Friday, 2 September 2016

Risk of PML an alternative view

ProfG does regular posts on the risk of PML.


A couple of years ago an article appeared on the internet, questioning the figures of Biogen and claiming that the risk of PML, if you were JC virus positive, had previously used a DMT and had been on for more than two years, was much higher than the 1 in 90 claimed

This was written by an unknown person called Julian Bochardt in a epublication, which you can read if you like (CLICK).

It was interesting that Berger & Fox came to a similar conclusion and suggested that the risk of PML was nearer 1 in 44. Reassessing the risk of natalizumab-associated PML. Berger JR, Fox RJ. J Neurovirol. 2016;22:533-5. 


We questioned (CLICK) if the work was peer reviewed. It is good to see that  Bochardt (apparently an independent statistical analyst) has teamed up with Dr Berger and present their idea in a peer reviewed article

Borchardt J, Berger JR.Re-evaluating the incidence of natalizumab-associated progressive multifocal leukoencephalopathy. Mult Scler Relat Disord. 2016 Jul;8:145-50. doi: 10.1016/j.msard.2016.03.005. Epub 2016.

OBJECTIVE:To estimate the prospective risk of developing PML during therapy with natalizumab in JCV-seropositive patients.
METHODS: We analyzed post-marketing data about the incidence of PML on natalizumab, and quantified the risk by either applying the Kaplan-Meier estimator or, where this was not possible due to the unavailability of the respective raw data, using formulae yielding very similar figures.
RESULTS: In JCV-seropositive patients with prior immunosuppressant (IS) use, the incidence of PML during months 25-48 of natalizumab therapy is about 19.5 per thousand. Without prior IS use, the incidence during months 25-48 is approximately 7.4 per thousand, and during months 49-72, it is approximately 10.8 per thousand. If one additionally assumes that the JCV index is in the range 0.9-1.5, then the incidence during months 49-72 is around 6.2 per thousand in comparison to 17.0 per thousand when the JCV index exceeds 1.5.
CONCLUSIONS: Biogen's statistics concerning the risk of PML on natalizumab, while in principle helpful, underestimate the true incidence systematically and significantly; realistic estimates of the long-term risk of PML are nearly double those previously published, with some patient groups carrying a risk that is almost nine times higher. Fortunately, a refined risk-stratification algorithm with the incorporation of such markers as L-selectin and CSF lipid-specific IgM bands has the potential to make natalizumab a considerably safer drug
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This eventually has prodded Biogen into a reaction (CLICK)

However, in the Words of Julian Brochardt "In a nutshell, they accepted my criticism as valid, but argued that, given the recent completion of four "large" clinical trials, estimates based on post-marketing data were de facto obsolete by now. I don't quite agree with the latter"

Julian has a few comments on ProfG's risk calculator too.

3 comments:

  1. Thanks for sharing all of this, I often felt MS nurses were not telling us the whole truth of the risks.... And when I mentioned this blog they even said they were not allowed to promote it to patients. Eye roll!

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  2. When I used to work in drug safety, post marketing drug surveillance was always a bit of a thankless task. Hours were spent trying to follow up individual case reports, often to no avail as enough data could not be collated to form a valid case (ie. patient identifiers, the event and clinical sign-off), resulting in a lot of lost to follow-up cases. Interesting post, it does make you muse about how much fudging goes on.

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  3. MS patients are still being told by neurological registrars that DMTs (Tysabri, Gilenya etc) are not associated with bacterial infections. Yet, patients are presenting to the neurological registers with new bacterial infections of they type they never had before or after starting new DMT. Patients' GPs are saying 'look maybe DMTs don't cause infections, but there is something going on"...

    "Fudging".

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