by Diana Ribeiro, MD – Freelance Medical Writing Consultant

In our modern world, we want our drugs to be effective, but most importantly, we want them to be safe. This is why drug safety is assessed during all phases of a clinical trial and beyond, well after its introduction in the market. The aim of pharmacovigilance is to improve patient care and patient safety regarding the use of medicines throughout the product’s life cycle (Nour and Plourde in Pharmacoepidemiology and Pharmacovigilance, 2019).

The history of pharmacovigilance started in a reactive way, as a response to the deaths caused by chloroform in the 1800s, the misguided introduction of heroin as an antitussive and analgesic in the early 1900s, and the now infamous thalidomide case in 1960 (Caron, 2016). But today, pharmacovigilance has shifted from reactive to proactive, collecting safety signals and taking pre-emptive measures to reduce the risks associated with medicines.

In this article, we will explore the characteristics of modern pharmacovigilance during the clinical research stage, the documents needed for a drug’s market approval, and how post-market surveillance is conducted.

Pharmacovigilance in clinical research
Drug safety is present in drug development since day 1 in clinical research—one could say that it is present even before, in pre-clinical studies, where the toxicology of a drug is thoroughly assessed. Regarding studies in humans, pharmacovigilance starts with clinical trials, which provide data on adverse events (AEs). These are analysed to determine which ones are linked to the drug, as opposed to AEs that arise from the disease or simply by chance.

Phase I clinical trials aim to determine the safety of the new drug and characterise its pharmacokinetic and pharmacodynamic properties, to establish the optimal dose for subsequent trials. The goals of phase II and III clinical trials are to collect data on both safety and efficacy.

Key elements during clinical research include the documentation of processes, including record management, audits, and corrective and preventative actions (CAPAs). But it is not enough to have documents and processes in place; these must be incorporated into a unified pharmacovigilance framework, seamlessly working together.

Some of the challenges faced by those involved in pharmacovigilance are:

  • Keeping up with the latest developments and regulations;
  • Working in an increasingly global environment;
  • Communicating effectively the risks associated with a drug;
  • Battling under-reporting of safety data in some regions of the world.

The adoption of automated tools for collecting adverse events and the integration of artificial intelligence in pharmacovigilance will considerably expand our knowledge of drug safety, by allowing the systematic and proactive use of medical databases in a cost-effective way.

Pharmacovigilance documents for market approval
Usually, regulatory approval depends on both efficacy and safety. In certain cases, such as the case of non-inferiority clinical trials, the emphasis is placed more on safety than in efficacy, with the new drug having to prove that it is safer than the comparator, while only having to prove it is just as effective but not more (Brody in Clinical Trials, 2016).

It is not surprising then, that pharmacovigilance documents have a central role in a marketing application for a new drug.

Although the process for marketing approval can differ between countries, there is a trend toward the harmonisation of procedures and documents, with the Common Technical Document (CTD) as an example. The CTD was designed to provide a common format for the registration of medicines across Europe, Japan, and the United States. Safety is addressed across the document, in sections 2.4 (Non-Clinical Overview), 2.7 (Clinical Overview), and 5.3.5 (Reports of efficacy and safety studies) (Jordan, 2014).

In Europe, companies are also required to submit a risk management plan (RMP) to the European Medicines Agency (EMA) when applying for a marketing authorisation. According to EMA, the RMPs should not be static documents; instead, they are continually modified and updated throughout the medicine’s life cycle, and include information on:

  • The medicine’s safety profile;
  • Strategies for prevention and minimisation of risks in patients;
  • Plans for studies and/or other activities to gain more knowledge about the safety and efficacy of the medicine;
  • A way to measure the effectiveness of the risk minimisation measures.

This approach to pharmacovigilance requires the continuous collection of data with the ultimate goal of knowing if a medicine’s benefits continue to outweigh its risks throughout its entire life cycle, thus ensuring patient safety.

Furthermore, if there is a potential safety issue, this should be identified as soon as possible, as taking a drug out of the market after its approval is costly and has a more damaging effect on the company’s reputation than stopping its development in the clinical stage. As an example, take the Vioxx® recall in 2004, among claims of scientific misconduct and fabricated efficacy studies (Curfman, 2005).

Post-marketing surveillance
The pharmacovigilance journey does not end with the placement of a new drug on the market. In fact, post-marketing surveillance data is a cornerstone of pharmacovigilance, since it allows or the long-term monitoring of the effects of drugs in patients who are usually excluded from clinical trials, like those with comorbidities or at an advanced age (in Clinical Pharmacy Education, 2019).

The studies conducted after a drug is on the market involve thousands of patients and are designed to collect previously unreported adverse effects, but also unapproved off-label use, and problems with orphan drugs or lack of paediatric formulations (Vlahović-Palčevski, 2011). These phase IV studies can confirm the therapeutic use of a drug in a real-world setting, re-evaluating its safety, efficacy, and dose.

In addition, there has been an effort to include proactive measures when analysing AEs for marketed drugs. Traditionally, this is a voluntary task with a poor reporting rate. The inclusion of trigger tools in retrospective reviews of hospital records have demonstrated a higher sensitivity and specificity for AEs than conventional methods, thus having the potential to quantify the true number of preventable adverse events, as shown by Augustino and colleagues (2022).

Medicines are an essential part of health systems, but they are not without risks. Pharmacovigilance is what enables us to monitor their safety and ensure that the risk-benefit balance remains tilted to the right. To achieve this goal, we must adopt a new mindset and embrace the concept of proactive pharmacovigilance, in which ensuring drug safety is not a cost for the company, but a task with a clear return on investment.

With the growing number and sophistication of new medicines, pharmacovigilance will continue to evolve, integrating an increasing amount of data. New areas such as eco-pharmacovigilance and the use of artificial intelligence to collect data on adverse drug reactions are starting to gain visibility in drug safety, adding to the complexity of the field.

There is a lot to know about pharmacovigilance, and this overview has only scratched the surface. Whether you are an aspiring pharmacovigilance professional or an established expert, there is always something new to learn, some knowledge to refresh. LS Academy routinely runs courses with a focus on pharmacovigilance, which you can explore on our training page.



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