#ClinicSpeak & #NeuroSpeak: alternative facts and PML

Pharma vs. the EMA: whose PML figures are more reliable? #ClinicSpeak #NeuroSpeak #MSBlog

A person with MS from Spain emailed me last week asking for advice. I assume he is on natalizumab and is JCV seropositive and is at risk of developing PML (progressive multifocal leukoencephalopathy) as a complication of his treatment. His neurologist has offered him a choice of dimethyl fumarate (DMF, Tecfidera) or fingolimod (Gilenya). He is however very concerned about the risk of PML on both of these options; the PML figures his neurologist gave him in relation to the number of cases of PML on both of these DMTs are very different to figures he found when searching online. He emailed me to find out which figures are correct. 

Biogen informed me a few weeks ago that a 5th case of PML had been reported on Tecfidera and that last case had had lymphopaenia with only one total lymphocyte count below 500/mm3 (0.5x109/L). Similarly, in December Novartis informed the MS community of the 9th case of PML on Gilenya unrelated to previous natalizumab exposure. I was therefore surprised when this patient referred me to the European database of suspected adverse drug reaction reports.

It is clear that in this database, as at 31st January 2017, there are at least 19 cases of PML reported on Tecfidera and at least 56 cases of PML on Gilenya. Which figures do we believe? I have asked both Biogen and Novartis to clarify, which figures are correct, i.e. their official figures of 5 and 9 cases of PML, respectively, or the EudraVigilance figures of 19 or 56 cases of PML, respectively. 

Please note that European database of suspected adverse drug reaction reports is an official website. All the data displayed in the web reports is taken from EudraVigilance, a system designed for collecting reports of suspected side effects, used for evaluating the benefits and risks of medicines during their development and monitoring their safety following their authorisation in the European Economic Area (EEA).

The following is a list of important facts about the source of the data you can view on this website for each web report:
  1. Each individual case in EudraVigilance refers generally to a single patient; an individual case is composed of at least one report, called the initial report, which might be complemented by follow-up reports.
  2. A web report shows serious spontaneous cases held in EudraVigilance since the medicine or active substance was authorised for use in the EEA. A case is classified as 'serious' by the reporter when a side effect is one that (i) results in death, (ii) is life-threatening, (iii) requires hospitalisation or prolongation of existing hospitalisation, (iv) results in persistent or significant disability/incapacity (as per reporter's opinion), (v) is a congenital anomaly/birth defect, or (vi) results in some other medically important conditions.
  3. A web report shows serious spontaneous cases where an authorised medicine or active substance is suspected by the reporter to have caused or contributed (e.g. by interacting with one or more other medicines) to a serious side effect. Reports where an authorised medicine or active substance is reported as a concomitant medicine are excluded. 
  4. The figure displayed is always the running total of serious spontaneous cases reported up to the end of the previous month. The figures are updated online on the 15th of the current month.
  5. Pharmaceutical companies that hold the marketing authorisation of a medicine, as well as national medicines regulatory authorities, are legally required to submit reports of suspected side effects that occurred in the EEA to EudraVigilance. This includes reports received from healthcare professionals and patients.
  6. Pharmaceutical companies that hold the marketing authorisation for a medicine in the EEA are also legally required to submit to EudraVigilance all reports of suspected unexpected adverse reactions that are serious and that occurred in a third country (non-EEA) where they hold a marketing authorisation.
  7. The web report does not include reports from studies (e.g. clinical trial, non-interventional study) or other types of reports (i.e. only spontaneous reports).
I was as confused as this Spanish person with MS who simply wanted to know the risk of PML on DMF and/or Fingolimod. The clarifications below are very helpful. The EudraVigilance figures are a crude indicator of an adverse event on a particular drug, but the numbers cannot be used to calculate incidences. 

Addendum Added 16h20, GMT, 15-Feb-2017:

I have now had a formal response from Novartis. The EMA, or EudraVigilance, figures are essentially from two sources. One from EU members states and the other from Novartis. The Novartis figures are global figures. The numbers in the 
EudraVigilance database are both suspected, and confirmed, cases of PML and as expected some of them will turn-out not to have PML and some will be duplicate entries. Novartis provide the EMA with information about whether or not the cases are associated with, or without, the previous use of natalizumab. 

The following are Novartis’ official and latest figures:

The overall rate of PML under fingolimod therapy not attributed to previous natalizumab treatment is very rare and estimated to be less than 1:10,000 patients.

10 PML cases in ~184,000 fingolimod treated patients (~397,000 patient-years) as of November 2016.

(Estimated risk (95% CI) is 0.054 (0.026, 0.1)/1,000 patients and incidence rate (95% CI) is 2.52 (1.21, 4.63)/100,000 patient-years exposure.)

Two cases presented with confounding factors, 1 case had previous natalizumab exposure for 10 months (3 years 9 months before PML diagnosis).

One additional case, PML occurred during 3-month natalizumab exposure, after 4.5 years fingolimod treatment, history of recent exposure to steroids.

Nine patients were within the age range of 49 to 63 years, while one patient was 32 years old.

In nine cases, fingolimod exposure ranged between 30 and 54 months, while one received fingolimod for 18 months.

None of the patients had sustained grade 4 lymphopenia.

Addendum Added 16h36, GMT, 15-Feb-2017:

The Biogen figures are 5 confirmed PML cases in ~230,000 dimethylfumarate treated patients (~330,000 patient-years of exposure) as of October 2016. 

CoI: multiple

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