Antegren/Tysabri approved!

A board to discuss the newly-released drug Tysabri, (formerly known as Antegren) as a treatment for Multiple Sclerosis

control groups to the rescue?

Postby rndlph » Sat Dec 04, 2004 9:14 pm

HarryZ wrote:If Tysabri reduced exacerbations by 66% without the help of steroids and this number holds true throughout the entire Phase III trials, then that would be great....but I guess we'll just have to wait and see.


Why does it matter if steroids were administered or not? In a double-blind study, the steroids would have been administered uniformly to both the treatment group and the control group. The study design makes this a nonissue, no?

This would equally apply to earlier comments by raven and OddDuck about the "subjective" nature of relapse evaluation during trials. Since this subjective nature exists across the entire study, it is controlled for, at least insofar as the study is adequately blinded. Thus, the subjectiveness does not per se create a "loophole" (as OddDuck implied) in the clinical trials. While I agree that adequate blinding did not exist in the CRAB trials, it clearly does in the case of Tysabri.

Dave
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Postby Observer » Sat Dec 04, 2004 9:51 pm

Rndlph, as an Observer, I'll make the following comments. Take them or leave them, as you wish.

1. I read your 4 Dec 04 8:12PM post and did not find anything useful in it relative to the goals of this Forum (the goal being dissemination and discussion of information about MS and treatments for it - I think). It was more of a rebuttal of OddDuck's comments about your previous post (Mon Nov 29, 2004 2:48 pm). You started the 4 Dec 04 post as follows:


I am utterly amazed that someone who has posted over 10% of the content in this public discussion forum could have such thin skin. Moreover, you really should read more carefully.


How does that advance the goal of this forum? Cmon.


2. In the 29 Nov 04 post, you said

ME:
Uh, there is no claim that the treatment is perfect. Moreover, this refers to ALL ARMS OF THE TWO STUDIES. This includes people who received placebo. A placebo is an inert substance with no treatment value. You do indeed seem to be confused. Or are you just being obtuse for snide effect?


Now, I ask what benefit was provided to ANYONE by final two sentences of that quote? The first part of it is useful and allows discourse, but the last two sentences just turn everyone off, me included.

Later in that same post you ask of OddDuck "Are you actually reading this?" What benefit does that comment provide?

Cmon, focus on the reasons for this forum and how best to get your point across.

3. One can say the same thing without making it personal, thus eliciting a response to the facts/comment as opposed to the personalisation:

This would equally apply to earlier comments by raven and OddDuck about the "subjective" nature of relapse evaluation during trials.


can just as easily be said as

"This would equally apply to other comments about the 'subjective' nature of relapse evaluation during trials."

See the difference? In the first, folks tend to focus on personalities, while in the second that is impossible and we must focus on the 'meat' of the statement - the subjective nature of relapse evaluation during trials.

4. Rndlph, I've personalised this post simply to ensure it meets the target audience. I think that you are favorably impressed by Tysabri, as am I. OddDuck and Harryz are more sceptical of it. That can and does make a healthy balance for give/take and discussion.

Stick to the facts, and realise that all here have the right to make a point; you may not agree with how they've made it, but focus on the point, not the method of delivery. We'll all be better off for it.

That's my bit. Hope you take the suggestion.
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Re: control groups to the rescue?

Postby HarryZ » Sat Dec 04, 2004 10:13 pm

Why does it matter if steroids were administered or not? In a double-blind study, the steroids would have been administered uniformly to both the treatment group and the control group. The study design makes this a nonissue, no?


The ONLY reason that steroids would be administered to a MS patient in a trial would be if the patient was experiencing an exacerbation. Steroids can have quite an effect on a patient and can certainly effect their overall reaction to the drug that they are using in the trial. They can mask symptoms and not allow a true assessment of the patient.

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putting out fires with gasoline

Postby rndlph » Sat Dec 04, 2004 10:46 pm

My Dear Observer,

Regarding your point 1, this statement was used to respond to some rather heated words addressed directly to me by OddDuck. I think I deserved some latitude here, but opinions apparently differ. These comments, like yours, are procedural in nature. Granted, these should be limited, but they are necessary to define the parameters of discourse. Since my entire post is a point-by-point response to one by OddDuck, I might ask why OddDuck's comments are not similarly criticized.

Regarding point 2, I have said all I care to on the merits of being obtuse to be snide. The "Are you reading this?" question was a rather benign rhetorical attempt to place focus back on the label text, where something truly noteworthy was being said about antibodies. Granted, my initial words were provocative, but I thought they would be taken in the spirit of debate. Boy, was I wrong.

Regarding point 3, how is citing the source of comments an inappropriate "personalization"? Isn't this common courtesy? Indeed, by default, when one pushes the "Quote" button, the source of the quotation is cited. By your analysis, the forum utilities themselves breed contempt.

Regarding point 4, I have seen very little specific refutation of my comments. All I have seen is general condemnation for my "method of delivery," largely from a member of this forum who appears to be immune from criticism. I found OddDuck's responses to me outrageous and clearly more inflammatory than anything I had previously written. Obviously, I am not unbiased in this assessment, but I stand by it.

Regardless of these niggles, your general point is well-taken. This off-topic bickering has to stop. The moderator really should step in and define some rules of decorum. Apparently there was some unpleasantness in this forum earlier, but the thread has been removed, so I can't look at what transpired. It might have been informative.

I have tried to explain my statements rationally, perhaps in painful detail. If my social compass is out of whack on this, I would like the moderator to point that out to me. It is his show.

Thanks,
Dave
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Re: control groups to the rescue?

Postby rndlph » Sat Dec 04, 2004 11:21 pm

HarryZ wrote:
The ONLY reason that steroids would be administered to a MS patient in a trial would be if the patient was experiencing an exacerbation. Steroids can have quite an effect on a patient and can certainly effect their overall reaction to the drug that they are using in the trial. They can mask symptoms and not allow a true assessment of the patient.


Yes, but why does the blinding not control for this? Why would this compromise the validity of the trial results? Everyone is being treated the same.

If steroids affect the overall reaction to the drug, and they are commonly used by neurologists in daily practice, then it seems to me that including the effect of such a combination in the initial phase III trial result is appropriate. When and if my next relapse occurs, my neurologist is probably going to recommend steroids, and I am probably going to take them. ("Better living through chemistry." Indeed.) Since I expect to be on Tysabri when this happens, I sure hope that combination use with steroids is a prominent component of Tysabri's safety and efficacy profile.

Comparing the efficacy of Tysabri alone against Tysabri with steroids in response to relapse symptoms sounds like a good topic for another study. But if a consistent treatment protocol is followed by the trial physicians, I still don't see how this would be a problem for the current trial.

Well, I have an appointment with an Avonex syringe. Better living through chemistry, indeed.

Cheers,
Dave
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Re: control groups to the rescue?

Postby HarryZ » Sun Dec 05, 2004 6:28 pm

Dave,

Why does it matter if steroids were administered or not? In a double-blind study, the steroids would have been administered uniformly to both the treatment group and the control group. The study design makes this a nonissue, no?


The typical protocol for steroid administration for an exacerbation is:

Agent Exacerbations:
I.V.Methyl Prednisolone 1gm. IV daily for 3-7 days, followed by an oral steroid taper with Prednisolone: 200mg x 4days then 100mg x 4 days then decreasing by 10mg daily until off, or Dexamethasone Taper:12mg x 4days then 8mg x 4days then 4mg x 4days.

Thus the steroid therapy can be 25-28 days and during such time mask symptoms indicative of more exacerbations occurring. And because steroids can actually impact gene expression in numerous cells in the body, they can have a fairly long residual effect .... from days to weeks. When your outcome measures are on symptoms such as the EDSS score or your measuring the frequency of exacerbations then the use of steroids can become a huge variable in the outcome measures.

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Postby MeadowStream » Mon Dec 06, 2004 2:32 am

Harry Z,

Not sure if this is the forum or not for this question, but are you the same Harry Z who made the claim on the BrainTalk forum that doctors involved in the Tysabri trial are less enthusiastic advocates for its use than doctors not involved? If you are, then I believe this is very irresponsible to claim - and as OddDuck would say, possibly opens you up to legal action on the part of BiogenIdec and Elan. The investigators that colleagues have spoken with are extremely enthusiastic, to the point where, as I understand it, heads of major departments have indicated that not to put MS patients on Antegren (Tysabri) would be unethical and possibly open themselves up to legal liability.

Will you please back up your claim with some numbers or articles or notes from meetings?

MS
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Postby Arron » Mon Dec 06, 2004 2:50 am

Dave, while we thank you for the portions of your post that are on-topic, the off-topic insinuations, sarcastic comments, and tete-a-tete rebuttals are neither productive nor welcome here. The overwhelmingly negative response to your posts from a varied cross-section of our community should be a good indicator that you have crossed the line from productive participant to an instigator of off-topic personal arguments.

Again, I thank you for the good information you shared, but this forum has zero tolerance towards personal battles (learned wisdom...). As such, it's time for some (forced) time off from the boards for things to cool down. I know you'll understand.
Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk.
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Postby Ptwo » Mon Dec 06, 2004 4:16 am

Harry, Given that the relapse rate was 66% & 54% less for the Tysabri groups than the placebo groups wouldn't the steroids have had more of an impact on the outcome for the placebo groups?

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Re: Harry

Postby HarryZ » Mon Dec 06, 2004 6:06 am

MS,

Yep, I'm the same Harry Z that appears in Brain Talk, The MS Foundation Forum, MS Watch, This Is MS, The Prokarin Patch, Alternative Medicine/Histamine, LDN Forum and the Spotlight MS Site!

And I'll stand by my earlier statement that a number of docs who have been part of the trials with Tysabri are the ones being cautious. This opinion has come from reading comments from some of these forums from patients who's neuros have been part of the trials and from some people who are involved in MS medicine who have made the comment to me. And if you want names and addresses, MS, you aren't going to get them from me. I suggest you read some of these forums if you wish to get an overall feeling on Tysabri. My medical friends will remain confidential. And like I have said many times before on all of the above forums...you can choose to either believe me or not...that is up to each person to decide.

I didn't realize that you were speaking on behalf of Biogen/Elan with the threat of legal action based on my opinion. I suspect that only an employee of these companies would make such a comment!

As for MS patients possibly taking legal action against doctors who don't prescribe Tysabri for them.....now I suppose this is something that Biogen/Elan would love to see circulating amongst doctors but really MS, we don't even have the second year data of the trials including the EDSS scores for ANYONE to review. And 6% of the patients have had to quit using the drug during the trials because of NABs Isn't this just "jumping the gun" a little bit?!!!

Harry
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Postby HarryZ » Mon Dec 06, 2004 6:14 am

Harry, Given that the relapse rate was 66% & 54% less for the Tysabri groups than the placebo groups wouldn't the steroids have had more of an impact on the outcome for the placebo groups?


There is no way of knowing that because of the widely varied effects that steroids have on MS patients. Not until Tysabri starts to get used outside the clinical trial atmosphere will be get a clearer picture of how the drug benefits or doesn't benefit MS patients. Hopefully Biogen will have a much better system of tracking the drug's record after one year of this kind of use than what the CRAB drug makers have done over the years. One of the big problems of CRAB drug effectiveness was the total lack of any system to show what was happening to patients after one year. There simply wasn't any data for reviewing.

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Postby MeadowStream » Mon Dec 06, 2004 2:53 pm

Harry,

I do not work for BiogenIdec or Elan, but have noted at conferences in Boston and London that investigators were very enthusiastic and not hesitant as you characterized them. I am only pointing out that if you make claims you should back them up and not leave yourself open to liability.

MS
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Postby Ptwo » Mon Dec 06, 2004 3:38 pm

. One of the big problems of CRAB drug effectiveness was the total lack of any system to show what was happening to patients after one year. There simply wasn't any data for reviewing.

Harry, I'm not sure that's the case. I think there's a boat load of data being mined by the drug companies. I've been on A, B and am on C and all 3 of the companies kept a chart on me. When ever I talked to one of the nurses they would pull up my chart and add any new information I provided.

Now these are big companies with lots of smart people and lots of big computers. I just have a hard time imagining them not using this data to follow trends with the medication, good or bad.
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Re: Harry

Postby HarryZ » Mon Dec 06, 2004 5:37 pm

MS,

I do not work for BiogenIdec or Elan, but have noted at conferences in Boston and London that investigators were very enthusiastic and not hesitant as you characterized them. I am only pointing out that if you make claims you should back them up and not leave yourself open to liability.


I have no doubt that there are many investigators that are quite enthusiastic about Tysabri. But at the same time, there are other MS docs who are very cautious about this drug which doesn't even have its two year, Phase III trials completed as yet. Each side have their reasons but only time will tell just how good or not so good Tysabri may be.

As for your concern about me leaving myself open to liability because of opinions and claims.....I wouldn't worry about that in the least. I won't get into a legal discussion here...it's not the proper venue. I believe that Biogen has a lot more to be concerned about if Tysabri doesn't quite work out the way they hope it will. After all, look at what happened over at Merck when Vioxx started seriously hurting people after it had received the FDA's blessing!

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Re: Harry

Postby Daunted » Mon Dec 06, 2004 6:16 pm

Harry,

He's right about the trial design. It's not a confound because both groups were treated with steroids when necessary. Given the sample size is large enough (and it surely is) they would have no effect on the results of the study, at least as regards a statistically significant difference in relapse rate.

The sniping I could do without. But his point is correct- at least within the limitations of practical research design, these studies appear to be cogently planned and executed.

You are correct that only time will tell- we need much more data.
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