P. Michael Dubinsky - The Fundamentals of Clinical Research

12 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.The sponsor will ensure that investigational products are manufactured, handled, and stored according to GMP. The sponsor will implement procedures for product handling, storage, and shipping from the distribution facility to investigators and for return, receipt, and destruction to the facility. The investigator will implement procedures for receipt, handling, storage, administration to subjects, and destruction or return of investigational product to the sponsor. The sponsor will also implement procedures to monitor the entire 'chain of custody' of the investigational products to ensure compliance with the protocol and applicable regulatory requirements. ( Chapter 17The Investigational Product (Clinical Supplies); Chapter 21Safety Monitoring and Reporting; Chapter 22Monitoring Overview).

13 2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented.All players, the IRB/IEC, investigator (and third parties), and sponsor (and CROs), will implement procedures that assure the quality of every aspect of the trial. Quality procedures include procedures for quality assurance and quality control, including establishing SOPs, training procedures, monitoring procedures, audit programs, ongoing quality control checks, and risk assessment and mitigation methods. (Source: ICH [1] Section on Quality in Clinical Trials).

The ICH E6(R2) presents a set of international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects (ICH E6(R2) Introduction). The Guideline includes principles that lay the foundation for the responsibilities and operational standards of GCP. It is important to understand the application of principles to guide the behavior and chain of reasoning for all who are involved in the conception, planning, and execution of a clinical trial in order to protect human subjects and ensure the integrity of trial data.

1 What is the definition of GCP?

2 What are the 13 principles of GCP?

3 How does each of the 13 principles of GCP apply to clinical research?

4 Overheard:“What is GCP?”Sponsor's associate responsible for filing documents in the trial master file.Comment and discuss:Why does the individual in this role need to know GCP?What aspect(s) of GCP would apply to his/her role?

1 1 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), Integrated Addendum to ICH E6(R1):Guideline for Good Clinical Practice, E6(R2) (2016). Current Step 4 version dated 9 November 2016. https://www.ich.org/page/efficacy‐guidelines

Karen A. Henry

Clinical trials should be conducted in accordance with GCP and the applicable regulatory requirement(s).

Who are the main players involved in the conduct of clinical research? To answer this question, let us first look at the reason clinical trials exist.

As we learned from the history of the evolution of clinical trials and drug development, there were incidents where many people were seriously or fatally harmed from using “medicinal” products that were sold on the market. The ensuing public outcry was heard by the government, and legislators created laws that evolved to ultimately require that a medicinal product must be proven to be safe and effective before it can be sold in the market place. ( Chapter 1Good Clinical Practice History)

Until a medicinal product is proven to be safe and effective, the product would be identified as “investigational.” The laws also state that the entity to decide if a product is safe and effective would be a representative of the government and that the method for first proving that a product is safe and effective would be through the conduct of a series of well‐controlled experiments, including trials on human subjects; hence, the requirement for clinical trials. The regulatory authorities established specific rules, regulations, and guidelines regarding clinical research for investigational products. The main players involved in clinical research conduct were identified as the Sponsor, Clinical Investigator, Institutional Review Board (IRB) or Independent Ethics Committee (IEC), the research participant, and the Regulatory Authority. The ICH E6(R2) guidance for Good Clinical Practice provides a unified standard for the generation of such clinical trial data that are intended to be submitted to regulatory authorities (ICH E6(R2) Introduction [1]).

ICH GCP Guidelines define roles and responsibilities for each player involved in the planning, executing, and reporting of a clinical trial: IRB/IEC, investigator, sponsor/CRO, regulatory agency, and research participant. This chapter will define the different types of players and describe their roles and interaction in clinical research. The details of each player's responsibilities are provided in the respective chapters for IRB/IEC ( Chapter 8), investigator and sponsor ( Chapter 9), the research volunteer ( Chapter 10), and the regulatory authority ( Chapter 11).

In this chapter topic we will answer the following questions:

1 Who are the main players involved in the conduct of clinical research?

2 How do the main players interact with each other in the clinical research arena?

The main players involved in the conduct of a clinical trial are: Sponsor, Investigator, IRB/IEC, Regulatory Authority, and Research Participant (Plate 3).

The Sponsor is the “owner” of an investigational product. The sponsor is interested in studying the clinical use of investigational product to determine its pharmacological properties, safety, and/or effectiveness in humans. By definition, the sponsor is:

An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. (ICH E6(R2) 1.53)

A Sponsor can be, for example, a pharmaceutical or biotechnology company, a nongovernmental organization (NGO), a governmental agency, an academic institution, a single individual or any entity that wants to take responsibility for the initiation, management, and/or financing of a clinical trial.

The Sponsor often is the financial owner and/or the developer of the product being investigated; however, the Sponsor may simply have access to the investigational product through an agreement with the financial owner or developer. In all instances, the Sponsor does not actually conduct the investigation (i.e., administer the investigational product to research subjects and record data from the study assessments), but will be legally responsible for all handling and use of the investigational product in the trial, the integrity of the trial data collected, and the submission of the trial findings to the Regulatory Authority. A Sponsor will usually be ultimately interested in getting approval for marketing their product or for publishing new information about the product.

The Clinical Investigator is the qualified doctor (or dentist) who administers the investigational product to the research subjects. By definition, an Investigator is: