Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Sasha]

Thanks to Kate_UK for posting about this on another thread:

http://www.investinme.org/Rituximab news-July13 01.htm

 

[Sasha]

Don't forget they're matching donations this week:

http://forums.phoenixrising.me/inde...on-matched-for-iime-uk-rituximab-trial.24428/

 

[Simon]

Interesting stuff. Looks like they have UCL lined up as the ideal place to run the trial in the UK. £300-400k now needed.

Looking at the research directions currently being pursued in ME/CFS, I am in no doubt that the usage of rituximab is one of the most promising. There is clearly enthusiasm for further trials. However, rituximab is not an easy drug to use and many doctors do not feel confident with using it. This may explain why studies have been slow to gain momentum outside Norway.

Safe and effective usage requires understanding of B cell life history and function. Each condition has to be considered differently, especially in terms of when treatment is repeated. But with experience its use is very effective and probably as safe as most drugs...

My feeling is that a trial should be carried out somewhere with detailed experience in use of rituximab in autoimmune conditions.

The UCL service set up when we started treating rheumatoid arthritis, lupus and a range of other conditions has the most extensive experience.There is laboratory expertise in B cell immunology under Dr Jo Cambridge.

UCL also has a new Clinical Trials Research Facility with staff appointed to manage trials of this sort.
Importantly, there is enthusiasm amongst local teams for a rituximab ME/CFS trial.

I have suggested to IiME that this would be the ideal centre for such a trial, to be set up in collaboration with clinicians with expertise in ME/CFS from around London, and in particular Dr Bansal. IiME have accepted this and this is the planned and preferred research base for this trial.

Clinical trials are costly. The trial planned in Norway to confirm the results from Fluge and Mella’s initial trial will cost something like £1-2M pounds. I think it would be most sensible to set up a smaller scale trial initially in the UK with a focus on trying to identify which patients are most likely to benefit. A trial treating about 30 patients, giving useful scientific information should hopefully be feasible for around £3-400,000. Trial design will require careful thought and some further preliminary laboratory work is likely to be needed before it is clear what design would be optimal.

Nevertheless, I am optimistic that a trial could be set up without major delay if funds can be raised. If the role of B cells in at least some ME/CFS, suggested by Fluge and Mella’s study, can be confirmed I think there is a genuine chance of getting to grips with the mechanism of the disease.

 

[Esther12]

I think it would be most sensible to set up a smaller scale trial initially in the UK with a focus on trying to identify which patients are most likely to benefit.

Speaking from a position of real ignorance here, but... only 30 patients? Are there any other small trials like this already going on? Are we likely to be able to identify sub-groups with such a small study? If only 10% of CFS patients would benefit (which would still be a great find), this finding could get lost in the noise.

If there are already smaller trials ongoing, maybe it would be better to wait for their results? If the larger Norwegian study is still being delayed by funding issues, maybe it would be better to pool resources?

Also, I'm always concerned by talk of 'clinicians with expertise in ME/CFS'.

 

[Mark]

Speaking from a position of real ignorance here, but... only 30 patients? Are there any other small trials like this already going on? Are we likely to be able to identify sub-groups with such a small study? If only 10% of CFS patients would benefit (which would still be a great find), this finding could get lost in the noise.

If there are already smaller trials ongoing, maybe it would be better to wait for their results? If the larger Norwegian study is still being delayed by funding issues, maybe it would be better to pool resources?

Also, I'm always concerned by talk of 'clinicians with expertise in ME/CFS'.

My understanding is that the large Norwegian study has enough funding now to get started, even though the full funding for the entire trial is not yet in place. So it seems fairly clear that the large trial will be happening.

Looking at the cost of that large trial, and the cost of a 30-patient trial, even the cost of the smaller trial seems a somewhat daunting target. It makes sense to me that duplicating the large Norwegian trial might not be the best use of funds. A 30-patient trial wouldn't mean ever so much on its own, but following on from the original two smaller studies and then the large Norwegian study, together all that evidence adds up. So the strategy of using the trial both as further independent confirmation of the Norwegian findings, and also to explore some detail, such as trying to identify which patients are most likely to benefit, makes sense to me.

What jumps out most to me though is that the MRC should be funding at least part of this trial. How long ago was it that they announced that £1.5m pot for ME/CFS research, with a big fanfare? At the time, there had been less than £100k of funding in the previous financial year, so the £1.5m pot was not a big new investment as they presented it; over 2 years it was merely restoring the historical average level of £800k-£850k per year. But that was, what, a year ago, 2 years ago? We're due something like £1.5m just to maintain the historical average - which is itself maybe 1/40th of what would be fair by comparison with other conditions. So the MRC really should be funding some study like this and the case for that seems very strong indeed for me. Time for some more questions in the house, perhaps, about ME/CFS funding levels over the last 10 years, to expose this funding cut?

 

[Esther12]

Looking at the cost of that large trial, and the cost of a 30-patient trial, even the cost of the smaller trial seems a somewhat daunting target. It makes sense to me that duplicating the large Norwegian trial might not be the best use of funds. A 30-patient trial wouldn't mean ever so much on its own, but following on from the original two smaller studies and then the large Norwegian study, together all that evidence adds up. So the strategy of using the trial both as further independent confirmation of the Norwegian findings, and also to explore some detail, such as trying to identify which patients are most likely to benefit, makes sense to me.

Maybe. I see some value from work on this by an independent group... I fear that there's a good chance that such a small study will lead to results which could be interpreted in a number of different ways, and won't do much to move things forward. I don't really know enough about B cells, how they test for abnormalities, etc, to have an informed opinion though.

 

[Bob]

Speaking from a position of real ignorance here, but... only 30 patients? Are there any other small trials like this already going on? Are we likely to be able to identify sub-groups with such a small study? If only 10% of CFS patients would benefit (which would still be a great find), this finding could get lost in the noise.

If there are already smaller trials ongoing, maybe it would be better to wait for their results? If the larger Norwegian study is still being delayed by funding issues, maybe it would be better to pool resources?

Also, I'm always concerned by talk of 'clinicians with expertise in ME/CFS'.

Maybe. I see some value from work on this by an independent group... I fear that there's a good chance that such a small study will lead to results which could be interpreted in a number of different ways, and won't do much to move things forward. I don't really know enough about B cells, how they test for abnormalities, etc, to have an informed opinion though.

I guess we have to start somewhere. The first UK study will be exploratory, and if they get some positive results then it will hopefully lead to a larger MRC-funded study. But, yes, there's always a chance that the results will be mixed or disappointing. There are so many variables for the heterogeneous CFS patient population. But if they get a small number of drastic 'recoveries' (or similar to a recovery), as they have done in Norway, then I hope it will gain a lot of media and scientific interest.

The Norwegians have their latest Rituximab study waiting to be published, so hopefully the results will demonstrate why IiME is so keen to get this research moving.

If a 30 patient trial looks at biomarkers (genetics, proteomics, viruses, antibodies etc.) (and the symptom profile, and medical history) of the participants, then it may be able to determine biomarkers, or other markers, for those patients who respond to Rituximab. This would be very helpful for a larger trial, because it would drastically increase the positive results.

 

[Sasha]

I think there's big value in getting even a small trial done in the UK, to get the attention of UK clinicians and researchers (yes, we're that parochial) and, not least, the UK media. The media here have paid no attention to the Norwegian trial despite being told about it - but if there was a successful UK trial I think they'd be all over it.

I agree the MRC should be funding this. I hope IiME are drawing up a funding application.

 

[Firestormm]

This is a good statement. I am pleased to hear from Prof. Edwards. I would be happier to hear from UCL with specific proposals. I don't like the use of the MEA in the way that they have been at the foot of this statement:

IiME will contact other organisations to invite them to donate to this cause. One organisation has already indicated it will support a rituximab trial – in fact the MEA chairman has publicly stated on 29th July to an IiME supporter - “Let us know when you find some good quality researchers with a peer reviewed proposal. We have £60,000 in a ring fenced pot awaiting such a development.”.

But that is for the MEA to thrash out I suppose.

I still remain skeptical that this has been shown to be true:

We now have the researchers willing to perform this trial in the UK.

But IiME have said they have some sort of commitment from Dr Cambridge at UCL and that may be - in the absence of actual money - all they can realistically hope for at this stage. But this remains to be seen I think - from conversations I have had I think you can do more before the funding is in place e.g. outline the actual study as a proposal and subject it to peer review.

I mean - with no personal experience you understand - wouldn't you be making a 'bid' for a contract? This is no different that any other team of researchers applying to e.g. the MRC for a grant.

No reason it can't be done now and from the statement it still seems that specifics have not been engaged in. What we have at best is a tentative agreement that yes, UCL is capable of doing a study, and would like to do one.

A firmer proposal can still be submitted and run the hurdles of ethics for example. Things can be established in advance of the money being available.

I don't want to discourage anyone from donating money, but I would like some greater substance to the claims that UCL are on standby and that funding is the only obstacle.

Other than that - crikey it is a lot of money, isn't it? We knew this going in of course, but still £400,000 just to try and replicate

The MRC are not going to step in. I wouldn't be surprised if for some (not necessarily the MRC) sitting back and waiting for the Norwegians is considered a (more) sensible step.

If realistically, it takes 2-4 years to raise enough from donations for a £400k 30 patient, 30 control, blinded, replication; then the Norwegians will at least have been able to publish I would have thought.

Then we will be able to decide if we want to go ahead and do a replication of our own in the UK. Might not want to if the Norwegian results do not replicate.

Then of course we have yet to hear about the US promised Trial. From OMI I think wasn't it? What's happening over the pond?

 

[Firestormm]

I think there's big value in getting even a small trial done in the UK, to get the attention of UK clinicians and researchers (yes, we're that parochial) and, not least, the UK media. The media here have paid no attention to the Norwegian trial despite being told about it - but if there was a successful UK trial I think they'd be all over it.

Yes UK media attention would be rather welcomed and has been absent I agree. The UK scientific community hasn't been uninterested I don't think - though I have little evidence for that I am afraid. Other than that Professor Stephen Holgate and others were highly interested in the initial study results. Scientists stepping forward and expressing their views publicly in an article or three would be rather nice.

I agree the MRC should be funding this. I hope IiME are drawing up a funding application.

It is not the remit of IiME to draft a proposal for e.g. the MRC. If IiME are the funding body then my understanding is, that researchers should be drafting proposals for IiME. And these proposals should run the gauntlet of approval - whatever that process is for IiME.

IiME holds the money effectively in trust on behalf of all the donors. Whatever the terms of their fund are - I don't know and haven't seen them - somehow they will determine who to give the money too.

That in itself is a possibly contentious decision - who makes it and how I couldn't possibly say: but it's not different than any charity decision to fund any study. Is e.g. UCL the only and the best for this study? Somehow they have to decide. And is their proposal the best?

But the IiME are not researchers. UCL could apply to the MRC if the MRC had made it apparent that they were setting funds aside - but I don't think this would come from an existing 'pot' of ME money. One would have to be created. And I am not yet convinced this is likely.

If the 3rd sector fund a study, and it replicates, AND if the Norwegians replicate; THEN the MRC might if needed step in. But they may not need to...

 

[Sasha]

It is not the remit of IiME to draft a proposal for e.g. the MRC. If IiME are the funding body then my understanding is, that researchers should be drafting proposals for IiME.

[...]

But the IiME are not researchers. UCL could apply to the MRC if the MRC had made it apparent that they were setting funds aside - but I don't think this would come from an existing 'pot' of ME money. One would have to be created.

You're right, of course, it's UCL that would apply - I was being a bit careless there! I don't see why the funds can't come out of the MRC ME/CFS pot, though.

 

[Simon]

Speaking from a position of real ignorance here, but... only 30 patients? Are there any other small trials like this already going on? Are we likely to be able to identify sub-groups with such a small study? If only 10% of CFS patients would benefit (which would still be a great find), this finding could get lost in the noise.

If there are already smaller trials ongoing, maybe it would be better to wait for their results? If the larger Norwegian study is still being delayed by funding issues, maybe it would be better to pool resources?

Also, I'm always concerned by talk of 'clinicians with expertise in ME/CFS'.

I think the expertise was in using rituximab, which is probably the most important thing as it's a very powerful drug with potentially nasty side effects. That's why Enlander abanadoned his trial, while Kogelnik/OMI have had some serious adverse reaction with their non-trial use of it.

My feeling is that a trial should be carried out somewhere with detailed experience in use of rituximab in autoimmune conditions.

I agree that it's pretty pointless doing a 30-subject study, esp as the Norwegians will have published a much larger study by time this one makes a journal, which will trump any findings of such a small study.

Also agree more overt committment is needed from UCL, and the MRC should be involved. So, I wonder if a better route would be for IiME to either fund UCL to do the work on a funding proposal for a ful-scale trial that would be submitted to the MRC (and maybe cofunded by IiME). Or perhaps fund a small pilot by UCL which would allow them to identify any practical issues, get some results and demonstrate their commitment too. Would be quicker and cost a lot less. Ah, the joys of speculaiton.

 

[ukxmrv]

If a UK team did a study on even 30 patients I think that it would make a huge difference. UK doctors, in my experience, don't give as much weight to research in another country - even if it is close by like Norway. There is always a question mark over any study done abroad (except if it suits some doctors interests).

The research may well be on another planet if it's not the UK. The NHS doctors I have seen are not interested in research in other countries. They don't "know" the doctors and are parochial. However, if it was one of their "own" and someone with a reputation in the NHS, AND if it did show a good effect, then it would be a ground breaker here.

A trial in the UK would be a huge achievement, even if it was 30 patients. We have had so few trials of anything to treat ME and CFS that young and old researchers are put off entering the field or like Dr Kerr, they lose their lab.

Nothing would be better to convince doctors that applying to the MRC for funds into clinical trails for actual treatments for ME and CFS is other than a huge waste of time and a career ending move.

 

[Sasha]

So, I wonder if a better route would be for IiME to either fund UCL to do the work on a funding proposal for a ful-scale trial that would be submitted to the MRC (and maybe cofunded by IiME). Or perhaps fund a small pilot by UCL which would allow them to identify any practical issues, get some results and demonstrate their commitment too. Would be quicker and cost a lot less. Ah, the joys of speculaiton.

Those are interesting points, Simon - why not email them and suggest it? They seem to welcome feedback and comment - especially constructive comments like yours.

 

[Sasha]

If a UK team did a study on even 30 patients I think that it would make a difference. UK doctors in my experience don't give as much weight to research in another country, even if it is close by like Norway. There is always a question mark over any study done abroad (except if it suits some doctors interests).

A trial in the UK would be a huge achievement, even if it was 30 patients. We have had so few trials of anything to treat ME and CFS that young and old researchers are put off entering the field or like Dr Kerr, they lose their lab.

Nothing would be better to convince doctors that applying to the MRC for funds into clinical trails for actual treatments for ME and CFS is other than a huge waste of time and a career ending move.

I think speed is an issue, too. What I like about IiME is their sense of urgency and, Simon's good comments above notwithstanding, a quick small trial has the benefits you point out here and we'd see them faster than a large, follow-up trial. Perhaps we need both but I wouldn't want to wait for a big trial if a small one could be done faster - we need to get some momentum going, like there was around XMRV (and although that disproved XMRV as a hypothesis, it moved the science forward rapidly).

 

[Purple]

Is this trial to be 30 patients in total - i.e. 15 receiving the drug and 15 receiving placebo, or 60 in total (30 and 30)? Assuming this is to be a double-blind placebo controlled trial.

 

[user9876]

I think speed is an issue, too. What I like about IiME is their sense of urgency and, Simon's good comments above notwithstanding, a quick small trial has the benefits you point out here and we'd see them faster than a large, follow-up trial. Perhaps we need both but I wouldn't want to wait for a big trial if a small one could be done faster - we need to get some momentum going, like there was around XMRV (and although that disproved XMRV as a hypothesis, it moved the science forward rapidly).

I think a small pilot trial that could be started quickly is worth doing. It could then form the basis of an application to the MRC to fund a bigger trial. Also getting someone like the group at UCL interested seems like a good move. I seem to remember reading somewhere that someone had put in a proposal to the MRC to fund a Rituximab trial but that it was turned down. Hence a sucessful pilot trial with an appropriate examination of different immune markers throughout might help make it impossible for some of those on MRC committees to block a bigger trial.

I think the trial should also aim to have more severly affected patients. Perhaps this also means putting a chunk of funding for the trial for hospital transport.

 

[Snow Leopard]

Speaking from a position of real ignorance here, but... only 30 patients? Are there any other small trials like this already going on?

In terms of funding it is generally nigh on impossible to get funding for a large study without a pilot study first. Those with funding tend to want all the ducks in line before they're willing to move.

As far as I know, there aren't any other trials with 30ish patients that have funding. Multiple small trials (if successful) is potentially better than one large trial, as it shows the results are maintained despite methodological differences. Regulatory agencies do one big meta-analysis when considering drug approval and small trials like this do help.

 

[Firestormm]

ukxmrv makes a good point. A trial does need to be completed (or more than one) in the UK but also to better enable licensing for the use of Rituximab in ME. I don't understand the processes, but from what others are saying - here and elsewhere - the important thing at the moment is replication.

With 30 patients (I assume) blinded, I imagine this to be the smallest number to achieve significance. Personally, I would want to spend at little money as possible to fund a trial of maximum significance. I don't think we need to replicate the exact amount of patients in the current Norwegian Trial - although it would be nice.

And as was also said above, the chances are that by the time e.g. £400k was raised for one independent trial of 30 patients - the Norwegians will have published. Their results may well determine whether or not the funds raised in the UK are actually spent in any UK trial.

Options will still be open.

More information to come from both UCL and Prof. Edwards hopefully.

 

[MeSci]

ukxmrv makes a good point. A trial does need to be completed (or more than one) in the UK but also to better enable licensing for the use of Rituximab in ME.

One of my several reservations about donating to a trial of a patentable drug is: If the trial is successful, a drug company will presumably apply for a patent for a licence for Rituximab (with a new brand name) to be prescribed for ME. They will then hold that exclusive patent for a number of years (20 in the UK), enabling them to charge a high price for it and prevent cheaper generic versions from being prescribed for the condition in question.

It seems to me that patenting a 'repurposed' drug like this could be extremely lucrative, as the company will not have had to bear the costs of early development.

If I am right, a fairer way for donors to fund such drug research would be to buy shares of some kind (not sure whether or how this could be organised) and therefore reap some financial rewards from future sales of the drug for the condition in question.

I know that people with ME are desperate, and donors presumably regard the potential availability of an effective treatment, or at least progress towards one, to be reward enough. I am just uncomfortable with the idea of potentially lining the pockets of a rich company.