Opinion: Hard lessons prime PV experts and regulators for present challenges

Perspective / 29 June 2021

Photo: iStock

In recent years, and notably during the current pandemic, significant strides have been made towards transparency and communication of drug safety monitoring, contributing to unprecedented public interest. In this opinion article, the authors argue that contrasting examples from pharmacovigilance’s past can help point the way to a more proactive and vital future.

The practice of pharmacovigilance – if not the name – is generally considered to have started more than 170 years ago, following the death of young girl in England after receiving a chloroform anaesthetic. That incident, and several other medicine-related harms in subsequent decades and other countries, became the impetus for creating a system to collect information and patient reports on adverse drug reactions, to establish appropriate measures and strategies to react and contain them. The booming of drug development and manufacturing in the beginning of the 20th century presaged the increased need for medicines surveillance and the demand grew to react faster and more effectively to adverse events.

And what about today? The vision of pharmacovigilance has also evolved not only to react, but also to anticipate. Thanks to the rapid evolution of automation and the integration of fields such as big data analytics and artificial intelligence, we are witnessing what may well prove to be an emerging golden era for pharmacovigilance. A proactive pharmacovigilance science is the holy grail that may one day completely revolutionise the way we perceive the field.

Maria Mantziri and Natália Hromníková : "Thanks to the rapid evolution of automation and the integration of fields such as big data analytics and artificial intelligence, we are witnessing what may well prove to be an emerging golden era for pharmacovigilance."

Any medicine has the potential to cause harm to patients in some circumstances. The role of pharmacovigilance is to search for signals of harms so that actions can be taken to protect other patients. Unfortunately, history is littered with examples of signals going unrecognised, or not acted upon, for too long.

One case which illustrates the potentially stark human cost of delay in safety surveillance systems has its roots in the 1990s, during a period of widespread commercialisation and use of appetite-suppressing products. Redux (dex-fenfluramine) and the combination product Fen-Phen (fenfluramine-phenteramine) were two examples of weight-loss aids prescribed to hundreds of thousands of patients around the world.  Such widespread use of a product is a major asset for safety data collection. Hence, even without the powerful data analysis and reporting tools we have today, numerous case reports started to emerge, connecting the use of anti-obesity medications with adverse events, including cardiovascular disorders. Publication and examination of these concerns resulted in marketing authorisation holders having to pull their product from pharmacy shelves world-wide, according to the decisions from national competent authorities and regulators. In 1997, fenfluramine-containing products were withdrawn, based on validated concerns of an unfavourable benefit–harm balance associated with serious cardiac valve abnormalities. Nevertheless, resolution came dangerously late for others.

Such was the case of Mediator, a product marketed by French pharmaceutical company Servier since 1976 as an add-on treatment intended for overweight diabetes patients. However, the product was widely prescribed off-label for weight loss. Its active substance, benfluorex, has a substituted amphetamine structure similar to fenfluramine, and during the late 1990s, evidence was mounting that benfluorex may have the same serious adverse effects of pulmonary arterial hypertension and heart valve disease. However, despite a French pharmacovigilance investigation in 1998, and the withdrawal of the drug by the manufacturer in Spain and Italy in 2003, the drug remained on the market in France until 2009, when validation of the safety signal linking the active ingredient to valvulopathies finally led to a worldwide product withdrawal. This case became one of the biggest health scandals in France, as the product had been marketed for an astounding 33 years, with an estimated five million people exposed to it at the likely cost of hundreds of deaths. A high-profile trial, which finally concluded in March 2021, resulted in a criminal conviction for the company and a steep fine for the regulator.

The role of pharmacovigilance is to search for signals of harms so that actions can be taken to protect other patients. Unfortunately, history is littered with examples of signals going unrecognised, or not acted upon, for too long.

By contrast, a more recent case demonstrates safety systems delivering a far more rapid and effective response. In 2018, N-nitrosodimethylamine (NDMA) contamination was detected in a Chinese company’s valsartan products. The company in question was also the supplier of valsartan as a raw material to manufacturers in other countries. NDMA has demonstrated evidence of carcinogenicity in a number of studies conducted on animals, so, following the safety trigger from the manufacturer, regulators took actions within weeks, ordering recalls of valsartan-containing medicines and thoroughly communicating the related risks to involved stakeholders. As regulatory and industrial review progressed, NDMA and the similar impurity risk factor N-nitrosodiethylamine (NDEA) were found in various other products, for which similar steps were followed.

Several corrective and preventive measures were swiftly put in place, including a two-year transition period during which marketing authorisation holders and manufacturers were expected to perform risk evaluation for the presence of impurities due to NDMA and NDEA in their products and introduce appropriate testing procedures to detect these at the lowest concentrations. Control strategies to prevent or limit patient exposure to the harmful contaminants have been set into motion with a thorough and clear reactive methodology from regulators, which aligns across multiple countries around the world.

And that brings us to the present. While some form of pandemic had long been warned of, no one could predict the full and devastating effect of SARS-CoV-2. For medicines safety monitoring, this has entailed a daunting task: the planning and development of a more proactive stance in preparation for looming pharmacovigilance challenges. With vaccine development and regulatory procedures stepping up to perform at an extraordinary level in terms of pace, collaboration, and communication, pharmacovigilance has had to prepare to respond to an unprecedented wave of data that will be collected and analysed, to be ready to provide safety evaluations as fast and as reliably as possible – all of this, under the additional scrutiny of the impatient media spotlight.

Therefore, COVID-19 can be seen as an important opportunity for the way we envision and work towards drug safety. The initial signs of the response indicate that regulators are up for the challenge and dare to create, expand, and enhance structures to ensure timely and comprehensive results. The endpoint is not only to react, but to protect against the impact of the disease and minimise the potential negative effects of new treatments on a major scale. Going the extra mile to include populations for which safety information usually becomes available many years after the authorisation of a product, such as pregnant women, is a worthwhile step in that direction. Specifically, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) joined forces with the Utrecht University and the University Medical Center Utrecht in an international collaboration to produce data on the impact of COVID‐19 on pregnancy. Project CONSIGN (abbreviated from “COVID‐19 infectiOn aNd medicineS In preGNancy”) aspires to produce real-world evidence for the monitoring of infection and treatments, which will be integrated in decision making and scientific opinions, on the optimal use of the medicines and vaccines from the responsible working groups and scientific committees.

"The endpoint is not only to react, but to protect against the impact of the disease and minimise the potential negative effects of new treatments on a major scale"

In another example of empowering health system through data-driven decisions, the US FDA has upgraded its Sentinel System – an integral part of the agency's surveillance system that leverages electronic health record data – for the assessment of post‐market medical product safety and the support of regulatory decisions. Incorporation of new data sources, development of protocols to assess the natural history of COVID‐19, and validation of a diagnosis‐code-based algorithm for identifying patients with COVID‐19 in claims data are some of the features that the FDA COVID‐19 Working Group enlisted to respond to the pandemic.

In Europe, the EMA has invested in infrastructure, reinforced by preparatory research on the monitoring of the coverage, safety and effectiveness of COVID-19 vaccines before they are introduced on the market. A primary example is project ACCESS or “‘vACcine Covid-19 monitoring readinESS’”, which concluded this February and provided insightful deliverables on the aforementioned targets. Meanwhile, in April 2021, the EMA also announced a joint effort with the European Centre for Disease Prevention and Control to invest in observational studies. In the EMA’s announcement, Executive Director, Emer Cooke, said of the collaboration, “Observational research is an important pillar in the post-marketing surveillance of COVID-19 vaccines and increased EU level collaboration is needed so that Member States can join forces and organise large studies that meet the needs of both medicines regulators and national institutes for public health and vaccination”.

Finally, it should be highlighted that during the COVID-19 pandemic, conscious steps are being made in the improvement of public engagement and communication concerning regulatory procedures and results, demonstrating an intention to be inclusive of and transparent towards healthcare workers and patients. This is a key foundation for a patient-centric public health system, respecting patients’ access to critical information and promoting their indispensable seat at the table of healthcare decision making.

The majority of regulations, procedures, and practices that we consider standard for the field of pharmacovigilance today were only established in recent decades. The ability of pharmacovigilance to perceive, adapt, and evolve can be seen in the examples discussed above, along with many other developments that have shaped today’s landscape. A retrospective look at some of these can be valuable, to avoid pitfalls and exploit future opportunities that have the potential to advance the medicines safety scenery. Acknowledging and learning from the challenges and uncertainties that have dominated 2020 and 2021 so far, it is as important to take a step back and see just how far we have come.


Disclaimer: The views expressed in this article are those of the individual authors writing in their individual capacities only and do not necessarily reflect the official policy or position of their respective employers. Responsibility for the information and views expressed in Uppsala Reports articles lies entirely with the authors. Articles do not necessarily reflect the policies or positions of Uppsala Monitoring Centre.



Maria Mantziri
MPharm, Quality Assurance and Medicines Safety Specialist, Greece

Natália Hromníková
PhD Candidate at the Faculty of Pharmacy, Comenius University, Slovakia

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