Efficacy of Disease-Modifying Therapies Review Study

[dreddk]

Our objective was to compare the clinical efficacy of currently approved first-line DMTs in patients with RRMS, applying an evidence-based medicine approach. We reviewed all phase III pivotal trials of DMTs. Six clinical trials of Avonex(R), Betaseron(R), Copaxone(R), Rebif(R) and Tysabri(R) in patients with RRMS were identified for analysis. Only randomized, placebo-controlled, double-blind studies were included. The clinical efficacy endpoints compared were: proportion of relapse-free patients at 1 and 2 years; annualized relapse rate at 2 years; proportion of progression-free patients at 2 years, and proportion of patients free of gadolinium-enhancing lesions at 1 year or 9 months.

Based on these analyses, Betaseron, Rebif, and Tysabri show comparable effects, whereas for several endpoints Avonex or Copaxone did not significantly differ from placebo. In the absence of head-to-head studies for all products used to treat RRMS, it still may be possible to compare treatment effects by applying evidence-based medicine principles.

http://www.ncbi.nlm.nih.gov/pubmed/1843 ... stractPlus

[HarryZ]

Now if I understand this correctly, the researchers, using the current scientific and medical methodology, found Betaseron, Rebif and Tysabri to be pretty much equal in their efficacy. Copaxone and Avonex showed the same results as placebo!!

I'd like to be a fly on the wall in the marketing departments of Biogen (Tysabri ,Avonex) and Teva ( Copaxone) as they prepare their press releases to counter these findings!

Harry

[dreddk]

From the study conclusion:

"Of the available agents, Tysabri and high-dose,
high-frequency IFNs (Betaseron and Rebif) appear to be
significantly more effective than placebo...Both Avonex and Copaxone show, in general, less robust effects, with no definite benefit over placebo for many of the endpoints studied."

Numbers needed to Treat to show one person progression free at 2 years:

Avonex 7.7
Betaseron 10.0
Copaxone 33.3
Rebif 9.1
Tysabri 8.4

[HarryZ]

Numbers needed to Treat to show one person progression free at 2 years:

Avonex 7.7
Betaseron 10.0
Copaxone 33.3
Rebif 9.1
Tysabri 8.4

Some have said that Copaxone doesn't do much, if anything, for MS. It took some number dredging to get the data from the Copaxone trials high enough to get FDA approval and orphan drug status.

Harry

[mjs]

Am a bit surprised that Tysabri was not shown to outperform the interferons.

Not surprised re Copaxone - the Cochrane Group found the same thing a few years ago. In its pivotal double-bind placebo trial, Copaxone just failed to meet statistical significance.

I guess the issue with Avonex is the dosage (it's otherwise chemically identical to Rebif). Frequent high dose interferons are considered to be more effective (if they can be tolerated).

Given the billions spent on these drugs, and the pain and suffering they impose on their patients (injections, side effects, etc), it is quite shocking that society allows it.

[HarryZ]

Given the billions spent on these drugs, and the pain and suffering they impose on their patients (injections, side effects, etc), it is quite shocking that society allows it.

Welcome to the slick world of MS medication marketing, with Biogen being at the top of that list.

I've attended many drug update seminars for these drugs over the years and they have the patients leaving all excited about how well the trial results have been. It's the local docs who do these presentations and they get a lot of money from these companies to not only present but also prescribe the drugs.

As for Tysabri.....I've been reading recently on a couple of other MS forums that some patients aren't doing well at all on the drug. Some people have no problems and do OK while others remain the same. Sound familiar with results from the CRABs over the years?

Harry

[10yearsandstillkicken]

I have been watching this forum for some time. After 7 years of betaseron and a bit of brain shrinkage and a few more lesions, my neuro switched me to rebif. With tysabri being more effective (apparently) than anything else, I wanted to know how others were doing which led me here. I was curious about how the NMSS would respond to this study. So I sent an email and have copied the response below. How can any of us know what is really effective? Is tysabri really this effective:

At the end of a 2-year study, TYSABRI reduced how often flare-ups occurred by 67% compared with placebo. The average number of flare-ups a patient had each year was 0.22 for TYSABRI and 0.67 for placebo <shortened url>

And rebif:

Significantly more people were relapse free at 2 years with Rebif 44mcg vs placebo (32% vs 15%) http://www.mslifelines.com/rebif/guide/ ... veness.jsp

I guess relapse and flareup are different? So if both are comparable, what are they comparing?

This was the response I got from the NMSS:
“There is abundant proof, published in peer-reviewed journals, that the approved disease-modifying therapies are significantly better than the inactive placebos against which they were tested. Building evidence also suggests that they not only impact relapses but also may slow the progression of disease. There is no substitute for well-designed, placebo-controlled studies that are done for extended periods of time. Most statisticians believe that it is very difficult to combine results from studies, such as was done for this article. The problem with mushing the results together is that each study used different patient populations (with differences in their recent relapse experience, age, time from disease onset, and many other variables) and different outcome measures and different timeframes of study. At the recent American Academy of Neurology meeting in Chicago this spring, a statistician (Dr. Gary Cutter, U Alabama) looked at this very issue and concluded, among other things, that head-to-head studies was the only way to compare results. “
Here is Dr. Cutter's abstract:

S02.001] Statistical Analysis of Clinical Endpoints in Studies of Disease-Modifying Therapies for Multiple Sclerosis

Gary Cutter, Birmingham, AL, Maria Sormani, Milan, Italy, Amy Pace, Hao Zhang, Cambridge, MA

OBJECTIVE: To evaluate statistical methodologies used to analyze clinical efficacy endpoints in placebo-controlled studies of multiple sclerosis (MS) disease-modifying therapies (DMTs). BACKGROUND: Interpretation of MS clinical study outcomes are complicated by variations in patient characteristics, study designs, and definitions/analyses of clinical outcomes. As new clinical trial results from studies of DMTs become available, the treating neurologist faces the challenge of interpreting these results to optimize patient care. DESIGN/METHODS: This review evaluates common definitions of relapse and disability endpoints and statistical methods used to analyze them in clinical studies of MS DMTs. Advantages and limitations of each statistical method are considered. RESULTS: Relapses have not been operationally defined, and the definition of disability progression based on Expanded Disability Status Scale score (which is often a noisy variable) differs among clinical studies. Treatment effects on relapse or disability endpoints may be estimated via relative risk reductions (RelRR), a measure of the difference in outcome on active treatment relative to placebo, or from rate ratios estimated from statistical models. RelRRs exhibit less variability across populations with different baseline risks, but do not discriminate between small and large treatment effects. Treatment effects on clinical endpoints may also be estimated via absolute risk reductions (AbsRR) and number needed to treat (NNT) to prevent one undesired outcome, a derivative of AbsRR. AbsRRs are derived from absolute differences between active treatment and placebo outcomes, and thus are highly dependent on placebo rates or proportions. The AbsRR lends itself to interpretability, although differences in patients baseline activities may inflate or diminish AbsRR outcomes. CONCLUSIONS/RELEVANCE: Differences in inclusion criteria, study patient populations, and placebo-group behavior make direct comparisons of treatment effects across studies difficult to interpret. AbsRRs/NNTs are not recommended for making comparisons between treatment effects among studies with different baseline risks or populations. Supported by: Biogen Idec. Editorial support provided by Scientific Connexions.
Category - MS and Related Diseases
SubCategory - Clinical Science

Additionally, I have included a link to our expert opinion paper on the disease modifying drugs.
http://www.nationalmssociety.org/download.aspx?id=8

[HarryZ]

Hi "10 years"....welcome to the forum.

The statisical quotes that you used for your message all come from the companies that make these drugs so naturally they are going to sound good. The NMSS, which is heavily sponsored by these very companies is obviously going to support them.

Yet, we have independent researchers, like the Cochrane Group who publish articles that say very differently. They stated a couple of years ago that Copaxone was virtually useless against MS. And now this recent study by another group gives us information about the CRABs and Tysabri that contradicts what the drug companies have been telling us. So how does the average person know what to believe or not?

It isn't surprising that almost immediately we see publications throwing doubt on these different points of view. MS drugs are a huge source of revenue and you can bet that the companies that make them are going to protect their cash cows.

What is certain is the efficacy of these drugs is as clouded as the disease is itself. I have a tendency to place more faith in those independent people who analyze these trial results and have no financial interest in these drug companies.

After years and years of research, mostly by the big drug companies, how much further are we really ahead in coming up with the elusive "cure"?

Harry

[10yearsandstillkicken]

The study http://www.ncbi.nlm.nih.gov/pubmed/1843 ... stractPlus is a review of phase III trial results. Aren’t the same results also available to the FDA and its European counterpart (Sorry, not sure what the name is)? Does either agency review the data against what the company reports prior to approval? I guess what worries/confounds me is that the study showed differing results based on the same underlying data. I took statistics in college so I know numbers can be manipulated to show what is needed. Shouldn’t someone review results like this study team did to verify that the data indicates what the trial authors report?

[HarryZ]

Drug trials are designed differently from one another, often with different end points. For years one of the main measurements for MS trials was the reduction of brain lesions over placebo. Brain lesions can come and go on their own. There is little correlation between brain lesions and MS symptoms. So you can see the interpretation of this one end point alone can vary quite a bit so is it no wonder that the docs may come up with very different conclusions?

So when a drug company provides the data to the FDA or any other regulatory body, it may not be seen in the same way by other scientists. Add MS into the equation, a disease that comes and goes on its own even if no drugs are involved, you can end up with some different opinions. You can be assured of one thing though....the drug company's marketing and sales people will pick out the best of the best data and use that to promote the drug.

I've seen this going on for years and nothing has changed. Only more and more money is at issue today so the intensity of the marketing wars between the companies has become even greater. And that is why I believe the comments and opinions by the scientists who work independently from these companies.

Harry

[10yearsandstillkicken]

So those of us with MS need to be more informed. I see my neuro this month and I'll ask about the study.

I did send an email to the NMSS about posting the reply I received. They asked that I hold off since they were reviewing the study. They didn't respond fast enough so I had already copied it here. I'll add or point to the offical response if it materializes.

[dreddk]

It's interesting because in the study I quoted, they talk about Rebif versus Tysabri.

The Tysabri study showed a substantially better effect compared to the Placebo group when compared against Rebif.

Now reading that you would think Tysabri was superior to Rebif. But the authors point out that is not the case as the placebo groups had quite different characterics and its simply not correct to say Tysabri is more effective than Rebif (In fact they concluded they were pretty similar in effect). The only way to compare drugs is if they use the same placebo group in a head to head trial.

Lies, damn lies and statistics...

[HarryZ]

Now reading that you would think Tysabri was superior to Rebif. But the authors point out that is not the case as the placebo groups had quite different characterics and its simply not correct to say Tysabri is more effective than Rebif (In fact they concluded they were pretty similar in effect). The only way to compare drugs is if they use the same placebo group in a head to head trial.

That is not the first time that I have heard a very different interpretation about Tysabri trial results. The Tysabri patients in the trials had very mild MS so the great results that Biogen has indicated to us aren't as good as Biogen would like us to believe. I have to admit, though, Biogen has one slick marketing department and they know how to hype their products.

Harry

[itsjustme]

Hi,

I just wanted to add how when I was working we would deal with statistics everyday. There were two concepts which were repeated frequently when discussing results comparing one product vs. another.
One idea was how you need to test "apples-to-apples". Otherwise you will have less confidence in your results if you are comparing "apples-to-oranges". The statistical analysis conclusion you come to might not be truly representative of the situation.

This is also why the second concept was always proving itself. This being if A > B; and B > C; this does NOT mean A > C.
No, you can not extrapolate. That would be lazy science. One would need to test A vs. C directly head-to-head.

But as Harry said, this would be counter indicative for the marketing divisions.

[stathis]

It is in the nature of the drug Tysabri to be more efficient in fighting immune diseases such as MS and Crohn's either you like it either you dont.

However due to it being more powerful in altering the immune system, that is why it is more dangerous than the other drugs. While on Tysabri, the infections are certainly more dangerous than being on rebif of avonex or copaxone and that is a FACT you cannot prove false, which means:

Tysabri extremely lowers the immune system response in the brain (and I would say in all the body) while all the other drugs modestly do.

Due to being a blockbuster drug in a few years it will be the worst efficienct drug for many propaganda out there trying to keep those CRABS on the surface which have nothing to do with fighting the disease.

I am a Tysabri user, and I DONT like the drug, however in neurological terms it really does something to keep em' protected. Unfortunately, it will certainly effect other parts of the body due to its nature of heavily altering ones immune system. And yes it cannot work for all, but isnt that something that can also happen with .... aspirins.

All we can do is hope for some famous people aka Bush, Madonna and Bin Laden to get this disease simutaneously so we can get a cure in no time ...