Friday, 7 March 2014

The Pathway to Prescription

Many people coming to the Blog don't read the comments
(you miss some corkers:-)

Some of these People are MS Charities and Funders of Studies, Some of them are Neuros,  
Some May be Regulators. 
This post is for You!  

Am I a non-clinical windbag-waffling on about the failure to translate animal studies to human health? 
Does the clinical fraternity have culpability in this lack lustre performance? 

Do they really have the right Big Picture? 

In response to a post by Prof G You Wrote. "I'm a risk taker and am 8 years post 2nd alemtuzumab infusion. Doing well and disease appears to be inactive. My niggling doubt is that something else may be going on - you've referred to slow burn inflammation .... However, there's no treatment option i.e I'd like to take a neuroprotective drug as an insurance policy. If one of the current trials of neuroprotective treatments came good, could these be an add-on to people like me, or will we face the usual 10 years of further trials and licensing?"

This is an excellent question but I will also rephrase it this way:

"I have progressive MS there's no treatment option. If one of the current trials of generic neuroprotective treatments come good, could these be given to me or will we face the usual 10 years of further trials and licensing?" 

So now more people with MS has a stake in the answer

                                    Yes it is a dollar sign in this will cost alot!

If the Pharmaceutical Company is answering the question it will be- Yes you have to wait 10 years because the regulators are going to make us (pharma) do a phase II trial (2-5 years) and then TWO phase III (Trials 5-7years) and then go to the regulators (FAD/EMA) for approval (1-2 years) and then hope NICE play Ball. 

There are agents in Phase III trials now it they work great....let's hope, but based on track record RRMS drugs have not done well at stopping progression. 

So Academia have taken up the guantlet and accepted the challenge to get prescription drugs to stop you progressing.

So I ask What is the pathway? 

If pharma have their way they would want to eliminate any "disruptive influences" (term taken from a financial report) in the profit forecast, such that they hope that cheap generic drugs don't arrive.

They would argue that you have to be fair and follow the same rules! So Phase II will need to be followed by two Phase III trials and licensing. 

In this respect have the academic neuros aiming to get you drugs that work thought this through. Can this be done in a timely fashion? 

First which Agency/Charity has the resource to do this? 

There is no academic merit of doing the same thing twice. You may be able to do one phase III but doing two Phase III trials is probably out of the question?  Am I wrong?

So do rules set for Pharma need to be broken, If they can be broken then why should Pharma have to play ball! Should the rules not be bent for them?

Should a fudge be done and declare Progressive MS an Orphan disease and so relax the requirements

Then there is the Licensing. 

Academics probably do not have the knowledge, skill sets or the resource to do this on the whole, scientists can do pre-clinical testing, neuros can do clinical trials, but what about dealing with the regulators?

I am told just to talk to the European regulators for a formal response on your development plan costs £30,000. To go to the UK regulators cost £3,000 but that only lets you get through in one country not the whole World. This is going to take years and loads of cash.....This is not where you want you charity cash to go but to get those prescriptions filled, this could be needed. Am I wrong? 

The system that has been created is funded by (I have been told that the MHRA is 100% pharma funded, the EMA about 85% pharma funded)...and is only accessible to, pharma because now it is such an expensive monster.

I have asked the question before. In the modern era name a drug that has been developed by an academic without pharma involvement. Yes techniques and treatments can be developed by academics...look at Bone Marrow Transplantation but this is hardly a universally applied solution for MS. Maybe a life or death situation but for a chronic disease. 

Government funding agencies and the Wellcome trust for example are asking for repurposed drugs to be developed. Pharma is doing this if there is a patent in place...(only tysabri and glaterimer acetate were developed from MS-related studies, the others have all been repurposed for use in MS after development in another condition). What the repurposing initative in UK may mean is taking cheap generic drug and finding a use to treat....MS. Admiral view but is this joined up thinking. Unless it is generic is the NHS doing company work? If it is a generic the trials then what happens.

They have thought it through as far as stimulating neuros to do trials but then I think the vision appears to blur. Have they thought about licensing. Who will hold and pay for the license. I understand this costs £100,000 a year. Maybe not, I am a scientist and not a regulator. Whats the solution? Based on comments there are people with a NICEview out there. If you have cheap drugs, there is no need for a NICE, but you will still have to pay to collect analyse the health economic data. The MHRA don't care about the cost, their concern is safety if the drug is cheap so what..they are not going to cut corners for that. will NICE give the nod?

This is why we may need the big pharma alternative to encourage and incentivise pharma to do studies with repurposed generic drugs. They invest millions of dollars in doing trials and have the infrastructure to licence the product. To do this they need to be able to recoup that investment. So maybe Governments need to rethink the patent rules to provide protection for pharma doing the studies. Maybe for neurological diseases where trials are long they need to relax the rules.

This is a political solution. We are not sure how long a trial to monitor successful treatments of progressive MS are but if trials are extended (at one point the regulators were being lobbied to have clinical disability endpoints adding years to trial programmes) patent life is eroded and it may be uneconomical to do long-term studies.

What is the select committee for MS or MSer MP'ss in the UK parliament doing? Surely this is a matter they should take interest in.

However this very issue is much bigger than MS as this situation is applicable to all conditions and particular Neurological diseases. The UK government and the G8 are ploughing money into Dementia more money for research. However, if they consider alternatives to the current mechanism of drug development they could have major impact for relatively little cost.

Do Neuros need a licence to be able to prescribe. Are we talking cloud cuckoo land or some form of utopia

In NICEtime it seems that neuros generally do not prescribe unless there is official approval because who will reimburse the costs (Want an example look at Fampridine and Sativex, these are not universally available throughout the NHS. In the States Alemtuzimab has no licence will neuros prescribe it).

If there is no alternative, neuros will sometime prescribe off-label, particularly if the drug is cheap and relatively safe, but will the insurance companies/Hospital Trust play ball? 

Do they need regulatory approval to re-imburse?

After an investigator-led trial, are neuros going to drop their reserve and say to hell with it and prescribe in the absence of any licence and importantly without the evidence that pharma has to provide (e.g. one phase III  verses two phase III?) 

This is the hope, but is this realistic? 

We have created a litigious society. So who gets sued when an unwanted side effect pops up? But hey who would be monitoring this (phase IV activity) because it ain't pharma doing the treating or the study. So you wait until it pops up in the literature (so publication submission to press can be 6 months-1 year, so if it is a rare fatal side effect at what cost?) Is a rare side effect a chance effect or a linked effect?

Now add to the mix that one pharmaceutical drug gets a licence will your neuro be forced or feel obliged to switch drug, because they will be now be legally exposed should something go wrong, with your unlicensed drug.

They are surely duty bound to use a licensed drug rather than go off-label (How many of you are prescribing an unlicensed DMT for relapsing MS?...except where the others have failed). Am I wrong?

Am I talking hogwash or do we really need to think this through and get our academic heads out of the clouds because if we don't we may be missing opportunities and we may be creating false hopes and wasting a lot of time. There needs to proper binding answers not some hairy-fairy wishful thinking that I have heard coming from a lot of eminent people. We can all be ideallists but what is essential is that we are practical.

The path to prescription needs to be clear before walking down the path not after you have spent several years walking down the path to find the gate is closed, and worse locked, at the end of this.

Is this nonsense? Ask what you are doing about positive data from phase 2's, but was it positive enough. Many people say no. There is a cost for a development. 

Waiting for a phase III? Is there going to be one or two? A pharmaceutical company would have planned phase III and would be starting this straight after phase II as to not loose time because in addition to "Time being Brain, "Time is also Money"

Even if there was a Phase III trial. Then what?  I haven't canvassed people doing academic-led phase III, there are plenty doing phase II. Maybe the answer is we'll cross that bridge when we come to it. Maybe it will show pharma a target, who will develop a patented drug for the same purpose.....Time is brain
If there is no real and realistic pathway to prescription, then is it unethical to start these studies? Should this be part of the ethical review process.

This is the debate and solution that needs to be addressed by the highest eschillons of the MS Power. Maybe this has occurred already. Lets hope so and I am just a rambling scientist.

The Pathway to prescription should be made clear 

If you want to respond, please do! Maybe ProfG will add a bit

You can email us and you could have a Guest Post 
(Send us a picture and conflicts of Interest statement). 

If you (neuro, regulator, insurance company, politician?) want to set us straight but don't want to do it in person, we can collate responses and do it "Anon"
There are always solutions but you need to focus the mind first. 

Have they been Focussing.


  1. Mousedr,

    Are there any other diseases that would require a similar change? I'm struggling to come up with any off the top of my head. I'm sure there are others that would benefit if it was instituted. A coalition of more than just ms researchers/groups for lobbying purposes would be useful.

    1. Any disease if you are repurposing drugs and there is no patent protection.

      In cancer I am sure this has been addressed but it is a rapid life and death issue, but for chronic conditions there may be a case. Alzheimers disease could be a case. Maybe one could argue the deterioration is quicker than in MS, but if they start looking a Alzheimers prophylaxsis. How long are the trials going to be/

      Maybe I should have written to Wellcome Trust to ask what is the route to repurposing

    2. P.S. I did write.....and got a quick response....the buck was passed without answer, so no clarity given...disturbing

    3. So not regulators reading....or no clue to the answer!


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