That brings me on to another issue with clinical trials. What constitutes a relapse? Many trials give percentages of relapse rates before and after treatment. How do you quantify a relapse? I have yet to find a definitive statement as to what qualifies as a relapse. How much do you have to deteriorate and for how long, before a relapse is confirmed? If the definition of relapse is subjective then surely the results of these trials are also subjective.
"The fact that an opinion has been widely held is no evidence whatsoever that it is not utterly absurd: indeed in view of the silliness of the majority of mankind, a widespread belief is likely to be more foolish than sensible"!
I start to wonder if the FDA "experts" are caught up in this scenario.
The accepted medical wisdom is that MS is a T cell mediated condition. If that is true then Tysabri will most definitely help.
I can and will offer my own opinions and views but they always come with the caveat that they are mine alone. I will under no circumstances encourage someone to take a particular medication, nor will I try and discourage them. I am always willing to discuss, but will leave advice to qualified professionals which I most definitely am not.
Also, they have recently found evidence of MS in the grey matter of the brain which doesn't contain myelin.
Harry....did you miss Robin and my "grey matter" discussions?
Question from Frank Savrile: Al, I was struck on page 15 of your presentation in the distribution slide of new and newly enlarging T2 lesions, how there is a mirror image almost between drug relative to placebo in 0 new lesions versus greater than or equal to 3. And I’m wondering, from historical studies, if you are look at this marker relative to EDSS score changes at two years in historical data, what has been seen in the past and how tightly correlative are these, and what can you say about that?
Al Sandrock: That’s a tough question. First of all, I think the T2 lesion data with Tysabri is better than what we have seen with the interferons. Certainly, if you look at the mean number, the reduction in mean number, it is greater. The 80% number is greater than what we have seen with other drugs which are in the 60% range. The question about correlation between MRI measures of any type, actually, and EDSS is a tougher one. I think the correlation is modest. It partly depends on the stage of disease. If you take relapsing MS as we did in these trials, the correlation is much better than if you take, for example, people who have relapsing-secondary progressive MS where the correlation is quite poor. And those in the later stages of the disease, you can have a very strong effect on MRI and no effect on EDSS as we seen with the interferon trials in various stages of secondary progressive MS. I do think the correlation is pretty good in relapsing remitting MS which is largely what we studied here. That’s the best I can do with the answer at this point.
Q. Can you comment on the potential relationship between relapses and EDSS progression?
Al Sandrock: Again, we have examples of drugs that are on the market now that have achieved the relapse endpoint in their Phase III trials, but were not able to achieve their disability endpoint in Phase III trials. We’ve looked, there was a recent paper published by Cutter and I think it was Loveland, looking at the Silvia Lori center where they collected MS trial data from a number of trials. And they looked at how many of the relapses actually end up with EDSS progression. It turns out that about 45% or so of relapses lead to a .5 change in EDSS. And about a 25% or 30% (I believe the numbers are in that range) of relapses lead to a 1 point change in EDSS, sustained. So, given that we have a very strong effect on relapses, and given that there is some correlation between relapses and EDSS progression, at least as seen in that study which had looked at a huge database, I predict that it would be hard [not to see EDSS improvement] … If we don’t get an effect on EDSS, we are going to have to rethink how we think about MS, because it would just be quite a surprise.
The exact relationship between MRI findings and the clinical status of patients is unknown. Changes in lesion area often do not correlate with changes in disability progression. The prognostic significance of the MRI findings in these studies has not been evaluated.
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