Principles and Practice of Clinical Research

John I. Gallin,Frederick P Ognibene

• Publisher: Academic Press
• Year: 2011
• ISBN:
  9780080489568
• Edition: 2
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

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

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...