Quality Control and Assurance in Clinical Research

Pharmaceutical companies recognize the benefits of carefully managing the quality of data from their drug development and clinical trials. To ensure clinical data accuracy and integrity, it is necessary to thoroughly review these data, to assess the validity of outlying data points, and to carefully document query identification and resolution throughout a study's duration.

Photography: PhotoDisc Art Direction: Paul A. Belci

Maintaining accuracy and quality throughout a clinical study is a continual, dynamic process. Although study requirements are carefully set forth initially in detailed documents such as an approved clinical protocol, a data management plan, and an accompanying project plan, expectations and requirements can change during a study. This ongoing process requires revising mechanisms and communicating these revisions clearly to all investigators and support staff.

Defining the terminology

Quality: the total set of characteristics of a product or service that affect its ability to satisfy a customer's stated or implied needs.

Quality system: the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management.

Quality assurance (QA): the systematic and independent examination of all trial-related activities and documents. These audits determine whether the evaluated activities were appropriately conducted and that the data were generated, recorded, analyzed, and accurately reported according to protocol, standard operating procedures (SOPs), and good clinical practices (GCPs).⁴

Quality control (QC): periodic operational checks within each functional department to verify that clinical data are generated, collected, handled, analyzed, and reported according to protocol, SOPs, and GCPs.⁴

The quality challenge

The ongoing challenge in managing the quality of clinical data is to continually monitor data collection procedures and data management practices at every level of the study. This includes:

• ensuring that data generated during the study reflect what is specified in the protocol (case report form [CRF] vs. protocol)

• comparing data in the CRF and data collected in source documents for accuracy (CRF vs. source documents)

• ensuring that the data analyzed are the data recorded in the CRF (database vs. CRF).

Quality surveillance continues after the trial has ended and plays an important role in ensuring that:

• data presented in tables, listings, and graphs (TLGs) correctly match data in the database (TLGs vs. database)

• data reported in the clinical study report (CSR) are the data analyzed (CSR vs. TLGs)

• all aspects of the data management processes are compliant with SOPs and GCPs.²

The quality plan

The quality plan describes how the quality control and quality assurance processes will be applied throughout the clinical trial. It definitively defines the various quality-related tasks in the study. A quality plan documents specific quality practices, resources, and activities relevant to a specific project. This includes both operational QC and QA activities.

Operational QC

It is critical that trial managers develop a QC plan for each key operational stage of the study that defines standards against which QC will be conducted, including:

• sampling plan to be used (if applicable)¹

• data source to be used for QC at each operational stage

• metrics to be documented

• acceptable quality levels

• appropriate methods to report and distribute results.

During the study design phase, QC personnel provide an independent review of the approved proposed protocol. The QC plan includes comparison of the study's CRF to the objectives set forth in the protocol to ensure that it is designed to collect all necessary data. A requirement to review CRF completion guidelines is also an element of the QC plan.

For overall site management, a complete QC plan addresses the following:

• investigator selection and qualifications

– experience in conducting clinical trials

– experience with the specific indication

– not on the FDA's restricted or debarred lists

– adequate staff and facilities

– personal involvement

• study conduct (monitoring)

– subject informed (signed informed consent form)

– subject's eligibility (inclusion/exclusion)

– protocol compliance

– adverse events (AEs) and concomitant medication

– drug accountability and storage

• source document verification

– medical records

– lab data

– progress notes

– diagnostic tests

• query resolution

– completed data clarification forms

• compliance with regulations

– 21 CFR 11, 50, 54, 56, 312

– EU Clinical Trial Directives 2001/20/EC and 2005/28/EC

– ICH/GCP Consolidation Guidelines (ICH-EG).

During the data management process, the accuracy of the initial data entry is verified by an independent entry of the same data and a subsequent comparison of both sets of data for nonagreement. The reality of the data is checked with a preprogrammed logic check program and a subsequent manual review. The database entries are then QC'd versus the CRFs. The TLGs that are generated as part of a statistical analysis of the data are also inspected to ensure their accuracy, as is any text in a CSR that refers to the TLGs.

QA activities

The QA activities to be conducted during a specific clinical trial are included in a QA audit plan. These activities include the number of investigator sites, selection criteria, and vendors to be audited, such as labs and drug packaging and distribution providers. This plan also specifies what internal processes of the study will be audited from initial study design, site and data management, statistical analysis, and the final CSR. It specifies audit team members and auditees for each study stage, as well as the standards against which the audit will be conducted, such as the protocol, CRF completion guidelines, SOPs, ICH/GCP guidelines, and FDA regulations.

Audits must also consider the standards of countries other than the United States, such as the recently adopted EU Clinical Trial Directives 2001/20/EC and 2005/28/EC.⁵

A thorough QA audit plan also clearly states the documents to be provided by the auditee, as well as the location, date, and expected duration of the audits. Preparation for QA audits should include review of the approved protocol and amendments, SOPs (both general and study-specific), any specialized training associated with the study, annotated CRFs, and the statistical analysis plan (SAP).

Internal process audits are another important QA responsibility. Internal audits review all the drug development processes employed across several studies to determine if there are systemic problems. This includes a review of employee training, compliance with SOPs and regulatory requirements, and documented evidence that QC was appropriately conducted on the output of each internal process, as well as the final deliverable to a client.

Site management metrics

Internal audits of the site selection and management processes ensure that qualified investigators are selected, that they have adequate facilities and adequately trained staff, and that the study was conducted in compliance with the protocol and all appropriate regulations.³ Several metrics commonly evaluated by internal process audits after the study has begun include:

• percentage of monitoring visits completed on time

• percentage of evaluable subjects (no protocol violations)

• percentage of serious adverse events (SAEs) reported within 24 hours to an Institutional Review Board (IRB) and sponsor

• percentage of properly executed informed consent forms

• number of queries/CRF pages reviewed

• number of missing data entries/CRF pages reviewed.

Computer Systems Validation

Computer systems validation examines all aspects of the data handling computer systems (hardware and software) to ensure the accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records. This includes initial installation and procedures that document how changes to a computer system are justified, approved, and implemented.

The validation process begins with examining user requirements, the results of the initial hardware installation qualification (IQ) tests, the operational qualification (OQ) tests, and the qualification and training of user personnel. The user acceptance test results (Performance Qualification) are then compared to the user requirements to ensure that these requirements are met. Having assurance that the data handling computer system is validated, data can then be entered.

Data management QC

Since an average error rate for keying text or numbers is about 1 per 300 keystrokes, the entered data is QC'd by having an independent data entry person enter the same data.² Both sets of data are compared electronically, and discrepancies are resolved by a senior data entry person. After all of the data has been entered and all discrepancies and questions resolved, the database is QC'd by comparing the database to the CRFs from which the data was entered.

Data management metrics

Examples of data management metrics for QA are:

• percentage of database errors

• percentage of queries manually generated

• time from last patient out to database lock

• number of times a locked database is opened.

Data management QA

Data entry and the database QC process are other critical areas of the data management process that are audited by QA personnel. The audits review the documented evidence that shows the data accuracy and integrity were verified and checked manually, independently, and programmatically to ensure the data were logical.¹ These audits also ensure that all data queries are resolved and that the overall database QC review was conducted according to the QC SOP.

Statistical analysis QC

After a study database has undergone a QC review, it is exported into a SAS (statistical analysis system) to develop analytical programs that create data TLGs that are to be included in a CSR. The TLGs are QC'd and validated by having independent programmers create programs for the same TLGs, and all discrepancies are then resolved.

Statistical analysis QA

QA of the statistical analysis process ensures SAS programs are validated for the generation of all TLGs by checking that all the requirements were met and boundary conditions were tested. QA also verifies that the SAP was developed according to the processes defined in the SOPs and that all statistical analysis plans are approved by the appropriate authority.

In addition to reviewing the statistical analysis process, QA also inspects a predetermined sample of TLGs. Numbers are checked against database listings, and tables are reviewed against format requirements specified in the SAP. The QA report will document the following information:

• percentage of TLGs with numerical or formatting errors

• percentage of SAS programs adequately validated

• time from database lock to final TLGs.

Study site audits

The QA group conducts site audits throughout the course of a trial to assess protocol and regulatory compliance, to ensure that the safety and welfare of subjects are addressed, and to confirm that problems reported by study monitors have been resolved. QA's criteria for site selection include:

• high patient enrollment

• high staff turnover

• abnormal number of AEs (high and low)

• high or low subject enrollment rates that are unexpected given the research site's location and demographics.

Site audits ensure adequate documentation of case histories (source documents), such as medical records, progress notes, hospital charts, drug accountability records, ECGs, laboratory test results, SAEs, and informed consents. Audits examine whether all clinical tests were performed at the time specified in the study protocol, and review specimen collection, storage and shipping packages (if applicable), and the timeliness of review of clinical test results.

QA site audits evaluate the timeliness of entering data into a CRF, and examine the accuracy of the data by comparing them to their respective source documents mentioned above. Audits also ensure all investigational product received by a site is adequately accounted for.

Corrective and preventative action process

The purpose of a corrective and preventative action process is to ensure that complaints, discrepancies, and noncompliances are visible, prioritized, and tracked, and that the root cause is determined and resolved. It also provides a system to track issues of nonconformity that have not been resolved. This process requires identifying a person responsible for defining and implementing corrective action.

Continual improvement process

QA also has a critical introspective role to continually monitor and evaluate its own activities and to improve all drug development processes. This continual process of improvement tracks and reports on metrics for key activities and deliverables of drug development, keeping in mind the adage that "what gets measured, gets managed." Other inputs to process improvement include a formal debriefing after project close, client and employee satisfaction surveys, and client audits.

Summary

Managing the quality of clinical data does the following:

• ensures management of compliance with the protocol, SOPs, and GCPs

• enables systemic problems to be resolved before the end of the study

• helps reduce data queries (industry average = $150/query)

• identifies ways to reduce cycle times for various processes

• ensures data integrity throughout the study's course and that the data collected are the data required by the protocol

• ensures the accuracy and consistency of data from entry into the CRF to final datasets reported in the final CSR

• plays a critical role in dealing with instances of nonconformity while carrying out clinical trials.

Martin Valania is executive director, corporate QA and compliance, with PharmaNet, 504 Carnegie Center, Princeton, NJ 08540, (609) 951-6690, fax (609) 452-5526, email: mvalania@pharmanet.com

References

1. I.J. Townshend and A.F. Bissel, "Sampling for Clinical Report Auditing," Statistician 36, 531–539 (1987).

2. R.K. Rondel and S.A. Varley, Clinical Data Management (John Wiley & Sons, New York, 1993).

3. U.S. Code of Federal Regulations Title 21, Part 312.

4. ICH/GCP Consolidated Guidelines, E6.

5. EU Clinical Trial Directives 2001/20/EC and 2005/28/EC.