Sunday, 21 January 2018

Has NICE got it wrong this time?

As you are probably aware NICE, true to past form, chose the Christmas period to toss a small grenade into the MS space. I assume they thought that by tossing it on Wednesday 20 December when most people were either away, or about to go away, on Christmas holidays the perceived explosion would be smaller than expected and the shrapnel would cause no collateral damage. NICE was wrong. They are wrong for several reasons.



At present the NICE ‘appraisal consultation document’ on the use of beta interferons and glatiramer acetate for treating MS in the NHS in England recommends that of these two classes of treatment that only Extavia is used to treat people with relapsing MS. Astonginglishly the appraisal states that Copaxone, Avonex, Betaferon, Plegridy and Rebif are not recommended. This proposed ruling only effects new patients; anyone already taking one of these drugs will not be affected by this guidance and can continue without change until they and their neurologist consider it appropriate to stop.

Shared-decision making

What about patient-engagement, shared-decision making, etc. The NHS has, or at least had, a policy of shared-decision making called concordance. This appraisal makes a mockery of shared decision-making. Extavia uses old technology. Of the interferon-beta preparations available it has the least friendly autoinjector and Novartis who market this product have not invested heavily in a support programme for patients starting Extavia. Our nurse specialists and pharmacists simply don't consider Extavia a treatment option and would opt for one of the other preparations.

Immunogenicity

We know from many earlier studies that interferon-beta-1b (Betaferon & Extavia) is more immunogenic than the other interferons. Over 30% of patients treated with IFNbeta-1b develop neutralizing antibodies (NABs) that stop the drug working. Why would anyone prescribe a more immunogenic biologic when there are less immunogenic alternatives?

Innovation

This appraisal flies in the face of innovation. In fact is a kick in the teeth for innovation. Please note Avonex and Rebif have both been reformulated over their life cycles to improve their tolerability and immunogenicity. Plegridy is actually a new product; it uses pegylation to extend its circulating half-life. Plegridy investment and many years to be developed and licensed. What kind of message does this send to Pharma and academia about innovation? I thought NICE was meant to include innovation as one the variables they took into account when they made their decisions. In fact, why is Plegridy being considered part of this MTA (multi-technology appraisal)? Surely it deserves its own STA (single technology appraisal)?

On the cheap

Ever since the NICE turned down interferon-beta and GA as part of the initial tranche of single technology appraisals they have not changed the threshold for approving drugs. In other words, the cost per QALY that NICE deem cost-effective has been static for 15 years. Healthcare inflation has gradually reduced the actual cost per QALY that the NHS is prepared to pay for MS drugs. In addition, they have yet to incorporate indirect, in particular social, costs into their modelling. This explains why the NHS pays so little for MS DMTs. Is this fair? Patients in the USA are paying more than 5x the price for DMTs that we are. 


Please note that Pharma profits are used for all sorts of things including R&D and new drug development. Why should the USA taxpayer continue to subsidize drug development for the rest of the world, including Britain? Don’t you think at a political level the NHS should pull its weight? When you look at drug costs as a proportion of the NHS budget these are going down compared to other countries. Is it realistic to expect this to continue long-term?

Lowering the bar

Another potential problem is that NICE use incremental costing models; they compare new high-cost drugs to a reference drug. If the Extavia ruling stands then all new DMTs will be compared to Extavia, i.e. this will lower the cost-effective price for all new drugs and possible existing licensed drugs as they come up for renewal. This may have consequences for pwMS in the future, i.e. we may not get access to newer, high-cost, innovative drugs. Pharma may stop dealing with NICE because of the potential consequences for them across Europe. Please note that many countries use basket pricing, i.e. they set a price for DMTs in their countries based on the average across many countries. The UK price is in the basket. The problem arises is if the negotiated NHS price for a drug gets out; if it does it automatically lowers the cost of DMTs in countries using basket pricing. Pharma is becoming increasingly wary about doing deals like this with the NHS. There has already been an example of the NHS deal price getting out for one MS drug that impacted on prices across Europe.

Bad Pharma

The public perception is that Pharma is all bad. This is wrong. Pharma is a big contributor to the UK’s economy. All the MS Pharma companies employ a large number of people to support their innovator brands. If the Extavia ruling goes ahead I am sure many hundreds of people will lose their jobs. Should we care? Yes, we should. With Brexit looming every high-skilled job is valuable to this country. Employed people are what make an economy work. Punishing Pharma unnecessarily threatens the livelihood of many people and an important part of the UK economy. 

The problem with NICE is that its brief is very narrow, i.e. to save money for the NHS. NICE is very effective at doing that, but what about the impact of its decisions on the wider economy. Politicians really need to consider the wider impact of NICE on the UK-based Pharma industry. Since NICE was established almost all of the big Pharma have closed down their R&D labs in the UK and moved them elsewhere. Why? If the NHS doesn’t reward innovation and support Pharma then they will vote with their feet. The tragedy is that this has happened already and not easily reversed.

Summary


In summary, I think the NICE ‘appraisal consultation document’ is flawed with an undefined long-term impact for pwMS living with MS in the UK. It ignores patient choice and the principles of personalised medicine. It is not good for UK PLC. It sends out a very negative signal to Pharma, i.e. that it does not value innovation. The ruling will widen the gap between the UK and our other rich world partners. It is only a matter of time before NICE triggers a trade war with other rich countries over drug pricing. Several hundred high-skilled jobs will be lost as a result of this ruling and for what? The MS community has moved on and injectables are not used very often. Therefore a decision to save the NHS a very small amount of money will end up costing the UK much more in terms of future patient care and access to innovator drugs, reputation, jobs and future investment. I sincerely hope when NICE respond to feedback from the community common sense will prevail. 

ProfG    

47 comments:

  1. Face the music you have all got it wrong .

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    1. I agree. I am sure MS is not autoimmune, but due to a viral infection. I think we have had wrong for sometime now.

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    2. You may be interested in a keynote lecture I am giving on Saturday on the viral pathogenesis of MS. I address this point exactly.

      https://www.multiplesklerose.ch/de/ueber-ms/fachkongresse/state-of-the-art/

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    3. Please let us know more about this.

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    4. Will you be sending out slides? Will it be recorded?

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    5. Really? Or are u humouring anon1? Surely this is massive news!!! Or u saying the friendly fire is initily caused by virus and then becomes a autoimmune response? So killing the virus will not cure MS. Why hasn't Bart done blog on this?

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    6. Anon1 would appear to be our resident troll (usually it's "you are all wrong and should be sacked" etc etc), however letting this comment slip through the moderator spam net has spurred something interesting by default ;-)

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    7. Thanks MD2. I'm Glad this time round anon1 served a useful purpose. But nevertheless still very exciting to see new insights into this henious disease!

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    8. That's what we're here for and hopefully will lead to better treatments and hopefully in the future, eradication.

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    9. Lol

      Is ProfG talking about the HHV6??

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    10. Face the music you are wrong .

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    11. Re: "Face the music you are wrong."

      May be I am but at least I putting forward a testable hypothese; it is called the 'MS Field Hypothesis". I have blogged about this in the past.

      https://multiple-sclerosis-research.blogspot.com/2016/02/thinkspeak-what-has-field-got-to-do.html

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    12. Lol Is ProfG talking about the HHV6??

      I doubt it

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    13. ProfG, could you post more about this to clarify what you mean. I have seen screenshots of your comment the MS is not autoimmune cropping up in other groups as justification for the view that all the MS drugs are ineffective and bad. Not sure that's in line with what you meant

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    14. Oh dear, ammunition for the naysayers, people will read into things whatever they want to justify their preconceptions. Not a new phenomenon.

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  2. Okay. But under what circumstances would barts prescribe injectibles to a newly diagnosed patient? Given he/she can have tecfidera fingolimod, caldribine, Alemtuzumab, Daclizumab, Natlizumab, etc. ALL superior to these drugs. Nice has deemed redundant. I how can you make this argument when NICE is first authority in the world to make caldribine available. The best drug according to barts. Yet in the same breath you say nice is not so nice. HEART of the issue is pharma, and the price all independent research institute pay for funding is to be seen talking the talk and walking the walk. Sorry this article in my opinion does not speak on the best interests of patients but pharma. Who have shifted the medical paradragim from cure to treatment.

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    1. Very rarely. Some women want to GA because of its safety record in pregnancy. I agree this won't affect many Barts-MS patients, but that is just the point. It is the few we should be looking out for.

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    2. Yes this post is about pharma and the role they play in society. If you have an alternative to Big Pharma I would be keen to hear about it.

      We, and others, have proposed a Big Pharma Alternative in the past, but it went nowhere. Too many vested interests may be? What we have to realise that we have created the beast and we have to live with it. This requires a bit of give and take from all parties.

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    3. "What George Freeman was saying that Pharma, in particular Big Pharma, is such a big part of or knowledge economy that we don't want to kill the goose that lays the golden eggs. In other words let Pharma innovate and make money, we will pay them, tax them and we will all live happily ever after. What this attitude doesn't address is the difficulty people have when they live in resource-poor environments, or are part of healthcare systems that require individuals to co-pay. Two thirds of personal bankruptcies in the US are triggered by ill-health. The article below from an American lawyer highlights the other side of the story, or the underbelly of Big Pharma; i.e. their predatory behaviour to milk the system. This is something we can't ignore and it is very prevalent in the MS space.

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    4. OK. Here's my point. MS Community is venerable. Do you really need to plug pharama amongst your most vunerable readers??? Then why pretend to be impartial? What's the difference between you and bearms?

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    5. Only part of this post is about Pharma. The other post is about standing up for MSers rights for choice. The current NICE guidance makes a mockery of patient choice. This is a position that is supported by many MS stakeholders.

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    6. Re: "What's the difference between you and bearms?"

      A hypothesis driven approach that is evidence-based, and I am prepared to change my position as new evidence emerges. The latter is called science. In comparison a believer can never change their position; it is called religion.

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  3. In Sweden they mainly use Rituxan and in Germany they dont use the injectables anymore and they mostly use Gilenya/Tecfidera as first line treatment, or even Lemtrada. Interferons are useful only for CIS patients, and even there Cladribine is better. Interferons are a bad paradigm for MS.

    The more we support Pharma's petite innovations, the more we are stuck with them. If we had intervened back then with Rituxan, we might had something more useful than Ocrevus now.

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    1. Copaxone remains the number one selling DMT in Germany. Why? It is easy to use with no monitoring. German people with MS are being under-treated.

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    2. I read that to a recent interview from a German neurologist. He was saying exactly that, that they have stopped using the injectables and they start with the orals as first DMT in Germany. But it could be too soon to be apparent. Will post it if I find it. Copaxone was the number one everywhere till now, we need to see what is happening from now on.

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  4. This post represents pharma and not the MS patient whatsoever.

    It is about time that health authorities, like NICE, around the world have "sensible" physicians and accountants that come together and realize that CRAB drugs are an economic and health disaster.

    If CRAB drugs do not stop progression in MS then what good are they to an MS patient and furthering MS research? They stop relapses about 30% above placebo but have no effect of progression of MS whatsoever above placebo? So what good are they when many other drugs are available that do partially stop progression?

    "Innovation" is not a term I would use for any current MS drugs. They are all pre-existing recycled drugs for other purposes, like cancer. I do not feels sorry whatsoever for the companies that you list in your conflicts of interest as they have made their billions with zero effect on MS progression. Shouldn't stopping MS progression be the goal of all MS drugs?

    Hopefully, now research can forward treatment of MS and can compare any new MS drug to the current best MS drugs, like alemtuzumab, cladribine or ocrezulimab, instead of low lying fruit like the CRAB drugs.

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  5. This will quite possibly affect me.

    I'm on DMF, but the side effects are taxing. I've been referred into another department to see whether there is anyway to improve them but it feels like grasping at straws.

    My other options are limited. I asked my consultant about alemtuzumab at onset and the response was a resounding no as they don't class it as first line. I was told they don't give teriflunomide to "women my age" and I suppose everything else is second line too, aside from the injectables.

    So if I have to come off DMF, I will have to use Extavia? It's a bit like telling me I've got to use a Nokia 3310 when I need and could have an iPhone 7.

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    Replies
    1. If you come of DMF can you make the case for secondline

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    2. magine Apple’s first iPhone is still on sale today. Now imagine it costs many times its original price of $599, and that the price goes up every time a new, competing phone is released.

      That bizarro world is what the market for multiple sclerosis drugs looks like, as described in a new paper in the journal Neurology. And doctors are calling for it to change.


      The three MS drugs approved in the 1990s—Bayer’s Betaseron, Biogen’s Avonex, and Teva’s Copaxone—had total U.S. sales of $2 billion in 2006, according to Bloomberg Intelligence data that track what pharmacies pay wholesalers. That figure tripled to more than $6 billion by 2014, even as several competing therapies were approved

      http://accessourmedicine.com/much-pay-old-drug-ms-fortune/

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    3. What about choice? There are a few people out there who are technophobes who would prefer the older more familiar technology. Because we are active treaters and have adopted newer treatments it doesn't mean should deny individuals choice. We mustn't forget that there is 25+ years of experience with IFNbeta and GA and because of this some risk-averse neurologists and patients go with these agents.

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    4. "The initial treatment of early active relapsing remitting MS should be with a potent induction therapy rather standard immunomodulation then escalation"

      https://onlinelibrary.ectrims-congress.eu/ectrims/2016/32nd/146950/gilles.edan.the.initial.treatment.of.early.active.relapsing.remitting.ms.html?f=media=1

      Obrigado

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    5. @ProfG
      Even if I am not crazy about the use of IFNs in MS, I can only agree with you about choice. It is undemocratic to deny patients an existant therapy, even if it might not be for their best interest.
      However, if we have to talk about choice, categorizing the DMTs as first line/second line according to their price and not patients benefit, well this doesn't sound very democratic either.

      As for innovation, the state of the art of DMTs are Ocrevus, Sinopimod and Monomethyl Fumarate. Do they remind anything to you? There is not much innovation going on really, only some opportunists who repatent old ideas. Its been a while since they came up with something new.

      What national health systems need to do is to create laws and funds and a supportive environment for the really innovative ideas, that mostly come from universities. What has been happening till now, was to kiss pharmas a** to give us what they will in an unregulated price, and feed their cartels. Patients and pharma have a serious conflict of interest and states have to intervene. And doctors have to pick sides.

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    6. The French are the only ones who really use an induction approach; i.e. mitoxantrone followed by interferon-beta or GA. Mike Boggild did try and get a trial of mitoxantrone followed by GA off the ground in Liverpool. However, with more effective maintenance therapies and IRTs the induction-maintenance approach has fallen out of favour.

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  6. Yep, I get r&d costs+risks and have friends+family employed by the pharmaceutical industry. What I can't get my head around is persisting with old less-effective treatments (with possible exception of glatiramer in pregnancy). Why is anyone starting on these drugs? (Nobody is being denied existing treatment).
    Pharma are having a laugh, they've had their 10 years' worth return on investment. If we stop spending money on less effective treatments there's more for highly effective drugs. And this applies everywhere, not just UK.

    Whilst on the subject, if a patient doesn't qualify for a highly effective treatment surely it is better for them to be treated off-label? Note, only if they don't qualify, it is right to reward the pharma who's invested in the best treatments. But propping up less effective drugs? Sorry, but no Doctor should be forced to make their patient risk their future when there is another option.

    #off-labelcladribine

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  7. Greed is good (Gordon gekko)

    First-generation DMTs, originally costing $8,000 to $11,000, now cost about $60,000 per year. Costs for these agents have increased annually at rates 5 to 7 times higher than prescription drug inflation. Newer DMTs commonly entered the market with a cost 25%-60% higher than existing DMTs. Significant increases in the cost trajectory of the first-generation DMTs occurred following the Food and Drug Administration approvals of IFN-β-1a SC (2002) and natalizumab (reintroduced 2006) and remained high following introduction of fingolimod (2010). Similar changes did not occur with TNF inhibitor biologics during these time intervals. DMT costs in the United States currently are 2 to 3 times higher than in other comparable countries.


    The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail?

    https://www.ncbi.nlm.nih.gov/pubmed/25911108


    Obrigado

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    Replies
    1. I think the point Prof G is making is that Pharma are making big profits in the US and not necessarily in the UK and Europe, where prices are fixed or falling. This is unfair for US citizens and hence at some stage US politicians will want to rectify it. I am not sure if this is a problem unique to MS, but applies across all therapeutic areas.

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    2. Re 12.37 Greed is good
      Thanks for fascinating (and horrifying) link Luis. Sounding very like the banks 'too big to fail'

      Usual open market competition rules simply aren't working for MS drugs. Ok, so they're biologicals but look at that comparison graph with similar compounds, almost like comparing linear v exponential growth! Would be really interesting to see underlying inflation plotted on same graph. How long does Gilenya patent have to run, 2 years? Could stir things up? Unlike the bio pharmaceuticals it might play the usual game where pharma get 10 years patent life to make their money before competition kicks in and price starts to fall.

      I'm not familiar with the licences for all the different MS drugs but the principle of having to jump through hoops to access a better treatment is wrong. You've got MS, but your symptoms are 'mild' so I can only offer you one of these old drugs... So 'lucky' pwMS get a couple more relapses and qualify for better treatments. But all the treatments cost about the same. Crazy. There's patient choice and side effect profiles to consider of course or should that be neurologist choice and hassle profiles? Who's brain is it anyway? I find it incredibly hard to believe that patients are choosing less effective treatments and injectable ones at that...

      I stand by my previous comment that people qualifying for a highly effective treatment should be offered the licensed drugs:
      Ocrelizumab
      Alemtuzumab
      Natalizumab
      Cladribine tablets
      (list in no particular order)

      And this rewards pharma who've developed the best drugs.

      Everyone else should be offered off-label cladribine injections. Justified as more effective than licensed products. Of course, should patients choose something less effective then it's up to them but I wonder how many* would?


      *women wishing to have children excepting

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  8. Copaxone, approved in 1996, is still the bestselling MS therapy, with 2014 retail sales of $3.4 billion in the U.S., according to data from Bloomberg Intelligence.
    Other data supports the Oregon researchers’ analysis. The three MS drugs approved in the 1990s—Bayer’s Betaseron, Biogen’s Avonex, and Teva’s Copaxone—had total U.S. sales of $2 billion in 2006, according to Bloomberg Intelligence data that track what pharmacies pay wholesalers. That figure tripled to more than $6 billion by 2014, even as several competing therapies were approved.
    Like big banks, pharma cannot be free to ravish the marketplace unfettered,” they write. “There is a need at times to grab the big banks or big pharma by the lapels and make it clear that they are seriously out of line and are hurting people.”

    http://accessourmedicine.com/much-pay-old-drug-ms-fortune/

    Obrigado

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  9. a little offtopic, but. would NABs produced in response to extava and all other interferon formulations neutralize endogenous ifn-b ?

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    Replies
    1. Yes, NABs are likely to neutralise endogenous interferon-beta. I have posted on this before:

      http://multiple-sclerosis-research.blogspot.com/2015/01/neutralising-antibodies-to-interferon.html

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  10. Interesting undercurrent of a comparison between licensed DMTs and HSCT. Does anyone have any idea how much innovation there is in the delivery of HSCT? HSCT didn't just emerge as a treatment; it tooks decades of research and refinement. Many other major improvements in the effectiveness and safety of HSCT have been pharmacological. The fact that is now a lot cheaper than it was in the past is because of drugs coming off-patent, better bone marrow support (laminar-flow units, transfusions and better antibiotics) and in particular the more rapid bone marrow recovery reduces the risk of infection. Has anyone thought about the biology and pharmacology of these improvements? Who developed them?

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  11. Isn't chemotherapy still the most effective treatment for cancer?

    No clear evidence that most new cancer drugs extend or improve life
    https://www.eurekalert.org/pub_releases/2017-10/b-nce100417.php

    This is not the case with MS therapies though (HSCT improved due to cancer, not MS)

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  12. Cyclophosphamide is a the main drug use in Hsct

    was synthesized and reported by Friedman and Seligman in 1954

    approved for medical use in the United States in 1959

    in the United States this dose by mouth is about 19.56 USD.[8]

    Methylprednisolone

    Methylprednisolone was approved for medical use in 1955

    in the United States a course of treatment typically costs less than 25 USD.[6]


    Busulfan

    Is a cancer drug, in use since 1959. Used with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow transplantation, especially in chronic myelogenous leukemia (CML) and other leukemia

    Filgrastim

    (G-CSF is also a potent inducer of hematopoietic stem cell (HSC) mobilization from the bone marrow into the bloodstream, although it has been shown that it does not directly affect the hematopoietic progenitors that are mobilized.[)

    Filgrastim was approved for medical use in the United States in 1991.[1] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[2] The wholesale cost in the developing world is about US$3.95 to US$94.66 per dose



    No doubt inovation as come across hsct in recent years

    Ex:( Granulocyte colony-stimulating factors allows the stem cells being

    taken from peripheral blood rather than the pelvis)

    The price of chemo drugs in hsct is very cheap

    Also hsct is a oe time procedure that ads to the saving cost

    Safety of hsct as to do with ,conditioning regime,(high ,intermediateorlow intensity)

    Age of the patient ,comorbilities, allogeneic transplant vs

    autologous ,graft vs host disease overall fitness of the patient

    More so than any innovative drug use

    Obrigado

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    Replies
    1. You forgot the laminar flow units, general infection control, new generation antibiotic and transfusion technologies. The latter is particularly important for platelets; this applies to their collection and treatment to make them safe. And then their is the cell harvesting and freezing. It looks as if HSCT depends on multiple rounds of innovation, which addresses the point I want to make in my post; as a society we need to respect, appreciate and reward innovation. We don't want to take it for granted.

      Delete
  13. NICE might got it right
    Brabio, 1st Generic Version of Copaxone for Relapsing MS, Launched in UK

    Brabio (glatiramer acetate injection), the first generic alternative to Copaxone for relapsing multiple sclerosis (MS) patients, was recently launched in the U.K. at an equivalent higher dose, its maker, Mylan, announced.

    https://multiplesclerosisnewstoday.com/2018/01/26/brabio-relapsing-ms-generic-high-dose-version-of-copaxone-launched-in-uk/?utm_content=buffer9c8a0&utm_medium=organic+social&utm_source=facebook.com&utm_campaign=buffer

    ReplyDelete
    Replies
    1. If NICE gets its way we can't even use this generic. I am sure Mylan is unhappy about the NICE decision; in short it kills their market. May they will buy Extavia from Novartis?

      Delete

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