P. Michael Dubinsky - The Fundamentals of Clinical Research

Contemporaneous with the development of the ICH GCP was the development of a set of GCP expectations by the World Health Organization [18]. Subsequent to the publication of the ICH GCP, a number of countries has published its own version by modifying the standard to include requirements that fit their regulatory model.

In the next Chapters we will outline the regulatory environment within which GCP is enabled.

The advent of the GCP Guideline and its adoption as a global reference for the conduct of human biomedical clinical trials is a story that emerges from a number of business and regulatory objectives that came together in the early 1990s. The chronology of regulatory legislation, historical incidents, and ethical policy development listed earlier formed the backdrop for the success of the ICH organization. It is noteworthy that GCP stood out as a key early guideline development project. Protection of trial subjects and the assurance that data can be trusted were central themes for regulators and the pharmaceutical drug manufacturers were keen to find the protocols which would have a universal appeal. The story of the ICH in general and the development of GCP in particular is one where everyone was a winner.

1 The emergence of legislative regulatory controls over pharmaceutical drug development and clinical trials was often prompted by:Protests from university medical students ______________Tragic outcomes from administration of unsafe and/or ineffective drug products_____________Promises made to voters by candidates for political office:______

2 Failure of medical researchers to apply ethical principles has never been a problem that needed solving? True ____ False ______

3 The Belmont Report was authorized by the National Research Act of 1974. True ____ False _______

4 The ICH Efficacy Guideline – GCP – is considered the industry standard for the conduct of human biomedical clinical trials with drug products. It was developed because:Of continuing abuses against study subjects by drug researchers _________The United States, Japan, and the European Union wanted manufacturers in their countries to have a monopoly on drug marketing _____________Manufactures and regulatory authorities wanted to establish harmonized standards to facilitate the mutual acceptance of clinical data supporting drug approval________

5 The ICH headquarters are located in the United States and the organization is under the US FDA. True __________ False ________

1 1 NIH1908. A short History of the National Institutes of Health, p. 3 http://history.nih.gov/exhibits/history/docs/page_03.html(accessed 11 November 2019)

2 2 Janssen, W.F. (1981). Story of the laws lehind the labels, Part 1. The 1906 Food and Drugs Act. https://wayback.archive‐it.org/7993/20170111191530/http://www.fda.gov/AboutFDA/WhatWeDo/History/Overviews/ucm056044.htm(accessed 27 November 2019)

3 3 FDA (2012). History of drug regulation in the United States, 1906–2006, p6, wayback.archive‐it.org/7993/20170114041745/ http://www.fda.gov/downloads/AboutFDA/WhatWeDo/History/ProductRegulation/PromotingSafeandEffectiveDrugsfor100Years/UCM114468.pdf(accessed 27 November 2019)

4 4 United States Holocaust Memorial Museum. United States Holocaust Memorial Museum Note https://www.ushmm.org/information/exhibitions/online‐exhibitions/special‐focus/doctors‐trial/nuremberg‐code(assessed 27 November 2019)

5 5 FDA (2012). Consumer updates, Kefauver‐Harris Amendments Revolutionized Drug Development http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm(accessed 27 November 2019)

6 6 World Medical Association (2018). WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects. https://www.wma.net/policies‐post/wma‐declaration‐of‐helsinki‐ethical‐principles‐for‐medical‐research‐involving‐human‐subjects/(accessed 27 November 2019)

7 7 Grady, C. Institutional review boards, purpose and challenges, commentary, chest, November 2015 (1148–1155) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631034/pdf/chest_148_5_1148.pdf(accessed 28 May 2020)

8 8 Centers for Disease Control and Prevention. U.S. Public Health Service Syphilis Study at Tuskegee. http://www.cdc.gov/tuskegee/timeline.htm(accessed 27 November 2019)

9 9 NIH (1908). National Research Act – Office of NIH History. https://history.nih.gov/research/downloads/PL93‐348.pdf(accessed 27 November 2019)

10 10 US Government Accountability Office. Federal control of new drug testing is not adequately protecting human test subjects and the public HRD‐76–96: published: Jul 15, 1976. publicly released: July 15, 1976. http://www.gao.gov/products/HRD‐76‐96. (accessed 27 November 2019)

11 11 US Department of Health and Human Services. Office of human research protections, the belmont report. http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html(accessed 27 November 2019)

12 12 ICH. The international council for harmonisation of technical requirements for pharmaceuticals for human use (ICH), http://www.ich.org/(accessed 27 November 2019)

13 13 ICH E6 (R2). ICH E6 (R2) (2016) INTEGRATED ADDENDUM TO ICH E6(R1):GUIDELINE FOR GOOD CLINICAL PRACTICE: International Council on Harmonization https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf(accessed 27 November 2019)

14 14 European Commission European commission directive 2001/20/EC, clinical trials. https://ec.europa.eu/health/human‐use/clinical‐trials/directive_en(accessed 27 November 2019)

15 15 ANSI WEBSTORE. Clinical Investigation of Medical Devices for Human Subjects ‐ Good Clinical Practice. International Standards Organization http://webstore.ansi.org/RecordDetail.aspx?sku=ISO%2014155:2011&source=google&adgroup=iso11&gclid=CO6fhuXkx70CFU5rfgodQGwA9Q(accessed 27 November 27, 2019).ISO 14155:2011

16 16 GPO. Federal register, 32467, Vol. 69, No. 112, Thursday, June 10, 2004 human subject protection; foreign clinical studies not conducted under an investigational new drug application – proposed rule http://www.gpo.gov/fdsys/pkg/FR‐2004‐06‐10/pdf/04‐13063.pdf(accessed 27 November 2019)

17 17 Authenticated U.S. Government Information. Federal register/Vol. 73, No. 82/Monday, April 28, 2008/Rules and regulations, human subject protection; foreign clinical studies not conducted under an investigational new drug application, final rule https://www.govinfo.gov/content/pkg/FR‐2008‐04‐28/pdf/E8‐9200.pdf(accessed 27 November 2019)

18 18 World Health Organization. Handbook for Good Clinical Research Practice. ISBN: ISBN 92 4 159392 X https://www.who.int/medicines/areas/quality_safety/safety_efficacy/gcp1.pdf.

P. Michael Dubinsky

Regulatory authorities along with medical institutions and professional groups form a network of controls which set the boundaries for human biomedical clinical trials thereby ensuring that GCP is followed.

Is it idealistic to think that all clinical research whether commercial, academic, governmental or otherwise will be conducted under ethical guidelines and according to best scientific and professional practices such as GCP? Unfortunately idealism has not always been the guiding force in human biomedical research and along the way governmental and professional oversight has been implemented to ensure that abuses are avoided. This chapter explores the regulatory environment that has evolved to oversee human biomedical clinical trials.