Je viens finalement de recevoir la réponse de l’EMA le 7 février.
Voici le document reçu et les échanges de mails:
Je viens de leur envoyer ce mail en réponse.
Dear Mrs Henry-Eude,
Thank you very much for your letter.
Unfortunately it does not answer to many of the questions of my last request sent on November 20th 2013.
Your answer confirms that you do not consider as problematic a truncated trial excluding from the per-protocol analysis patients who are getting more benefit from the placebo than from the product you approve, even if it is clearly demonstrated that there is not increase of the efficacy with time on study. You are just considering that, as the trial was prematurely stopped, there might be some “inherent” risks linked to the lack of complete data. It is surprising that no one investigated on those risks.
You are then considering that, since the approval of the product, the amount of evidence supporting the efficacy and the safety of Avonex “has grown substantially”.
Concerning the efficacy, let me remind you that, since 1997, Avonex has been compared to the two other interferons: studies showed that Avonex was less efficient (for example ref 10 & 11 in my article). I haven’t found any other Avonex randomized clinical trial in relapsing remitting multiple sclerosis showing its better efficacy over an approved product and no placebo controlled study confirming the results of the MSCRG trial used for approval. The Cochrane review hasn’t find such a study neither. Thus, I am not sure that the post marketing studies are confirming any efficacy of Avonex as it has never been shown superior to any competitor, placebo included. May be have you received such a study demonstrating the efficacy of Avonex in relapsing remitting multiple sclerosis. If it is the case, thank you for sending me the documents. If not, I am afraid it should be concluded that post-marketing studies demonstrated in fact the weak efficacy of Avonex.
Then, You conclude that the benefit/risk balance remain positive, “based on the totality of evidence and the extensive experience gained with this medicinal product”. This is a surprising conclusion as the experience gained actually demonstrates that Avonex has a much weaker efficacy than the one you evaluated in 1997. Nevertheless, the safety profile of Avonex being not so bad, this conclusion is possible, surprising but possible. A lot of product with weak efficacy are on the market.
You are also arguing on the fact that the “extensive clinical practice experience accumulated in the years since its authorization have helped to place it among other products from its pharmacological class”. Logically, Avonex should be considered as less efficient as other products from its pharmacological class. Unfortunately, your statements in the SPC and in the scientific discussion are positioning Avonex as probably the most efficient product of its class.
Two examples of your statements, already noticed in my previous mail are wrong and the demonstration of these errors is available in my article. These wrong statements were written in the official documents because you received from the sponsor wrong and incomplete information.
- in the SPC “During the first year there was no statistically significant difference between the two groups in number of exacerbations. Over two years a statistically significant difference was seen between the two groups in exacerbation rate (p=0.002). During the second year the exacerbation rate difference between the two groups increased though there was no statistically significant difference in the proportion of patients who were exacerbation-free.”
- In the Scientific discussion : “It was also shown that there was a one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment.”
You did not answer to my questions asking you to justify these sentences or dealing precisely with the bias of the MSCRG study and the way you analyzed this study.
Your letter does not answer to these points corresponding to the following questions in my previous mail (copy of my previous mail in italic, questions are in red).
- EMA will accept results based on a subgroup of randomized patients obtained after exclusion of patients, for whom the verum has a deleterious effect. Furthermore, you consider that the results on this subgroup should apply to the whole population of patients to be treated. Pharmaceutical Industry should be informed of that : they can exclude placebo patients doing well and verum patients doing bad to get a good trial and a good p value to get approval, CHMP will accept these data! Do you think it is a fair way to analyze a clinical trial?
- EMA validate data on the best responders without evaluating who are the patients doing worse on the verum. Can we speak of any benefit for those patients? What is the benefit/risk for these patients? What has been done to evaluate if some patients should not receive Avonex?
As stated in your 1997 evaluation, the approved benefit is -32% on relapses rate. As this result is based on a specific cohort, It should thus also be stated that for some other patients, Avonex may have a deleterious effects. For those patients followed up for a shorter duration, Avonex increases the relapse rate and of course provide no benefit on the disability outcome. Is it ethical to hide this information for the patients ? Accepting the -32% figure is justified by an increase of the benefit of Avonex with treatment duration, which is untrue ! It is also of course untrue to state that patients should take Avonex for more than one year to obtain a benefit ! I recognize that you did not state this point specifically, but it is a consequence of what you stated.
Consequently, it is difficult to consider that you still validate a benefit on relapses of -32%.
The bias also impacts disability progression outcome which should be also re-evaluated when defining the benefit/risk ratio.
Could you then explain why the new information on the different cohorts does not change for you the evaluation of efficacy and what is the benefit that you consider best represents the efficacy of Avonex for both outcomes? Why do you still think that untrue characteristics of the trial are still valid?
So if some aspects of my previous query are re-iterated, it is just because you did not answer to my questions.
Contrary to your statement, my request for information has not been fully addressed because you did not answer to the above questions and thus did not bring any argument against my demonstration of the bias of the MSCRG trial. This absence of argument seems to validate the bias of the MSCRG study and thus the weak efficacy of Avonex and the wrong evaluation you provided European people with.
Thank you for answering to the complete set of questions.
Best regards
Alexis Clapin
