Antegren/Tysabri approved!

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

Postby HarryZ » Mon Nov 29, 2004 7:32 am

First, the study was designed and all protocols were agreed with the FDA. IMHO, the charge of manipulation is unfounded (as you'll see from my other comments below), but the reader can make their own judgment.


The study protocol will state that patients were randomized into the various study groups. But this is all that FDA or the Institutional Review Board gets involved. No one from these agencies will follow-up to insure that true randomization was done. It is public knowledge some of the corruption in the FDA, for instance the FDA trying to turn a blind eye on the heart attacks resulting from Vioxx, or the FDA allowing Rezulin to remain on the market for 30 months after the FDA had been receiving reports of liver failure and death due to Rezulin. Four of the 12 voting members of the FDA advisory panel that approved Rezulin, and voted to keep it on the market for another 30 months, had financial ties to the company that made Rezulin, Warner Lambert. According to the Cochrane Review, the FDA stated that they suspected that Teva had done “data dredging” when they submitted the information to the FDA seeking approval for Copaxone. Despite this possibility of “data dredging” the FDA approved Copaxone rather than required further disclosure of data.

Second, the bold statement that MRI findings and clinical status of patients is simply a fact, and all of the drug makers and the FDA agree that this is a fact.


Exactly, there is no correlation between the MRI findings and the symptoms or progression of the disease. So there is no logic or scientific reason to continue to determine that a drug is effective in treating MS based on the drug’s effect on the lesions in the MRI. What is the point of saying your MRI's are showing great pictures of reduced lesions but your symptoms or MS in general aren't getting any better at all?!

Third, the FDA and many physicians believe that MRI findings ARE clinically significant, its just tying them to disease progression that is unknown.


“believe”, meaning not yet proven. They used to “believe” that germs didn’t cause disease or illness, until science proved otherwise.) So after hundreds of millions of dollars of research, science has still been unable to tie MRI findings to disease progression. Yet this warrants MS patients and or their insurer, paying billions of dollars for these so called treatments that continue to fail to beneficially impact the disease progression or the symptoms that continue to plague the MS patient? And it is these same people who refuse to acknowledge the science that the immune system is not attacking the myelin and not the sole cause of the symptoms in MS (Behan, Persani, Prineas, Barett)


Comment: The FDA and Biogen Idec/Elan agreed that EDSS scores would be the primary endpoint of the 2yr P3 study, and that 1 yr data are too early to assess improvement in EDSS scores. My problem is that the poster is criticizing the companies for not reporting something which the Companies never intended to report at year 1. The primary endpoint of Year 1 was relapse, with the MRI as secondary endpoints.


First of all, the study’s primary endpoint is determined and SET prior to the commencement of the study. The fact that Biogen Idec/Elan decided to submit the data early to the FDA (at 1 year versus 2 year), then they should have had convincing data regarding their primary endpoint and that was the EDSS scores. Iif the EDSS scores would have shown improvement then there wouldn’t have been any reason not to disclose this information since it was after all the primary endpoint. This is a big no-no in scientific research, but unfortunately the FDA allowed it.

The EDSS measures a change in symptoms such as bladder and bowel incontinence, walking, dexterity, etc. These are measured in 0.5 increments with 0=no symptoms and 10=death. It would be very easy to determine a change in the EDSS score within 1 year or less, but it would not be as easy to determine a decrease in the frequency of exacerbations as frequency can vary from 0 to several exacerbations a year, so only over a prolonged period of time could it be determined if the frequency was altered and then it is only a probable determination because unless you have a clone of each person could you know if they would have had an exacerbation without the medication. Also as the duration of the disease increases, the frequency of exacerbations decreases without any drug intervention. But as the disease duration increases, generally so does the symptoms, so a change in the EDSS score is a better indicator of drug effect.

Some of the other MS drugs have done this, submitted data early to the FDA rather than complete the full time allotted for the study and submit all of the data. Berlex did this exact same thing when they submitted their information on Betaseron for FDA approval. The reason Berlex and most companies do this is because the results are not promising for the longer term. I quote from the Physician’s Desk Reference 2001 regarding Betaseron, “At the end of 2 years on assigned treatment, patients in the study had the option of continuing on treatment under blinded conditions. Approximately 80 % of patients under each treatment accepted. Although there was a trend toward patient benefit in the Betaseron groups during the third year, particularly in the 0.25 mg group, there was no statistically significant difference between the Betaseron-treated vs. placebo-treated patients in exacerbation rate, or in any of the secondary endpoints.” Thus, Berlex decided to submit only the first two years of data.

I don't understand the criticism in the quote, but I do note that the writer makes assumptions about the data, stating twice 'most likely.' It is generally not good to make assumptions when analysing data.



If Biogen Idec/Elan would divulge all of the information such as the median EDSS score in the various groups at baseline, baseline lesions, etc then a person would not have to use terms such as “most likely”. You said that, “We do not know how many lesions the patients had prior to the study, but it is quite possible that many/most patients had lesions (since this is one of the tools used to dx MS).” How is “most likely” different than saying “quite possibly”? You stated that “It is generally not good to make assumptions when analyzing data”. Yet that is what you just did! In fact, that is what the FDA, physicians etc are doing when they analyze the data from the MRI findings and then assume that this data has an impact on the clinical status of MS.

First, 'median' is a sample statistic which means half of the sample are less than the median value, and half of the sample are more than the median value. It is important to know this, therefore, new lesions could have indeed formed, while some lesions may have gone away.


That is not what the study was measuring, it was measuring, the median change was 0.0. What benefit is gained if you lose a lesion but gain one ? Furthermore, the T2-hyperintense lesion measurements showed a difference between the Tysabri group and the placebo group, but remember that the T2 weighted scans are not very dependable because they will show an abnormality or change by any change in tissue composition. In other words, they pick up too much noise and variability. The Gadolinium enhancing lesions are much more accurate for finding new or enlarging lesions and active lesions. Note that there was no difference in change between the Tysabri group and the placebo group with the Gd-enhancing scans.


We do not know how many lesions the patients had prior to the study, but it is quite possible that many/most patients had lesions (since that is one of the tools used to dx MS.)



Although they failed to divulge all of the information as to lesion load etc at baseline, it doesn’t matter because there was NO change in new or newly enlarging lesions from baseline between the Tysabri group and the placebo group according to the findings from the more accurate Gd-enhancing scans.


One has to wonder why would a company withhold information when they proclaim a drug to have such a great effect? After all, they supposedly came to this conclusion of the drug being so beneficial from reviewing all the data, so the data should show the great effect as well.

Again, hopefully all the data will be released soon so that it can be peer reviewed. But so far, we have only seen what Bigoen has wanted us to see and when that happens, a lot of questions and uncertainty take place.

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Postby OddDuck » Mon Nov 29, 2004 7:51 am

Harry,

Well said.

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Postby Arron » Mon Nov 29, 2004 10:33 am

I haven't had the opportunity to read this entire thread yet, but given our last experience in the Antegren (oh I'm sorry, "TYSABRI") forum, I'm going to chime in here and remind people that all comments should be directed at what the other person SAID, and not the other PERSON themself.

Insinuations about a person's motivations, talents, etc. are unacceptable and unnecessary-- an academic reply will suffice and get all your points across.

If you have any issues, please send me a private message.

Thanks
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Postby Observer » Mon Nov 29, 2004 8:21 pm

Harryz, thanks for the reply. Several comments/rebuttal, and apologies that these are so long-winded.


The study protocol will state that patients were randomized into the various study groups. But this is all that FDA or the Institutional Review Board gets involved. No one from these agencies will follow-up to insure that true randomization was done.


Can you provide some proof of the limited involvement by the FDA that you suggest? How do you know the FDA did not follow the trial quite a bit closer than you suggest? And one instance of anecdotal evidence does NOT mean that such a practice, if it indeed happens, is widespread. This is a serious charge - a suggestion that true randomization may not have been done - and it would be useful to find reference to evidence supporting such a charge. Surely you are not questioning the professionism of the researchers, or are you?

Please help in this regard, as this is very interesting and indeed disturbing, IF TRUE.


Exactly, there is no correlation between the MRI findings and the symptoms or progression of the disease. So there is no logic or scientific reason to continue to determine that a drug is effective in treating MS based on the drug’s effect on the lesions in the MRI. What is the point of saying your MRI's are showing great pictures of reduced lesions but your symptoms or MS in general aren't getting any better at all?!


The FDA seems to think there is validity to use of MRI findings, and so do physicians. Should clinicians and the MS community ignore MRIs?

I think the difficulty is drawing the correlation between MRIs and EDSS - I have not looked at the MS trial data in its entirety so I am not sure of what these difficulties are. However, there are several indisputable FACTS:

1. The FDA believes that MRI findings are important in judging efficacy of MS treatments.
2. Doctors routinely use MRI findings to confirm MS dx.
3. Doctors routinely use MRI findings to help them judge the progress of MS.

These alone suggest use of MRI is useful in a qualitative sense. Its the quantitative bit that is difficult, I guess.



First of all, the study’s primary endpoint is determined and SET prior to the commencement of the study. The fact that Biogen Idec/Elan decided to submit the data early to the FDA (at 1 year versus 2 year), then they should have had convincing data regarding their primary endpoint and that was the EDSS scores. Iif the EDSS scores would have shown improvement then there wouldn’t have been any reason not to disclose this information since it was after all the primary endpoint. This is a big no-no in scientific research, but unfortunately the FDA allowed it.


The trial protocals were published in the journal Neurology for all to see before the trial began. I don't have the reference but I believe it was mid-2001. These protocols included 1 yr and 2 yr endpoints. EDSS was NOT an endpoint for yr 1, relapse rate was. MS clinicians generally agree that 1 year is too short a period to evaluate EDSS reliably. So why is this no-no? And the FDA agreed to this - why?

Furthermoe, the FDA asked the companies to file on the 1yr data, NOT the other way around. I can provide press releases to this effect.

I don't understand why this is an unfortunate occurrence given that Tysabri produced a 66% reduction in relapse rate. Isn't this a marvelous result for folks seeking relief from this disease?

The reason Berlex and most companies do this is because the results are not promising for the longer term. I quote from the Physician’s Desk Reference 2001 regarding Betaseron, “At the end of 2 years on assigned treatment, patients in the study had the option of continuing on treatment under blinded conditions. Approximately 80 % of patients under each treatment accepted. Although there was a trend toward patient benefit in the Betaseron groups during the third year, particularly in the 0.25 mg group, there was no statistically significant difference between the Betaseron-treated vs. placebo-treated patients in exacerbation rate, or in any of the secondary endpoints.” Thus, Berlex decided to submit only the first two years of data.


I would like to see some proof for the statment 'most companies do this is because the results are not promising for the longer term.' I believe this is PURE supposition, unless you can provide some statistically valid basis for it. The fact that Berlex may have done this (OUT OF THE 1000s of CLINICAL STUDIES CONDUCTED YEARLY) does NOT prove that 'most companies' follow this practice. Please provide proof.

I might add, if one is willing to accept nnecdotal evidence as 'proof', please explain the wonderful success of the 5 yr old girl who had an aggressive from of MS. Is this 'proof' that Tysabri works? See post:

http://www.thisisms.com/modules.php?nam ... opic&t=598

In sum, we all must be careful about ANECDOTAL evidence for anything. One could easily gather a number of anecdotal reports of Tysabri's excellent results (such as that above) and use that as proof. Is it? Yes, in a way, but it is NOT statistically valid nor consistent with good decision making. This is also applicable to the negatives - because Merck did this, Berlex did that, does NOT mean that all companies are running around trying to hide data and dupe the FDA and the public. I just don't buy this grand conspiracy theory.

How is “most likely” different than saying “quite possibly”? You stated


There is a HUGE difference between quite possibly and 'most likely' 'Quite possibly' says NOTHING about the quantitatve outcome, 'but most likely' makes a CLEAR quantitative statement. Quite Possible, Most Likely - different? I think so.

While this is semantics, I note that we apparently agree that it is not good to make assumptions in analysing data, which was the point I was making in my original post. Further, the poster ignored the fact that lesion load was normalised at study start.

And in the end, the poster's charge that the data were 'manipulated' was not supported, IMHO. That was the main point of most of my post. I note this point has not been challenged.

In fact, that is what the FDA, physicians etc are doing when they analyze the data from the MRI findings and then assume that this data has an impact on the clinical status of MS.


MRI was a secondary enpoint for the 1yr portion of the Tysabri studies. Primary was relapse rate, and there was a 66% reduction in annualized relapse rate compared to placebo in the Tysabri-only study. Isn't that fantastic? I am amazed that anyone can simply ignore this FACT. Obviously, however, the decision on what to focus upon is each individuals.


Although they failed to divulge all of the information as to lesion load etc at baseline, it doesn’t matter because there was NO change in new or newly enlarging lesions from baseline between the Tysabri group and the placebo group according to the findings from the more accurate Gd-enhancing scans.


Sorry, beg to differ. There was a SIGNIFICANT change in new or newly enlarging lesions (hope this table posts OK):

Gd-enhancing lesions Tysabri Placebo
Median 0.0 0.0
Percentage of patients with:
0 lesions 96% 68%
1 lesion 3% 13%
2 or more lesions 1% 19%

So we see that 32% of Placebo patients developed additional Gd lesions during the study, while only 4% of Tysabri patients developed additional Gd lesions. That means Tysabri is 8x (EIGHT TIMES) as effective as placebo or doing nothing at all! That's one way to interpret it.

I cannot comment on whether Gd lesions or T2 lesions are more or less important or eaiser to diagnose, but the results are startling - they clearly show the efficacy of Tysabri in reducing lesion load.

One has to wonder why would a company withhold information when they proclaim a drug to have such a great effect? After all, they supposedly came to this conclusion of the drug being so beneficial from reviewing all the data, so the data should show the great effect as well.


What information? They NEVER planned to release EDSS at 1 year, so why should they release information that could be misleading or inaccurate? I understand that the full AFFIRM data will be released in early 05 at a technical conference - I hope my understanding is correct.

The FDA has conducted a full analysis of the data and approved Tysabri. Despite some errors (vioxx, others) the FDA usually gets it right. Anybody have statistics on the numbers of drug recalls as a percentage of the number of approved drugs? I would bet << 1%, but I don't have the numbers at hand to prove this.

My bet, however is that the FDA knows full well what the EDSS results say, as many subsets of the 2 yr study are probably already in. I'll bet they are very good. BUT THAT IS ONLY A GUESS. I'm sure we ALL hope the EDSS results are fantastic.


Again, Harryz - I enjoy the discourse. Thanks.
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Postby HarryZ » Mon Nov 29, 2004 9:09 pm

I'm trying to cut these replies down a fair amount and have really shortened my answers.

Can you provide some proof of the limited involvement by the FDA that you suggest?


I suggest that you write the FDA and ask them if their people check that companies such as Biogen conduct the proper randomization that they state has been done.


The FDA seems to think there is validity to use of MRI findings, and so do physicians. Should clinicians and the MS community ignore MRIs?


"Seem to think" doesn't "prove" it! I am not suggesting that MRI's be ignored....just that they should not be used as a main criteria to determine if a drug is having a major efficacy on MS. No correlation to disease progression means just that!

I think the difficulty is drawing the correlation between MRIs and EDSS - I have not looked at the MS trial data in its entirety so I am not sure of what these difficulties are.


They CAN"T draw correlation between MRIs and EDSS. That's the problem. Having reduced lesions on your brain has no proven relevancy to what your MS is doing.


[quote' The FDA believes that MRI findings are important in judging efficacy of MS treatments.[/quote]

They just can't scientifically prove it.

Doctors routinely use MRI findings to confirm MS dx.


They use it as one of many tests to try and confirm MS. They DO NOT rely totally on an MRI for dx....if you have many lesions on your brain but you don't display the proper neurological signs then you won't get a MS dx.

Doctors routinely use MRI findings to help them judge the progress of MS.


Now how can they possibly do that when everyone is stating (even Biogen) that there is no correlation between MRIs and disease progression?

So much for indisputable facts!


The trial protocals were published in the journal Neurology for all to see before the trial began. I don't have the reference but I believe it was mid-2001. These protocols included 1 yr and 2 yr endpoints. EDSS was NOT an endpoint for yr 1, relapse rate was. MS clinicians generally agree that 1 year is too short a period to evaluate EDSS reliably. So why is this no-no? And the FDA agreed to this - why?


If the EDSS was a primary end-point and the main measurement for conducting the trials, why did Biogen push up the approval process by one year? As for the FDA's action in all of this....I guess you would have to ask them. May be the same people that were involved with Vioxx are also involved with Tysabri :-))

I don't understand why this is an unfortunate occurrence given that Tysabri produced a 66% reduction in relapse rate. Isn't this a marvelous result for folks seeking relief from this disease?


If the relapse rate translates into similar EDSS scores, then that would be great. Otherwise, it's not of much benefit to the patient if they continue to get worse.

I might add, if one is willing to accept nnecdotal evidence as 'proof', please explain the wonderful success of the 5 yr old girl who had an aggressive from of MS. Is this 'proof' that Tysabri works?


Simply read the various MS forums on the net and see how many MS patients have made wonderful recoveries form trying several different types of non-conventional remedies.

because Merck did this, Berlex did that, does NOT mean that all companies are running around trying to hide data and dupe the FDA and the public. I just don't buy this grand conspiracy theory.


No but it certainly means that the possibility is there and that openly believing what a drug company tells us is the truth has long since passed.

There is a HUGE difference between quite possibly and 'most likely' 'Quite possibly' says NOTHING about the quantitatve outcome, 'but most likely' makes a CLEAR quantitative statement. Quite Possible, Most Likely - different? I think so.


Yeah, right!!

And in the end, the poster's charge that the data were 'manipulated' was not supported, IMHO. That was the main point of most of my post. I note this point has not been challenged.


Go back and read many of the early CRAB drug trials (you'll have to find them on your own) and then tell me there wasn't any manipulation.

[quote}Sorry, beg to differ. There was a SIGNIFICANT change in new or newly enlarging lesions (hope this table posts OK):[/quote]

Guess we agree to disagree.

The FDA has conducted a full analysis of the data and approved Tysabri. Despite some errors (vioxx, others) the FDA usually gets it right. Anybody have statistics on the numbers of drug recalls as a percentage of the number of approved drugs? I would bet << 1%, but I don't have the numbers at hand to prove this.


When it comes to drugs and health, "usually" isn't good enough...especially if you are the one who is lying 6 feet under because of someone's error.

My bet, however is that the FDA knows full well what the EDSS results say, as many subsets of the 2 yr study are probably already in. I'll bet they are very good. BUT THAT IS ONLY A GUESS. I'm sure we ALL hope the EDSS results are fantastic.


Then why are you saying that the EDSS data hasn't been tabulated as yet? How can the FDA know about something that supposedly isn't done? Yes, I hope that the EDSS results are good but until the data is peer reviewed, we won't really know.

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Postby Observer » Mon Nov 29, 2004 11:20 pm

Harryz

Thanks again for the reply. Agree we need to shorten this, so I'll do so (at least I thought I would).

This will be my last post on this topic - as Bill O'Reilly says, I'll give you the last word.

So here I go:

I suggest that you write the FDA and ask them if their people check that companies such as Biogen conduct the proper randomization that they state has been done.


Whoa, you're making the statement that the only FDA involvement is up-front. YOU write the FDA and prove YOUR claim. The FDA approved the trial design, the trial conduct, thoroughly reviewed the data and APPROVED THE DRUG. That says to me that they have been fairly heavily involved in all aspects of the process.

I stand to be proven otherwise.

"Seem to think" doesn't "prove" it! I am not suggesting that MRI's be ignored....just that they should not be used as a main criteria to determine if a drug is having a major efficacy on MS. No correlation to disease progression means just that!


Does one believe the FDA and physicians or not? That is the question. I don't think they are using MRI as the MAIN criteria, but simply as additional information. Agree with you that no other symptoms of MS other than MRI, one is not likely to be dx'd with MS (but I'm not a doctor - this is just what I undertand).


Quote

Doctors routinely use MRI findings to help them judge the progress of MS.

EndQuote

Now how can they possibly do that when everyone is stating (even Biogen) that there is no correlation between MRIs and disease progression?



Are you saying that Doctors do NOT use MRIs to help them judge disease progression? I am shocked - I was certain they did. If they do not, why are MRIs routinely conducted?

And my FACTS have not been disproven, but perhaps that is a matter of opinion.

If the EDSS was a primary end-point and the main measurement for conducting the trials, why did Biogen push up the approval process by one year? As for the FDA's action in all of this....I guess you would have to ask them. May be the same people that were involved with Vioxx are also involved with Tysabri )


EDSS and relapse rates are the primary END POINTS AT 2 YRS, RELAPSE RATE IS THE PRIMARY END POINT AT 1 YR. The FDA agreed with this. I cannot make this any clearer, but here is the link on this point, please see the section 'About the Antegren MS Clinical Trials':

http://www.elan.com/News/full.asp?ID=496126


Furthermore, Biogen Idec and Elan did NOT push the approval process up by one year, THE FDA DID. How many times must this be stated? Here is a reference (one of several available):

http://www.tixx.com/lehman.htm

from Lars Eckman, Elan VP of R&D, at the Lehman Brother's Healthcare Conference in March, 2004, held about 2 weeks after the 1yr Antegren (Tysabri) filing was announced, discussing Antegren (Tysabri):


.... And as Kelly mentioned, a few weeks ago we announced that based on our Phase III data, the Agency has encouraged us to file with one-year data -- something that to my knowledge has not happened before in this space.

So, why is the Agency excited about Antegren? Well, there were two reasons. When we presented the Phase II data two years ago, we presented two things or three things. One was that the galinieum enhanced lesions, the new lesions, were reduced by 90%. We did prove that we could reduce the number of relapses with 50% to 60 % in the two categories. And we had excellent safety data. Safety data that did not reveal any difference between placebo and control in any aspect. At the time the Agency said: “If you can provide exceptional data,” and by that they said “in this space” then they would consider a one-year filing.

Since then, we have delivered 2, 200 patients in two trials, one is a monotherapy trial, the Affirm trial. The other one is a combination [trial] with Avonex, [the Sentinel trial]. It’s Avenex vs. Antegren plus Avenex in partial failures. This data has now been presented to the Agency. The Agency came back to me or to us as a team and said, “We want to meet you. We want to have a pre-NDA meeting.” We had the meeting. It was a very constructive meeting and they encouraged us to file.


Now, one might say 'I don't believe that. He's lying.' I would reply - 'does anyone really think he is going to put words in the FDA's mouth, in a public forum?'

I'll let the reader decide this, but the fact that it is PUBLIC suggests the speaker would stand behind the comment. This is likely more credible than unamed sources and hearsay, IMHO.


If the relapse rate translates into similar EDSS scores, then that would be great. Otherwise, it's not of much benefit to the patient if they continue to get worse.


Are you saying that a patient should be unconcerned with relapses? Wouldn't a reduction in relapses lead to a better quality of life? I don't know, and am seeking a simple answer to these questions.


Go back and read many of the early CRAB drug trials (you'll have to find them on your own) and then tell me there wasn't any manipulation.



My post had nothing to do with the CRAB drug trials. I was referring to the Tysabri trials and the posted charge of manipulation. That charge has no basis in fact, at this time. I am NOT saying there has been no manipulation, only that it is unproven at this stage. (And frankly I doubt there has been any manipulation, similar to the vast majority of approved trials and reporting thereon.)

When it comes to drugs and health, "usually" isn't good enough...especially if you are the one who is lying 6 feet under because of someone's error.



I agree, it only takes one to be a tragedy. Unfortunately, all of life is a tradeoff - risk/reward. If we wanted to be completely safe, we'd NEVER leave our house. Do you take the risk in leaving home, crossing a street, driving a car, etc? Of course - the risk/reward tradeoff is evidently made.

Now, how does that relate to Tysabri? Well, if we can help improve the life of thousands of people, is that worth the risk of SOME side effects. The FDA thinks so, and so do the vast majority of physicians and patients. Nothing in life is risk-free. Good heavens, look at chemotherapy if you want to talk about side effects!

And I might add that the FDA's 99+% success rate in being correct in approving drugs is a heck of a lot better than 'usually.' It is basically, well, 99% of the time, for lack of a descriptive adjective. (And that is even more than 'most likely.')

Then why are you saying that the EDSS data hasn't been tabulated as yet? How can the FDA know about something that supposedly isn't done? Yes, I hope that the EDSS results are good but until the data is peer reviewed, we won't really know.


I thought I made that clear in an earlier post, but the fact is drug trials don't start, say, 1000 patients at exactly the same date. They may be several months or even quarters between the first patient and the last enrollee. Given that, wouldn't you think:

a. there are 2-yr trial patients who have completed the trial (there definitely are), and
b. their EDSS would be available, and
c. the FDA would say 'Give us all the data, or we won't approve your drug' and
d. the companies would say 'Yes, OK, here it is'

Nah, wouldn't happen like that. Or would it? If I was the FDA, with the power to approve or not, I am sure as heck going to ask/demand ALL available data from the Companies. Even more so in light of the Vioxx withdrawl. I'm going to be extremely careful.

When the TOTALITY of the trial results (EDSS) are known, tabulated and analysed, they will be released to the public (top line only probably) and the full data in a peer-reviewed meeting and later a journal.

Over to you, and thanks again for the discourse. Apologies to other readers for the length of this.
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Postby Observer » Tue Nov 30, 2004 1:11 am

Talk about making the companies jump thru hoops - look at the 7 page Tysabri approval letter from the FDA!

http://www.fda.gov/cder/drug/infopage/n ... efault.htm

After reading this, does anyone think the FDA is not being careful? Look at some other approval letters (Avastin, for example); the few I've seen are substantially less detailed.

Whew!
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Postby OddDuck » Tue Nov 30, 2004 4:56 am

Ok....here I go again. This is an interesting discussion, and I would like to participate a little. And by now, everyone knows my position and from what perspective and focus I come from (legal), but hopefully that will only provide another interesting "take" on this subject, as that is only what my intent is, i.e. to provide another perspective.

Anyway......in looking at the link to the FDA very quickly that Observer posted here, I took a cursory glance at the Q&A section. (And no, I didn't do an in-depth analysis on this, either. In casually reading, this simply popped right out at me!)

I apologize, but this kind of wording (pasted below) just sends a red flag and puts immediate questions in my mind! Here's what the FDA itself answered to Question number 8. I'm going to highlight the wording that indicates the possible "risk" to the public the FDA decided to take. In my sole opinion, IF the FDA truly thought they were confident with Tysabri and its effectiveness and benefit, etc., - enough to put the drug on the market - why would they feel the need to put any type of disclaimer in their answer? (That's a valid question.) My "faith" in the FDA is NOT based on them putting something on the market in the interim WHILE they wait for "proof" that something is beneficial or not. I'd prefer they wait until they can say for CERTAIN that it is beneficial. Note they say that if it proves to NOT be beneficial, they can simply pull it back off the market. I'm sorry, folks, that kind of statement from an agency I rely on for safety and efficacy doesn't make me feel any better. It just seems like (to ME) that the FDA is willing to take too big of risks still when approving drugs. I'd like more definitive statements from them, such as they give early approval to drugs that DO show efficacy, not to the ones that "appear" to show efficacy. The FDA in this says the data is "suggesting" that the drug is "reasonably likely" (there's our vague terminology that a couple of people here were referring to). That is still saying "take at your own risk", in my opinion. Now THAT'S a secure feeling!:

"8. What is accelerated approval?

Accelerated approval is a program the FDA developed to make new drug products available for serious or life threatening diseases when they appeared to provide a benefit over available therapy (which could also mean there was no existing effective treatment). Under this program, natalizumab is being approved on the basis of early clinical study evidence (such as data from only one year of study) suggesting that the drug is reasonably likely to have a valuable effect on symptoms.

Several other products are already available for the treatment of MS, including Betaseron, Avonex, Rebif, Copaxone, and Novantrone. One of the clinical studies with natalizumab was performed in patients already being treated with Avonex. The addition of natalizumab resulted in a further reduction in the occurrence of relapses, beyond the benefit that those patients had already received from Avonex.

The approval is granted on the condition that the manufacturer must continue testing to demonstrate that the drug indeed provides therapeutic benefit to the patient. If it does not, the FDA can withdraw the product from the market more easily than usual."

Ok....my main question would be: Why not wait until you know for CERTAIN before approval? It feels to me like they are using the general public as additional guinea pigs. I know that sounds like a strong statement, but notice I said "it feels to ME".

Thanks.

Deb
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Postby raven » Tue Nov 30, 2004 5:58 am

Hi Deb,
We may find ourselves on the opposite sides of the fence for once! :wink:

I agree that not enough is known about the long term effects of Tysabri to say that it is 100% safe. However there has to be a trade off between the time taken to establish absolute safety and the need of MS patients for effective treatments now. For an example look at the petitions and clamour for Aimspro. That's without people knowing what it is, how or if it works and whether it's safe!

The decision to try Tysabri has to be taken by each person in consultation with their neurologist. They should be made fully aware that the treatment is new and as such there is a margin of risk involved. Also that the long term benefits are unproven.

For myself, I would refuse the treatment but that is an entirely personal view and should not influence others.

Robin
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Postby HarryZ » Tue Nov 30, 2004 6:08 am

This will be my last post on this topic - as Bill O'Reilly says, I'll give you the last word.

I agree and I'll make this last comment VERY short :-))
Whoa, you're making the statement that the only FDA involvement is up-front.

Let's say my source is someone who has gone through the clincial trial exercise with the FDA and knows how they work.
Are you saying that Doctors do NOT use MRIs to help them judge disease progression? I am shocked - I was certain they did. If they do not, why are MRIs routinely conducted?

Docs used to think that MRIs WERE the answer to following MS. Then they discovered that healthy people had lesions showing on their MRIs. Until they improve the tool (it is getting much better BTW) it is just another tool because of the lack of correlation factor.
time the Agency said: “If you can provide exceptional data,” and by that they said “in this space” then they would consider a one-year filing.

Sounds more like "if you can" as opposed to "stop the trials, we are ready for you".

I'll let the reader decide this, but the fact that it is PUBLIC suggests the speaker would stand behind the comment. This is likely more credible than unamed sources and hearsay, IMHO.


After the episode with Vioxx and Merck, I simply don't trust the FDA to be a squeeky clean organization any longer.

Are you saying that a patient should be unconcerned with relapses? Wouldn't a reduction in relapses lead to a better quality of life? I don't know, and am seeking a simple answer to these questions.


No, what I'm saying is that the EDSS score and how the patient feels is far more important than relapse rate.

Now, how does that relate to Tysabri? Well, if we can help improve the life of thousands of people, is that worth the risk of SOME side effects. The FDA thinks so, and so do the vast majority of physicians and patients. Nothing in life is risk-free. Good heavens, look at chemotherapy if you want to talk about side effects!


Do you remember when the CRABs first started to appear in the early 90's? The same kind of benefit was being touted by the drug companies and the FDA. Over time we found out differently to the point that some MS scientists have recently written that a drug such as Copaxone is useless in the treatment of MS. Yet the FDA approved this drug on some of the most questionable data, even acknowledging the marginal benefit. I hope the same thing doesn't happen with Tysabri .

When the TOTALITY of the trial results (EDSS) are known, tabulated and analysed, they will be released to the public (top line only probably) and the full data in a peer-reviewed meeting and later a journal.


Agreed....but until then we don't have ANY info on the EDSS scores which is the kingpin in measuring how a drug is doing. Time will tell.

Talk about writing a precise :-)))

Harry
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Postby OddDuck » Tue Nov 30, 2004 8:05 am

Hi, Robin!

We may find ourselves on the opposite sides of the fence for once!


Well, not necessarily.........or should I say not "entirely".

I agree that not enough is known about the long term effects of Tysabri to say that it is 100% safe. However there has to be a trade off between the time taken to establish absolute safety and the need of MS patients for effective treatments now. For an example look at the petitions and clamour for Aimspro. That's without people knowing what it is, how or if it works and whether it's safe!


I agree with the above, also. I guess what it boils down to is that the percentage of safety is still not high enough for me personally, whereas it may indeed be high enough for others. Perhaps you included. So ok, we may differ on percentages that provide each of our individual comfort levels. And I do agree and have attempted to make that very point that you have just made, using Aimspro as an example. I just personally am sometimes concerned (maybe overly so, but perhaps that comes from being exposed over the years through my type of work to the "underside" or "behind the scenes" things that go on).......not only referring to pharmas, but with everything in general. If people only knew............. :?

They should be made fully aware that the treatment is new and as such there is a margin of risk involved. Also that the long term benefits are unproven.


Robin, that's my point EXACTLY! But in my mind and from my information (and speaking only on behalf of myself, of course), that appears to not be the case as of yet. (i.e. that people are being fully informed.) As a matter of fact, I do believe that I have stated my concern regarding that previously. But that's from my "legal" brain (and probably passionate concern for the rights and safety of others)........"the right to know", etc. etc. etc. :wink:

So, we're not so far off from each other. I just counter the passionate claims FOR Tysabri, with equally matching passionate concerns. :wink:

Deb
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Postby raven » Tue Nov 30, 2004 8:28 am

Actually Deb I do agree with you, it would be an interesting debate if we ever did find ourselves diametrically opposed on an issue. I could see the rest of the board running for cover! :lol:

Speaking solely for myself the risks are less important than the benefits. I am unmarried and have no dependants, so am probably more willing to take risks in my search for a cure than others.

However in the case of Tysabri I do not believe that the benefits warrant any risk. I don't believe that lesions are the main cause of disability. Tysabri inhibits the infiltration of leukocytes into the brain parenchyma. As I have stated in other threads it is my belief that already resident glial cells are primarily involved in the progression of MS. As such Tysabri will have an effect upon lesions and possibly relapses but will have very little long term effect upon disability.

Robin
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Postby OddDuck » Tue Nov 30, 2004 8:43 am

Robin,

...it would be an interesting debate if we ever did find ourselves diametrically opposed on an issue. I could see the rest of the board running for cover!


Can you imagine? That would be a gas, though, wouldn't it? Actually, I can't imagine it ever turning into an "argument", though. But we sure would try to top each other with rhetoric (in the good sense of the word) and abstract thinking! HAH! :lol:

I know it appears that I agree with you simply to be agreeable, but that's really not the case. I find you to be so down-to-earth, logical, and analytical (and your opinions are measured and weighed before you speak), so it's extremely difficult for me to ever NOT stop and give your words the serious thought and consideration they deserve. (Yuck....mutual admiration society, huh?) :wink:

Ok....Tysabri. The other thing I find...........well, not exactly "disturbing", but just "curious" maybe............is the indication (I found it previously, but don't have it immediately handy; and that Biogen doesn't/hasn't addressed this particular issue in depth as it pertains to MS) that macrophages and APCs are NOT prevented from infiltrating the BBB with Tysabri. Only leukocytes.

SO...what if "some" types or patterns of MS are arising from antigen presenting cells? Tysabri may be good for some "types" of MS in particular cases, etc. (as you mentioned....you're unmarried, etc., and I mentioned earlier that for us oldie-moldies a lot of my concerns wouldn't even apply as far as personal risk assessment goes), but what about types of MS that may NOT be strictly "immune system" derived?

Deb

EDIT: Oh, yea.........

As such Tysabri will have an effect upon lesions and possibly relapses but will have very little long term effect upon disability.


Well, I have to say AGAIN, that based on my information and belief, I have to agree.
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Postby raven » Tue Nov 30, 2004 8:59 am

Yuk indeed, but the respect is mutual! :D

And I wouldn't call 49 an oldie mouldy, although at 39 I suppose I'm a young un :wink:

Anyway only time will tell if our concerns over tysabri are correct or not.

Robin
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Postby HarryZ » Tue Nov 30, 2004 9:16 am

Robin,

As such Tysabri will have an effect upon lesions and possibly relapses but will have very little long term effect upon disability.


I wish you would have written this a few days ago because it pretty well summarizes what I have been trying to say but perhaps not doing a very good job of it :-))

If this indeed is the best we get from Tysabri then one has to ask the question of whether the huge cost versus benefits is worth it. I guess that's the decision the MS patient is going to have to make. In the meantime we'll just have to wait and see what unfolds in the next year or so.

Harry
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