In 1968, the World Health Organisation (WHO) Programme for International Drug Monitoring was initiated and ten members participated in this program1. This can be seen as the beginning of the global pharmacovigilance (PV) effort. Nowadays, global PV is arguably more important than ever due to globalisation of the world economy2, internet pharmacies, increased use of technology and increased movement of people and medicines around the world3. Therefore, how is it, that after all this time, having a truly global PV system remains a struggle?
Challenges from Emerging Territories
Historically, the most sophisticated PV systems have been in the most economically developed countries, namely the founders of the International Council for Harmonisation (ICH): Europe, Japan and the USA. However, this approach does not tally with real world requirements and does not enable analysis of PV data globally.
In reality, low and middle income countries (LIMC) are where new treatments (for example vaccines for malaria) are being released onto the market to large populations, with limited clinical experience, due to urgent requirement. Simultaneously, this is where the PV systems are weakest. The WHO have reported that most LMIC PV systems do not yet contribute significantly to the WHO global ADR database (VigiBase). This is challenging because the majority of these products target neglected diseases and diseases of poverty and will therefore be launched exclusively in LMICs, without the benefit of experience in high income countries (HICs). Even when adverse event reports are collected in LMICs, there is often no capacity to analyse the data or implement decisions4.
To illustrate this, a recent analysis conducted by the WHO found a difference in the drugs for which reports were submitted, based on country income. Returning to the above example, 2% of reports associated with anti-malarial drugs came from countries in sub-Saharan Africa—an area that accounts for 86% of malaria cases, whilst HICs, where malaria is controlled, accounted for 84% of reports3.
To combat these challenges, the WHO is working with charities such as The Bill and Melinda Gates Foundation and regulators such as the Medicines and Healthcare products Regulatory Agency (MHRA) to set up projects like Project Smart Safety Surveillance (Project 3-S), which was presented by Mick Foy at the 2019 PIPA Conference. The involvement of the MHRA in this project will ensure scientific and regulatory expertise are developed within the national centres5. The WHO has also developed guidance on “Minimum Requirements for a functional Pharmacovigilance System”. Both of these approaches aim to ensure that regulation and expertise are developed hand in hand, so that the regulatory requirements do not outstrip the capabilities of the country’s PV system6.
Is Harmonisation Achievable?
Alongside the countries that are seeking advice from well-established regulators to develop a bespoke system tailored to their country’s needs, there are also the countries that have rapidly moved from having next to no PV system, to attempting to replicate the European model. For example, the Arab Good Pharmacovigilance Practices (GVPs) have been developed by the League of Arab States and adopted fully or partially by Egypt, Iraq, Jordan, Kuwait, Oman, Tunisia and Saudi Arabia. Furthermore, the Eurasian Economic Commission, which comprises Russia, Belarus, Kazakhstan, Armenia and Kyrgyzstan, have developed the Eurasian GVPs7.
In fact, recently estimated figures suggest that over 40 countries now have the requirement for a qualified person for pharmacovigilance (QPPV)8, and over 30 countries have the requirement for a pharmacovigilance system master file (PSMF)9, and this will continue to rise. Whilst on the surface this may appear helpful in terms of harmonisation, it is not quite as straightforward as this. Firstly, although good intentions are there, it may not always be appropriate to apply a sophisticated and well-established PV system to emerging territories that often lack the resources to implement it properly.
The adoption of a national QPPV in multiple territories (both within and outside of the EU) has proved a challenge for many marketing authorisation holders (MAHs). The requirements for the national QPPV tend to vary from country to country. For example, the Arab GVP requirements are equivalent to the EU-QPPV. However, MAHs may struggle to find an individual with the right level of expertise that resides in these countries, where PV is in its infancy. This in turn has led to another difficulty, which is how to ensure sufficient oversight of the PV system by all of the national QPPVs, and which QPPV should have the overall say. The solution by global pharmaceutical companies has been to develop a “QPPV Office” and in the majority of cases, the EU-QPPV has been renamed as the “Global QPPV” or “International QPPV”. Although no such position officially exists in any PV legislation or guidance, this seems to be a workable solution.
Similarly the PSMF, a mandatory requirement in the EU, has also been duplicated in other territories. Countries governed by the League of Arab States accept the EU-PSMF, but require an additional document called the Pharmacovigilance System Sub-File. Whereas the Eurasian GVP requires a Eurasian Union PSMF7.
All this has led to some parties asking for greater attempts at harmonisation. But whilst this would be wonderful in an ideal world, is this really possible? Major differences persist between the Food and Drug Agency (FDA) and MHRA regulation, and full alignment is not anticipated despite working towards the same objectives and both being established in HICs10. Even within a geographical area governed by one agency, such as the EU, national differences in legislation prevent complete harmonisation. This discord is recognised by the initiation of the Strengthening Collaboration for Operating Pharmacovigilance in Europe (SCOPE) by a team of European regulators in 2013 to gather information on how regulators in Member States run their national pharmacovigilance systems. Overall, differences in national pharmacovigilance systems among regulators were observed, these included:
- various systems for processing ADR reports,
- legal specifications in addition to the EU legal requirements,
- resources and budgets,
- and various IT systems11.
It seems that despite the effort to harmonise systems, there will always be outliers for one reason or another. Moreover, political and economic unions are not set in stone, as demonstrated by the United Kingdom’s (UK) exit from the European Union (EU). The future relationship between the UK and the EU remains to be defined. However, it is certain that this will have an impact on pharmacovigilance as we know it, and likely lead to more dissonance than harmony, due to introduction of a UK QPPV and other UK specific requirements.
Donzanti10 believes that a lack of globally harmonised PV regulations and guidance documents has led to confusion and unnecessary complications about what and how MAHs should report certain adverse events to regulatory authorities. He names causality assessment, adverse event reporting from solicited, non-interventional programs and risk management as the three main areas that could benefit from harmonisation. It is understandable that a lack of harmonisation can put increased strain on industry and lead to non-compliances due to outliers from the main system.
James Strachan12 explains that there are three key types of harmonisation: bilateral, regional and global. Bilateral agreements are between two countries, or between one country and a group of countries, such as the long-standing collaboration between the EMA and the FDA. In 2007/2008, the agencies signed up to promote cooperation in inspections, biomarkers, counterfeit medicines, risk management, scientific advice, biosimilars, paediatrics, and advanced therapies. The success of this has led to further collaboration on pharmacovigilance, orphan drug development, and inspections.
The second type of harmonisation initiative is regional. The best known example is the EU, but there are an expanding number of additional regions, including the Pan-American Network for Drug Regulatory Harmonisation (PANDRH), the Gulf Cooperation Council (GCC), the Southern African Development Community (SADC), the Association of Southeast Asian Nations (ASEAN), and Asia-Pacific Economic Cooperation (APEC). As well as the aforementioned League of Arab States and Eurasian Economic Commission.
The final and increasingly important harmonisation initiative is global – involving many organisations and countries. Global harmonisation of medicine regulations is not a new concept. In 1990, ICH was formed, with the mission to align global pharmaceutical regulatory requirements13. Its key achievements to date include the harmonisation of Good Manufacturing Practice (GMP) and pharmacovigilance activities, the creation of the electronic Common Technical Document (eCTD) and standardisation of medical terminology through MedDRA. Additionally, as already indicated, the WHO has been instrumental in regulatory harmonisation efforts. Its achievements include development of the Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) classification system for drugs, the International Pharmacopoeia (Ph. Int.) and standards for pharmacovigilance through the WHO Program for International Monitoring, and funding, in conjunction with the World Bank and non-governmental organisations (NGOs), of various harmonisation projects such as Project 3-S, mentioned above14.
However, recent progress has seemed slow, which is likely due to the various challenges faced that are outlined above, including rapidly emerging markets, no “one-size fits all” and the complexities of the global pharmaceutical supply chain. According to a report by the EMA, there is even a lack of integration and a common goal in the many organisations created to drive harmonisation. This is something the International Coalition of Medicines Regulatory Authorities (ICMRA) has been tasked with working on15.
In conclusion, global harmonisation of PV is a work in progress, something we all need to pay attention to, whether we are a leading think tank or a small PV service provider. Those of us who are located within the EU may still see the EMA regulations as the gold standard. However, we must be open to accept that not all regulatory authorities, in particular those from emerging territories, will be able to reach this standard. Therefore, a perfectly streamlined approach to processes cannot be achieved, as there will always be exceptions to the rule. Ultimately, more effective PV through international cooperation leads to earlier detection and responses to potential safety issues, thereby improving patient safety14. However, in an ever-changing world (both within and outside of pharmacovigilance), global harmonisation may never be achieved. In the meantime, having an adaptable internal PV system, as well as a strong regulatory intelligence component, is key to overcoming the challenges presented in the variable landscape of global pharmacovigilance.
- Fornasier G, Francescon S, Leone R, Baldo P. An historical overview over Pharmacovigilance. International Journal of Clinical Pharmacy (2018) 40:744–747. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132952/pdf/11096_2018_Article_657.pdf [Accessed 26/05/2020)
- Kumar V. Challenges and Future Consideration for Pharmacovigilance. Journal of Pharmacovigilance. 2013, 1:1. Available from: https://www.longdom.org/open-access/challenges-and-future-consideration-for-pharmacovigilance-2329-6887.1000102.pdf [Accessed 26/11/2019]
- Dal Pan, G.J. Ongoing Challenges in Pharmacovigilance. Drug Saf 37, 1–8 (2014). Available from: https://doi.org/10.1007/s40264-013-0123-x [Accessed 26/11/2019]
- Macolic Sarinic V. 2018. Pharmacovigilance new challenges for WHO [PowerPoint presentation]. WHO TBS – Essential medicines and health products. 05/10/2018. Geneva. Available from: http://origin.who.int/medicines/technical_briefing/tbs/TBS2018_Pharmacovigilance_Challenges.pdf [Accessed 27/11/2019]
- Medicines and Healthcare products Regulatory Agency (2017). MHRA awarded over £980,000 for collaboration with the Bill and Melinda Gates Foundation and the World Health Organisation [Press release]. 15/12/2017. Available from: https://www.gov.uk/government/news/mhra-awarded-over-980000-for-collaboration-with-the-bill-and-melinda-gates-foundation-and-the-world-health-organisation [Accessed 27/11/2019]
- World Health Organisation (2010). Minimum Requirements for a functional Pharmacovigilance System. Available from: https://www.who.int/medicines/areas/quality_safety/safety_efficacy/PV_Minimum_Requirements_2010_2.pdf [Accessed 27/11/2019]
- Pharmacovigilance: A Practical Approach, edited by Thao Doan, Cheryl Renz, Fabio Lievano, Mondira Bhattacharya, Linda Scarazzini. 2018, Elsevier Health Sciences. Available from: https://books.google.im/books?id=l-pmDwAAQBAJ [Accessed 26/11/2019]
- DIA QPPV Forum 2019
- PIPA conference 2019
- Donzanti BA. Pharmacovigilance is Everyone’s Concern: Let’s Work It Out Together. Clin Ther. 2018 Dec;40(12):1967-1972. Available from: https://www.clinicaltherapeutics.com/article/S0149-2918(18)30491-0/fulltext [Accessed: 27/11/2019]
- Radecka, A., Loughlin, L., Foy, M. et al. Enhancing Pharmacovigilance Capabilities in the EU Regulatory Network: The SCOPE Joint Action. Drug Saf 41, 1285–1302 (2018). Available from: https://link.springer.com/article/10.1007/s40264-018-0708-5 [Accessed: 26/05/2020]
- Strachan J (2017). ‘Harmonization: Regulation Goes Global’. The Medicine Maker. 13/10/2017. Available from: https://themedicinemaker.com/business-regulation/harmonization-regulation-goes-global [Accessed: 02/12/2019]
- Singh A, Twomey K, Baker R. Global pharmacovigilance regulations: Call for re-harmonization. Clinical Trials (London, England). 2018 Dec;15(6):631-632.Available from: https://europepmc.org/article/pmc/pmc6236640#free-full-text [Accessed 02/12/2019].
- Alvaro D, Branch E, Challener CA (2019). ‘From Regulatory Convergence to Global Regulatory Harmonization’. Pharma’s Almanac. 28/10/2019. Available from: https://www.pharmasalmanac.com/articles/from-regulatory-convergence-to-global-regulatory-harmonization [Accessed 02/12/2019]
- European Medicines Agency. Connecting the dots: Towards global knowledge of the international medicine regulatory landscape: mapping of international initiatives. Available from: https://www.ema.europa.eu/en/documents/leaflet/connecting-dots-towards-global-knowledge-international-medicine-regulatory-landscape-mapping_en.pdf [Accessed 02/12/2019]