Global trials and tribulations

Looking for answers: comparing notes

OR

How global trials work

Yes, it isn’t good statistics to compare between (or among) different clinical trials, but the temptation is there.

So, how do we reconcile the impressive TRANSFORMS data (Fingolimod did over 50% better than Avonex in terms of annualized relapse rate), while FREEDOMS showed an almost similar (a little more) reduction in annualized relapse rate for those receiving Fingolimod rather than placebo.

In other words, if Fingolimod beat Avonex by so much, why didn’t it beat placebo even more?

Also, why don’t we (so far) ee the cancer risk we saw in TRANSFORMS, in FREEDOMS.

People and countries.

FREEDOMS was ex-US, so maybe the melanoma detection wasn’t as good as in the global trial, TRANSFORMS or maybe you need two things to develop melanoma from Fingolimod:

1. An underlying risk factor (genetic or environmental) for melanoma

2. Exposure to Fingolimod.

Maybe the patients in TRANSFORMS are fundamentally different from those in FREEDOM. Before we celebrate the relative lack of cancer in FREEDOMS, we need to wait for FREEDOMS II to help us further understand this risk.

FREEDOMS was placebo-controlled, which means that patients enrolling in the trial were more likely to be milder than those entering TRANSFORMS, where there was an active comparator (Avonex). This means that the reason the placebo arm in FREEDOMS did so well is the same reason why the CLARITY placebo arm did well, because the patients weren’t that sick (otherwise they wouldn’t have been enrolled in a placebo-controlled trial. So, if the patients enrolled in FREEDOMS had been similar to those enrolled in AFFIRM (Tysabri compared to placebo), then we may have seen an even greater reduction in annualized relapse rate in those receiving Fingolimod vs. those receiving placebo.

If we assume that Fingolimod’s annualized relapse rate reduction is superior to Cladribine (TRANSFORMS vs. CLARITY ), then why didn’t Fingolimod blow away placebo even more than it did in FREEDOMS?

At a certain point, even with a relatively mild patient group (where even the placebo will have a low annualized relapse rate), the arm receiving active drug cannot get below a certain annualized relapse rate. Remember, patients in these trials have had a relapse in the last year (or two in the last two years), so it would be hard for any drug to reach an annualized relapse rate below a certain threshold,. So, for example, if Fingolimod is superior to Avonex and even more so to placebo, we might not see that huge a reduction because the annualized relapse rate (almost by definition) is constrained (and will never become much lower, in the absence of a “cure”).

So, Cladribine got to an annualized relapse rate of 0.14 – 0.15 with the mildest patient population (see the placebo arm); Fingolimod got to an annualized relapse rate of 0.16 – 0.18 with a slightly sicker patient population (than the CLARITY study), and when the population was a little more severe (TRANFORMS), Fingolimod’s annualized relapse rate was 0.16 – 0.20. Finally, in AFFIRM, Tysabri’s annualized relapse rate was 0.25 in the sickest of all these MS populations.

What would have happened in a Tysabri vs. Fingolimod vs. Cladribine trial?

- Dr. Daniel Kantor, MD BSE
Medical Director
Neurologique

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