Perspective on Clinical Research

Chapter 2 Ethical Principles in Clinical Research

Chapter 3 Researching a Bioethical Question

Chapter 4 Integrity in Research

Chapter 5 Institutional Review Boards

Chapter 6 The Role of Independent Institutional Review Boards

Chapter 7 The Regulation of Drugs and Biological Products by the Food and Drug Administration

Chapter 8 Data Management in Clinical Trials

Chapter 9 Data and Safety Monitoring

Chapter 10 Unanticipated Risk in Clinical Research

Chapter 11 Legal Issues

Chapter 12 Rules to Prevent Conflict of Interest for Clinical Investigators Conducting Human Subjects Research

Chapter 13 National Institutes of Health Policy on the Inclusion of Women and Minorities as Subjects in Clinical Research

Chapter 14 Accreditation of Human Research Protection Programs

Chapter 15 The Role and Importance of Clinical Trial Registries and Results Databases

Chapter 16 The Clinical Researcher and the Media

Chapter 17 Clinical Research

Chapter 1

A Historical Perspective on Clinical Research

John I. Gallin

National Institutes of Health Clinical Center, Bethesda, Maryland

Chapter Outline

The Earliest Clinical Research

Greek and Roman Influence

Middle Ages and Renaissance

Seventeenth Century

Eighteenth Century

Nineteenth Century

Twentieth Century and Beyond

Acknowledgment

Summary Questions

References

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 the book, a broad definition of clinical research from the Association of American Medical Colleges Task Force on Clinical Research is used.¹ This task force defined clinical research as

“a component of medical and health research intended to produce knowledge essential for understanding human disease, preventing and treating illness, and promoting health. Clinical research embraces a continuum of studies involving interaction with patients, diagnostic clinical materials or data, or populations, in any of these categories: disease mechanisms; translational research: clinical knowledge; detection; diagnosis and natural history of disease; therapeutic interventions including clinical trials; prevention and health promotion; behavioral research; health services research; epidemiology; and community-based and managed care-based research.”

The Earliest Clinical Research

Medical practice and clinical research are grounded in the beginnings of civilization. Egyptian medicine was dominant from approximately 2850 bc to 525 bc. The Egyptian Imhotep, whose name means “he who gives contentment,” lived slightly after 3000 bc and was the first physician figure to rise out of antiquity.² Imhotep was a known scribe, priest, architect, astronomer, and magician (medicine and magic were used together); he performed surgery, practiced some dentistry, extracted medicine from plants, and knew the position and function of the vital organs. Imhotep likely provided the first description of cancer in one of his 48 clinical case reports. In case 45, he reported, “If you examine (a case) having bulging masses on (the breast) and you find that they have spread over his breast; if you place your hand upon (the) breast (and) find them to be cool, there being no fever at all therein when your hand feels him; they have no granulations, contain no fluid, give rise to no liquid discharge, yet they feel protuberant to your touch you say concerning him: ‘This is a case of bulging masses I have to contend with…’ Bulging tumors of the breast mean the existence of swellings on the breast, large, spreading, and hard; touching them is like touching a ball of wrappings, or they may be compared with unripe hemat fruit, which is hard and cool to the touch.”³

Evidence also shows that ancient Chinese medicine included clinical studies. For example, in 2737 bc, Shen Nung, the putative father of Chinese medicine, experimented with poisons and classified medical plants,⁴ and I. Yin (1176–1123 bc), a famous prime minister of the Shang dynasty, described the extraction of medicines from boiling plants.⁵

Documents from early Judeo-Christian and Eastern civilizations provide examples of a scientific approach to medicine and the origin of clinical research. In the Old Testament, written from the 15th century bc to approximately the 4th century bc, ⁶ a passage in the first chapter of the Book of Daniel describes a comparative “protocol” of diet and health. Daniel described the preferred diet of legumes and water made for healthier youths compared with the king’s rich food and wine:

Then Daniel said to the steward…

“Test your servants for ten days; let us be given vegetables to eat and water to drink. Then let your appearance and the appearance of the youths who eat the king’s rich food be observed by you, and according to what you see deal with your servants.

So he harkened to them in this matter; and tested them for ten days.

At the end of ten days it was seen that they were better in appearance and fatter in flesh than all the youths who ate the king’s rich food. So the steward took away their rich food and the wine they were to drink, and gave them vegetables.”

Daniel 1:11–16

The ancient Hindus excelled in early medicine, especially in surgery. Sushruta, the father of Indian surgery, resided in the court of the Gupta kings in about 600 bc and wrote medical texts about surgery, the most famous being Sushruta Samhita, an encyclopedia of medical learning. In addition, there is evidence of Indian hospitals in Ceylon in 437 bc and 137 bc.⁷

Greek and Roman Influence

Although early examples of clinical research predate the Greeks, Hippocrates (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.⁸ These case studies describe, among other maladies, malarial fevers, diarrhea, dysentery, melancholia, mania, and pulmonary edema with remarkable clinical acumen.

On pulmonary edema, he wrote the following:

Water accumulates; the patient has fever and cough; the respiration is fast; the feet become edematous; the nails appear curved and the patient suffers as if he has pus inside, only less severe and more protracted. One can recognize that it is not pus but water…if you put your ear against the chest you can hear it seethe inside like sour wine.⁹

Hippocrates also described the importance of 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.”¹⁰

Hippocrates used the Greek word for “crab,” karkinos, to describe cancer. The tumor, with its clutch of swollen blood vessels around it, reminded Hippocrates of a crab dug in the sand with its legs spread in a circle.¹¹

Hippocrates’ teachings remained dominant and unchallenged until the time of Claudius Galen of Pergamum (ca. 130–200 ad), the physician to the Roman Emperor Marcus Aurelius.¹² 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 reflected the balance of four humors (blood, phlegm, black bile, and yellow bile), and veins contained blood and the humors, together with some spirit.¹² Inflammation, described by Galen as a red, hot, and painful distention, was attributed to excessive blood. Tubercles, pustules, catarrh, and nodules of lymph, all cool, boggy and white, were attributed to excesses of lymph. Jaundice was an overflow of yellow bile. Cancer was attributed to black bile as was melancholia, the medieval term for depression. Thus cancer and depression were closely intertwined.¹³

Middle Ages and Renaissance

In the Middle Ages, improvements in medicine became evident, and the infrastructure for clinical research began to develop. Hospitals and nursing, with origins in the teachings of Christ,¹⁴ became defined institutions (although the beginnings of hospitals can be traced to the ancient Babylonian custom of bringing the sick into the marketplace for consultation, and the Greeks and Romans had military hospitals).

The Persian al-Razi (865–925) 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 methodology, 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 customhouse at the port of Acre (1191–1291) show a lively traffic in aloes, benzoin, camphor, nutmegs, and opium.¹⁹ Influences 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 (980–1037), a leader in phar...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Acknowledgments
• Part I Ethical, Regulatory and Legal Issues
• Part II Biostatistics and Epidemiology
• Part III Technology Transfer, Protocl
• Part IV Clinical Research Infrastructure
• APPENDIX 1. Answer Key to Summary Questions
• APPENDIX 2. Principles and Practice of Clinical Research, 3rd Edition Acronyms by Chapter
• Index