Pharmacovigilance: FAQs on drug safety

Pharmacovigilance is a fundamental activity to ensure drug safety globally. Since its inception in the 1960s, significant progress has been made. However, this activity continues to raise questions and doubts. In a constant effort to raise awareness about the importance of this practice, we have collected and answered the FAQs about pharmacovigilance. Here they are below.

What is pharmacovigilance?

Pharmacovigilance, according to the World Health Organization, is the scientific discipline dedicated to the collection, assessment, understanding, and prevention of adverse effects related to the use of drugs. This practice not only focuses on identifying side effects but also aims to better understand their impact on public health and to identify any risks associated with drug use. Pharmacovigilance is essential to ensure the effectiveness and safety of drugs, thus contributing to protecting patients’ health.

When was pharmacovigilance born?

Pharmacovigilance originated in response to the tragic thalidomide incident that occurred in the 1950s and 1960s. This drug, prescribed as a painkiller and antiemetic for pregnant women, caused severe fetal malformations. This event highlighted the need for closer monitoring of drugs after they are marketed, leading to the establishment of pharmacovigilance.

What is the goal of pharmacovigilance?

The primary goal of pharmacovigilance is to ensure drug safety and the best risk/benefit ratio to protect public health. This goal is made possible by the constant monitoring of drug tolerability and efficacy, the timely identification of adverse effects, and the adoption of risk minimization measures associated with drug use. For this purpose, the stakeholders analyze data to search for a signal that indicates an unexpected outcome.

What is a signal in pharmacovigilance?

In pharmacovigilance, a signal refers to information suggesting an unexpected outcome, such as a new possible association between a drug and an adverse event or an increase in frequency or severity. The emergence of a signal involves further investigations and in-depth evaluations of the drug’s effectiveness or associated risks. The research and management of the signal are regulated processes governed by pharmacovigilance regulations and guidelines.

How is a signal managed in pharmacovigilance?

In pharmacovigilance, signal management follows a rigorous process regulated by specific regulations and guidelines. This process consists of several phases:

Signal Detection: This phase involves analyzing various relevant sources to identify potential signals of adverse events related to drug use.
Signal Validation: Here, the data supporting the identified signal are evaluated to determine if there is a sufficiently documented cause-effect relationship.
Signal Analysis and Prioritization: Signals requiring immediate attention are identified, including those posing significant risks to public health or affecting the risk-benefit ratio of a drug.
Signal Assessment: An in-depth assessment of the validated signal is conducted to identify any new risks or changes in causal associations with the drug and to determine any necessary regulatory actions.
Recommendations for Actions: The need for further actions in response to the signal evaluation results is assessed.
Exchange of Information: All parties involved in pharmacovigilance exchange relevant information to ensure effective and timely signal management.

By following this structured approach, accurate assessment and appropriate management of drug safety signals can be ensured.

You can read more in the article: Signal Management: the process phases

Which drugs are subject to pharmacovigilance?

All drugs must undergo pharmacovigilance, including newly marketed drugs and those already approved and used. This includes various types of drugs, such as generic drugs, biologics, and over-the-counter drugs. Continuous surveillance is essential to identify and evaluate any adverse reactions or drug safety issues.

Who is involved in pharmacovigilance?

Pharmacovigilance involves various stakeholders working together to ensure drug safety and protect public health. These include:

Pharmaceutical companies, responsible for drug marketing and compliance with safety regulations.
Regulatory authorities such as the World Health Organization (WHO), the European Medicines Agency (EMA), the Italian Medicines Agency (AIFA), and all National Competent Authorities (NCA), overseeing and regulating drug approval, marketing, and monitoring.
Healthcare professionals, required to report patients’ adverse reactions to competent authorities to contribute to drug safety monitoring.
Patients or caregivers, who can directly report any adverse effects or reactions related to drug use to competent authorities or pharmaceutical companies.

What are the regulatory authorities’ roles in drug safety surveillance?

There are numerous agencies responsible for pharmacovigilance. Each country has its own national agencies responsible for the approval, regulation, and surveillance of drugs within its territory. For example, in Italy, there is the Italian Medicines Agency (AIFA), in France, there is the National Agency for the Safety of Medicines and Health Products (ANSM), in Spain, there is the Spanish Agency of Medicines and Medical Devices (AEMPS), and so on.

Pharmacovigilance is then coordinated by continental-level entities. In Europe, this responsibility falls on the European Medicines Agency (EMA), which collects, manages, and analyzes reports of suspected adverse drug reactions through the EudraVigilance database. In the United States, drug safety surveillance is managed by the Food and Drug Administration (FDA), which plays a fundamental role in the approval, monitoring, and regulation of drugs marketed in the USA. For example, in Asia, there is the Japanese authority Pharmaceuticals and Medical Devices Agency (PMDA), closely aligned with Western guidelines.

However, pharmacovigilance is centrally coordinated globally by the World Health Organization (WHO), which is committed to monitoring and coordinating drug safety activities on a global scale.

What are pharmaceutical companies’ responsibilities in monitoring the safety of their products?

Manufacturers are responsible for monitoring the safety of their drugs through risk management plans, including pharmacovigilance programs aimed at collecting and evaluating adverse reaction reports and taking necessary measures to reduce risks to patients. Pharmaceutical companies holding Marketing Authorization are required to have a pharmacovigilance responsible person.

Who is and what does the pharmacovigilance responsible do?

The pharmacovigilance responsible, also known as the Qualified Person for PharmacoVigilance (QPPV), is a key figure within a pharmaceutical company tasked with managing and coordinating pharmacovigilance activities. Among their main tasks is the continuous monitoring of reports of adverse reactions and other adverse events related to the use of drugs. Additionally, the pharmacovigilance responsible is responsible for managing the safety database dedicated to pharmacovigilance, communicating with relevant regulatory authorities, ensuring compliance with current regulations, and managing related documentation, such as the Pharmacovigilance System Master File.

What is a pharmacovigilance safety database?

A safety database represents an essential tool for pharmaceutical companies in monitoring and managing pharmacovigilance cases. These databases allow for the recording, collection, and sharing of reports related to adverse events associated with the use of drugs.

Pharmaceutical companies are legally required to collect all pharmacovigilance reports and conduct periodic analyses to promptly identify potential risks to drug safety.

Moreover, regulatory requirements mandate that pharmacovigilance reports be transmitted between companies and regulatory authorities in a standardized electronic format, currently ICH E2B (R3). This format enables, among other things, a data encryption system during transmission to ensure the security of sensitive information.

Thanks to safety databases like SafetyDrugs, pharmaceutical companies can centralize all information related to pharmacovigilance cases, facilitating management, analysis, and data sharing in compliance with current regulatory provisions.

Can you delve deeper by reading the article: Why a safety database is convenient for a pharmaceutical company?

What is the Pharmacovigilance System Master File?

The Pharmacovigilance System Master File (PSMF) is a mandatory document required by European legislation on pharmacovigilance for all marketing authorization holders of medicinal products for human use in the European Union. The PSMF contains a detailed description of the company’s pharmacovigilance system, including procedures, responsibilities, and resources employed for drug safety monitoring.

What does active pharmacovigilance mean?

Active pharmacovigilance is a proactive approach to drug safety surveillance, contrasting with passive pharmacovigilance. In active pharmacovigilance, active methods are used to identify and collect information on adverse drug effects, rather than waiting for spontaneous reports from physicians, patients, or healthcare providers.

Active pharmacovigilance activities may include post-marketing clinical studies, monitoring of health databases, epidemiological investigations, and other systematic research methods to identify potential signals of adverse drug reactions. This approach allows for the more timely and comprehensive identification of drug adverse effects, thereby contributing to improving the safety and quality of pharmacological therapy.

What is passive pharmacovigilance?

Passive pharmacovigilance relies primarily on voluntary reports of adverse events from drug users. These reports are sent to regulatory agencies and pharmacovigilance centers, where they are recorded, analyzed, and evaluated to determine any correlations between the drug and the reported adverse event.

Passive pharmacovigilance has some limitations, such as underreporting of cases, lack of detailed data, and inability to establish the cause of reported adverse events with certainty. However, despite these limitations, passive pharmacovigilance remains a fundamental tool in monitoring drug safety after their marketing and in protecting patients’ health.

What is the difference between pharmacovigilance and pharmacosurveillance?

The main difference between pharmacovigilance and drug surveillance lies in the approach and objective.

Pharmacovigilance is a system that deals with the collection, analysis, and interpretation of data regarding adverse drug effects after their marketing.

Pharmacosurveillance is a broader concept: it refers to the comprehensive monitoring of drug safety, efficacy, and appropriate use throughout their life cycle, including development, approval, marketing, and clinical use phases. Therefore, pharmacovigilance is a specific component of pharmacosurveillance.

How to report pharmacovigilance?

In Italy, patients can report an adverse reaction to their doctor or healthcare provider, or they can directly fill out the reporting form available on the AIFA (Italian Medicines Agency) website and submit it to the competent authority or the involved pharmaceutical company.

Pharmaceutical companies, on the other hand, generally receive reports electronically from authorities through safety databases. However, they may also be the first to receive a report through specific channels made available to the public and subsequently submit it to the competent authority.

What are serious reactions?

A reaction is defined as serious when:

It is fatal
It has caused or prolonged hospitalization
It has caused severe or permanent disability
It has endangered the patient’s life
It has caused congenital abnormalities and/or birth defects
It reports a clinically relevant event regardless of consequences (IME Important Medical Event list)
Lack of efficacy is reported for some products such as life-saving drugs, contraceptives, vaccines
It is any suspected transmission of an infectious agent through the drug
It is any reaction attributable to:
- congenital, familial, and genetic disorders
- benign, malignant, and unspecified neoplasms (including cysts and polyps)
- infections and infestations

What is the IME list?

The IME list, acronym for Important Medical Event, is a list published by the European Medicines Agency (EMA) containing specific terms used to classify suspected adverse drug reactions in terms of severity. This list is used as a tool to facilitate the classification of adverse reactions and to support the assessment of drug safety.

The terms listed in the IME list are considered important because they indicate events that can have a significant impact on the patient’s health or require particular attention during clinical use of drugs. The IME list is used by healthcare professionals and pharmacovigilance experts to quickly identify and classify suspected adverse reactions based on their severity and to support the analysis of drug safety data.

It is important to emphasize that the IME list is dynamic and subject to periodic revisions to ensure its accuracy and relevance in assessing drug safety. Healthcare professionals and pharmacovigilance experts should refer to the most recent version of the IME list provided by the EMA to ensure a correct and updated assessment of adverse drug reactions.

What does off-label use of a drug mean?

Off-label use of a drug occurs when a medicinal product is prescribed, administered, or used in a manner different from that approved by competent regulatory authorities. In other words, off-label use occurs when a physician uses a drug for an indication, dose, route of administration, or category of patients different from those specifically approved.

Off-label use generally occurs in cases where there is a lack of approved alternatives to treat a specific medical condition, therefore, it is lawful, but it is important that the physician has a valid clinical basis for prescribing the drug off-label and that the treatment is supported by scientific evidence.

Since off-label use involves the absence of specific data on efficacy and safety for the unapproved indication, it may entail additional risks for patients, who must be carefully monitored for any adverse outcomes.