With the increase in awareness of good clinical practices (GCP) requirements and strive for acceptance of clinical research data in the international market, the focus of clinical research in India is shifting from cost advantages to quality.
Maintaining the integrity, accuracy and above all quality throughout a clinical trial is a challenging, dynamic and continual process. The regulatory environment in the pharmaceutical industry is undergoing a continuous change. With the advent of many advanced systems like Electronic Case Record Forms (eCRF) and Electronic Data Capture (EDC), it has become mandatory for all stakeholders involved in clinical trials to adhere to ICH - GCP, international and national regulatory guidelines.
The most important factors that emphasize the need of quality in today's clinical research scenario are:
■ Overwhelming costs associated with clinical research
■ More studies, more sites, greater volume at each site
■ Expansion and fluidity of clinical investi-gator pool
■ 'New' players in new roles (CROs, SMOs)
■ New technologies (electronic record-keeping)
■ More participation by 'vulnerable' subjects
■ Global expansion (areas new to GCP)
There is a need to realize the importance of maintaining the quality right from the first step of clinical trial. To meet the needs and requirements of a highly demanding market with respect to quality, a quality assurance (QA) unit is mandatory in a clinical research set up. There of course is a difference between quality control activities, which reside with the operational units and quality assurance activities, which assesses the efficiency and integrity of the control systems.
Quality
To define quality in discrete terms is a difficult process. As per ISO 9000, quality is a set of characteristics that a product service must have to satisfy needs expectations of the customer.
A product is an output from a process. From the perspective of clinical research, the output from the process is information. Therefore, in clinical research, quality may be defined as the reliability and credibility of information that provide an answer to a scientific question.
Processes involved in a clinical trial
As per ISO 9000, which is a family of standards for quality management system (QMS), clinical research quality is defined as a set of interacting elements established to direct and control an organization. It includes the organizational structures, responsibilities, procedures, processes and resources for implementing quality management system and to achieve quality objectives based on customer's requirements. With respect to clinical research, these objectives are reliability and credibility of trial data and compliance with GCP, ethical and regulatory standards.
Standard tools of QMS
The standard tools of quality management system (QMS) in clinical research include quality control and quality assurance.
A typical Pyramid showing components of Quality management System
Quality assurance should not be confused with quality control. As per the definitions of quality control, these are the periodical operational checks within each functional department to verify that clinical data is generated, collected, handled, analyzed and recorded according to protocol and GCPs. As the definition says, quality control is primarily the responsibility of the people carrying out the work, such as the monitor, investigator or data manager. Quality assurance encompasses QC and audit. As per the definition of QA, it is a systematic and independent examination of all trial related articles, documents, processes and functions. This activity is performed by the people, who are not involved in the research process. In short, QA is a process to make sure whether QC has been performed as required and that the outcome of a protocol is correct.
Quality assurance activities
For a clinical trial, the QA activities that are planned to be conducted prior, during and at the end of the trial shall be included in the QA audit plan. Ideally, this audit plan shall be prepared before the trial starts at the sites. However, the number of sites to be audited may be added later depending on the trial onset. Typically, an audit plan shall include the following:
■ Type of audit
■ Number of investigator sites/CRO/laboratory /outside agencies planned/ selected for audit
■ Audit methodology
■ Documents and processes to be audited
■ Details of audit team members and auditors
■ Standards against which the audit will be conducted such as clinical trial protocol, CRF filling and completion guidelines, SOPs, ICH/GCP guidelines and local regulatory guidelines
■ It also should specify the expected duration of audits. However, the date should be mutually accepted by the site team and the monitor
The QA unit is involved in the various aspects of audits, including:
■ Investigator site audits
■ Independent database audits
■ Trial master file audits
■ Vendor audits/ assessments
■ Clinical study report and integrated report audits
■ Audits of pharmacovigilance activities
■ Computer systems validation audits/advice
■ Regulatory inspection preparation visits
■ Laboratory audits
■ Audit of pharmacokinetic data analysis and reporting
■ Contract research organization audits
In addition, audit of the internal processes is also one of the responsibilities of the QA team. It includes review of drug development process by way of continuous interaction with all the units involved in the drug development stage, review of employee training(s), analyzing the needs and areas where there is a scope of improvement, SOP and regulatory compliance. Apart, audit of QC activities is done at each step.
The QA unit also carries out GCP training for monitors and investigators and GCP advice and problem-solving. Clinical auditors can become involved in all aspects of clinical research from protocol development to the final clinical report and regulatory submissions. Apart, computer system development, electronic data capture systems and CRO selection evaluation visit are some of the areas clinical auditors are becoming more involved with.
Systems audit/ process audit
Systems audit or process audit is a new trend seen in the global and Indian CROs. Now, pharmaceutical companies are involved in this type of audit. By definition, it is a selected process plus all related activities, resources, organization and documents (including SOPs and records, facilities and equipments).
Reasons for conducting systems audit are:
■ Potential for regulatory inspections
■ Aim and desire to improve efficiency and effectiveness
■ Satisfying concerns of higher management
■ Benchmarking against other departments
The objectives of the systems audit include:
■ To determine if existing SOPs are sufficient and relevant
■ To determine if there are any flaws or gaps in operations and workflow
■ Process improvement: Assessment of trial data integrity
■ To perform due diligence as part of merger, acquisition etc.
Types of systems audited:
■ Audit of computerized data collection systems (validation audit)
■ Audit of monitoring system
■ Audit of IP management and distribution system
■ Audit of document management and archiving
■ Audit of central lab and other service providers
■ Audit of sponsors pharmacovigilance system
To initiate an audit of a system, the auditors, quality assurance and sponsor management must define the plan and activities within each sub type to be carried out.
Personality trials of an auditor
To excel in the clinical research audit, the auditors must be confident and competent. Otherwise they shall loose their credibility. In addition, they should possess attention to detail, excellent interpersonal communication skills, problem solving ability and even a good sense of humor.
Auditors need to have a good knowledge of the regulations and guidelines. It is important that auditors are able to set the big picture. Also, the auditor must be able to quickly assess whether non-compliance to a particular SOP is a problem or not. Auditors need to have a reading habit to maintain up-to-date knowledge of what is happening in the regulatory world.
Benefits of managing quality of clinical data
1. Performing audits during a clinical trial enables the evaluation of following:
■ Per cent of monitoring visits completed on time
■ Per cent of protocol deviations and violations
■ Per cent of SAEs reported within 24 hours to the industrial review board (IRB) and sponsors
■ Per cent of properly executed informed consent forms
■ No of queries, Data Clarification Form (DCFs) raised and resolved
■ Average query resolution turn around time
■ No. of missing data entries/CRF page received
■ Under reporting of AE (if any) by the sites
2. Corrective and preventive action process
The QA department focuses on measures to prevent, detect, investigate, assess and correct errors/violations associated with the conduct of clinical trials. The primary focus is on preventing violations rather than detecting them retrospectively.
(The author is Assistant Professor in Clinical Research, Institute of Clinical Research, Bangalore)