New Rituximab ME/CFS open-label phase II study with rituximab maintenance treatment

[Jonathan Edwards]

Private insurance in the UK may not cover existing conditions.

Yes, that's what I meant. It isn't much help for those diagnosed unfortunately. But I used to think private insurance as well as NHS was crazy and change my mind three years ago. I have already had good value from my private policy.

 

[Jonathan Edwards]

That's an interesting point. If the phase iii trial is successful then patients in the UK could seek a high court judgement against NICE if they refuse to license rituximab for ME/CFS, because they'd be denying treatment to patients despite excellent evidence that it's effective. And US patients can probably go through a similar process. I hope it doesn't come to that, but even the threat of legal action might make them sit up and take the situation seriously.

I think it is worth polishing up a few cutlasses in the meantime. Even if it is just to frighten them into sense.

 

[cornwall13]

Assuming the rituximab results from norway are positive.

My apologises if this has been mentioned before

So if you went privately in the uk, Drs maybe willing to prescribe, just with the results from Norway phase 3 trial (assuming they are really positive)? Just seems that the hoops accessing it via the nhs will be like wading through butter.

What would the costs be approximately? Ive no idea the costs involved, but i can imagine its a lot a lot a lot of money.

 

[deleder2k]

I think 500mg is around £1000. The schedule is now approximately 1g at day 0 and day 14, then 500mg at 3 months, 6 months, 9 months and 12 months. The cost of the drug for one year is roughly 2000+2000+1000+1000+1000+1000= £8000. If given privately i assume you would need to add infusion costs (4-7 hours each time), appointment with doctors, and perhaps blood tests.

 

[panckage]

The cost of the drug for one year is roughly 2000+2000+1000+1000+1000+1000= £8000. .

That's cheap! But I guess its because its already off patent there. It doesn't go off patent in the USA until December of this year according to http://newdrugapprovals.org/patent-expiry/

 

[alex3619]

I think each country has a different set of rules.

I think this is the heart of the question. Here doctors might be able to use it off label, but it will probably not be covered by insurance for some time. So the issue is not only can doctors use it, but who pays for it. Those are two different paths requiring approval (or many paths if you consider all the myriad forms of health insurance).

 

[BurnA]

We have discussed it a bit but I am not sure anybody knows all the answers. Doctors can prescribe rituximab for ME in most countries if there is a source of funds and they are prepared to take on the responsibility of off label treatment. They are doing so in the USA and have done so in other countries.

Do they keep you informed of response rate or results ?

 

[Snow Leopard]

But I used to think private insurance as well as NHS was crazy and change my mind three years ago. I have already had good value from my private policy.

It's crazy when you are young and healthy, smart when you are older and at risk.

Hence the "incentives" scheme in Australia: http://www.privatehealth.gov.au/healthinsurance/incentivessurcharges/lifetimehealthcover.htm

As far as I know, preexisting conditions in Australia are covered, but there is a waiting list.
http://www.phio.org.au/facts-and-advice/the-pre-existing-conditions-rule.aspx

But all of this is theoretical for Australians as insurance schemes are extremely unlikely to cover the drug, it is more likely to be approved by the PBS (subsidised), even then it will only happen if it is approved elsewhere as Australians are rarely leaders of this sort of thing.

 

[deleder2k]

That's cheap! But I guess its because its already off patent there. It doesn't go off patent in the USA until December of this year according to http://newdrugapprovals.org/patent-expiry/

I don't think EMA has approved any rituximab biosimilars yet, but I think one will be approved in 1-2 years.

I don't know why the price of Rituximab is so high in the U.S. With the strength of the U.S dollar at the moment I would look for options in Europe if funding is a concern.

The Norwegian krone has depreciated heavily due to the oil meltdown. 1 gram of Mabthera is now $3,050 in Norway.

 

[Riley]

That's cheap! But I guess its because its already off patent there. It doesn't go off patent in the USA until December of this year according to http://newdrugapprovals.org/patent-expiry/

Wow, google tells me that 8000 pounds is equal to 12,555 dollars. That is very cheap (relatively speaking).

As an aside, is NICE not the most terrifyingly Orwellian name for a government bureaucracy? Especially one that controls access to healthcare.

 

[Jonathan Edwards]

Wow, google tells me that 8000 pounds is equal to 12,555 dollars. That is very cheap (relatively speaking).

As an aside, is NICE not the most terrifyingly Orwellian name for a government bureaucracy? Especially one that controls access to healthcare.

Not quite right, Riley: nearly.
NICE is the name of a most terrifyingly Orwellian government bureaucracy.
But maybe you're right as well - all in the doublespeak.

 

[Aurator]

As an aside, is NICE not the most terrifyingly Orwellian name for a government bureaucracy? Especially one that controls access to healthcare.

Not quite right, Riley: nearly.
NICE is the name of a most terrifyingly Orwellian government bureaucracy.

You have to question what kind of person would want to work for them.
I can feel a slogan coming on:
"Nice people don't become NICE people."

 

[BurnA]

I've extracted the following from http://www.cortjohnson.org/blog/201...ute-takes-on-chronic-fatigue-syndrome-me-cfs/

"Kogelnik felt the success of the early Rituximab trial shifted the conversation for chronic fatigue syndrome (ME/CFS) in a good direction but he’s cautious about the future of Rituximab in ME/CFS. Since researchers tend to pick patients they think will prove their theory early, small studies runs the risk of having inflated results. Dr. Peterson has warned about this as well."
"The fact that Kogelnik’s worried about patient selection suggest, however, that he’s not getting the kind of jaw-dropping results Fluge and Mella did."

Could someone explain how there could be a bias in the selection process in Norway ?
Given that biomarkers are hard to identify for CFS nevermind for potential responders to rituximab am I correct in assuming any Bias would be completely unintentional ?

 

[deleder2k]

dr. Olav Mella mentioned this in his presentation at Invest in ME in May. Results from phase 3 trials, especially multi-centre, produces lower results than earlier phases where less patients are included. It is almost impossible to make sure the study does not consist of bias at all, especially for small studies done at one hospital. One can however minimise bias.
I do not remember how the patients from the two Phase 2 studies were selected, but it could be that they are more homogenous, than those included in the bigger multi-center trial. The former were all included at the same hospital (Haukeland). Maybe they were a more homogenous group since they wanted to sacrifice themselves for science. Perhaps different doctors at different hospitals in Norway choose different patients since there is no biomarker. They only include patients that fit the Canadian criteria, but if they have some sort of other disease they could be excluded from the study. What if one doctor thinks that patients with some sort of disease should not be allowed, while a doctor at another hospital thinks that it is safe to go ahead? I am sure all hospitals speaks frequently with Haukeland about this stuff.
I wouldn't worry much about it. I am sure the results will be good. I think Mella said his intuition was 10% placebo response and hopefully at least 50% response with RTX.

 

[deleder2k]

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917255/ This one is interesting

 

[Jonathan Edwards]

I've extracted the following from http://www.cortjohnson.org/blog/201...ute-takes-on-chronic-fatigue-syndrome-me-cfs/

"Kogelnik felt the success of the early Rituximab trial shifted the conversation for chronic fatigue syndrome (ME/CFS) in a good direction but he’s cautious about the future of Rituximab in ME/CFS. Since researchers tend to pick patients they think will prove their theory early, small studies runs the risk of having inflated results. Dr. Peterson has warned about this as well."
"The fact that Kogelnik’s worried about patient selection suggest, however, that he’s not getting the kind of jaw-dropping results Fluge and Mella did."

Could someone explain how there could be a bias in the selection process in Norway ?
Given that biomarkers are hard to identify for CFS nevermind for potential responders to rituximab am I correct in assuming any Bias would be completely unintentional ?

This is a very interesting question. Cort is right to say that researchers tend to pick patients that they think will confirm their theory. I did this in RA. But the irony is that if you can pick the 'right' patients that more or less shows you are theorising in the right direction. If your theory was wrong they wouldn't do better.

So it turns out that there is a confusion here. What researchers tend to do in early studies is pick patients that look as if they have a good chance of response (an RA patient who is not already too crippled to ever get better) and ones that they think really have the sort of process the treatment might be aimed at (RA patients with positive antibody tests). You can maybe select in the first way for ME but so far nobody really knows how to select the second way. If you select like this you will tend to get better results in an open study. However, there is no way that you can 'inflate' 'real' results in a double blind controlled trial like the Norwegain phase 2 study. There cannot be any bias that produces a difference that is not there. Even if you chose very 'placebo sensitive' cases, which does not seem to be true because the controls did not respond, the difference cannot be inflated.

But we are left with the problem that if you take all the patients attending a clinic such as OMI who conform to CCC criteria (or whatever) then the rate of response generated in Norwegian trials may not pan out. What may be important is that the Norwegian phase 2 patients had been referred to a government run health service neurologist. That may mean that they are a different subset of CCC conformers than those attending OMI - for all sorts of reasons.

What we do not know is whether the Norwegian referral system or referral to OMI is most representative of ME patients as a whole.

 

[deleder2k]

I think Haukeland made information about a phase 3 study available online. It was also discussed at several forums, there was information in a magazine by the Norwegian ME association. According to Haukeland they got roughly 1500 applications for the study. Haukeland forwarded the applications to the other hospitals included in the study. Some patients also sent applications to their nearest local hospital directly.

All that was needed to apply was a ME diagnosis by a GP or a specialist. At Haukeland they "re-diagnosed" each patient that was to be included in the study again to see if they fulfilled the Canadian criteria. I am sure every hospital in the study did the same.

 

[Nielk]

One difference is that patients who went to OMI for Rituximab had to pay for it. I am not sure if that is meaningful. It might represent patients who are more severely affected that they were willing to pay a lot of money to try this treatment?

 

[A.B.]

And the very severely affected didn't do as well in Fluge and Mella 4 patient study.

 

[Jonathan Edwards]

One difference is that patients who went to OMI for Rituximab had to pay for it. I am not sure if that is meaningful. It might represent patients who are more severely affected that they were willing to pay a lot of money to try this treatment?

That would not be my experience in RA. The patients who came to me wanting to pay for rituximab at the time when I was doing trials were no more severe than the ones who I chose from my service clinic. I think they were less consistently severe - both in terms of activity of disease and amount of irreversible damage. It may be of interest that when I briefly opened a paying clinic for people interested in rituximab (the money went to the trials) I saw about 50 cases but I only thought one of them was suitable enough for treatment to transfer her to my NHS list and treat her on the NHS. On the other hand of the three or four patients who got referred to me by NHS colleagues and who indicated that they could pay at a time when I had no funds, all were treated because they clearly had very active disease. I am not sure what that shows, if anything, and things may be different for ME because of problems severe patients have in getting to treatment facilities.