Ensuring Quality Throughout The Clinical Process

By Annette Horner, Ph.D., and Beth Kline

Most GCP requirements call for common sense procedures designed to make a clinical trial safe for study subjects. Even small pharmaceutical companies expend huge resources proactively monitoring clinical trials in an effort to protect subjects and maintain conditions for the collection of valid and reliable test data.

Beyond the risk to individual study subjects and data quality posed by GCP infractions, there is a great social risk: A clinical trial could be wasted as a result of such infractions. Clinical trials are too important and too resource-intensive to waste. Human subjects and clinical resources are not a commodity anywhere in the world. The history of clinical trial conduct has been and continues to be fraught with ethical issues, but it is the most acceptable way that modern culture has found to bring new pharmaceutical products to market. But, we must not waste the precious human and medical resources required.

Thus, when large, respected sponsor companies and CROs are confronted with the quantity of basic GCP infractions highlighted in recent warning letters, our experience tells us that these companies have QC and QA systems in place. But those systems are not working — at least not as intended.

And that is why clinical operations and clinical quality assurance management industrywide must pay attention to recent warning letters. Managers in clinical operations (ClinOps) must look critically at improving routine procedures and quality controls during clinical trials. Managers in clinical quality assurance (CQA) must look critically at improving procedures and tools to detect GCP compliance issues and risks.

How can both groups work toward improved GCP quality? How can a sponsor company or participating CRO know that it is, in fact, conducting clinical trials in a manner that is compliant with GCPs? How can a sponsor company build in GCP quality, so that when it gathers all its research results for a particular product into a marketing application, it knows its investigator sites and its internal processes are “inspection ready?”

Managing GCP Compliance
CQA units have traditionally been the GCP compliance detectives, and the audit has been their tool of choice. Such audits, while not required by FDA or ICH (International Conference on Harmonization), are acknowledged by both bodies as important sponsor tools “to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.” Furthermore, both FDA and ICH guidance documents acknowledge that a series of internal audits, vendor audits, or investigator site audits can be helpful to a sponsor or CRO in identifying systemic compliance risks, such as ineffective study monitoring or other quality control issues. However, the problem with audits is that they identify compliance issues at the end of the process. Sponsors and CROs need ways to identify compliance issues, and patterns of issues, during the clinical process, using a quality systems approach. Such an approach has been in use within industry manufacturing divisions for some years. In recent years, the basic tenets of a quality systems approach have been codified into the ICH Q9 and ICH Q10 guidance documents. Increasingly, sponsors and CROs are applying a similar quality systems approach to the complex and vendor-driven clinical trials process. The quality systems approach to GCP compliance is also familiar to clinical operations and data management professionals who have used metrics to manage clinical trial process elapsed times, all rooted in quality systems approaches.

A Quality Systems Approach To GCP Compliance
Taking a quality systems approach to clinical trial processes and patient data quality means following these steps with regard to each key clinical process:

• Define clear performance standards.  
• Communicate those standards effectively to those doing the work of clinical trial conduct.  
• Determine areas of clinical conduct that may not be in compliance with policies, procedures, or regulatory requirements.  
• Put plans into action to prevent future noncompliance in identified areas. 

Continue to monitor processes and patient data to ensure that both are meeting compliance targets.

Quality System Steps 1 and 2: “Defining clear performance standards” and “Communicating those standards” are accomplished within most sponsors and CROs by the clinical operations function, which establishes clinical policies and SOPs.

When applied, for example, to ensuring patient data quality, clinical operations must consider the following:

• The most important outcome of clinical research is reliable and credible patient test data. 
• There should be systematic checks that are performed at every step of the clinical trial process to ensure that patient data is of the highest quality. 
• The quality checks start at the protocol level with sponsor review, approval, and sign-off. 
• The checks continue with investigator collection of patient data according to the protocol requirements and monitoring of investigational sites. 
• Quality checks continue once the patient data is in the study database with proofreading, validation, and generation of queries. 
• There must be an analysis of outlier data as well as variability and trends in the data. 
• For multicenter studies, these quality checks must be repeated for all investigator sites, domestic and international. 
• Finally, the clinical study report is approved and signed off. 
• Each of these steps requires organizational systems be defined, implemented, and adhered to by those doing the work.

Quality System Step 3: “Determine areas of clinical conduct that may not be in compliance with policies, procedures, or regulatory requirements” is a quality step traditionally performed by CQA.

In order to know the state of GCP compliance within a sponsor company, CQA would first assess the current quality systems in place, taking into consideration recent regulatory trends and warning letters to others in the industry, as well as the organization’s history of compliance and known compliance issues particularly related to the product under development. This assessment might include an internal audit program: reviewing sponsor GCP-controlled documentation against regulations and current practice, as well as conducting interviews with those closest to the clinical trial processes. The audit program should also include selected vendors and investigator sites to examine informed consent processes, data quality issues, effectiveness of monitoring, trial master file documents, accessibility of study records, and other issues critical to GCP compliance.

This audit program will help CQA identify regulated areas for which there is inadequate or no existing compliance mechanism.

In addition to a program of internal, vendor, and investigator site audits during the pre-approval period, CQA can make frequent and repeated use of GCP compliance checklists. The use of checklists by both clinical operations and CQA is cost-effective and can be flexibly applied during the conduct of a clinical trial to detect GCP compliance risks, whether systemic within the sponsor/CRO or isolated to a specific investigator site.

Checklists can be very effective in investigating compliance trends across sites or in identifying sites that might require the rigor of an audit. They allow for ease of communication between clinical operations and CQA and can provide powerful feedback on the effectiveness of policies, procedures, training, review and documentation processes, and other in-process quality measures.

One approach to checklists would be to create one for GCP systems at the sponsor/CRO level and another for a specific clinical trial or investigator site. The headings would vary somewhat, and the level of detail would be quite different between the two checklists, but checkpoints would be complimentary between the two lists. The lists below suggest key headings for two types of GCP compliance checklists:

Key Headings For GCP Systems Checklist:

• Organization and Personnel  
• Facilities and Equipment  
• Sponsor/CRO Operating Procedures:  

1. Monitoring  
2. Investigational Medicinal Product  
3. Sample Management  
4. Safety and Adverse Event Reporting  
5. Data Handling and Clinical Trial Reporting  
6. Documentation Archival  
7. Sponsor Audit and Quality Assurance System  
8. Delegation of Duties

Key Headings For Specific Clinical Trial Checklist:

• Implementation and Termination of the Clinical Trial  
• Monitoring  
• Investigational Medicinal Product  
• Safety and Adverse Event Reporting  
• Case Report Form Data Verification  
• Clinical Trial Documentation and Archiving  
• Audits  

Once the current state of clinical compliance is identified, whether through audits, GCP compliance checklists, interviews with staff, or a combination of these methods, a sponsor or CRO can begin to work toward a cohesive inspection readiness state.

Quality System Step 4: “Put plans into action to prevent future noncompliance in identified areas” is also supported by the use of GCP compliance checklists. Checklist results often suggest the potential root cause of noncompliance. Once the root cause is identified, clinical operations can develop corrective actions to remedy immediate issues, and design preventative actions to avoid future noncompliance in the identified area. This sequence follows CAPA strategies, familiar from Manufacturing QA. Developing CAPA approaches for clinical research is important because health authority inspectors are increasingly expecting to see CAPA (corrective and preventive actions) approaches by a sponsor, CRO, investigator, or IRB cited for GCP infractions

When the results of the GCP Compliance Checklist suggest that compliance risks exist, then a sponsor or CRO will want to consider a range of solutions to address identified areas of noncompliance. These could be as simple as updating policies and SOPs that would impact the day-to-day clinical tasks being conducted or as complicated as redesigning a faulty or confusing process.

Quality System Step 5: “Continue to monitor processes and patient data to ensure that both are meeting compliance targets” is also supported by GCP compliance checklists. Checklists provide a less labor-intensive approach than auditing for ongoing compliance monitoring. From the perspective of “Inspection Readiness,”

checklists can be used at intervals during a study to ensure the information required for pre-approval inspections is accessible and organized from the beginning throughout the duration of a trial.

Once areas of noncompliance have been addressed and are operating within identified compliance targets, additional Step 5 controls can be put in place to ensure that compliance targets continue to be met monthly, quarterly, and/or annually. Adding more rigorous Step 5 controls to a GCP Quality System might include designing and implementing a clinical compliance metrics program that would keep

clinical management informed on an ongoing basis about data-driven areas that should be operating within compliance targets at all times.

Avoid That Nervous Feeling Before An Inspection
It is important for clinical operations and clinical quality assurance management to apply quality systems approaches to GCP compliance. By expanding the number and variety of in-process quality control measures, sponsors and CROs can avoid the feelings of dread and panic that generally ensue before a health authority inspection. There are a growing number of quality control and quality assurance measures that when applied in a broad organizational way can allow a company to be ‘inspection ready’ at all times.

About The Authors
Annette Horner, Ph.D., is senior director of clinical compliance services for Compliance Implementation Services (CIS), a consulting firm specializing in compliance strategies for pharmaceutical companies, from global clinical R&D through U.S. commercial compliance and government programs. She has 23 years of experience, and her specialty is implementing process improvement programs in international pharmaceutical R&D settings.

Beth Kline is a clinical compliance specialist and project manager for CIS. Over the last 12 years, Beth has provided sponsor management of clinical trial sites, implemented new safety systems, conducted training needs assessments, and developed compliance training materials.

Used with permission from Life Science Leader magazine.