Wednesday, 14 March 2018

Off-Label Use. Is it bad for business? Should it be allowed?

Should we have off-label use of MS treatments, if it competes with pharma interest?

There are many that would not contemplate this view. 

What do you think? 
Rituximab is a CD20 depleting antibody that was originally developed for B cell cancers. Many years ago it was shown that rheumatoid arthritis responded well to deppletion of CD19 and it was only a matter of time before neurologists copied the arthologists and put it into MS. Prof Huser took up the challenge, being a stones throw from Genetech who made the antibody by creating a chimeric antibody of mouse monoclonal antibody against human CD20 and having human antibody tail.

It worked well in phase II studies but rather than plough on, development paused. 

It was realised that rituximab did not have a long patent life and but by the time the clinical development for MS was completed the patent life would be over. Being a chimeric antibody it would be likely that an antibody response will get developed against this, so why not develop the humanised version and an antibody that was even more potent than rituximab?

As a consequence ocrelizumab was born and off they (Genentech (Roche)) went and started to develop ocrelizumab for lupus, arthritis and MS. Only one major problem happened.

This was that ocrelizumab was so good at getting rid of B cells, people started dying of infections, so the development of lupus and arthritis was halted. MS development was continued as it is a more serious problem (so people accept more risks) and MS is a cash cow when it comes to drug prices.

Ocrelizumab works very well to control MS, but that creates a problem because it says that rituximab can work very well. So what do you do? Do you use ocrelizumab with a price tag of  $65,000 (2017) when rituximab costs $4,000?

So we have three papers

Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - Commentary.Cree BA. Mult Scler. 2018 Feb 1:1352458518760717.

Dr.Cree asks


Should lower cost alternate medications with comparable mechanisms of action, but without the proof from registration studies, be used in lieu of branded medications with proved efficacy and safety?



Piehl F, Hillert J. Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - Yes. Mult Scler. 2018 Feb 1:1352458518757930.

Professors Piehl and Hillert argue that comparative effectiveness studies support use of rituximab as a MS disease modifying treatment (DMT), and that possible differences in association with malignancies found for ocrelizumab, but not associated with rituximab, make rituximab a better option


Rituximab is an acceptable alternative to ocrelizumab for treating multiple sclerosis - No. Wallin MT. Mult Scler. 2018 Feb 1:1352458518757931. 

Professor Wallin takes the opposing view that ocrelizumab offers an advantage over rituximab with regard to proof of efficacy and patient access


Prof Cree thinks the argument  to favor rituximab (or other lower cost offlabel medications) is economic
  • Most third party payers do not authorize off-label variant 
  • Prescribing clinicians inevitably favor approved, accessible medications. 
The US taxpayer has been funding institutions (NIH) has had little interest in promoting development of lower cost treatments that compete with branded medications over medications that effort

So what was said.
Prof Piehl says "Yes" or I guess Ja

"Three anti- CD20 targeting monoclonal antibodies have been tested in multiple sclerosis (MS); rituximab (mouse chimeric), ocrelizumab (humanized), and ofatumumab (fully human) and work".


Actually there are a few more, so safe ground to say that B cell depleting therapy is beneficial for controlling relapse.


The tack is to base the argument on medical arguments leaving the legal and cost issues aside. However, surely cost and the legal is the real battle ground as we know rituximab can work.


But for Prof Piehl the battle group is efficacy, immunogenicity and safety.


MT Wallin says "No"


It is argued that the antibodies are not the same.

Yes we know about the price but what about the biology?


It is argued "The choice of RTX or OCR should be based on efficacy and safety issues. Although costlier than RTX, it can be argued that OCR is a more effective B cell–depleting agent with the potential for a greater likelihood of stabilizing MS activity in the right patient".


1. Not as good. 

It is argued by the No camp that that "Both mAbs differ in the mechanism for depleting B cells. OCR has a higher capacity for antibody-dependent cellular cytotoxicity and weaker complement-dependent cytotoxicity compared with RTX. OCR, thereby, provides a more direct path for eliminating B cells which could make OCR a more effective agent with less untoward effects on the immune system".


Is this however true? 



Because 98% of B cells do not live in the blood but in the bone marrow and the lymphoid tissues. So to kill there you have to get antibody and cells together verses antibody and complement which is a small molecule that will be easier to get in small spaces. It has been suggested that alemtuzumab kills in this way and this way does not appear to purge the bone marrow, based on results in transgenic mice and the suggestion that fingolimod stops alemtuzumab from working.

Now to the arguments

2. Efficacy...

The yes camp made a case that rituximab works.

It stops the rebound associated with discontinuation of natalizumab.

It stops relapse, etc.

A case that one was better than the other was not really effectively made by the No camp.


Yes it did better in PPMS, but if you did a trial in PPMS knowing the result of the ocrelizumab trial would you be able to get the same result


3. Immunogenicity. Infusion reactions and upper respiratory infections are the most common untoward effects overall for both RTX and OCR.


The no camp says there is greater immunogenicity with rituximab, the yes-camp accept this and say it occurs in 25% of people.


 "There was a significant association between presence and titers of ADA (Anti drug antibodies), and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. 


However it is at the individual level we we see the effect


"With regard to ocrelizumab, anti-drug-binding antibodies were found in 0.4% and 1.9% "


Yes we would expect that. This is a problem if you have to give rituximab forever, but do you have to do that? 


Maybe not if it has induction therapy potential. 


4. Safety


Is one safer than the other? 


I think the case was not really made in the No-camp and the debater may have killed his cause talking about Breast cancer with ocrelizumab. 


Is the breast cancer signal real? Should have been the question addressed.


If one is more effective, then it could be less safe as the mechanism for control autoimmunity and infection would be the same. You can't have it both ways


Indeed Prof Piehl makes the argument that


"The development program for ocrelizumab in rheumatoid arthritis (RA) was been terminated and a negative safety signal for serious infections was evident"  and make the argument for cancer as an issue. 


Conflicts.


Prof Piehl has a few mentioned a few including links with Roche. However, there was no mention of a big grant from PCORI to test rituximab in MS...maybe not a financial conflict but in the case of the debate clearly an academic conflict as the surely Prof Piehl is passionate that they are doing the right thing.

Prof  Wallin one the other hand had no relevant conflicts suggesting that Pharma have not used his services in this area, and so the pharma side of the argument was not really made. So the debate is perhaps not coming from a place of passion. You need someone willing to give the pharma perspective, but most people would not want their neck to be put on the block. 


However, there is more to the story that efficacy and safety and where did rituximab come from in the first place...yes pharma innovation....yep using academic knowledge.


Maybe we could do another debate


DrK. Subcutaneous cladribine (Litak) is an acceptable alternative to oral Cladribine (Mavenclad) for treating multiple sclerosis- Yes


ProfG. Subcutaneous cladribine (Litak) is an acceptable alternative to oral Cladribine (Mavenclad) for treating multiple sclerosis- No

Yep we have this debate going on since 2012 within the lab, it is a relevant debate to be had. We should also have as you know where the holes in your argument lie.

ProfG. Subcutaneous cladribine (Litak) is an acceptable alternative to oral Cladribine (Mavenclad) for treating multiple sclerosis- Yes


DrK. Subcutaneous cladribine (Litak) is an acceptable alternative to oral Cladribine (Mavenclad) for treating multiple sclerosis- No

However, you could you argue for

(a) Price of Innovation.


(b) Society benefits from a healthy pharma industry


(c) People with MS benefit from a healthy pharma industry


(d) Pharma involvement has educated lots of neurologists in 

     MS leading to better Care

(e) Pharma involvement has put MS nurses, centre stage


(f) etc, etc, etc


What stance would ProfG argue on


Whats more we could even do


Is Dimethyl fumarate (Skilarence) is an acceptable alternative to Dimethyl fumarate (Tecfidera).

Whats skilarence?

Tecfidera costs $7,698 for 60 240mg tablets or 1,802 for 14 120mg tablets (Drugs.com) and on the internet you can find it at about $2000 for 56 tablets (Biogen a US company).

Do on same websites and you find Skilarence.

This is a new 120mg tablet variant of DMF that was licenced in 2017(Allmiral a Spanish Company) for Psoriasis.

However, it costs $666 for 180, 120mg tablets, so about  eight times below the price of tecfidera milligramme for milligramme on the web site
In the UK the NHS list price for Tecfidera 120mg (14 tablets) = £343. However for Skilarence it is £381.60 for 120mg tablets but you get 180 tablets.  So 180 tablets of Tecfidera is £4410 so that is eleven times more expensive.

So it shows you that there is clear price gouging for MS drugs because here you have two licensed drugs doing the same thing and there is a massive price difference.

So why do companies do this?.

Because they can....and they (Pharma) know that people with MS will pay more for their drugs. It has nothing to do with the cost of manufacture.

But have you asked How much is it to do an MS trial and how much does it cost to do a psoriasis trial?


Is it eleven times more?


We have this debate within the group all the time and have been living this debate since 2012. We don't always agree and we don't always have the same fixed position either.

16 comments:

  1. Very interesting discussion. The Rituxan versus Ocrevus debate will rage on, I suspect, until we have hard safety/efficacy data on Ocrevus after it's been used for about three years. My gut feeling is that the problems that cropped up during the lupus and rheumatoid arthritis trials may show up again, and that cancer signal is very worrying. Hopefully, the worst-case scenario does not come to pass, but if hundreds of MS patients start coming down with cancer in 2-3 years, the maelstrom that will follow will be intense.

    This is especially so as we do have safety/efficacy data on Rituxan dating back at least a decade, and on both counts it is quite strong.

    In regards to the general question as to whether or not off label use is good for Pharma, to put it bluntly, I don't give a rats ass. The pharmaceutical company business practices are horrendous. Granted, they are, for the most part at least, legal, but that does not make them right. Spending more money on marketing than research, engaging in legal bribery with the doctors who prescribe their products, etc. makes my heart tend to not bleed when the violins come out for the pharmaceutical companies.

    Throw in obvious collusion in pricing of MS drugs (how in the world can the interferons be priced in the same range as the newer monoclonal antibodies, when the interferons have been on the market for 20+ years?), And any argument about putting pharmaceutical company interest first seems absurd.

    Yes, we can be grateful that drugs have been developed that effectively improve the quality of life of relapsing patients, and may even delay onset of progression to SPMS. But at the same time, the success of these drugs has severely impacted the direction of MS research, such that any search for a cure seems to have been put way on the backbench, while research into newer "me too" drugs that refine but replicate the mechanisms of drugs already on the market proliferates. In effect, the very success of the more effective MS drugs may have actually set back the ultimate search for a cure.

    Since my diagnosis, I've watched MS go from a medical backwater to a cash cow, $25 billion a year industry. An industry with a momentum all its own, in which treating has become the status quo. Not saying that finding a cure is a simple endeavor, but it certainly can't be accomplished without a coordinated, robust effort. Such an effort no longer exists, primarily due to the success of the DMTs.

    Is it any coincidence that therapies such as HSCT have been in trials for at least a decade, without gaining traction? Not much profit for the Pharma companies in such a treatment regime, so nothing by way of head-to-head trials with existing DMTs. And HSCT is not even a cure.

    The one disease that has been cured by Pharma in the last decade is hepatitis C, and the company that found the cure, Gilead pharmaceuticals, has seen their stock punished as a result. A cautionary tale for other pharmaceutical company executives, I'm sure…

    ReplyDelete
    Replies
    1. An excellent and insightful summation of the situation, WK.

      Delete
    2. Damning indictment of the process. If true then the future will be status quo unless there is a shake up by individual(s) without ties to pharma.

      Delete
  2. Do you ever discuss that this pharma money milking could also inhibit the process of resolving the problem? That in order to find new expensive pattents, simpler and easier solutions will be put aside, often putting patients health at risk? I am afraid that this is where we are at the moment. Could a drug that costs 50$ per month be better than most MS drugs? It seems like it.

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  3. Mabye this can be a solution to fix the MS postcode lottery currently happening? I mean if people are unable to get access to the expensive drugs because of pricing, why not give them something that works in the same way but is cheaper.

    ReplyDelete
    Replies
    1. You need to remind yourself that the only reason why off-label prescribing of cladribine and Skilarence can occur is because Merck-Serono and Biogen did large phase 3 trials. If you don't support the innovator drugs in class Pharma will think very hard in future about repurposing existing drugs. Do you want this?

      Delete
    2. That argument is absolute BS. Most, if not all, of these drugs were designed already for another disease, like cancer, SLE, RA and psoriasis. Most of the R&D is done and then they are being repurposed for MS by gouging a sick, desperate patient population.

      Ask yourself what innovation have we got for the 25 billion per year generated by the partially effective DMDs. All of them have less than 50% NEDA, excluding the CRAB drugs which have zero effect over placebo on disease progression. We have absolutely no remyelination, no neurodegeneration and no neurorestoration products.

      For the 25 billion a year that Pharma makes we should be much closer to a cure today for the patient right now. I believe that an EBV vaccine has been around since 2007 and as EBV was thought to cause MS, why has this trial not been completed to prevent MS from ever happening?

      I can hardly wait until some altruistic researcher puts Pharma and many of its associated neurologists completely out of business. This will happen, mark my words.

      Delete
    3. I would like to see pharma putting it's undoubted weight behind the development and testing of neuroprotective agents for MS. There are any number of promising candidates of a number of classes/targets which our lab have identified and published over more than a decade, yet no progress to getting any of these into clinical trials is being made.
      It is hugely frustrating for us and I'm sure even more frustrating for pwMS, as indicated by NG above.

      Delete
  4. "So why do companies do this?"

    They need to pay their staff :)


    Kenneth C. Frazier,(Merck,Ceo) 2016 $ 21,781,170 = $59 674 per day

    Robert M. Davis,Executive Vice President,
    Global Services and
    Chief Financial Officer 2016 $ 7,519,473 = $20601 per day

    Etc

    K.C. Frazier 2016

    Counseling &
    Tax Preparation
    Services
    ($) $ 10,000

    Company
    Aircraft
    ($) $ 10,822

    Company
    Car and
    Driver
    ($) 2016 $ 55,783

    Installation,
    Maintenance and
    Remote Access
    of Home Security
    ($) $ 5,096

    Savings Plan
    Company
    Match and
    Credits
    ($) $ 220,767


    Its one hell of a party :) :(

    https://s21.q4cdn.com/488056881/files/doc_financials/2016/annual/MRK004_PXY_Bookmarked.pdf

    Obrigado

    ReplyDelete
    Replies
    1. yep, this is not benefitting anybody other than the fat cats that hould be put to shame and disposed of.

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    2. CD20 cell: BTW, most pharma companies are public held, that is they have shares in circulation. Each shareholder ( even the one who has 1 share) has the right to attend the shareholders meeting and speak there. So if you have the guts, buy one share and go ridicule the b...ds. I think we should :-)

      Delete
  5. Off-label use of MS DMTs is too difficult for the average MS patient to take advantage, unless your provider is on-board institutionally, as in Sweden's or in the Kaiser Permanente (US) use of rituximab. I don't think that it's widespread.

    Another reason OCR was developed is that RTX was developed by Idec and is jointly owned by Biogen and Genentech. Genentech doesn't have to share revenue for OCR, I think.

    The bargain that we have with pharma is that these things eventually go generic. Once fingolimod and especially oral cladribine go generic, prices should drop. The biosimilars haven't saved much money yet, however.

    As far as searching for a cure, or a cause of MS, how does that happen without drug trials ($$$) in humans? The MS animal models aren't very much like human disease. No one knew that the new HepC drugs would eradicate the virus until the late-stage clinical trials. Drug companies would love to find (or purchase) a cure for a disease like Gilead did. Even though their revenue is now falling, they made tens of billions off of it.

    The obscenely high prices that our healthcare systems pay for MS drugs ensures a lot more research and drug development, with better prospects for patients, compared to when I got it in 1985. Unless there is a good chance of making money, not much investment will be happening.

    ReplyDelete
    Replies
    1. Biogen I believe will also get a share of ocrelizumab royalties

      Delete
  6. This is old CD20 cell, but I somewhow lost my old sign-in: can we please stop brownnosing Big Pharma and do what is right for our patients, and that is to stop spending money like a drunk man( or woman, not to offend anybody) in a pub, but try to make an educated choice?
    If Mousedoctor wants to buy a house or a car, he goes out and looks in the market for the best value for his buck.
    I am really sour, because due to this wonderful scheme where Norwegian neurologists did not want to give me rituximab, I got a 3 autoimmune diseases-for-1 after Lemtrada. It is difficult to describe how this feels. It has cost the taxpayer 411 235 Norwegian kr so far(not including costs of monitoring), at today's exchange rate that is 38229 GBP). Makes sense? NO way.

    ReplyDelete

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