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Pharmacovigilance: how to investigate if a medicine already in use has an unexpected effect

This article was published on
July 30, 2021

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“Regulators must strike a balance between making new medicines available to patients as soon as possible and gathering sufficient information on their quality, safety and efficacy,” explains the European Medicines Agency (EMA). A carefully designed system detects unexpected events in covid-19 vaccines that clinical trials could not detect as early as possible.

“Regulators must strike a balance between making new medicines available to patients as soon as possible and gathering sufficient information on their quality, safety and efficacy,” explains the European Medicines Agency (EMA). A carefully designed system detects unexpected events in covid-19 vaccines that clinical trials could not detect as early as possible.

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Information and context on vaccines. Article written by the science journalists of the SINC agency with the analysis and review of expert sources.

With the covid-19 vaccination, the international pharmacovigilance system is being put to the test like never before. “We are in an exceptional, unique situation, and weare monitoring very closely, almost in real time,” says an expert from the SpanishAgency for Medicines and Health Products (AEMPS), which is responsible for pharmacovigilance in Spain. At a European level, the body in charge of this is the EMA.  

The aim, the AEMPS adds, is to “detect effects that may not appear in the early stages of trials, but only when a medicine is administered to many people. Without pharmacovigilance we would have a false sense of security.”

Previous trials have not failed

The appearance of an unexpected effect in a drug that has already been approved does not imply a failure in previous clinical trials. There are variables that are impossible to account for even in the best-designed trials.

There are effects that emerge only after very prolonged exposure or because of drug interactions. Their incidence may be very low.

As the EMA states, “patients may be taking other medicines, [or the effect may emerge]only when the drug has been used by a very large number of people or for a long time.”

The rarest effects, for pharmacovigilance

The covid-19 vaccines available in Europe have been tested on thousands of volunteers. These trials answer “questions about efficacy, and about the incidence of fairly common adverse events” such as pain at the puncture site or headaches, Hilda Bastian, a contributor to Cochrane, a global network of researchers and clinicians that generates health information without commercial interests, tells Nature.

Rare effects, which affect one case in hundreds of thousands and begin to show after the inoculation of millions of doses, are only detected with pharmacovigilance.

Coincidence intime or causal relationship?

The great challenge of pharmacovigilance is to determine when an effect that coincides in time with drug administration (days or weeks) is actually caused by the drug.

Pharmacovigilance starts when the drug comes on the market and lasts as long as the drug is inuse. The EMA’s European Network of Centres for Pharmacoepidemiology and Pharmacovigilance was established in 2007. But the process is open to the general public: in addition to healthcare professionals, all members of the pub can report any event they consider suspicious.

International databases

Notifications go to a large AEMPS database called FEDRA, which is linked to another database in Europe, EudraVigilance. Spanish and European experts —fromthe European Committee for Risk Assessment in Pharmacovigilance, the PRAC— analyse the information.

“This assessment takes into account all available data worldwide,” explains the AEMPS, and its recommendations “are applied in all EU countries.”

“All notifications are thoroughly analysed,” the AEMPS says. They check in detail ifthere are other factors that may have caused the events and whether thenumber of cases is higher than expected under normal conditions: “It must be taken into account that in the period in which a drug or a vaccine is administered, other diseases do not disappear".

In 2018, in two months, there were 205 hospital admissions per million inhabitants for acute myocardial infarction; 357 admissions for acute cerebrovasculardisease; 77 admissions for asthma; 123 new cases of epilepsy or convulsions; and 580 new cases of diabetes mellitus.

Alarm bells may ring if the frequency of a reported adverse event is higher than what is considered usual.

An adverse event is not an adverse reaction

Experts’ analysis decides when an adverse event —thereporting of a coincidence in time—becomes an adverse reaction—the drug is confirmed to be at the origin—.

Information on a confirmed adverse reaction must be included in the package leaflet of the medicine.

In addition, experts will try to discover the biological mechanism that triggers the adverse reaction, which may take time.

This article is also available in Spanish.

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