Norwich Clinical Services: the Global Pharmacovigilance Landscape -- Considerations Beyond the U.S. and the EU

Published: Oct 25, 2012

October 25, 2012 -- The World Health Organization describes pharmacovigilance as the process of detecting, assessing, understanding, and preventing adverse events associated with medicinal products, with the aim of enhancing patient care and safety.

While the goal of pharmacovigilance remains constant, the methods, resources, and regulations that are designed to reach this goal are continuously being updated and optimized. Adding to this inherent complexity, pharmacovigilance also involves the coordinated interaction of multiple players, including patients, healthcare professionals, pharmaceutical companies, and multiple regulatory authorities across various regions.

Over time, the pharmacovigilance process has become more proactive in the monitoring, assessment, and reporting of drug-related adverse events. In addition, the pharmaceutical industry itself has also gone through a period of transition, in which the concept of the fully integrated pharmaceutical company was challenged by a variety of factors, including increasing economical and productivity pressures, expansion of the generic marketplace, and globalization of manufacturing and clinical research. Pharmaceutical companies operating as completely virtual enterprises are also entering this arena. As such, specialized contract organizations have become partners to pharmaceutical companies in order to supplement their core service offerings, including the outsourcing of manufacturing, clinical trial execution, and, in the case of virtual companies, any activity that requires physical assets or infrastructure. More recently, the clinical and regulatory expertise of contract research organizations (CRO) has also been utilized by pharmaceutical companies for the initiation and implementation of pharmacovigilance processes and procedures throughout the lifecycle of their products.

The concept of pharmacovigilance is recognized globally; however, specific regulations are mandated by various country- and region-specific authorities. In the US, the passage by Congress of the Food and Drug Administration Amendments Act of 2007, which was aimed at enhancing the safety of medical products, increased the oversight and authority of the FDA over investigational and marketed drugs, and created new standards for integrating risk evaluation and mitigation strategies into the review of new drugs and post-marketing activities.

Similarly, the European Union is currently at a pivotal point in pharmacovigilance history, with the implementation of legislation that calls for a greater transparency in the collection and reporting of adverse events. Each country that functions under the EMA also issues information for marketing authorization holders that provides guidance on what the centralized legislation means and how practices should be implemented at the national level. For example, the Hungarian Regulation of the Ministry of Human Resources on Pharmacovigilance released Norwich Clinical specific directives on adverse drug reaction reporting, periodic safety update reports, risk management plans, and the pharmacovigilance system master file submissions, which highlight the changes that came out of the new legislation.

Currently, 27 member states, as well as the European Economic Area (Iceland, Liechtenstein, and Norway), fall under the centralized processes, including good pharmacovigilance practices (GVPs) of the European Medicines Agency (EMA). These practices apply to marketing-authorization holders and regulatory authorities in EU Member States, and cover medicines authorized centrally via the EMA as well as medicines authorized at national level. Although there are standard regulations within the EU, pharmacovigilance practices need to take into account the numerous countries that operate outside of EMA jurisdiction, especially as these areas become increasingly involved in the recruitment process and implementation of clinical trials, including registration and post-marketing studies.

Central and Eastern Europe (CEE) provides a good illustration of the complexity of the regulatory landscape under which pharmaceutical companies must function. This region represents the largest number of global clinical trial initiations outside North America and Western Europe. Multiple factors are driving this trend, including their greater access to drug-naive patients, lower labor costs, a higher concentration of patients near sites, and closer relationships between doctors and patients. The 25 countries that make up the CEE—including Austria, Bulgaria, the Czech Republic, Hungary, Poland, Romania, etc—cross not only regional boundaries, but also the boundaries of various regulatory agencies and requirements.

Pharmaceutical companies conducting clinical trials and marketing drugs in this region need to have processes and procedures in place not only to meet the strict requirements of the EU market but also the specific, national regulatory and pharmacovigilance requirements of non-EU countries. This is a continuously evolving dynamic, with many of the CEE countries who are not currently part of the EEA seeking membership and changing their in-country regulatory systems to mirror the current processes of the centralized system. For example, in January 2011, the EMA, together with the Agency for Medical Products and Medical Devices of Croatia (HALMED), started a pre-accession process for product information in order to facilitate the phasing-in of decisions on EMA-authorized medicines once Croatia joins the EU in 2013. In addition, individual case safety reports sent to HALMED will be entered into the local EudraVigilance (European Union Drug Regulating Authorities Pharmacovigilance) data processing network and management system to document suspected adverse events, but they will not be transmitted onward to the EudraVigilance database of the EMA before Croatia becomes an EU Member State.

While the Croatian Agency was created from two national health institutes and inherited a considerable amount of expertise that has aided them in building a tightly controlled regulatory process, started without such previous experience, further suggesting the highly variable nature of the region in terms of regulatory requirements for clinical trial oversight and pharmacovigilance implementation.

In many cases, pharmaceutical companies sponsoring trials or marketing drugs in regions such as CEE do not have a physical presence in the region, rendering them at a disadvantage to manage concerns or to mitigate risks on a day-to-day basis. Alignment with a CRO partner that has experience and capability in the territory will allow that CRO to function as an extension of the trial sponsor’s team to deal with issues as they arise and ensure the appropriate guidelines are followed. Qualified personnel responsible for pharmacovigilance will be able to provide support in establishing and maintaining the Market Authorization Holder’s pharmacovigilance system, oversee product safety profiles and emerging safety signals, report and track suspected unexpected serious adverse reactions, and act as a single point of contact for the regulatory agencies.

Effective pharmacovigilance practices, whether through internal management or via a partnership between the pharmaceutical company and a CRO, require that processes are in place to keep up with the evolving landscape, including updates on new legislation and how revised pharmacovigilance regulations may impact processes and procedures across multiple regulatory agencies and through various stages of the drug lifecycle.

1. World Health Organization. The importance of pharmacovigilance: safety monitoring of medicinal products. Geneva; 2002.

2. Food and Drug Administration Amendments Act (FDAAA) of 2007. Information available at: t/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/def ault.htm. Accessed: September 25, 2012.

3. European Medicines Agency; Good Pharmacovigilance Practices. Available at: _listing_000345.jsp&mid=WC0b01ac058058f32c. Accessed: September 25, 2012.

4. Hungarian Regulation of the Ministry of Human Resources on Pharmacovigilance. Information for marketing authorization holders on the translational arrangements of the new pharmacovigilance legislation. Available at: Accessed: September 25, 2012.

5. Central and Eastern Europe: Outsourcing Trends and Growth Opportunities in Clinical Trials, CenterWatch store, Accessed: September 25, 2012.

6. Instrument for Pre-accession Assistance (IPA). Available at: ng/document_listing_000221.jsp&mid=WC0b01ac058003529c. Accessed: September 25, 2012.

7. The Agency for Medicinal Products and Medical Devices of Croatia. Available at: Accessed: September 25, 2012.

8. Tomic S, et al. Regulating Medicines in Croatia: Five-year Experience of Agency for Medicinal Products and Medical Devices. Croat Med J. 2010;51(2):104-112.

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