Building Quality in Clinical Trials With Use of a Quality Systems Approach
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Cynthia F. Kleppinger and Leslie K. Ball Division of Scientific Investigations, Office of Compliance, Center for Drug Evaluation and Research, US Food and Drug Administration
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Silver Spring, Maryland
There is an increasing focus on having quality systems in place during the planning stages of clinical trials. Such systems require the development and implementation of standards for each step. Although this is not imposing something totally new on clinical research, a systematic approach will produce a more reliable and useful end product-high-quality data obtained without compromising the protection of human subjects' rights and welfare. A suggested quality system with standards for each step is addressed in this article. Defining and measuring quality in the clinical trial setting can be difficult. The most important variable involved is the ever-unpredictable human, and advancements, such as electronic data capture and internationalization, are constantly altering the clinical trials landscape. Defining quality often accounts for the satisfaction of customers in meeting their needs and expectations. However, the stakeholders (customers) in the research community are numerous and varied and include but are not limited to the public, the medical community, the clinical research community, investigators, sponsors, contract research organizations, academia, government agencies, and institutional review boards. Moreover, the standard level of quality acceptability of the customer is not a static target. This forces focus on the importance of having continual process improvements for all stages of performance in the clinical trial enterprise, to guarantee quality (Figure 1). No clinical trial is perfect, and therefore, no dataset is perfect. Even if complete accuracy of the records could be achieved, it cannot define a quality clinical trial, because a useful study design, well-defined end points, assurance of subject safety, and the assurance of unbiased observations must also be affirmed. In other words, if one were to accurately record ingestion of an investigational product in an appropriate, healthy population that led to the demise of each participant, one would not argue that the clinical trial was inadequate. In attempting to define quality in the clinical trial, the Institute of Medicine's Roundtable on Research and Development of Drugs, Biologics, and Medical Devices has instead defined high-quality data: data strong enough to support conclusions and interpretations equivalent to those derived from error-free data [2]. In other words, for regulated products, the data must allow the US Food and Drug Administration to make accurate regulatory decisions about the safety and efficacy of the product, and the data should be able to support the sponsor's labeling claims. Although the research community is in agreement that certain data points (eg, the primary efficacy end point and adverse events) should receive the greatest attention toward guaranteeing 100% completeness and accuracy for decision-making purposes, the most cost-effective and efficient monitoring and auditing techniques to achieve this are still being debated [3-7]. In light of these issues, the CTTI, a public-private partnership involving industry, government, patient advocates, trade organizations, professional societies, academia, and nonacademic investigators, was formed in
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THE CLINICAL TRIALS
TRANSFORMATION INITIATIVE (CTTI)
Figure 1. International Standards Organization quality framework [1].
Four key areas of concern: management responsibility (policy, objectives,
planning, quality management system, and management review), resource
management (human resources, information, and facilities), process
management (customer satisfaction, design, purchasing, and production), and
measurement, analysis, and improvement (audit, process control, and
continual improvement).
November 2007 to identify practices that will increase the
quality and efficiency of clinical trials [8]. The CTTI has
characterized quality as the ability to effectively answer the intended
question about the benefits and risks of a medical product
(therapeutic or diagnostic) or procedure, while assuring
protection of human subjects [9]. One of the first projects planned
and approved under this initiative is Effective and Efficient
Monitoring as a Component of Quality Assurance in the
Conduct of Clinical Trials. Although current regulations [10, 11]
require sponsors to ensure proper monitoring of clinical
investigations of products subject to Investigational New Drug
Applications and Investigational Device Exemptions,
monitoring methods that are ineffective or overly burdensome may
inadvertently contribute to poor data quality. A white paper to
be developed from this project will establish the key
qualityassurance objectives in clinical trials and promote effective and
efficient monitoring, both in the United States and
internationally.
A CHANGING LANDSCAPE
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