The Fundamentals of Clinical Research. P. Michael Dubinsky

GCP from as many vantage points as we can, and have expanded our discussion of the elements of GCP to include regulatory, scientific, technological, site investigator, sponsor, quality, and IRB viewpoints, as appropriate.

      We have focused the scope of our clinical research discussion on trials involving humans in a biomedical context. From an investigative product/test article perspective, the text favors pharmaceutical drugs since they are associated with the majority of clinical trials. Biological products fit into the same niche. We have also addressed medical devices, though we recognize that despite the similarities in areas such as regulatory controls in the United States, there is a plethora of differences. While we cannot discuss all of these differences, we have highlighted some of the most significant ones.

How to Use this Book

      This text is divided into sections that contain relevant chapters on the history of GCP, drug development in the regulatory environment, the GCP framework, GCP for the individual clinical trial, and quality in clinical trials. Each chapter builds on a key GCP concept and contains chapter objectives, content, a summary, and a set of knowledge check questions so that the reader can self‐check their learning and comprehension. The ICH‐GCP Guidelines serve as the glossary of terms and definitions. Plates visually summarize the content for certain chapters, and the reader is also able to cross‐reference details in pertinent chapters from the plates. Figures, tables, and other illustrations also enhance the text materials.

Opinion of the Authors

      The authors of this text have a combined approximately 76 years of experience working in various areas of clinical research, as well as approximately 25 years of experience as part‐time instructors in university‐sponsored classrooms and online courses of study designed to introduce students to the clinical research industry. They have also developed some of the educational and learning materials that make up these university‐sponsored courses. This text is written from their individual viewpoints as they have interpreted and applied the GCP Guidelines. Except for direct references to the ICH E6 (R2) Guideline or other sources, all statements are the opinions of the authors.

      The authors would like to thank Kay Ranganathan for introducing them to the instructional arena for clinical research; their esteemed colleagues for their review of the manuscript; and their families for their patience and support through the times when writing this book got in the way of family life.

About the Authors

P. Michael Dubinsky has more than 40 years of experience in the field of GxP quality and compliance in government and industry. He has worked with the FDA and as a regulatory consultant for private corporations. He was also an Instructor in the areas of clinical trial compliance, regulatory audits, and quality at the University of California Berkeley Extension Programs.

      Karen A. Henry has worked as a clinical research professional since 1990. She has expertise in regulatory medical writing, standards and processes, trial management and monitoring, biostatistics, and data management. She is also a Lead Instructor for the Certificate Program in Clinical Research Conduct Management at the University of California Berkeley Extension Programs.

About the Authors

      This book is accompanied by a companion website.

       www.wiley.com/go/dubinsky/clinicalresearch

      This website includes:

       Solutions to the Problems

       Further References Section

      Protocol Synopsis and Schedule of Trial Activities Template

Part I Good Clinical Practice History

1 History

       P. Michael Dubinsky

      GCP Key Point

       Good Clinical Practice might be termed a cultural approach to applying ethics and integrity to human biomedical clinical trials with investigational products.

1.1 Introduction

      This chapter will briefly outline the history of biomedical clinical trials from the standpoints of regulatory oversight and ethical expectations and the emergence of good clinical practice (GCP).

1.2 Objectives

      The objectives of this chapter are to:

       Provide an outline of legislation, events, and circumstances which provide the background and history for the development of the ICH GCP Guideline E6 R2.

       Offer thoughts and points of view on why the GCP mindset emerged among the global regions most involved in pharmaceutical drug development occurred.

1.3 Chronology

If you research the history of GCP, you will find that it is aligned with the events which form the stepping stones on the pathway of clinical trial regulation. The best known events involve abuses of humans during medical experimentation and the subsequent legislative and regulatory initiatives to prevent the recurrence of those abuses. The following events, policies, and legislation stand out.

       1902 – The Biologics Control Act [1] is enacted by the US Congress requiring licensing of vaccines, serums, and similar products. The legislation was prompted by the distribution of a contaminated batch of diphtheria antitoxin contaminated with tetanus which killed 13 children. This legislation eventually became part of the Public Health Service Act and serves as the primary regulatory control for the same group of products which now includes cell therapies and many biotechnology‐derived products.

       1906 – The Food and Drugs Act [2] is passed by the US Congress and gives the Federal Government control over misbranded or adulterated drugs.

       1938 – The US Congress enacts the Federal Food, Drug and Cosmetic Act (FFDCA) [3] in part due to the Elixir of Sulfanilamide [3] episode in which 107 deaths occurred. The new law required proof of safety prior to marketing and drew cosmetics and therapeutic devices into the regulatory scheme.

       1949 – The Nuremburg Code [4] is born out of the criminal trials of Nazi researchers who conducted unethical experiments on humans during WWII. The Code is a set of 10 points that establishes a foundation for voluntary consent of research subjects as well as most of the key ethical principles which emerge in subsequent documents.

       1962 – The Kefauver–Harris Drug Amendments to the FFDCA [5] required that drugs must demonstrate efficacy as well as safety and the investigational new drug (IND) application as we know it today is launched in the regulations. One of the driving forces behind these legislative amendments to the FFDCA was the thalidomide tragedy of 1961 when newborns suffered severe birth defects. The FDA’s IND regulations followed circa 1963.

       1964 – The Declaration of Helsinki [6] takes the ethical principles for conducting research on humans to a new level through the efforts of the World Medical Association.

       1965 – The US National Institutes of Health proposed that their research involving humans be examined by an impartial panel of peers to ensure ethical integrity. By 1971 the Public health Services’ policy of ethical review for human research was expanded to include Department of Health Education and Welfare research however the policy