Very interesting article of the #Prescript on the #Mediator .
#Androcur (and #Lotéran #Lotényl ) #Médiator , same years same consequences, on pharmacovigilance and the role of the agency in these two files.
Epidemiological studies are there for these 3 drugs, and yet many gynecologists still deny the risk, despite the efforts of Alain Weill , Epi-Phare , and Isabelle Yoldjian of the ANSM National Agency for the Safety of Medicines and Health Products , and of course Professor Sebastien Froelich .
What is it like other proof for gynecologists to listen and adapt their practices? (apart from what is set up by the ANSM National Agency for the Safety of Medicines and Health Products , which has learned from the Mediator, and even if pharmacovigilance remains very imperfect).
Extracts:
A lack of curiosity and critical distance from the firm data
Regarding Mediator °, for years, the agency and its experts rested on the only data of the Servier firm, without questioning them or questioning their limits. A posture all the more problematic as the firm has not shared all its knowledge on Mediator °.
An almost blind confidence in the firm data. Initially, information on a new drug is owned by the firm that developed it. According to a prosecutor, the Servier firm should have transmitted any document to the agency in its possession on Benfluorex, at the very least during AMM renewals (in 1997, 2002, 2007). The firm did not do it. She supported the trial that she should legally provide the data related to the indication she asked, and which was not weight loss. But, as a lawyer for the victims noted, was it possible for the agency to make "pharmacology in fog", that is to say without knowing the blood levels of Norfenfluramine, metabolite common to Mediator °, weighting ° (fenfluramine) and isomeride ° (dexfenfluramine), two other anorexigens of the same firm with the same firm in 1997 reason for their side effects?
A representative of the CRPV responsible for investigating Mediator ° admitted: “The laboratory told us that there was no similarity [of Mediator ° with isomeride ° and weighting °], we believed the laboratory. She says she supposed that the firm had transmitted all the information, and received this documentation "with confidence". According to the agency's representative at the time of the trial, the firm data was transmitted to the agency by this CRPV without being analyzed. "What failed is a critical analysis within the agency," he admitted. It appeared that the pharmacovigilance survey, presented at trial as mediocre, had only collected notifications. A representative of the CRPV in question admitted it: "We did not investigate scrupulously".
It has not been exhaustive research of documents, even public, on Mediator °, and no bibliography was attached to the CRPV report. However, a study already showed in 1971 that benfluorex was partly metabolized in Norfenfluramine in humans. For his part, in court, Irene Frachon cited copies of scientific publications from the 1970s that prescribed her. An Inspector General of Social Affairs, quoted as a witness, said that documentation existed, even if it was not easily accessible.
Asked about the lack of insight of the drug authorities in France (unlike other countries such as Switzerland) on the anorexigenic amphetamine of Mediator °, Jean-Michel Alexandre retorted that experts of the time could not be "extralucid". Being simply lucid would have been enough to at least wonder about the nature of this substance close to other anorexigens. Months of trial were not enough to dispel the mystery on such a lack of clairvoyance from this pharmacologist unanimously described as brilliant and which said, at the hearing, to be at that time "one of the best". A former vice-president of the AMM commission regretted having been "laxist and incompetent" about Mediator °.
A fascination for drug innovation. Some agency experts have shown admiration for drugs and new products, for example: “There are so many medicines. And beautiful drugs ”; "People come [in AMM committee] because there is a new product, that's what interests them." Likewise, justifying his so -called public pantouflage trajectory to the private sector, an expert explained that he wanted to "go to the other side" by leaving the agency, in turn to develop medicines rather than assess them. Did not this attraction for novelty have exercised to the detriment of a vigilance on risks?
A lack of global reflection on the drug
To withdraw mediator ° from the market earlier, it would have been necessary, according to expressions used during the trial, to "bring together" between various information, "reconstruct the file", or even to collect "all the parts" of the "puzzle", among which: in pharmacovigilance, notifications of undesirable effects certainly in appearance rare but serious; In pharmacology, the foreseeable nature of the effects of benfluorex because of its proximity to the fenfluramine (ex-lard) and dexfenfluramine (ex-isomeride °), of the same Servier firm. A puzzle not so complicated, in fact, whose resolution would have made it possible to exercise the precautionary principle, due to the suspicion of dangerousness alone; The benefit of this drug for the patient being ill -established in his indications, why make him run the slightest risk?
Institutional partitions and between areas of expertise. At the Agency, the AMM Commission, in charge of analyzing the benefits of drugs, preceded the National Pharmacovigilance Commission, which studied the risks. In the 1990s, meetings common to the members of these two commissions were not in the culture of the agency. Some actors have put this partitioning into perspective, such as an old head of the Department of Pharmacovigilance, which however specified: "It could have happened that we did not have all the grouped elements. Once the synthesis was made, he returned to the Director General to make a possible decision.
This partitioning, in certain cases exacerbated until rivalry, also existed between areas of expertise: pharmacology, toxicology, pharmacokinetics, clinic, epidemiology, etc. One of the experts, asking about the pharmacological properties of Mediator °, said: "Toxicity manifests itself clinically on the cardiac valvular system, and I, sorry, I am not a doctor, I do not know how to diagnose a HTAP, I work on cell cultures". Another expert indicated that he was not a pharmacologist and could therefore not know the chemical kinship of Mediator ° with isomeride ° and weighting °.
A social security lawyer noted that, to recognize the toxicity of a drug, the firm awaited formal evidence of the mechanism leading to undesirable effects, while epidemiological signals could already be taken into account. According to the analysis of a prosecutor, the agency has shown a narrow conception of pharmacovigilance, based almost exclusively on notifications of adverse effects, with the obsession of the "pure case" and the dogma of absolute proof. A global and transversal vision of the drug was lacking.
A representative of the agency recognized a lack of "medical sense, that is to say turned towards the patient".
Pharmacovigilance signals wrongly considered to be reassuring. The usual sub-notification of the undesirable effects of drugs by health professionals has undoubtedly been accentuated in the case of Mediator °. Indeed, the risks of valvulopathy and htap, even when they started to be known, were not made public in the characteristics summary (RCP), any more than the chemical kinship of benfluorex with other anorexigens. This absence of information did not help make the link between a valvulopathy or a HTAP, relatively rare and which can for the second manifest years after treatment, and the taking of Mediator °. At the time, this catch was considered by a number of caregivers and patients as harmless, even banal.
On the material level, anecdotally but revealing, for the notification of the Valvulopathy case spotted by Georges Chiche in 1999, the computer software used by the Marseille CRPV did not include the title "Aortic insufficiency". This case was then seized by the CRPV as "mitral insufficiency" in its title. However, as the cardiologist explained to the hearing, a mitral insufficiency could be attached to a heart attack that the patient had, which could "clear" a possible link with Mediator °.
According to several testimonies, when, despite these obstacles, undesirable effects were notified, the functioning of the pharmacovigilance system consisted more in excluding cases than to retain them. Doubt benefited from the protection of the firm and its medication and not that of patients. The trial made it possible to publicly raise various questions: from how many notifications of undesirable effects of the same drug should be worried, to consider the facts as a signal to evaluate, and to launch an epidemiological study? Do you need a minimum number of notifications? How to put these side effects in perspective with the expected benefits? Shouldn't we consider notifications of adverse effects the complaints of patients before a civil jurisdiction?
Pharmacological reasoning by analogy wrongly ignored. Benfluorex with chemical kinship with fenfluramine and dexfenfluramine, pharmacological reasoning should have alert. Until proven otherwise, it is prudent to consider that a new drug exposes, a priori, at least to the undesirable effects of drugs of the same pharmacological group. The Swiss authorities, for example, had followed this reasoning in 1996, and they questioned the firm on this point. In 1998, she preferred to give up requesting an authorization in this country for her specialty based on Benfluorex.
According to the representative of the French agency at the trial, this reasoning by analogy could have been carried out in France in 1999, due to the data then sent by the firm to the agency. Similarly, the suffix -orex, specific to anorexigens, and retained by the World Health Organization (WHO) for the International Common Name (DCI) Benfluorex when it was created in 1971, "could have made its ear", according to a pharmacologist. But at the time, substances were rather designated, in particular by health professionals, under their trade name than under their DCI. It should be noted that the firm sought, without achieving it, to have the suffix --orex to the WHO in 1973. And, as a prosecutor pointed out, it "positioned" Benfluorex in diabetes more than as a FAIM.
Several experts had relatively early the proximity of Mediator ° with other amphetamine anorexigens. But "we were not used to thinking by family," said one of them. "We have attached a lot to his indications and not to his pharmacology," said a former head of the agency's pharmacovigilance department. According to another witness, a former head of the agency's pharmacovigilance, it seemed that the metabolisms of Norfenfluramine and Benfluorex were different. Even more confusedly, an former external expert, also a consultant for the firm, distinguished the medication Mediator °, "who has a MA, a dosage, a formulation, a mode of administration" of the "Benfluorex active principle".
The firm, it claimed to the hearing that a reasoning by pharmacological analogy was "not scientific". A note released in 1999 by the old number 2 of the firm, Jean-Philippe Seta, said: "Mediator ° is radically distinguished from fenfluramines both in terms of chemical structure and metabolic pathways and efficiency profile and tolerance". "This is the truth from Servier," said his lawyer at the trial. According to the defense, it was a question of avoiding a misuse of the "anti-diabetic" mediator ° as an appetite suppressant, and not of concealing its true anorexigenic nature. A prosecutor has in any case qualified as myth, even mystification, this desire to distinguish Mediator ° of weight and isomeride °, from the same Servier firm.
Article on the site to prescribe here:
https://www.prescri.org/fr/218/1902/61199/0/positiondetails.aspx
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