A patient reads the package inserts for his medication at home. MASSIMILIANO MINOCRI
All medications have potential side effects. Some of them are discovered in mandatory clinical trials before they come to market. However, when they are no longer tested on a few thousand strictly controlled patients, but on several million people, it is very common for new ones to emerge. After the three phases of experimentation before commercialization, the fourth phase, testing in the real world, begins. And to achieve this, it is necessary that medical professionals and ordinary users get involved by reporting the suspicion that sometimes arises after taking a medicine that something has not worked well.
The word “suspicion” is crucial, emphasizes Edurne Lázaro, head of the pharmacovigilance department of the Spanish Agency for Medicines and Health Products (AEMPS), who is taking part this week in #MedSafetyWeek, an annual international awareness campaign on the importance of reporting.
We need to talk about suspicion because just because something happens after taking a drug doesn’t mean it was caused by that drug. This was very clear with the Covid vaccines. Almost the entire population was infected with it in a short time, so that after the campaign there were deaths, strokes or heart attacks, as would have been the case even without vaccination.
Pharmacological monitoring attempts to clarify which of these events are due to the drug and which are due to chance. And then assess whether these side effects are worth risking to get the improvements the product offers. This is the so-called risk-benefit ratio.
This suspicion can arise in various ways. Each autonomous community has its own system that collects and sends data to the AEMPS, which in turn sends it to all EU countries. On the notificaRAM website, every citizen can anonymously report the side effects they have experienced.
Toilets also have their own indoor system. Higinio Flores, vice president of the Spanish Society of General and Family Physicians (SEMG), explains that in his career he has only reported on one case that he saw very clearly. It was an anti-cholesterol drug that apparently caused a headache in a patient. “It was strange because even though it had been on the market for a long time, this side effect did not appear in the technical data sheet. The headaches started right when I started taking the medication and subsided when I stopped,” he says.
A decisive factor in ensuring that no further side effects are reported is the lack of time during the initial consultations. Francisca González, from the Spanish Society of Family and Community Medicine (semFYC), assures that detective work must be carried out when a patient reports complaints to find out whether a medication could have caused them. “Most of the time we don’t have it prescribed, but rather by a specialist,” he explains.
In the opinion of this doctor, awarded the AEMPS Pharmacovigilance Prize in its first edition (2009), not only serious effects should be reported. He gives an example: “Because we assume that antibiotics can cause diarrhea, many people don’t report it. But it is important because we need to know not only the severity but also the frequency. Because maybe it causes diarrhea in 25% of cases and the package insert says that in one case in a thousand. To force pharmaceutical companies to change, you need to collect as much data as possible. And it’s important to know that because ultimately, these seemingly mild side effects ultimately impact health care capacity and sick leave.”
González believes that most health workers lack the habit of reporting warnings because it is something “you see in passing during the race.” “Many do not come forward because they are not sure whether it is the drug that is causing the adverse reaction. But that’s not necessary; We report suspicions and it is the agency’s technicians who decide,” he adds.
More than 60,000 suspected cases in 2022
Thousands of signals are received every year, but very few ultimately result in changes to the medicines’ package inserts or technical data sheets (to add unknown effects), their recommendations for use or, in the most serious cases, their withdrawal from the market.
Before the pandemic, notificaRAM received between 3,000 and 4,000 reports per month. With the Covid vaccination, the number shot up to over 27,000 in 2021. In addition, there is information from the autonomous communities and the pharmaceutical companies themselves about their products. In 2022, 60,261 suspected cases were raised, of which 22% were serious.
Again, this does not mean that many side effects occurred. There are many that go unreported because they are minor, because they are known, or because they are not identified. And a large percentage of the cases counted may not necessarily have been caused by the drug, but simply occurred accidentally while taking it.
In order to distinguish one or the other, these large databases are brought together, suspected new risks are analyzed and evaluated together with all countries in the European Union. Lázaro explains that different methods are used to determine causality: “There are times when we make decisions spontaneously. Imagine, it is very well documented, many tests rule out that there could be other alternative causes, that there is an improvement when the drug is stopped, and not only that, but also when it is taken again, the undesirable effect occurs again. For such clear-cut cases, there is no need to further modify the technical data sheet.” Most of the time, it is necessary to collect more cases, collect more data and do more research.
As soon as the authorities are sure that the undesirable effect was caused by the drug, a risk-benefit assessment is carried out. AEMPS’s Lázaro explains that the new risks may be acceptable or only for a part of the population: “Perhaps we will find that we cannot give the drug to the population with kidney failure.” Or it may be that when the drug is approved There was no alternative to the drug and now there is a safer one, which changes the assessment.” Risk-benefit is not an exact science; It is constantly checked.