Introduction
Pharmacovigilance (PV) is central to ensuring patient safety in the pharmaceutical industry. It encompasses the monitoring, assessment and prevention of Adverse Drug Reactions (ADRs), safeguarding public health while enabling the continued use of essential medicines. However, as pharmaceutical companies expand globally, they encounter a labyrinth of diverse regulatory environments, each with its own set of requirements, priorities and limitations. Implementing PV audits across these varied landscapes presents significant challenges, particularly when harmonising global practices with local regulatory expectations.
This article explores the complexities of conducting PV audits in different regulatory contexts, highlighting regional disparities, the impact on drug safety and strategies to address these challenges effectively. It also incorporates insights from the scientific literature to provide a well-rounded view of this critical issue.
Outlining the Challenges
Diverging Regulations
Regulatory frameworks for PV vary significantly across regions, creating compliance challenges for Marketing Authorisation Holders (MAHs) operating globally. While the European Union (EU) has established detailed and harmonised guidelines under its Good PV Practices (GVP), other regions, including parts of the Middle East, North Africa (MENA), Commonwealth of Independent States (CIS) and Latin America (LATAM), often follow less stringent or fragmented regulations. This disparity necessitates a tailored approach PV systems and audits to align global standards with local requirements.
For instance, in the EU, MAHs must appoint a Qualified Person for PV (QPPV) and Deputy who reside within the European Economic Area (EEA) and are accessible 24/7 to address urgent safety concerns. This requirement ensures oversight and rapid response to ADRs. Conversely, some CIS and LATAM countries do not mandate 24/7 QPPV availability or the appointment of a deputy.
In the majority of MENA countries, the Local Safety Responsible (LSR) is required to be present on the distributor’s side to facilitate communication with health authorities, this requirement ensures local representation but adds complexity for multinational companies working with distributors who may lack sufficient PV expertise.
While the United Arab Emirates (UAE) and Kingdom of Saudi Arabia (KSA) require having an appointed QPPV residing in the country or even to be a country national, others are exploring different approaches. For example, Oman allows QPPVs to be located in any GCC state, offering flexibility but requiring robust oversight mechanisms to maintain compliance.
Reporting and Documentation Disparities
Variations in reporting requirements are a major challenge for global PV. Periodic Safety Update Report (PSUR) submission requirements also vary. In the EU, PSURs must adhere to fixed submission timelines aligned with the European Medicines Agency’s (EMA) centralised procedures. The majority of MENA countries follow the same rule. However, in Latin America the submission schedules may differ, with some countries imposing country-specific timelines or requiring additional regional adaptations. The authorities mandate the PSUR schedule to be based on the registration dates in the country, as is the case in Peru and Ecuador. This misalignment complicates global PV operations, as companies must tailor their reporting schedules and produce various reports to meet divergent regulatory expectations.
ADR reporting practices vary significantly across regions, and Qatar serves as an illustrative example. In Qatar, there are no explicit regulatory requirements for collecting or reporting ADRs. However, some countries mandate the inclusion of not only domestic ADR cases but also international cases in their reports. This means that ADRs originating in Qatar must be reported to these health authorities, even though Qatar itself does not impose such obligations. Resource-limited local representatives in Qatar often adhere strictly to the minimal local requirements, further complicating the efforts of international companies to maintain consistent global pharmacovigilance practices. However, resource-limited local representatives often resist exceeding the minimal requirements of their jurisdictions, creating further challenges for international companies striving to maintain global consistency.
Furthermore, literature monitoring is often not explicitly mandated in these regions, with some countries skipping the requirements completely while others only relying on a global literature search. This gap can lead to missed safety signals, underscoring the need for MAHs to implement additional oversight mechanisms.
These disparities in reporting and documentation reveal the significant burden placed on MAHs, particularly in regions where resources to support comprehensive PV systems are limited.
Resource Constraints
Resource constraints are a pervasive challenge in developing regions, where financial, infrastructural and human resources are often insufficient to establish effective PV systems.
In Lebanon, for example, the development of a national PV system relied on external funding and technical support from organisations like the World Health Organisation (WHO). Without such assistance, achieving compliance with global standards would have been particularly challenging.
Smaller MAHs may lack the capacity to conduct detailed audits or implement corrective actions identified during these audits.
Even for multinational companies, balancing the cost of global compliance with the operational realities of resource-limited regions is challenging. Advanced tools like electronic safety databases, which streamline reporting and data management, are often unavailable or underutilised, further exacerbating disparities in PV practices.
Cultural and Language Variations
Cultural differences significantly impact the effectiveness of PV systems and the success of audits. In many countries, ADR reporting is not widely accepted or understood, resulting in chronic under-reporting. This lack of engagement often stems from limited awareness, societal stigma or scepticism about the importance of PV activities.
For example, in some MENA countries, healthcare professionals may hesitate to report ADRs due to fear of legal repercussions or a belief that such reports will not lead to meaningful action. Similarly, patients in these regions are often unaware of their role in PV, in contrast to the EU, where patient reporting is a vital component of the system. Cultural attitudes also influence partnerships. In regions where distributors handle local PV obligations, the lack of a reporting culture can hinder timely and accurate communication with health authorities.
Furthermore, the cultural emphasis on confidentiality in some Arab countries adds another layer of complexity. While these cultural norms reinforce the protection of patient data, they often lead to a reluctance to engage in open data-sharing practices, even when confidentiality can be maintained. This duality requires MAHs to navigate a challenging landscape, balancing respect for local privacy norms with the need for global PV compliance.
Additionally, Standard Operating Procedures (SOPs) in many regions are written in the local language to align with local regulatory requirements and improve accessibility for local teams. While this ensures that procedures are clearly understood by local stakeholders, it can complicate oversight by global PV teams, who may not be familiar with the language. Translation of SOPs into English for global review and audits introduces additional burdens and potential discrepancies, increasing the risk of miscommunication and misalignment with global standards.
Language barriers and inconsistencies in reporting systems further exacerbate these issues. In multilingual regions, ADR reports often require translation into English for integration into global databases, increasing the risk of errors or delays. Additionally, some countries in MENA rely on a combination of paper-based and electronic systems, complicating the process of collecting and consolidating safety data.
These cultural challenges intersect with operational barriers, such as data privacy laws, further complicating global PV efforts.
The Complexities of Various Partnerships
An added layer of complexity arises when the partner in a territory is not an MAH but only a distributor. Unlike MAHs, distributors often lack the infrastructure, expertise or dedicated personnel to fulfil PV obligations. This can lead to significant gaps in ADR reporting, literature monitoring and compliance with local PV regulations. Very often, PV metrics are not part of the KPIs or self-inspections.
In Qatar, ADR reporting is not explicitly required by local regulations, distributors often interpret this as a reason to minimise their involvement in PV activities, leaving the MAH responsible for bridging the compliance gap, as some countries request the reports from outside that country to be also reported to the Health Authorities (HAs). This brings another point of potential non-compliance to the multinational MAH.
This disparity often necessitates a detailed Safety Data Exchange Agreement (SDEA) that clearly delineates the responsibilities of both parties. For instance, the MAH may need to train the distributor’s staff on ADR collection and reporting processes or provide templates and tools to ensure adherence to global standards. Without robust agreements and continuous oversight, the risk of non-compliance increases significantly, complicating the overall PV framework in the territory.
Given the challenges posed by regulatory inconsistencies, cultural and operational barriers and various types of partnerships, implementing effective PV strategies becomes essential. A targeted and adaptable approach can address these complexities while ensuring global compliance.
Bridging the Gap: Strategies for Effective PV Audits
Understanding the Regulatory Landscape
Implementing effective PV audits across diverse regulatory environments requires a combination of a strategic and comprehensive approach. These strategies must prioritise the unique challenges posed by regional disparities, resource limitations and cultural differences, supported by the comprehensive SDEA or a PV part of the distribution agreement.
Risk-Based Auditing
Risk-based auditing is a pragmatic method for optimising PV efforts by focusing resources on areas with the highest compliance risks. By identifying and prioritising regions or activities where gaps are most likely to occur, MAHs can ensure that critical safety issues are addressed effectively while maintaining regulatory compliance.
This approach is particularly valuable in countries with developing PV infrastructure, where ADR reporting systems may be inconsistent or underutilised. For example, in regions where healthcare professionals are not fully engaged in ADR reporting, audits can focus on assessing the robustness of local data collection processes and identifying barriers to compliance. This ensures that safety data is accurately captured and reported, minimising the risk of overlooked signals.
The prioritisation of audits can also be informed by historical compliance data. Regions or products with previous findings of non-compliance or repeated regulatory observations are likely to present ongoing risks. Auditing these areas proactively helps mitigate future issues and demonstrates a commitment to continuous improvement. By focusing on critical issues, MAHs can address potential safety gaps more effectively.
A risk-based strategy also extends to evaluating high-risk products, such as those with complex safety profiles or those undergoing Post-Authorisation Safety Studies (PASS). By focusing audits on these areas, companies can proactively identify and mitigate risks.
While risk-based auditing allows MAHs to prioritise high-risk areas, ensuring robust partnerships through SDEAs is equally critical. These agreements provide the framework for consistent and effective PV across diverse regions.
Building Robust Safety Data Exchange Agreements
Effective collaboration and clear SDEAs are critical to navigating these complexities, but they require meticulous planning and oversight beforehand to ensure all safety data is consistently captured and reported.
These agreements are especially critical in regions without stringent PV requirements or diverse regulations with significant differences to the MAH location regulation, ensuring that safety data is collected, shared and escalated in line with global standards.
An effective SDEA specifies timelines for ADR reporting, communication channels and procedures for resolving discrepancies in safety data. For example, SDEAs may detail the submission process for PSURs, ensuring alignment with local requirements while maintaining global consistency. By establishing clear guidelines, SDEAs reduce ambiguity and enhance collaboration between MAHs and their partners. It can also outline additional responsibilities of local literature monitoring if the country doesn’t mandate its screening. If SDEAs are not in place, the Distribution Agreement (DA) shall include a detailed chapter on PV responsibilities and be enforced.
These agreements are instrumental in bridging regulatory gaps and fostering accountability.
Enhancing Training and Capacity Building
Training and capacity building are other critical components of effective PV systems, particularly in regions with less established regulatory frameworks. Providing local teams with training on global PV standards ensures consistent reporting practices and fosters a culture of safety.
Training programmes should cover essential topics such as ADR reporting, signal detection and the detailed process of timeline adherence while stressing the importance of PV in general.
Tailored programmes can also address cultural differences, which play a significant role in PV practices. In regions where ADR reporting is not widely practiced, educational initiatives that emphasise the importance of PV and its impact on patient safety can encourage higher reporting rates. Mobile applications and digital platforms can also be leveraged as training tools to improve accessibility and engagement.
Conclusion
The global PV landscape is as diverse as the regions it serves, presenting unique challenges for harmonisation and compliance. Auditors navigate complexities firsthand, witnessing the intricate interplay of regulatory frameworks, cultural nuances and operational realities. This article highlights the multifaceted nature of these challenges, from addressing regional regulatory disparities to tackling resource constraints, cultural barriers and the complexities of distributor partnerships. While these issues complicate global PV operations, they also present opportunities for innovation and collaboration.
A key theme is the urgent need for harmonisation. Discrepancies in PV practices, such as ADR reporting, QPPV requirements, PASS and additional Risk Minimisation Measures (aRMMs) implementation, underscore the necessity of globally aligned standards.
Regulatory initiatives led by organisations like the International Council for Harmonisation (ICH) offer a path forward, promoting consistency and reducing operational burdens for MAHs.
Capacity building and education remain foundational. Empowering local stakeholders through tailored training programmes and integrating PV into medical curricula can foster a culture of safety and accountability, ensuring that all regions contribute effectively to global PV efforts.
Ultimately, achieving a unified PV framework requires a collective commitment from regulators, industry stakeholders and healthcare professionals. By fostering collaboration, leveraging technology and addressing region-specific needs, the pharmaceutical industry can build a system that not only meets regulatory demands, but also safeguards patient safety on a global scale. Harmonisation is not merely a goal – it is a necessity to protect public health and maintain trust in medicines worldwide.
References
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Atia A. PV in Libya: current status and future trends. Sultan Qaboos Univ Med J. 2021 May;21(2):e161–3. doi:10.18295/squmj.2021.21.02.014.
Jose J, Al Rubaie MH, Al Ramimmy H, Varughese SS. PV: basic concepts and an overview of the system in Oman. Sultan Qaboos Univ Med J. 2021 May;21(2):e161–3. doi:10.18295/squmj.2021.21.02.015.
Orsini LS, Berger M, Crown W, Daniel G, Eichler HG, Goettsch W, et al. Improving transparency to build trust in real-world secondary data studies for hypothesis testing – why, what, and how: recommendations and a road map from the real-world evidence transparency initiative. [Address correspondence to: Lucinda S. Orsini, DPM, MPH, 505 Lawrence Square Blvd South, Lawrenceville, NJ 08648, USA].
Author Profile
Alina is a Pharmacovigilance/Regulatory Affairs professional and an experienced GxP Auditor. With a career spanning various regions, she holds an MBA and MSc in Pharmacovigilance from UK universities.
Since moving to the Middle East from Asia, Alina has worked as a freelancer in Pharmacovigilance, Regulatory Affairs and Quality improvement initiatives.
Currently, she covers GCC, LATAM and CIS regions for regulatory submissions while working with UK, US and EU companies on PV projects. Alina is a frequent speaker at forums, conferences and training programs, sharing her expertise on various topics. She has presented at GCC Regulatory Affairs/ PV Summits, Drug Safety Symposiums and other industry events within the MENA region.
Published in Quasar Magazine by Research quality Association (RQA), February edition
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