"Obviously today, a posteriori, with everything we know, it may seem surprising," concedes before the Paris Court of Appeal Isabelle Tupinon-Mathieu, who represents Servier.

"But let's go back to the time ... At Servier, we do not have this feeling of risk, of alert," says the rheumatologist by training, who warns against "retrospective rereading bias and anachronism".

The second largest French pharmaceutical group and its former CEO Jean-Philippe Seta have been on trial since 9 January, including for aggravated deception and manslaughter and involuntary injury.

Mediator, marketed as an antidiabetic since 1976 and improperly prescribed as an appetite suppressant, has caused serious cardiovascular effects in thousands of patients and many deaths.

Mediator: from scandal to judgment © Riwan MARHIC / AFP

At first instance, in March 2021, the Paris Criminal Court considered that Servier laboratories "had, from 1995, sufficient elements to become aware of the deadly risks" related to Mediator.

The drug agency (Afssaps, now ANSM), found guilty of having taken too long to act, did not appeal.

In 1995, a study concluded that two Servier appetite suppressants, Isomerid and Weight, increase the risk of pulmonary arterial hypertension (PAH), a rare and very serious disease.

For the prosecution, Servier should have alerted the authorities of the chemical relationship of Mediator with these drugs, banned in 1997. Once ingested, all three lead to the formation of the same molecule, an amphetamine derivative toxic to the lungs and heart valves.

'Strong alert'

The health authorities had "all the information" on the presence of this molecule, called norfenfluramine, maintains Isabelle Tupinon-Mathieu, long director of therapeutic research at Servier.

Moreover, "the chemical structure, by itself, does not predict (...) potential deleterious effects," she observes, giving the example of drugs that are very similar but do not cause the same side effects.

A box of Mediator, drug accused of causing the death of hundreds of patients © Fred TANNEAU / AFP / Archives

Finally, "at the time we have nothing that points to norfenfluramine as responsible for valvular heart disease and PAH," she said, when asked about an internal report at the Afssaps of March 1999 which evokes a concern related to this molecule.

In October 1999, an Italian report concluded that "patients treated with benfluorex (the scientific name of Mediator, editor's note) are exposed to a potentially toxic level of norfenfluramine".

And in December 2000 a scientific study demonstrates the mechanism of toxicity of norfenfluramine in the appearance of valvular heart disease.

"It's not a certainty, it's a little more complicated than that," says Isabelle Tupinon-Mathieu.

But as early as 1996, the Swiss health authority requested recent data from Servier, considering that in view of the "very similar structure" of Mediator and Poids and as long as the risk of adverse effects is not excluded, it "must consider that this risk exists".

"This is a strong alert that should have led to more investigations," said the attorney general.

After two first cases of PAH and valvular heart disease reported in 1999, there will be "no more reports of cases until 2003", argues Isabelle Tupinon-Mathieu.

"We can't say we didn't care about security, that's not true," she said.

Both Servier and Afssaps "perhaps" underestimated "the real significance of these cases, which appeared sporadic, isolated," admits Jean-Philippe Seta, 69.

When Servier finally launched a clinical trial on Mediator in 2005, "we still have great confidence in both the efficacy and safety of this drug," says the former director.

"I know it may sound a little crazy with the eyes of 2023, but at the time it's the truth."

The study will show in 2009 that patients treated with Mediator are much more likely to develop a heart valve leak than those who took another antidiabetic drug.

Despite these results, Servier will simply propose to the AFSSAPS to mention the risk in the leaflet of the drug. The agency will decide for a ban.

© 2023 AFP