Suzanne Tran

	Over the years, clinical study management has become more fragmented. There are more organizations participating in a study, each bringing their own experiences, interpretations of requirements including how quality is defined. How is it possible that requirements and quality be interpreted so differently?

	To start, the Code of Federal Regulations (CFR) items pertaining to Good Clinical Practices (GCP) do not mention the term “quality” directly.  Any reference to the use of “quality” is typically associated with an attribute.  For example, in 21 CFR 312, it refers to quality in terms of “scientific quality” and “quality” of the drug substance, whereas the term “quality” on its own is used in numerous parts of 21 CFR 58 (

Good Laboratory Practice for Nonclinical Laboratory Studies

):  Part 38 alone addresses the requirement for a quality assurance unit (QAU) to monitor nonclinical studies.

	Quality practices as they relate to GCP are more visible in the

 Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance (1996)

. The introduction states, “This guidance should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities.” Since quality control and quality assurance are not mentioned directly in the CFRs but in guidances such as ICH E6, does this mean that quality is not important in GCP? No.

	Essentially, quality involves a set of principles/practices an organization uses to verify that requirements are being fulfilled.  Applicable standards, regulations, and customer requirements as well as guidance and industry-wide practices comprise “requirements” to be fulfilled.

	Despite the role an organization has in GCP, there is need for the requirements to be clearly established and controlled systematically throughout the clinical study. Why? A study is only as strong as the weakest participating group. Essentially, a process is an activity or group of activities that takes an input, adds value through the use of resources, and provides an output to internal and/or external customers. The value added by a process comes in exchange for the resources it uses, including people, equipment, material, money, and time. For example, if site monitoring is not a well-defined activity and is performed without proper oversight, the weakest organization has the potential to introduce more variation in the execution of the study protocol and thus potentially compromise the study results.

	It should be noted that relying on one area of quality, such as quality control activities, is not enough. At a minimum, there is a need for both quality control and quality assurance activities. As defined in ICH E6:

		Quality Control (QC):  The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.

		Quality Assurance (QA):  All of those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with GCP and applicable regulatory requirement(s).

	In other words, QC includes many activities (operational techniques) to ensure that a protocol is being followed, such as with clinical site monitoring and the establishment of an Institutional Review Board (IRB). QA includes the actions taken to ensure that the activity is conducted effectively and efficiently. It encompasses the use of established practices that include, but are not limited to:  management commitment, written standard operating procedures (SOPs), audit reports, computer system validations, and training records.

	To aid in controlling process variation, a well-established process approach should be used throughout the study and understood as well as practiced by all participating organizations. This practice breaks down the life cycle activities in terms of smaller interrelated processes. It also maintains focus on how the quality of one process affects the quality of the next.

	As with the difference between QC and QA, there is a difference between what demonstrates a quality system and a quality management system. A quality system typically focuses on a few areas of quality practices (techniques), such as written SOPs. While a quality management system is more comprehensive. Quality management is focused not only on product and service quality, but also on the means to achieve it. Quality management therefore uses QA and control of processes to achieve more consistent quality.

	A good model for establishing a quality management system is the ISO 9001 standard.  Developed and published by the International Organization for Standardization (

), an international standards writing body, ISO 9001 standard is a set of requirements.  The ISO 9001 requirements reflect time-proven, universally accepted business practices. This standard is probably the best known international standard for quality management.

	What does ISO 9001 demonstrate? By implementing the requirements, the organization is capable of demonstrating that: (1) it has the ability to consistently provide products or services that meet customer and applicable statutory and regulatory requirements; and (2) the organization aims to enhance customer satisfaction through the effective application of the system, including processes for continual improvement of the system and the assurance of conformity to customer and applicable statutory and regulatory requirements.

	In general, the ISO 9001 requirements address the following:

		Implementing structure by establishing a quality management system

		Establishing responsibilities by involving top management

		Providing resources to achieve goals through resource management

		Designing and performing to requirements (such as customer, statutory, regulatory)

		Raising the bar by measurement, analysis, and improvement activities

	The quality, not just compliance, in GCP therefore comes from organizations that collaborate in conducting a clinical trial that protects human subjects and meets the applicable statutory and regulatory requirements, as well as proactively improve the use of resources to gain regulatory approval in a timely manner so that others may reap the benefits of the new therapy.

Suzanne Tran is a QA Compliance Specialist for TRI. She has over 20 years of experience in the quality field. She is an ASQ Senior Member and an ASQ-Certified Manager of Quality/Organizational Excellence, Quality Auditor, and Software Quality Engineer.

Articles

Over the years, clinical study management has become more fragmented. There are more organizations participating in a study, each bringing their own experiences, interpretations of requirements including how quality is defined. How is it possible that requirements and quality be interpreted so differently?

Suzanne Tran

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Where is the “Quality” in GCP?