VISIO REUNION OF December 16, 2020
Temporary scientific committee
Lotényl / Lotéran and risk of meningioma
The members of the temporary scientific committee are:
Sébastien Froelich, président (neurochirurgien)
Geneviève Plu-Bureau (gynecologist)
Etienne Richer (gynecologist)
Jacques Young (endocrinologist)
Henry Dufour (neurosurgeon)
Martine Alt-Tebacher (CRPV pharmacologist)
Thierry Brillac (general practitioner)
Alain Weill (epiphare epidemiologist)
Sabine Trébaol (in charge of institutional relations of the Endofrance association)
Marianne Niosi (Executive Director of the National Confederation of Family Planning)
Angèle Mbarga (President of the Fibrome Info France association)
Axelle Ayad (representative of the Endomind association)
Emmanuelle Huet-Mignaton (president of the AMAVEA association)
Discussion around MRI
It is recalled that the reference technique to detect meningiomas is magnetic resonance imaging (MRI) with contrast product injection (Gadolinium). In case of contraindication to MRI, a scanner with injection can be offered.
The goal is to secure the treatment as much as possible, by passing MRI adequately.
- The cost of systematic MRI must be taken into account.
- Attention aux femmes qui ont un méningiome et qui ne le savent pas, et qui souvent finissent pas être opérées, car le méningiome est découvert trop tardivement. Plus un méningiome est découvert tôt, plus on a de chance d’avoir une prise en charge la moins lourde possible.
- De même les grossesses sont un accélérateur de croissance fréquent des méningiomes (progestérone naturelle que le corps de la femme produit pendant la grossesse).
- Watch out for patients with Risk factors for meningiomas Who are:
- History of cranial radiotherapy in childhood
- Family context or history of neurofibromatosis (NF)
Quelque soit l’âge de la patiente, on fait une IRM au bout d’un an de traitement. Et pas à l’initiative du traitement, car, Alain Weill, épidémiologiste, a précisé que la moitié des femmes arrêtent le traitement avant 6 mois, donc il n’est pas logique de faire d’IRM systématique avant de commencer un traitement, alors que dans 1 cas sur 2, il sera arrêté rapidement.
Too systematic MRIs update "small" problems, which would have gone unnoticed all life without this screening, and which will however be necessary to monitor. This situation generates additional anxiety.
On the other hand, systematic screening makes it possible to detect an aggressive tumor at an early stage, which can be held and heal more easily.
On peut constater que les méningiomes présents avant le traitement ne régressent pas à l’arrêt de ce dernier. D’où l’intérêt de détecter le plus possible de méningiomes, surtout chez des femmes jeunes ( il n’a pas été retenu de « cut-off » d’âge pour planifier des IRM, c’est à dire une surveillance » différente selon l’âge de la patiente).
Just as we do not know if a meningioma can appear after stopping treatment, be it androcur, luteran or lutenyl. If no MRI was made before the treatment initiative, or during treatment, it is impossible to assess.
The indications for these treatments
Cette réunion avait aussi pour but d’empêcher, à l’avenir, l’utilisation massive et abusive de ces 2 médicaments que sont le Lutéran et le Lutényl
The indications selected are (they will be detailed when the committee has validated them):
- Mainly those where the ovaries must be blocked, or for women awaiting surgical intervention (during these periods of Cavid, the wait can be long)
- Only when the therapeutic alternatives have failed or there is a contraindication to other treatments.
I personally specified what is written on the website of the Ministry of Health for the outset indications, that is this text:
Off-Amm prescriptions
En France, lorsqu’ils prescrivent, les médecins doivent respecter les AMM des spécialités pharmaceutiques. Les prescriptions non-conformes aux AMM sont possibles mais encadrées.
A pharmaceutical specialty can only be the subject of a non-compliance prescription to its MAM only in the absence of an appropriate drug alternative with an AMM or an ATU cohort and subject to the specialty for the purpose for the envisaged use of a temporary recommendation of use (RTU) drawn up by the ANSM or, in the absence, the prescriber judges essential, with regard to the data acquired from the science, Specialty to improve or stabilize the patient's clinical condition.
The doctor must relate to the prescription the mention "prescription outside the marketing authorization" and inform the patient of this out -of -AM use by presenting the advantages and risks of this prescription.
- Consulter les articles L. 5121-12-1 et R. 5121-76-1 à R. 5121-76-9 du code de la santé publique
Isabelle Yoldjian indicated that the Outside AMM is to be proscribed in general, and that to withdraw a MA, European arbitration is needed. A product marketed in France must go through Europe (Ema- European Medecines Agency) to be modified.
Learned companies have the freedom to offer other additional clinical situations which they deem relevant via more detailed recommendations and under their responsibility (expert opinion or level of evidence based on literature).
Problem of meningiomas detected in a young woman, in desire for pregnancy, or in a woman whose treatment has a certain benefit
It was discussed the need to set up a multi-disciplinary consultation, with gynecologist/endocrinologist and neurosurgeon (and radiotherapist if necessary). This is a problem raised for over a year with Professor Froelich and which I also discussed with Gay Professor, president of the SFNC (French Society of Neurosurgery).
Is also discussed the need to make pre-conceptual consultations for women with meningiomas.
Risk of meningiomas with other progestins
According to Alain Weill, epidemiologist: if all the progestins could give meningiomas, given the number of women who take contraceptives, we have been able for a long time.
Meta-analyzes on the TSH (hormonal substitute treatment) reveals a small meningioma ride. TSH is less prescribed in France, due to the risk of breast cancer. These treatments are much less prescribed than 15 years ago, and over a shorter period.
Il n’y a pas de méta-analyses sur les microprogestatifs et le risque de méningiomes.
(Précision de l’association : la demande d’une étude épidémiologique a été formulée à la réunion du CSP Pharmacovigilance du 15 décembre 2020, sur initiative de l’association AMAVEA) .
Information to professionals and patients
Compte tenu de l’importance de l’information à délivrer aux professionnels et aux patientes concernant le risque de méningiome poru ces 2 traitements (comme ça l’a été pour l’Androcur en 2019), il a été décidé qu’une réunion uniquement dédiée à cette thématique serait programmée en janvier 2021 afin de discuter notamment de la mise en place de documents patients (ex, attestation de soin).
Emmanuelle Huet-Mignaton
To go further on AMM for a drug
Réponse ici sur un site officiel , Vie-publique.fr, un site d’information réalisé par la DILA (Direction de l’information légale et administrative), rattachée aux services du Premier ministre.
Drug legislation in France is very strict for health security reasons. New drugs (as well as vaccines) go through a long process in order to obtain a marketing authorization (MA). Back in nine questions about this market to market.
What is marketing authorization (AMM)?
L’entreprise pharmaceutique qui souhaite commercialiser un nouveau médicament doit déposer un dossier d’autorisation de mise sur le marché (AMM) auprès des autorités de santé compétentes, nationales (Agence nationale de sécurité du médicament et des produits de santé – ANSM) ou européennes (l’agence européenne d’évaluation des médicaments European medicines agency – EMA).
This file includes the results of the numerous research and clinical and preclinical research works. He must guarantee:
- pharmaceutical quality (composition, stability, sterility, large -scale reproducibility, etc.);
- employment safety (undesirable effects, precautions for use, etc.);
- the effectiveness of the drug (test data concerning the experimental pharmacological efficiency of the product).
The AMM is issued, depending on the procedure, either by the ANSM or by the EMA. She is accompanied:
- the summary of the characteristics of the product (RCP) (name, composition, contraindications, undesirable effects, etc.);
- of the manual for the patient;
- labeling.
ATU, RTU, AMM: What differences?
Une autorisation temporaire d’utilisation (ATU)(nouvelle fenêtre), délivrée par l’ANSM, permet l’accès à des médicaments n’ayant pas, ou pas encore, d’AMM. Ils sont, en principe, destinés à des patients atteints de maladies rares ou graves qui ne disposent pas d’un autre traitement approprié et disponible. Leur efficacité et leur sécurité d’emploi sont présumées en l’état des connaissances scientifiques et la mise en oeuvre du traitement ne peut pas être différée. L’ATU est délivrée pour une durée limitée.
La recommandation temporaire d’utilisation (RTU)(nouvelle fenêtre) concerne des médicaments qui disposent déjà d’une AMM. La RTU autorise un autre usage thérapeutique. L’ANSM délivre cette recommandation « hors AMM » pour une durée maximale de trois ans.
What is the role of the ANSM in the medication course?
The ANSM was created in 2012 after the Mediator® crisis. It has administrative police powers in terms of health products for humans and scientific expertise. Its main mission is to assess the benefits and risks of health products and to guarantee their safety throughout their life cycle:
- It assesses the quality and safety of drugs, monitors their undesirable effects;
- It inspects establishments that produce drugs or carry out clinical trials;
- It authorizes drugs by delivering MA (whether it can also suspend or remove).
- It allows clinical trials;
- It releases lots of vaccines and blood derived from blood;
- It authorizes and controls medical devices.
What are the tests carried out upstream of clinical tests?
When the most promising compounds against a specific disease were selected during a first step in the research laboratory, they are subject to so-called pre-clinical trials. The purpose of these tests is to understand the mode of action of the compounds, to assess their effectiveness and their toxicity. Possible side effects are sought. The tests are carried out mainly on the animal.
Note
Animal experimentation for drugs is considered essential to study the interactions between the different structures of an entire organism and assess side effects. This experiment is based on the 3R rule: replacement (replace the animal experiences as much as possible), reduction (limit the number of trials and animals), refinement (use techniques with the least possible constraints for the animal).
What are the four phases of a clinical trial?
The first clinical trials on humans start after obtaining satisfactory results during the pre-clinical phase. They are strictly supervised by law and can only start after favorable advice from the Person Protection Committee and authorization from the ANSM. The four phases of a test are as follows:
- Phase I : essais effectués sur un petit groupe de volontaires non malades (vingtaine) afin de vérifier les doses tolérables du médicament chez l’homme et son devenir dans l’organisme ;
- Phase II : essais effectués sur quelques centaines de participants atteints de la maladie ciblée. La posologie optimale du produit est déterminé et les effets secondaires observés ;
- Phase III : essais effectués sur une grande population de volontaires atteints de la maladie ciblée (jusqu’à plusieurs milliers), sur plusieurs sites. Il s’agit de comparer l’efficacité du médicament en développement à celle d’un traitement déjà existant et/ou à celle d’un placebo, c’est-à-dire un traitement sans activité pharmacologique. Cette phase, qui dure plusieurs années, vise à répondre à la question du bénéfice du médicament pour le patient ainsi qu’à identifier les risques potentiels. On parle de rapport bénéfice/risque. En parallèle, se déroule une phase de développement industriel qui détermine le mode d’administration et conditionnement du principe actif. C’est à l’issue de la phase III que le dossier AMM constitué peut être soumis à l’ANSM ou aux autorités européennes de santé ;
- Phase IV : essais en phase de surveillance effectués à grande échelle et sur le long terme, après l’obtention de l’AMM. On parle de pharmacovigilance.
What do we mean by "benefit/risk ratio"?
The essential objective of a medication is to benefit the patient, to cure him or to alleviate his symptoms. But taking a medication is not without risk. The MA should only be given if the benefit/risk ratio is deemed favorable. For some very severe diseases such as cancer, this report is evaluated differently and it will be accepted that there are risks such as hair loss or nausea. In other circumstances, these risks will be deemed unbearable.
What is happening after the marketing of the drug?
Once a drug is put on the market, its impact is studied on a very large population in order to prevent and follow its undesirable effects. It is pharmacovigilance.
Born in 1974, the French pharmacovigilance system is based on the spontaneous notification of health professionals (doctors and pharmacists essentially who signal the side effects of drugs). Health scandals, in particular that of the Mediator® medication, have questioned this device, its independence and the competence of the actors responsible for the control of drugs, from health agencies to prescribing doctors. The integrity of the pharmaceutical industry was also interviewed.
C’est dans ce contexte qu’a été adoptée la loi du 29 décembre 2011 relative au renforcement de la sécurité sanitaire du médicament et des produits de santé(nouvelle fenêtre). Elle vise à clarifier les rôles des différents acteurs et étend le cercle des notificateurs aux patients et aux associations de patients. La loi du 26 janvier 2016 de modernisation du système de santé a initié une réforme nationale des vigilances sanitaires.
Why can a drug be removed from the market?
Depending on the severity of the side effects and the benefit/risk ratio noted or in the event that the conditions for granting the AMM is not respected, the ANSM may suspend, modify or withdraw a market for market.
The decision to suspend an AMM intervenes in particular when it appears that the drug is harmful under normal conditions of employment or that the therapeutic effect is lacking or that the drug does not have the quantitative and qualitative composition declared.
In some cases where the undesirable effects are important but the drug remains very useful, its dissemination and its administration can then be limited, for example, in the hospital environment.
ANSM meeting of December 16, 2020 - CST "Lotényl / Lotéran and risk of meningioma"
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