Feature Article

GCP - What Is It and Why Does It Matter To Me?
June 2010 Issue

Sylvia Baedorf Kassis, MPH
Regulatory Education Manager, CRRO
Author has nothing to disclose with regards to commercial support.

Educational Objectives:

At the end of this activity, participants should be able to:

• Define “GCP”;
• Explain why GCP is relevant to all clinical (human) research studies;
• List the thirteen core principles of GCP; and
• Identify resources to guide the implementation of GCP in the conduct of clinical research.

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• Introduction
• Defining GCP
• Why should I follow GCP?
• How do I follow GCP?
• Consequences of Not Following GCP
• Conclusion
• References
• Quiz

Introduction

Whether conducting research involving a new drug, a behavioral intervention, or an interview/survey, Good Clinical Practice (GCP) provides investigators and their study teams with the tools to protect human subjects and collect quality data.  In this article, the author will define GCP, explain the benefits of following GCP for all types of human research studies, and provide some resources to assist investigators in implementing the tenets of GCP for their own research studies.

Defining GCP

Most clinical investigators are familiar with the term Good Clinical Practice (GCP), although their interpretation of its meaning and applicability vary enormously.  According to “Good Clinical Practice: A Question and Answer Reference Guide”, published in May 2010, GCP has traditionally been a general term used by United States (US) government agencies, industry, and clinical researchers to describe the collection of related regulations and guidelines that, when combined, define the clinical study-related responsibilities of sponsors, investigators, monitors, institutional review boards, and others involved in the clinical research processⁱ.   For many years, GCP responsibilities in the US were defined primarily in four Food and Drug Administration (FDA) documents released in the 1980s:

• a 1981 regulation on the informed consent of clinical research subjects (now 21 CFR Part 50)
• a 1981 regulation on the responsibilities of Institutional Review Boards (now 21 CFR Part 56)
• the 1987 Investigational New Drug (IND) regulations which defined the responsibilities of the investigator and the sponsor (now 21 CFR Part 312); and
• The 1988 “Guideline for the Monitoring of Clinical Investigations,” which outlines the responsibilities of study monitors.

Beyond the scope of the aforementioned documents, however, GCP is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjectsⁱⁱ.

History has provided more than enough evidence to demonstrate the need for a comprehensive, international research standard to protect human subjects and generate valid, reproducible research study data.  The human experimentation atrocities of World War II led to the creation of the Nuremberg Code and Declaration of Helsinki, which was an initial step.  However, medical tragedies, such as the effects of thalidomide on newborns in the 1960sⁱⁱⁱ and the complex problems obtaining marketing authorizations for drugs in multiple countries with differing research standards, have created a further demand for an international standard to be developed.

In an attempt to provide consistency among clinical trials, in 1996 the US, European Union, and Japan established a unified standard, called the International Conference on Harmonisation’s “Good Clinical Practice: Consolidated Guideline,” (herein, ICH-GCP). Initially, ICH-GCP focused on drug and biological products trials.  In the United States ICH-GCP has most often been associated with FDA-regulated research (adopted by the FDA as a guidance in 1997).   Recently, however, the general concept of GCP as being essential to any research study involving human subjects has been gaining ground (with ICH-GCP being just one example of an international standard).

Part 2 of the ICH-GCP guidance outlines thirteen core principles of GCP (see Table 1 below).  These principles delineate the responsibilities of individuals and organizations involved in or associated with the activities of a clinical trial. 

Additionally, ICH-GCP provides guidelines for Institutional Review Board (IRB) review, details investigator and sponsor responsibilities, provides guidance related to data and safety monitoring, and makes recommendations for the structure of essential clinical trial documents such as protocols, amendments, and investigational brochures. Some clinical trials professionals go so far as to call ICH-GCP “the bible” for the proper conduct of research^iv .  However, the introduction of a new guidance on top of so many other research requirements has some investigators fearing a greater administrative burden rather than welcoming a tool of integrity and efficiency.

Why should I follow GCP?

 While ICH-GCP iswidely considered to be the gold standard for the conduct of clinical trials, some investigators of studies that are not actual clinical trials wonder whether or not they have to follow GCP.  Comments such as, “It seems like a lot of extra work” and “If it’s not required, why should I follow it?” are commonly heard.  Furthermore, investigators on non-FDA regulated studies argue that they see no reason to have to follow guidelines if they are not mandated to do so.

Ethically, however, every research team must be interested in protecting participants and collecting quality data, irrespective of the human subjects research being conducted.  Although some principles of GCP may not apply to all types of research on human subjects, the World Health Organization (WHO) strongly encourages consideration of GCP wherever applicable as a means of ensuring the ethical, methodologically sound and accurate conduct of human subject’s research, regardless of the type of research being undertaken^v.    

The main tenets of GCP require that the research involve good science, be verifiable, monitored, well-documented, and that the study comply with the highest ethical standards^vi.  Following ICH-GCP is one of the best ways to substantiate the quality of any research study and its resulting data.  Vijayananthan and Nawawi (2008) provide further justification for following GCP, stating that it leads to increased ethical awareness, improved trial methods, better understanding of clinical trial concepts, reduced research and development costs, increased competition, and mutual recognition of data^vii.  Following GCP helps to ensure that its two main goals are met:  1) to protect participants enrolled in research and, 2) to ensure the accuracy and credibility of the data and reported results.   Meeting these two goals is of paramount importance in any clinical research study.

How do I follow GCP?

Perhaps, after reading the thirteen principles of GCP, you might say to yourself, “What is the big deal about GCP?  We already do all of this on our study!” While the tenets of GCP seem simple and self-explanatory, the challenge lies in their implementation.  During the process of a study audit, it is always sobering to see how many ”basic” GCP tenets are not, in fact, adhered to over the course of an entire research study.  Study audits frequently reveal that new staff members are not trained adequately, ineligible subjects are enrolled, out-of-date consent forms are used, data is not recorded properly or stored according to the written protocol, modifications to the protocol are not approved by the IRB prior to implementation, and so forth.  Frequently, because investigators have not implemented sound documentation procedures and monitoring plans, or have failed to follow the plan they originally proposed, ”small” errors become large scale problems that impact the entire study, wasting precious resources of time and money, and worse, putting subjects at risk for naught because their study data has been compromised. 

So, where does an investigator turn to, who wishes to implement the tenets of GCP into his/her study?

Once a scientifically valid research idea has been proposed and approved, the key to successful implementation of the study lies in the documentation.  Many are no doubt familiar with the adage, “If you didn’t document it, it didn’t happen.”  The validity of research data rests in the documentation.  Resources, such as checklists and templates are available to assist investigators in implementing, and documenting that they followed GCP.  Regulatory Binder Tabs developed by the Clinical Research Resources Office (CRRO), are an excellent starting point and can help facilitate adherence to GCP principles.  If such materials have not been provided by the study sponsor, then these tabs can be modified to enhance the organization of study documents, and can help create checks and balances to ensure the investigator and study team members are conducting the research per protocol.

For example, tenet 2.8 of ICH-GCP relates to the education and training of study staff and the delegation of study-related tasks.   Tools such as task delegation/signature logs allow investigators to document that only sufficiently qualified study staff, with the necessary credentials (as applicable), are assigned to perform research-related activities.   In addition to the task delegation/signature log, training logs and license/certification logs, accompanied by regularly updated CVs and certifications of study personnel should be kept as further documentation of the qualifications of study team members.

Consequences of Not Following GCP

Countless examples of research studies with “issues” can be easily found by searching FDA warning letters .  From these letters, it is easy to see serious problems that were caused because GCP was not followed. In most cases, the problems identified by the FDA were not issues specific to the drugs or devices being studied, but rather were conduct issues that would be considered problematic whether or not the study was FDA regulated.   One such example occurred at Princess Margaret Hospital within Toronto’s University Hospital Network. The FDA found that data management and investigator oversight issues were significant enough to result in some data having to be discarded. Subsequently, the sponsors and investigators had to inform subjects that their data could not be used and apologize to them.  The failure by the researchers, which resulted in the data not being able to be used, represented a breach of the agreement between the subject and those conducting the trial^viii .  In this case, it did not matter whether it was a drug trial or a socio-behavioral research study; the problems resulted from issues in the basic conduct of research which could have been minimized or eliminated if the investigators had actively been conducting the trial in accordance with GCP.

Conclusion

According to Van Dongen (2001), ultimately it is not difficult for investigators and their study teams to follow GCP – it is simply a question of writing down procedures, documenting what is being done, and preparing for inspection (or at the very least , conducting the study as though they were preparing for an inspection)^ix.  He goes on to say that there are considerable rewards, not the least of which is the confidence that the data was obtained through a GCP-compliant research study.  Regardless of the type of human research study being conducted (whether it be a drug trial, a behavioral intervention, or a survey study), following GCP, the international standard, supports the quality of the conduct of the study and the ensuing results.

References

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