Tuesday, 20 June 2017

If you want to make a real difference in this world, it's a lot harder than it seems

As I watched Larissa Sansour's short exhibition entitled "In the Future, They Ate From the Finest Porcelain" at the Barbican today, it dawned on me that science, medicine, and new discoveries all create alternative realities. A reality that cannot be predicted precisely by historians or politicians come to that. In essence, the work becomes a historical intervention - a de facto truth of the future, and not the past.


"We are depositing facts in the ground for future archaeologists to evacuate. These facts will confirm the existence of this people we are positing.
So only in the future will people learn that the civilization ate from the finest porcelain?
Yes, only then.
Very few raptures are instantaneous."

In practice I have often used the PRISMS-15 study (see below for the abstract, 15y outcome of the original RRMS trial in PwMS receiving interferon beta-1a, 44ug or 22ug, three times a week compared to placebo) as evidence that higher dose exposure and longer time on treatment, improves clinical outcomes. The proportion of individuals with EDSS≽4 in the high dose group (31.8%) was almost half that in the low dose group (60.7%), while the proportion with EDSS≽6 was a quarter in the high dose (13.9%) of that seen in the low dose group (52.1%). Around half of the low dose group (52.1%) converted to secondary progressive MS compared to a fifth in the high dose group (20.8%). The 15 year analysis also revealed that change in EDSS from start of the trial to 24 months and medication possession ratio (calculated as 100 x time [in days] on treatment from the start to the 15y visit) predicted secondary progressive MS conversion, suggesting that early treatment and adherence to treatment were important factors in obtaining good clinical outcomes. 

This real-world data is very informative; information that would not have been known back in 1998 when the original study was published. My hope is that more clinicians and PwMS adopt these principles when managing MS rather than living in the past.

J Neurol Neurosurg Psychiatry. 2015 Nov;86(11):1202-7. doi: 10.1136/jnnp-2014-310024. Epub 2015 Sep 15.
 

Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15.


Kappos L, Kuhle J, Multanen J, Kremenchutzky M, Verdun di Cantogno E, Cornelisse P, Lehr L, Casset-Semanaz F, Issard D, Uitdehaag BM.

Abstract
 

AIM:

An exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) β-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing-remitting multiple sclerosis (RRMS).
 

METHODS:

Patients in the original PRISMS study were invited to a single follow-up visit 15 years after initial randomisation (PRISMS-15). Outcomes over 15 years were compared in the lowest and highest quartile of the cumulative sc IFN β-1a dose groups, and according to total time receiving sc IFN β-1a as a continuous variable per 5 years of treatment. Potential prognostic factors for outcomes were analysed.
 

RESULTS:

Of 560 patients randomised in PRISMS, 291 returned for PRISMS-15 and 290 (51.8%) were analysed. Higher cumulative dose exposure and longer treatment time appeared to be associated with better outcomes on: annualised relapse rate, number of relapses, time to Expanded Disability Status Scale (EDSS) progression, change in EDSS, proportions of patients with EDSS ≥ 4 or ≥ 6, ≤ 5 relapses and EDSS <4 or <6, and time to conversion to secondary-progressive MS (SPMS). Higher dose exposure was associated with lower proportions of patients with EDSS progression and conversion to SPMS, and longer time on treatment with lower risk of first relapse. Change in EDSS from baseline to 24 months was a strong predictor of evaluated clinical outcomes over 15 years.
 

CONCLUSIONS:

These findings suggest that higher cumulative exposure to sc IFN β-1a may be associated with better clinical outcomes, and early change in EDSS score may have prognostic value, over many years, in RRMS.

10 comments:

  1. A large detailed study by Tremlett et al. came up with a very different conclusion in 2012 in JAMA. 2012;308(3):247-256. doi:10.1001/jama.2012.7625:

    "Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability, despite using a clinically relevant, important, and irreversible disability milestone as the main outcome"

    If CRAB drugs are not shown to stop progression then what use are they, clinically and economically, to a RRMS patient?

    RRMS patients should be scared of relapses but they should be terrified of progression. Patients should always question their neurologist about their choice of medication, as I firmly believe CRAB drugs have no place in treatment of MS.

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    1. Nobody believes the Tremlett paper it is an outlier. Most people with their ears to the ground have serious concerns about the validity of the data. Apparently they still use a paper-based system with very few quality controls.

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    2. "Most people with their ears to the ground have serious concerns about the validity of the data."

      We should have similar concerns, especially when being served corporate interpretations of secret corporate data, as the Rebif study in this case.

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  2. JAMA, a reputable journal, seemed to believe Tremlett's group as evidenced by the publication.

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  3. How little we really know...Tuesday, June 20, 2017 5:17:00 pm

    What about those who do not respond to beta interferon, those who develop antibodies? Do they end up worse off than without beta interferon?

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    1. :) the thing about low avidity drugs is that they're also not good at stimulating neutralizing antibody formation (which have a potential to block their biological action). So less the quarter of non-response i.e. relapses on interferons could be explained by Nab formation! Back to the drawing board I think...

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    2. How little we really know...Wednesday, June 21, 2017 12:00:00 pm

      I just worry about those for whom beta interferon didn't work, for whom it was too late. I know of two such people.

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  4. There are two clear differences between the two studies; the Tremlett one is a cohort study - this is critical to understand this and then they have compared with two control groups which would have been prone to selection bias whichever way you cut it. The original PRISM study was a randomised controlled trial, the follow up study is then forced to keep to the original control group (the placebo arm), so there is less randomness in the factors influencing treatment and placebo groups. My criticism of PRISM-15 is that they weren't able to get back more patients for the final analysis as they could have, but the authors do point out those that they failed to recoup didn't vary in their characteristics from those who did come back, so may not make much of a difference. Don't be fooled by the fact that a study is published in JAMA that this makes it good evidence, it's very much who you know...
    I do hope that more pharma would in fact re-evaluate their pivotal trials for long-term outcomes, this avoids clinicians putting together random cohort studies to answer questions on long term efficacy (so-called real life data).
    As far as treatment efficacy is concerned there are more supportive studies than opposing ones, so probably publishing negative studies in high impact journals is a good thing!

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    1. Wouldn't a large selection bias would also be present in the randomized control trial as well? I am sure that the patients who "withdrew" from the trial did not respond to the interferon therapy with a relapse(s), had progression of their disease or had severe adverse reaction. These patients would not be reported/included in the final "positive" results. The only patients who remained in the trial that were accounted for were patients who had a "positive" outcome, whether or not this could be attributed to interferon or just an individual's course of MS.

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    2. The analysis in randomised controlled trials is something called intention to treat analysis which is quite conservative and includes everyone who is randomised and compensated for drop outs, non compliance to treatment or any other deviations after the start of the study. This is a must for all clinical trials to avoid bias in the trial. The only caveat is if your trial drop outs are significant, in which case an intention to treat analysis would be unwise.

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