What is the situation with MB-treated plasma in France?
On October 12th 2011, Macopharma became aware of an official press release by Afssaps (French Drug and Medical Device Regulatory Body) regarding the gradual stop of the use of therapeutic plasma treated with methylene blue.
Currently, three plasma inactivation technologies are used in France: treatment with solvent-detergent (SD plasma, manufactured by EFS, French Blood Service), treatment with amotosalen (IA plasma, Intercept, Cerus) and treatment with methylene blue (MB plasma, THERAFLEX MB-Plasma, Macopharma).
We would like to draw your attention to three main points in the press release:
- “Afssaps has observed an increased number of infrequent allergic reactions following transfusions with MB plasma in comparison to other types of plasma (1 in approximately 16 000 bags of transfused plasma)”
- “The continuous monitoring of the quality of blood products, performed jointly by Afssaps and EFS, has identified a larger variability in the concentration of fibrinogen in MB plasma than in other therapeutic plasma. The withdrawal of MB plasma is therefore a means of providing increased safety in addition to optimising the quality of transfused products.”
- “Afssaps has taken the decision to remove MB plasma from the list of approved blood products. In order to guarantee that plasma requirements are fully met, EFS in close collaboration with Afssaps, will progressively substitute MB plasma by the two other types of plasma until March 2012.”
Upon reading the press release, it appears as if two reasons are the basis for the decision to gradually stop the use of plasma BM: the frequency of allergic reactions after MB plasma transfusion and variability in the concentration of fibrinogen in MB plasma compared to the other types of plasma marketed in France.
Macopharma, being the only company in France with a Market approval for a plasma pathogen reduction technology using methylene blue and visible light, has still not been « directly and officially » informed by Afssaps about their decision.
Macopharma’s response to the press release is the following :
Afssaps has apparently not taken into consideration the recommendations made by its own Allergy Working Group (GT) related to the last 20102 Haemovigilance report: “GT experts recommend that the results (the results of the full analysis of all allergic cases related to plasma reported between 2005 and 2009) should be interpreted with great caution, due to the following unresolved issues; exhaustivity of reporting, incomplete reports in some of the records (reporting before 2008) and because of the weakness of the analysis related to infrequent events …
The lower frequency of reports of serious allergic reactions to Methylene Blue treated plasma outside of France confirms the French nature of the controversy.
Out of 2.5 million units of MB plasma which have been treated worldwide using the THERAFLEX MB-PLASMA process, 510 000 plasma units have been transfused in France between 2008 and 2010. So far, the only “more frequent serious allergic reports” are those observed by the French haemovigilance network.
Fibrinogen is an important coagulation factor. However, there are no clinical studies demonstrating what mean concentration of fibrinogen is required in a therapeutic plasma unit.
Additionally, according to French, European and American guidelines, the only indicator of quality which is considered for therapeutic plasma is factor VIII.
During the last French transfusion congress (SFTS congress, Lyon, May 2011) Doctor Rachel Petermann (Afssaps) presented the quality control data of different therapeutic plasmas approved in France. The mean fibrinogen value for MB plasma was 2.3g/l ±0 1 and 2.2g/l ± 0.8 for IA plasma. Based on Afssaps desire to have a mean value greater than 2g/l, it was calculated that 71.8% of MB plasma units were above this mean with only 60.9% for IA plasma. In conclusion the IA plasma fibrinogen rate is lower than for MB plasma.
Following various observations and internal validations by Macopharma, we can state that the variability in the concentration of fibrinogen in MB plasma cited by Afssaps can be explained by the fact that the analysis is based on inadequately prepared quality control plasma samples and not due to the therapeutic unit to be transfused.
Based on these observations, the position of Afssaps is questionable.
The THERAFLEX MB-Plasma procedure has a long record of successful worldwide usage. It is designed to treat single units of plasma which eliminates the risk of cross-contamination.
The broad target range of the THERAFLEX MB-Plasma procedure minimizes the risk of transmission of a wide variety of enveloped and also non-enveloped viruses.
The substantial additional order of THERAFLEX MB-Plasma systems by the EFS underlines the confidence of the French transfusion services in the procedure.
One of the consequences of ceasing to use MB plasma will be the increased use of other therapeutic plasmas that may not be any safer in terms of adverse events.
In conclusion, the Mediator case has seriously cast aspersions on (criticised) the way in which Afssaps operates (see B.Debré/P.Even report3), which also acts today as the French Transfusion Regulatory Body. Consequently they are in the process of re-analysing the benefit/risk ratio of many drugs leading to an overreaction with respect to the THERAFLEX MB-Plasma Process.
Macopharma remains at your disposal for any questions you may have at this stage related to the content of this communication.1 http://www.afssaps.fr/Infos-de-securite/Points-d-information/L-Afssaps-recommande-l-arret-progressif-de-l-utilisation-du-plasma-therapeutique-traite-par-le-bleu-de-methylene-Point-d-information