A Clinical Trials Manual From The Duke Clinical Research Institute

Lessons from a Horse Named Jim

Margaret Liu, Kate Davis

• Publisher: Wiley-Blackwell
• Year: 2011
• Print ISBN: 9781405195157
• eBook ISBN: 9781444357882
• Edition: 2
• Topic: Medicine
• Subtopic: Pharmacology

"The publication of the second edition of this manual comes at an important juncture in the history of clinical research. As advances in information technology make it possible to link individuals and groups in diverse locations in jointly seeking the answers to pressing global health problems, it is critically important to remain vigilant about moral and ethical safeguards for every patient enrolled in a trial. Those who study this manual will be well aware of how to ensure patient safety along with fiscal responsibility, trial efficiency, and research integrity."
— Robert Harrington, Professor of Medicine, Director, Duke Clinical Research Institute, Durham, North Carolina, USA

The Duke Clinical Research Institute (DCRI) is one of the world's leading academic clinical research organizations; its mission is to develop and share knowledge that improves the care of patients around the world through innovative clinical research. This concise handbook provides a practical "nuts and bolts" approach to the process of conducting clinical trials, identifying methods and techniques that can be replicated at other institutions and medical practices.

Designed for investigators, research coordinators, CRO personnel, students, and others who have a desire to learn about clinical trials, this manual begins with an overview of the historical framework of clinical research, and leads the reader through a discussion of safety concerns and resulting regulations. Topics include Good Clinical Practice, informed consent, management of subject safety and data, as well as monitoring and reporting adverse events.

Updated to reflect recent regulatory and clinical developments, the manual reviews the conduct of clinical trials research in an increasingly global context. This new edition has been further expanded to include:

• In-depth information on conducting clinical trials of medical devices and biologics
• The role and responsibilities of Institutional Review Boards, and
• Recent developments regarding subject privacy concerns and regulations.

Ethical documents such as the Belmont Report and the Declaration of Helsinki are reviewed in relation to all aspects of clinical research, with a discussion of how researchers should apply the principles outlined in these important documents. This graphically appealing and eminently readable manual also provides sample forms and worksheets to facilitate data management and regulatory record retention; these can be modified and adapted for use at investigative sites.

1

Lessons from a Horse Named Jim and Other Events in History Affecting the Regulation of Clinical Research

In this Chapter

Milestones in the history of food and drug safety -from the first food laws to the founding of the FDA to the Privacy Rule

“It had become clear to me that medicine could hardly hope to become a science until… qualified men could give themselves to uninterrupted study and investigation. I knew nothing of the cost of research; I did not realize its enormous difficulty; the only thing I saw was the overwhelming and universal need and the infinite promise, world-wide, universal, and eternal.”

John D. Rockefeller (1839-1937), American Industrialist and Philanthropist

A Clinical Trials Manual From The Duke Clinical Research Institute: Lessons From A Horse Named Jim, 2^nd edition. By Margaret B. Liu and Kate Davis. Published 2010 by Blackwell Publishing

The First Clinical Trial?

The Book of Daniel in the Bible describes a comparative trial – in which Daniel experiments with feeding youthful palace servants legumes and porridge rather than the rich meats eaten by the king and his court.

The Result?

“And at the end of ten days their countenances appeared fairer and fatter in flesh than all the children which did eat the portion of the king’s meat.” (Daniel 1:15 KJV)

The Jungle by Upton Sinclair

Published in 1906, this novel described the lives of people working in Chicago stockyards and slaughterhouses. Sinclair wrote about poisoned rats being ground up in meat, the slaughter of diseased animals, and chemicals used to disguise the smell of rotten meat. The description of meat factories as unsanitary and rat-infested outraged the public. When the sales of American meat dropped dramatically, meat packing companies lobbied the U.S. federal government to pass legislation for improved meat inspection and certification. Their efforts contributed to the passage of the Meat Inspection Act and the Food and Drugs Act of 1906.²

From the earliest days of civilization, people have been concerned about the quality, safety, and integrity of foods and medicines. The first known English food law was enacted in 1202 when King John of England proclaimed the Assize of Bread, a law prohibiting the adulteration of bread with ingredients such as ground peas or beans.¹ One of the earliest food and drug laws in U.S. history was enacted in 1785, when the state of Massachusetts passed the first general food adulteration law regulating food quality, quantity, and branding.

Since then, many events, often accompanied by tragic outcomes, have raised additional concerns related to food and drug safety. This has led in turn to the creation and adoption of regulations that affect the way we investigate and manufacture new products, including medicines and medical devices. The following are only some of the events and subsequent laws or responses, largely drawn from events in the past 150 years of American history that have shaped and defined how we conduct clinical research of investigational products in the U.S. today, as well as how we currently bring these products to market.

1848 The first U.S. federal regulation dates to this year, when American soldiers died as a result of ingesting adulterated quinine during the Mexican War. In response to these deaths, Congress passed the Drug Importation Act, requiring U.S. Customs to perform inspections aimed at stopping the importation of adulterated drugs from overseas.

1901 A horse named Jim was used to prepare an antitoxin for diphtheria. After 13 children who received the antitoxin died, authorities discovered that the horse had developed tetanus, thereby contaminating the antitoxin. This tragedy prompted Congress to pass the Biologics Control Act of 1902, giving the government regulatory power over antitoxin and vaccine development.

1906 In the early 1900s, the federal government completed a study about the effect of colored dyes and chemical preservatives on digestion and health. Study results, which showed that certain food preservatives and dyes were poisonous, drew widespread attention and public support for a federal food and drug law and resulted in the Food and Drugs Act of 1906. The original Food and Drugs Act prohibited interstate commerce of misbranded or adulterated food, drugs, and drinks. The Act also mandated truth-in-labeling, authorizing the federal government (enforced by the Bureau of Chemistry) to monitor food purity and the safety of medicines. Unfortunately, truth-in-labeling did not prevent companies from making false health claims about their products.

1931 As part of a Congressional effort to provide more thorough regulation of food and drug marketing, the Bureau of Chemistry was reorganized and renamed the Food, Drug, and Insecticide Administration in 1927. A few years later in 1931, it was again renamed, this time to its current title of the U.S. Food and Drug Administration (FDA).

1932 The Tuskegee Study of Untreated Syphilis in the Negro Male was initiated under the auspices of the U.S. Public Health Service. Research subjects, many of them poor African-American sharecroppers, included 399 men with latent syphilis and 201 without the disease who served as controls. The men were told that they were being treated for “bad blood” and were not told the purpose of the study. When penicillin became available in the 1950s, treatment was not offered to the men with syphilis. It was not until 1972 – 40 years after this study began – that it became widely known that the study followed the untreated course of syphilis and that subjects were deprived of effective treatment in order not to interrupt the project.³

1937 Sulfanilamide, introduced in 1935, was very effective in treating bacterial infections, but the pills were barely palatable. To make the drug easier for patients, especially children, to swallow, a chemist created a liquid solution in which the sulfanilamide was dissolved. Soon after this sulfanilamide product came on the market, there were reports of 107 deaths after patients, mostly children, ingested the medication labeled “elixir of sulfanilamide.” It was then discovered that it was not an elixir (by definition an alcohol solution), but a diethylene glycol (antifreeze) solution. The FDA successfully removed the product from the market, not because it proved fatal, but only because it was mislabeled. This incident highlighted the need for assuring drug safety before marketing.⁴

1938 The following year, Congress passed the Food, Drug, and Cosmetic Act of 1938. The Act expanded the FDA’s role, requiring proof of safety of new drugs before marketing, and extended the FDA’s control to include cosmetics and medical devices.

1940–45 At the end of World War II, the international community became aware that Nazi medical personnel had conducted medical experiments on non-German civilians and prisoners of war in concentration camps such as Auschwitz and Dachau. These experiments, which were done without the consent of the subjects and had no potential benefit to individual participants, included sterilization and euthanasia, as well as exposure to temperature extremes, simulations of high altitude (with reduced air pressure/oxygen), bacteria, and untested drugs.

The Nuremberg Code

1 Voluntary consent is absolutely essential

2 Results must be for the good of society and otherwise unobtainable

3 Trials must be based on animal experiments and knowledge of the natural history of the disease or condition

4 Trials must avoid unnecessary physical and mental suffering

5 Trials must not be conducted if injury or death is expected

6 Risks must be less than the importance of the problem

7 Subjects must be protected from harm or injury

8 Trials must be conducted by qualified people

9 Subjects have the freedom to stop at any time

10 Investigators have an obligation to stop if harm occurs

A Trial Account by Douglas O. Linder

“No trial provides a better basis for understanding the nature and causes of evil than do the Nuremberg trials from 1945 to 1949. Those who come to the trials expecting to find sadistic monsters are generally disappointed. What is shocking about Nuremberg is the ordinariness of the defendants: men who may be good fathers, kind to animals, even unassuming – yet committed unspeakable crimes.”⁶

1946–47 In 1946, the U.S. convened the Doctors’ Trial in Nuremberg, Germany, to try 20 German physicians (as well as three other Nazi officials) accused o...

Table of contents

• Cover
• Series page
• Title page
• Copyright
• Foreword
• Preface
• Abbreviations
• 1: Lessons from a Horse Named Jim and Other Events in History Affecting the Regulation of Clinical Research
• 2: The Process: Developing New Drugs, Biologics, and Devices
• 3: Good Clinical Practice and the Regulations
• 4: Informed Consent and the Regulations
• 5: Institutional Review Boards
• 6: Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others
• 7: Monitoring, Audits, and Inspections
• 8: The Principal Investigator, the Clinical Research Coordinator, and the Study Site
• 9: The Protocol
• 10: Study Feasibility: Reviewing a Specific Protocol
• 11: Study Activities
• 12: Study Documents/Essential Documents
• 13: Management of Study Drugs, Biologics, and Devices
• 14: Managing Clinical Trial Data
• 15: Global Health and International Trials
• Appendix A
• Appendix B
• Appendix C
• Appendix D
• Appendix E
• Epilogue
• Glossary
• Index