If the Norway Rituximab trials are a success - Will it be available worldwide?

[MEMum]

Yes we are lucky.
Hopefully the insurers/health providers will see that it would be financially as well as humanly preferable to treat people once there is something effective, even if it is only for a subset.

 

[maybe some day]

Yes we are lucky.
Hopefully the insurers/health providers will see that it would be financially as well as humanly preferable to treat people once there is something effective, even if it is only for a subset.

I really hope so. We've come along way with answers than ever before

 

[Jonathan Edwards]

It isn't hype at all. He said people are responding. October unveiling is a formality.

They may be responding to the placebo as much as the drug. If that is the case we will have a lot to think about - and Dr Knoop will have to stop claiming that ME does not respond to placebos.

Nobody knows yet whether this is a real lead or a false scent and nobody is clearer about that than the Norwegians themselves.

 

[Kenny Banya]

They may be responding to the placebo as much as the drug. If that is the case we will have a lot to think about - and Dr Knoop will have to stop claiming that ME does not respond to placebos.

Nobody knows yet whether this is a real lead or a false scent and nobody is clearer about that than the Norwegians themselves.

They are clear about it due to research obligation
It would be a massive placebo response if so & would contradict (to some extent) Phase II, hence I am working on balance of probabailities which is that it is highly unlikely to be placebo effect. Hence why I said that October unveiling will be a formality.

 

[Aurator]

Hence why I said that October unveiling will be a formality.

Perhaps I'm less fortunate than you in having no crystal ball, but I'm prepared for anything and would be surprised by nothing.

 

[Kenny Banya]

Perhaps I'm less fortunate than you in having no crystal ball, but I'm prepared for anything and would be surprised by nothing.

It would be a massive surprise (as to be improbable) if the statistically significant response was in the placebo group

 

[Snow Leopard]

Perhaps "hype" was the wrong word. Rumor is a better word.

The fact is they haven't analysed the data. It's all speculation at the moment.

 

[Kenny Banya]

Does anyone know if Fluge/Mella are applying for registeration of Rituximab with the European Medicines Agency?
Is it standard procedure to apply? Norway is not a member of the EU, but the EEA
http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000109.jsp

Once granted by the European Commission, the centralised marketing authorisation is valid in all EU Member States as well as in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway.

Can @Jonathan Edwards give some insights?

 

[Murph]

Hence why I said that October unveiling will be a formality.

I'm overall an optimist, but I also like to follow good scientific practice in making predictions. So we should find a good background probability for establishing whether the Rituximab Phase III trial will report a success.

My reading suggests that in some fields, around 40 to 60 per cent of Phase III trials fail. (1, 2, 3)

Source: Clinical Development Success Rates 2006-2015

Rituximab is a Phase III trial so if we want to argue it is a higher chance of success than its peers, we need good reasons.

We can perhaps adjust our background probability for research coming from a stable European country, for researchers with no financial stake, and also for a disease with such strong Phase II trials. (Edit: some other good reasons to be more confident have been suggested below.) But there is no way the Ritux Phase III trial result unveiling is just a formality.

There remains a serious chance (perhaps 25 per cent?) that it comes back unable to reject the null hypothesis. I think it's important to keep this in mind so the patient community doesn't fall into despair if it happens - we have many irons in the fire at the moment and for once, not everything is riding on one research team or one study.

 

[Kenny Banya]

Rituximab is a Phase III trial so if we want to argue it is a higher chance of success than its peers, we need good reasons.

Because Dr Fluge said they were getting a significant response.
I would be interested to know what percentage of Phase III trials got a significant placebo response, when the Phase II trial of said drug had a response rate north of 65%
I would bet it's never happened in the last 20 years & if it has I would bet it is a 'false equivalence'

FYI, false equivalence is my favourite logical fallacy of late!

 

[BurnA]

Because Dr Fluge said they were getting a significant response.

I think he said they were getting reports of responders but that he didn't know if they were placebo or not.

 

[Murph]

Because Dr Fluge said they were getting a significant response.
I would be interested to know what percentage of Phase III trials got a significant placebo response, when the Phase II trial of said drug had a response rate north of 65%
I would bet it's never happened in the last 20 years & if it has I would bet it is a 'false equivalence'

FYI, false equivalence is my favourite logical fallacy of late!

That Fluge quote is definitely another factor to build in. It should increase our confidence. Perhaps Fluge is poring over the data whenever it is collected, trying to guess who is treatment and who is placebo and doing statistical transformations that try to figure out the odds the patterns he sees are explained by chance! This is certainly plausible!

But it's also possible he's focussing on his oncology patients and has just heard from the trial workers that some patients are going well. Given we don't know how closely they've looked at the data yet - and that it is all still blinded - the background probability is still pretty salient.

 

[Marc_NL]

My reading suggests that in some fields, around 40 to 60 per cent of Phase III trials fail. (1, 2, 3)

I agree that approval is definitely not a formality but I think the percentages for drugs that are already approved for other indications (like Rituximab) are a bit more favorable because safety issues are better known.

 

[ghosalb]

If one looks at the phase 2 results, responders are of younger age and of low to moderate level sickness.....whereas non responder are of all ages and all level of sickness.....granted that sample size is small, but may be there is more than placebo effect.

 

[Kenny Banya]

Here is some detail of the research into immunosignatures to evaluate potential for responsiveness to Rituximab

http://www.meresearch.org.uk/our-research/ongoing-studies/immunosignature-for-rituximab/

 

[Kenny Banya]

http://www.medscape.com/viewarticle/871787?src=soc_tw_share#vp_3

Key takeaway:

Moreover, the pattern of delayed responses after B cell depletion and of subsequent relapses seen in both of the small rituximab trials are similar to what is seen in some better-characterized autoimmune diseases, Dr Mella noted. Additionally, the delayed response also argues against a placebo effect.

I would bet there are hardly any drugs that take 6 months to have an effect - more reason that I'll bet there has been no Phase III drug trial in the last 20 years anywhere in the world that had a placebo effect, when the actual drug effect was so relatively high in Phase II

 

[Forbin]

It would seem like a complex placebo effect to manifest. Based on the earlier studies, the duration of the effect seems to be linked to how quickly it appears. In other words, someone might have a placebo effect that was inconsistent with the expected pattern of the b-cell depletion effect. So, it would not just be whether someone shows an effect. It would be whether they show the expected effect.

 

[Jesse2233]

@Forbin but what about those who (for various biological reasons) clear the autoantibodies faster? they might see a response in 2 months that is not a placebo

 

[Forbin]

@Forbin but what about those who (for various biological reasons) clear the autoantibodies faster? they might see a response in 2 months that is not a placebo

From what I understand, the sooner the effect has occurred the longer it has lasted. This is thought to be because the sooner it occurs the more time there is before the b-cells repopulate. So, you could have an early response, but it would be less consistent with the hypothesis if that response were short. Conversely, a delayed response would be more consistent with the hypothesis if it were shorter in duration.

 

[Kenny Banya]

It would seem like a complex placebo effect to manifest. Based on the earlier studies, the duration of the effect seems to be linked to how quickly it appears. In other words, someone might have a placebo effect that was inconsistent with the expected pattern of the b-cell depletion effect. So, it would not just be whether someone shows an effect. It would be whether they show the expected effect.

Additionally, the size of the effect is important.
Is there a correlation between reported symptom reduction & the treatment group?
That is, is the symptom reduction greater in the drug group than the placebo group?
But, most importantly to me, on what measures of symptoms?
OBJECTIVE or SUBJECTIVE measures?

I think the lesson to be learned from psychological studies (& scientific research in general), is to pay far less credence to subjective measures