Regulatory agencies have made it clear that quality is integral to drug safety, and pharmacovigilance (PV) quality management systems constitute the foundation of PV operations.
The International Conference on Harmonisation (ICH), European Medicines Agency (EMA) and US Food and Drug Administration (US FDA) have laid out their expectations with respect to quality management systems (QMS) for PV.
EMA’s Good Pharmacovigilance Practices (GVP) Module I – PV Systems and their Quality Systems and on FDA’s Guidance for Industry – Good PV Practices and Pharmacoepidemiologic Assessment (Mar 2005). Though a lot of ICH and FDA quality publications relate to manufacturing, there is an expectation that these will also be applied to PV. FDA’s Office of Regulatory Operations has also issued the ORA Quality Manual in March 2012.
EMA’s GVP Module I enumerates the following quality objectives of a PV system:
- Complying with legal requirements for PV tasks and responsibilities
- Preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside the terms of marketing authorisation or from occupational exposure
- Promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public
- Contributing to the protection of patients’ and public health
The goals of a QMS are compliance with the law, prevention from harm, promotion of safe drug use and patient/ public health protection. Quality documents and guidances across regulatory bodies state that a QMS addresses quality planning, quality adherence, quality control/quality assurance and quality improvements, and comprises of organisational structure, responsibilities, procedures, processes, resource management, compliance management and record management.
Organisational structure, responsibilities and resource management pertain to the availability of a sufficient number of competent and appropriately qualified and trained personnel with clear roles and responsibilities (job descriptions), and also pertains to the availability of other infrastructure such as computers and facilities. Quality planning is about being prepared for and anticipating issues and problems, along with the need to stay up-to-date on new regulations, technology and processes.
Compliance management refers to the need to have execution and controls in place to manage compliance with requirements outlined by the Competent Authorities (CAs) with respect to quality, completeness of PV data, assessment and timeline compliance, independence of PV activities and effective communication. A key element of compliance management is to have valid, traceable processes with audit trails and to have the right technology.
Other aspects of compliance management are defining and monitoring of key performance indicators (KPIs), ensuring root cause analysis (RCA) and corrective and preventive action plans (CAPAs) and conducting periodic audits. Compliance management processes to monitor the performance of a PV system also include evaluation of the effectiveness of actions taken with medicinal products for the purpose of minimising risks and supporting their safe and effective use in patients.
Few examples of KPIs:
- Regulatory reporting compliance (per cent cases submitted to regulators on time), e.g., 7-, 15-day reports, EU submissions)
- Late reports into Drug Safety, e.g., from study monitors
- Late workflow steps within Drug safety, e.g., triage within 24 hours, case closure by day 7, coding, medical review, due diligence requests
- Late reports business partners (license partners as per PV agreements).
- E2B reporting failures
- Case quality metrics
- Late & on time aggregate reports (e.g. PADERs, PSURs, DSURs)
- CAPA commitments done on time, done but late, not done
- SOPs updated on time & training done as required.
Record management is about documentation of a quality system; everything should be documented in a systematic and orderly manner in the form of written policies and procedures, quality manuals and quality records. Data security and privacy are critical requirements. Quality system documentation by the marketing authorisation holder (MAH) in the PV system master file (PSMF) is also a part of record management.
Audits: It is expected that all functions of PV (home office, subsidiaries, vendors, partners, etc.) should be audited periodically. FDA does not specify the frequency but many companies do audits of major operations yearly and smaller or less critical PV units or functions every 2-4 years. FDA and EMA maintain a 2-4 year inspection cycle of companies unless for cause when inspections are more frequent. There should be an internal company compliance function or group to handle this. They should not be part of PV or drug safety.
Most of the above requirements are similar in the FDA and EMA guidances. The EMA has more requirements, for example, with respect to training (even personnel with no direct PV responsibilities are required to have adequate training) and is more specific and explicit in stating certain requirements, which are mentioned below.
- Continuous monitoring of PV data, risk minimisation.
- Scientific evaluation of all information on risks particularly regarding ARs from off-label or occupational exposure
- Examination & submission of non-serious ARs
- Integrity, quality & completeness of data
- Processes to avoid duplicate submissions.
- Effective communication with public, HCPs & CAs on all safety matters
- Updated product labeling as new information becomes known
- Written SOPs & procedural documents
- Good PV record management & data security/privacy
- Organization charts, HR management within PV, job descriptions
EMA identifies certain PV processes as critical, and quality requirements for these processes are outlined in the respective GVP modules. PV processes identified as critical include:
- Continuous safety profile monitoring and benefit-risk evaluation
- Risk management and risk minimisation
- Collection, processing and reporting of individual case safety reports (ICSRs) from any source
- Signal management
- Aggregate safety reporting/periodic safety update reports
- Meeting commitments and responding to requests from the CAs
- Interaction between PV and product quality defect systems
- Communication about safety concerns and changes to the benefit-risk profile between MAHs and CAs, and also notifying these changes to the patients and healthcare professionals
- Keeping product information up-to-date
- Implementation of variations to marketing authorisations for safety reasons
- Written SOPs & procedural documents
The QMS is essential to, and needs to drive, the PV operations. It is not a mere obligation or a mandate. It needs to be a living system that determines the way the PV system works in the company and needs to lay down the framework that guides compliance and quality of the PV system. Whether explicitly stated or not, all guidances have similar expectations from a QMS, though some are more specific than others.
References:
- Guidelines on good pharmacovigilance practices (GVP), Module I – Pharmacovigilance systems and their quality systems; EMA, June 2012
- FDA’s Guidance for Industry – Good PV Practices and Pharmacoepidemiologic Assessment (Mar 2005)
- ICH Quality documents Q8, Q9, Q10, Q11
- Pharmaceutical Quality for the 21st Century: A Risk-Based Approach
- ORA Quality Manual, March 2012, Document # ORA-QMS-POL.002, version #2.0, Department of Health and Human Services, FDA Office of Regulatory Affairs and Quality Management System
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