How to Tip Off a GCP Auditor in 25 Words or Less

Great article by Laurie Meehan

http://mastercontrolinc.blogspot.com/2015/05/how-to-tip-off-gcp-auditor-in-25-words.html

The 7th System: Integrating Clinical Systems into a Comprehensive Quality Audit Program

Clinical quality systems are often managed independently of manufacturing and laboratory operations.  This can result in a fractured view of each compliance area (GCP, GMP and GLP) and a failure to provide adequate oversight of an organization’s overall compliance.  Using FDA’s six-system inspection model as a starting point, this article will discuss how to integrate the requirements of clinical quality systems with a GMP compliant quality program to provide a system for comprehensive quality oversight. (View the original article)

The goals of a quality audit program are: 

• to provide an accurate view of compliance across the organization, including suppliers and vendors; 
• to identify and prevent or correct compliance issues; and 
• to inform management of the compliance status of the organization.  

However, differences in the implementation of GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice) compliance programs may occur due to the different focus of each program.  The GMP audit program is concerned with ensuring the identity, strength, safety, purity and effectiveness of the product or device, whereas the GCP audit program is focused on subject rights and safety, protocol conduct and data integrity.

Communication between the manufacturing and clinical disciplines may be obstructed in part by the use of different terminology, or by not using terms in the same manner to appropriately compare audit observations.  For example, use of the audit observation type “Validation” may describe an issue related to methods, equipment, packaging, or computer systems.  Without an appropriate description, this audit observation type is too ambiguous to be useful in assessing, preventing or correcting compliance issues.  “Investigational Product” is a common audit observation type used by clinical auditors, but this term is not sufficiently descriptive when relayed to manufacturing personnel as it does not describe whether the issue is related to the use, storage, labeling, or quality of an investigational product.

The use of different audit observation terminology and separate reporting systems may also obstruct an accurate assessment of the impact of systemic compliance issues and weaker compliance signals may be lost because they are maintained and reported separately. 

The accurate assessment of compliance with Standard Operating Procedures (SOPs), personnel training, vendor management, and complaints requires the ability to view issues across the organization, and the use of separate terms and reporting procedures may make it difficult to accurately quantify the total compliance risk of these activities or identify cross-functional issues that could impact investigational product integrity and/or subject safety.  Information from inspections of raw materials, production activities, packaging, labeling, warehouse and distribution, and clinical use may not be communicated effectively if issues are reported and communicated separately.

A shared quality system, using integrated audit observation categories, terminology and reporting can help to improve communication across functions and better meet the objectives of the quality audit program.  It should be noted that integrating the GMP and GCP quality audit programs does not necessitate a particular organization of the Quality Unit, although it is recommended to use the same system for assessing, reporting and resolving audit observations across the organization.

The Six-System Inspection Model defined by the U.S. Food and Drug Administration (FDA) provides an excellent foundation upon which to define the categories of a quality audit program. The model defines the following six systems:
• Quality System
• Facilities and Equipment System
• Materials System
• Production System
• Packaging and Labeling System
• Laboratory Control System

Most of the systems defined in the six-system model are readily transferable to audit observation categories useful for the inspection of both manufacturing and clinical activities.  Many clinical requirements can be integrated into the six-system model.  Within the Quality System, observation types such as audit program, complaints, deviations, personnel training and qualification, Standard Operating Procedures, and vendor qualification may be appropriate to both GMP and GCP activities.  Audit observation types related to the Facilities 
and Equipment System, such as calibration/preventive maintenance, equipment management, facility security, cleaning, and sanitation may be appropriate to both GMP and GCP functions.  However, audit observation types related to contamination controls, environmental monitoring, HVAC systems and water systems may be used primarily 

for manufacturing rather than clinical activities.  Although the six-system model provides an excellent starting point, not all clinical audit observations fit well into the six-system model.  

The addition of a seventh Clinical System can accommodate the addition of clinical audit observation types within an integrated inspection model.  Examples of audit observation types within the Clinical System may include: adverse events, case report forms/source documents, ethics committee, informed consent, monitoring, protocol compliance, regulatory approval, serious adverse events, trial management and oversight, and trial master file. Although it may be appropriate to create additional systems or categories (e.g., to distinguish safety from other trial management activities) for the purpose of this discussion we will 

create only one additional category for Clinical Systems (Figure 1).  With the integration of clinical requirements into FDA’s inspection model, and the addition of a Clinical System to accommodate additional GCP observation types, the seven-system inspection model provides an integrated structure of audit observation categories to help achieve the goals of the quality audit program.  The use of audit observation terms in the same manner to define, report and compare audit observations promotes improved transparency and communication between GMP and GCP functions, and a more accurate view of compliance across the  organization to effectively assess, communicate and resolve compliance issues identified by the quality audit program.

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Conducting Effective Clinical Investigator Audits

The audit of clinical investigator sites is often related to monitoring activities.  Like the monitor, an auditor ensures that reported trial data are accurate and complete, and that the trial is conducted in compliance with Standard Operating Procedures (SOPs), Good Clinical Practice (GCP) and applicable regulatory requirements.  These activities help to ensure that the rights and well-being of subjects are protected, viable product candidates reach the public with fewer obstacles, and potential risk or liability to the Company is reduced: i.e., protect the patient, protect the product, protect the Company.

Although both the auditor and monitor share these directives, the auditor differs from the monitor in the scope and performance of their work.  Whereas an individual monitor may be concerned primarily with overseeing the progress of a clinical trial at a particular investigator site(s), an auditor is guided by the importance of the trial in submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s) with a particular trial or clinical program.  The scope of an audit also includes an assessment of monitoring activities as they relate to the conduct of the trial.

To perform this function, the auditor must be independent of the monitoring and QC (Quality Control) functions to reduce any potential bias from experience with a particular study or investigator site and appropriately evaluate the risks inherent to a particular clinical trial relative to concurrent clinical development activities.  It is from this vantage point that clinical investigator sites are selected for audit based on criteria defined in the audit plan for the trial.

Auditors are qualified and selected to conduct investigator site audits based on their training and experience.  An auditor must be proficient in the practice of audit conduct, particular aspects of the trial and interpreting relevant information to identify compliance trends.  Preparation for a clinical investigator audit typically includes a review of the Investigator’s Brochure, Protocol and amendments, Informed Consent Forms, CRF’s (Case Report Forms), CRF completion guidelines, monitoring reports, SAE (Serious Adverse Event) reports, site correspondence and other relevant documentation in the Trial Master File.  The audit should be scheduled such that the Principal Investigator (PI), Site Coordinator(s) and other key staff will be available during the audit.  The auditor(s) will discuss site performance and any identified issues with the clinical project team prior to visiting the site.

During conduct of an audit, auditors will perform a detailed review of site regulatory files, informed consent forms, study correspondence, investigational product/material accountability records, and selected patient files including a comparison of information recorded on source documents with data recorded on case report forms.  Interviews will be conducted with the Principal Investigator, Study Coordinator and other site staff to discuss trial roles and responsibilities as well as the conduct of study activities, including procedures for gaining informed consent.  An auditor should use appropriate interview techniques to gain additional information to identify potential issues and performance trends as well as the attitudes and behaviors that led to any identified data discrepancies or events observed.  For example, is the Investigator reluctant to admit or correct mistakes?  Is the data recorded deliberately misleading or is it the result of a limited number of staff taking on too large a volume of work?  

These observations may result in the discovery of protocol violations, discrepancies in data or differences between site staff description and performance of trial activities.    It is an essential part of effective audit technique not only to be able to relate individual observations and data points to identify trends and patterns that may seem hidden among individual discrepancies, but to interpret the value and context of these trends relative to the risks to data integrity and compliance for the trial as a whole. 

If illegal or unethical activity is indicated, the auditor should record their observations, safeguard evidence and obtain copies of pertinent records.  A key distinction between demonstrating fraud and misconduct on the part of an investigator is the ability to prove intent.  Records and testimony collected during an audit may prove essential to being able to make this legal distinction.

During the audit exit interview, audit findings are presented and specific questions asked by both the site staff and auditor(s) to ensure accuracy.  There should be no ‘surprise’ audit findings if an auditor has been communicating effectively with site personnel throughout the conduct of the audit.  The auditor should also communicate with investigators and site staff to identify any issues or concerns that may fall within the influence of the Sponsor.

As a representative of the Sponsor, it is important that an auditor carry out their work in a professional manner.  How an auditor conducts her/himself, both on site and in correspondence, could have a potential impact on the liability of the Company.  Inappropriate conduct on the part of the auditor may be subject to actions related to securities laws, antitrust laws, violation of due care, or even aiding and abetting.  In addition to the standards of ensuring confidentiality and avoiding conflicts of interest, an auditor should not make any promises to site personnel on behalf of the Sponsor or tell auditees how to do their work (thereby inheriting partial liability for work conduct).  

Audit reports may be notoriously dry and matter-of-fact, but this approach is both to mitigate legal liability and provide a report of site performance with limited bias.  It is not enough, however, to just write an audit report and file it away.  Timely follow-up and correction of audit observations will help to keep site operations compliant and data accurate.  Particular site observations may indicate more general actions for the study that can improve the compliance, accuracy, speed and/or costs of conducting the trial.

Conducting effective clinical investigator audits requires auditors to maintain standards of professional conduct and proficiency to provide an independent, unbiased report to management on the conduct of a clinical trial.  Clinical investigator audits, as part of an overall quality oversight program, help to effectively manage the risks to trial subjects, ensure data integrity and limit potential regulatory or legal liability associated with the conduct of clinical trials.