The notion that the role of Quality Assurance (QA) in clinical development should be relegated to reviews, audits and quality control (QC) checks is an antiquated one that could well run medical product developers afoul of FDA and international regulations. The role of QA in clinical development has evolved significantly over the last two decades, and savvy companies will see that incorporating QA throughout the clinical study process can ensure that execution of the trial—including risk management—will meet both regulatory requirements and align with overall business strategy.

US regulations covering clinical trial conduct (21 CFR 50, 54, 56 and 312) do not specifically require a quality management system throughout all stages of trial design and execution, although some of the product sponsor responsibilities outlined in Section 312—such as auditing—are usually carried out by the QA unit. Because of this, QA’s role historical role in GCPs was often limited to auditing. But the FDA and international regulators have developed expectations beyond the bare regulations that reflect ever-evolving best practices. And simple compliance with US regulations is no longer enough. FDA and harmonized international guidances must be considered, as well as current industry standards and best practices.

Over the years, the evolution and intersection of QA and Good Clinical Practices (GCP) expectations have provided medical product companies with both responsibilities—in the form of compliance with regulations plus meeting expectations outlined in FDA and international guidances—and opportunities—the ability to define and re-define the roles and responsibilities of the quality unit supporting GCP compliance in ways that make the most sense in terms of meeting business goals.

A well-integrated GCP QA unit can add real value to costly clinical trials by focusing on overall excellence in study execution. Better execution yields better data, which can help speed a new product application through the FDA approval process with fewer hiccups along the way. This support can continue all the way through commercialization of new products. Specifically, the GCP QA can cover the following critical clinical trial roles and responsibilities:

Development, implementation and maintenance of the GCP quality system. This can include developing GCP quality metrics and implementing a quality management review process for senior management in a sponsor company’s research and development division. The system should focus on identifying all potential risks to trial reliability and GCP compliance and proposing actions to mitigate that risk in line with existing business needs and strategies.

From the quality metrics and related review plan will arise a risk-based GCP quality plan, including goals and objectives that are integrated into the overall business plan for the investigational new product.

Quality and compliance oversight of all GCP-related activities throughout clinical trial design, preparation and execution. This role should include review of the clinical trial protocol, the risk management plan and the oversight and monitoring plans, including scrutiny of informed consent forms and other essential documents, such as those referenced in pertinent FDA regulations and guidances like the International Conference on Harmonization (ICH) Guideline for Good Clinical Practice (E6).

Document review is particularly important. In this role, the QA unit may act as a prevention-focused quality engineer, ensuring not only that all documents meet pertinent regulatory requirements, but that they also are free from inconsistencies or problematic wording that could increase the likelihood of protocol deviations or violations. The unit also should look for opportunities to improve the informed consent form and the protocol itself in ways likely to reduce user error during both the informed consent process and during trial execution.

Establishment of a third-party supplier quality management process. This is important to ensure that CROs, laboratories, clinical investigators and others involved in clinical trials adhere to the sponsor’s QA/QC system and remain in compliance with current GCP and data integrity requirements. Specific activities conducted may include:

• Development and implementation of supplier quality metrics, through which the sponsor may monitor GCP compliance by all material and service suppliers;
• Periodic audits of third parties to ensure compliance;
• Periodic internal audits of clinical operations, regulatory affairs, clinical development and medical safety units to ensure GCP and safety reporting compliance; and
• Partnering with in-house GMP auditors for periodic auditors of R&D laboratories and production operations that support clinical trial material manufacture and testing.

Development and implementation of a risk management plan and process. Risk management is the watchword for FDA inspectors and sponsors need a solid plan in place to ensure that all potential risks associated with an investigational product and clinical trial are identified. Any risks deemed major or critical needs to be mitigated and communicated to senior management of the sponsor company. Periodic management review of the GCP quality system should be part of the process to ensure that senior management is aware of the nuts-and-bolts of the system and is able to prioritize actions to address critical quality and compliance risks.

Other key QA activities may include periodic GCP training for clinical operations, regulatory affairs, clinical development and medical safety staff and review of monitoring reports from site visits to ensure that identified issues are addressed promptly and appropriately, along with escalation of critical quality and compliance issues discovered during conduct of a clinical trial and preparing for and leading FDA Bioresearch Monitoring (BIMO) inspections.

Additionally, the QA unit should periodically report certain GCP quality and compliance metrics to the clinical operations, clinical development and regulatory affairs departments. These include:

• Performance metrics for the contract research organizations (CROs) and principal investigators;
• Protocol deviation trends;
• Corrective and Preventive Action (CAPA) effectiveness in reducing critical risks to trial reliability;
• Timeliness of safety reporting; and
• Internal and external GCP audit findings.

Creating a GCP QA unit that covers these responsibilities will move sponsors to the head of the new product development pack. In order to successfully create an effective and compliant QA unit and system, however, companies must be well-versed not only in applicable regulations and guidances, but in current industry standards and best practices, which we will address in a forthcoming article.