Thursday, 9 April 2015

ClinicSpeak & OffLabel: unlicensed vs. off-label prescribing

Unlicensed vs. Off-label prescribing. Do you know the difference? #ClinicSpeak #MSBlog #MSResearch #OffLabel

"I attended an interesting meeting yesterday when off-label, and unlicensed, prescribing in MS was discussed in detail. This is particularly pertinent to the ongoing debate about the use of the cheaper, but off-label, bevacizumab (Avastin) rather than the licensed, but more expensive, ranibizumab (Lucentis),  to treat age-related macular degeneration."


"Unlicensed prescribing refers to the prescribing of a drug that has never been licensed for an indication and hence is not manufactured by a pharmaceutical company. An example of this would have been the prescribing of 4-aminopyridine for MS-related walking problems in the past. You could not write a prescription and expect your local pharmacy to dispense an unlicensed drug . In the case of 4-aminopyridine, you would have had to get a compounding pharmacist to make-up the drug and formulate it for you. This was not without problems; for example there were several case reports of accidental over-dosage with compounded 4-aminopyridine. Some of the latter overdose were life-threatening. Compounding pharmacists simply do not  have the resources and time for adequate quality control. However, once 4-aminopyridine was formulated into a slow- or delayed-release formulation (Famridine or Dalfampridine) and was licensed for walking-impairment in MS things changed. 4-aminopyridine was now being produced, marketed and sold by a Pharmaceutical company as a specific licensed product. With a license, or more correctly marketing-authorisation, comes  the responsibility of ensuring a supply of the drug, quality control and a whole raft of post-marketing responsibilities, including safety updates. With the licensing of the 4-aminopyridine the prescribing of an unlicensed formulation became illegal under EU law. This is why legal action was taken against several European compounding pharmacies to stop them formulating 4-aminopyridine."

"In comparison, off-label prescribing is when you prescribe a drug that is available on the market for an indication that is not covered by its license. For example, prescribing bevacizumab (Avastin), which is licensed as a cancer treatment, for age-related macular degeneration. Off-label prescribing is not illegal if there are no other licensed drugs for that indication. It only becomes illegal when there is a licensed drug; in the case of age-related macular degeneration bevacizumab (Avastin) should not be prescribed because ranibizumab (Lucentis) is the licensed drug. The legislation protecting licensed drugs from off-label, and unlicensed competition, was clearly put in place to protect the pharmaceutical industry and to make sure incentives exist for the pharmaceutical industry to innovate. I am aware that some of you disagree with this legislation, but I would urge you to take a wider view of drug development and pharmaceutical innovation in particular. At present it is very difficult to develop drugs outside of Pharma; with very exceptions academics don't have the resources or skills to do this. We only know this too well; our experience with VSN16 our putative anti-spastic drug  is a typical example. We have had to wait for Big Pharma investment to get the drug into phase 2. We currently have an active drug discovery programme for progressive MS that have stalled simply because we need investment of an order of magnitude higher than we can get from typical academic funding sources. We have two very exciting classes of compound that are neuroprotective in our animal model of progressive MS, but can't take them forward without Pharma-level investment. As someone who is faced with the unmet needs of progressive MSers on a daily basis this is very frustrating."

"You have to realise that the short-term costs to the NHS, and other healthcare systems, for prescribing expensive innovator drugs is the result of the deal our politicians have struck with the Pharma industry. In return we get the promise of cheaper drugs in the future when the innovator drugs come off-patent and we get the promise of continued innovation by the pharmaceutical industry as they use the profits from the sale of their current drugs to reinvest in R&D and new product development. Do you want this system to change? If you do then we need to get our politicians engaged. I personally think we need new legislation to re-purpose off-patent generic drugs. We need some form of incentive to encourage Pharma to invest in off-patent drugs or a new system to allow non-profit organisations to license off-patent drugs cheaply without the expensive post-marketing commitments. This is what we refer to as the BPA (Big Pharma Alternative) in our recent commentary (Giovannoni et al. The problem with repurposing: Is there really an alternative to Big Pharma for developing new drugs for multiple sclerosis? Mult Scler Relat Disord. 2015 Jan;4(1):3-5)."



"The following piece in last week's BMJ summarizes, very succinctly, the legal issues I refer to above in relation to unlicensed and off-label prescribing."

David Lock (Queen’s Counsel, London, UK). Briefing: Avastin and Lucentis: a guide through the legal maze. BMJ 2015; 350 doi: http://dx.doi.org/10.1136/bmj.h1377 (Published 01 April 2015) Cite this as: BMJ 2015;350:h1377

Excerpts:

....... Many doctors believe that bevacizumab (Avastin) is a clinically acceptable alternative to ranibizumab (Lucentis) for patients with wet age related macular degeneration (AMD) and presents a more cost effective alternative for the NHS. However is a doctor acting lawfully when prescribing bevacizumab for patients with wet AMD? ......

...... Every drug for clinical use needs a marketing authorisation, commonly called a licence, before it can be lawfully marketed by a drug company in the UK. The marketing authorisation defines the patient group for which the drug can be advertised. A drug that does not have a marketing authorisation is unlicensed and (broadly) can be sold in the EU only if there are no licensed alternatives. But the licensing regime does not impose legal obligations on doctors to use drugs only for the conditions set out in the licence. Using a licensed drug for conditions that are outside those described in the licence is commonly called “off-label” prescribing.......

.... Could a doctor who prescribes bevacizumab for wet AMD be prosecuted for a breach of the criminal law? .....

..... There is nothing to suggest that a doctor who appropriately prescribes bevacizumab for someone with wet AMD acts in breach of the criminal law. ......

...... Could a doctor who prescribes bevacizumab for wet AMD be sued in negligence? .....

...... It is highly unlikely that a doctor would breach a duty of care by appropriately prescribing bevacizumab provided the patient made an informed choice to select the drug. NHS patients who come within the clinical guidelines set by the National Institute for Health and Care Excellence for ranibizumab have a legal right to be prescribed it on the NHS..... 

..... Could a doctor who prescribes bevacizumab for wet AMD be reported to the GMC? ......

..... There is a theoretical possibility that a doctor could be reported to the General Medical Council for prescribing bevacizumab rather than ranibizumab for wet AMD. GMC guidance requires doctors to make resource allocation decisions that take account of their responsibilities towards patients and the wider population. However, the GMC guidance about prescribing off-label suggests that doctors should not make prescribing decisions for resource allocation reasons......

..... Can a CCG  (clinical commissioning groups or payers) make arrangements to provide bevacizumab for NHS patients?...

..... Because NICE has conducted a technology assessment of ranibizumab clinical commissioning groups (CCGs) must fund the drug for patients who meet NICE criteria. However, this does not prevent CCGs offering alternative treatments to NHS patients.... 

38 comments:

  1. Bredrin’, if it’s not Don Giovannoni strutting is stuff on Comic Relief: Strictly Come Dancing, then it’ Dr. Jeremy Chatsalot on BBC news giving it large about repurposing old meds for fixing progressive MS.

    If you need legislation for the repurposing of old meds then why didn’t Dr. Chatsalot say that to the BBC? What a wasted opportunity. Instead, we get a lot of nothing about plans and intentions and hopes, and some unfortunately very disabled geezer with SPMS. It was a news report that told us nothing, bro.

    In three generations, Big Pharma has delivered nowt in terms of new meds. All the neo-DMTs are in fact old chemotherapy agents from the ‘60s and ‘70s repurposed for MS. All this nonsense regarding pharmaceutical research and development is a bluff because even now the main investment comes from Government. That’s right, we pay, not Big Pharma. Universities get funding from us tax-payers, not Big Pharma.

    In all truth, despite what the blokes running this blog tell you, they haven’t got a Scooby Doo how to beat MS. As my homie Public Enemy says, “Don’t believe the hype.”

    If MS can be cured, then you need to know why it happens, which you don’t. Then you will almost certainly require bespoke medication, which Big Pharma has no interest in because it costs too much and most likely may fail. This means that all you’re getting right now is either nothing or some toxic concoction that can potentially mess you up further and perhaps very badly.

    You’re better off on no DMTs than the crap you’re being offered. Get some exercise and sit in the sun. Trust in my homeboy, Jesus Christ.

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    1. Well well, our resident nihilist is back, it really hasn't been long enough ;-)

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    2. I agree with everything that Dre says, but not the Christ part.

      MD2, we need nihilists in life. People like Dre stir up anger and frustration in me, making me question Big Pharma. He's right in saying there's been no proper all-inclusive breakthroughs in MS medication. Things are pretty bleak.

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    3. Dr. Dre should come up with a new rap rhyme for his position on the progress of MS treatments. It could be a number one hit!

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    4. I think his homie Chuck D needs to write him some new material first. The current best of is getting a bit stale now.

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    5. "MD2, we need nihilists in life. People like Dre stir up anger and frustration in me, making me question Big Pharma. He's right in saying there's been no proper all-inclusive breakthroughs in MS medication. Things are pretty bleak."

      We need sceptics (I'm a huge one and no fanboy of Big Pharma) but not nihilists who offer no alternative and no hope. I would disagree with you that things are bleak, they are certainly much less so than when I started researching into MS 30 years ago (God that ages me!) and in my opinion getting better year by year and what's more the pace is increasing. We're even seeing movement on neuroprotection now (at last).

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    6. Re: "All the neo-DMTs are in fact old chemotherapy agents from the ‘60s and ‘70s repurposed for MS."

      What about natalizumab? Natalizumab is a hypothesis-designed drug that was developed to treat MS. Arguments are lost and won on the detail.

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    7. "All the neo-DMTs are in fact old chemotherapy agents from the ‘60s and ‘70s repurposed for MS."

      Tysabri?
      Gilenya?
      Tecfidera?

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    8. If we listen to Dr.Dre...unfortunately the bad rap he will be singing will be about walking aids if you sit back and do nothing.

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    9. Here's a little REAL music for you Dre, that's rather pertinent ;-)
      https://www.youtube.com/watch?v=UKwVvSleM6w

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    10. Dre has a point. looked up the agents MD2 listed and they're all nearly ancient. These drugs are old. Also, there s nothing for progressive MS. You're taking care of easy business because the major problem of progressive MS is too hard for you.

      It's almost been 50 years since we went to the moon yet MS remains a great unknown. Shameful.

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    11. Tysabri and Gilenya are hardly old. We've been spending all our time on the thorny problem of progressive MS, on which we have published some of our experimental work and which is now about to start bearing fruit clinically, keep checking the blog folks!
      We have nothing to be ashamed of.

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    12. This whole war against Dre is nothing short of bullying. No word he doesn't post as often as she/ he used to.

      Dre has an opinion. Let's respect that.

      Delete
    13. if we dont agree with the opinion should we not say so?
      Too hard......think again

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    14. "Jesus Christ"? Don't bring religion here, Dre. We need tangible facts and hopes, not absurdities.

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    15. Oh Dre, we U.S MSers salute you.

      As much as I am a fan of your comments, I think the scientists beat you tonight. Prof G's natalizumab curveball hit you in a way you didn't see coming, and MD2's list of modern neo-DMTs totally knocked out of the park.

      Love you, Dre.xx

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    16. Dre makes this blog worth visiting. Don't listen to the Yanks, I call this round in your favour.

      Delete
    17. Come back Vassilis

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    18. "Dre has an opinion. Let's respect that."
      We do respect that, everyone is entitled to their own opinion but not their own facts.
      Opinions are like a***holes, everyone has one but many shouldn't be aired in public ;-)

      Delete
  2. Trust in Jesus Christ? Are you on drugs, Dre?

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  3. Dre is clueless about drug development. Let's hope he (or her) doesn't get a cancer that needs a targeted therapy that is potentially cured by a new precision medication. Dre would be forced to eat his/her words; we wouldn't want him (or her) to get indigestion, or would we?

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  4. Prof G you forget to mention the cost of marketing drugs. if I am not mistaken Pharma spend more on this than they do on R&D. Shouldn't we ban advertising and marketing of drugs and reduce the costs that way?

    ReplyDelete
    Replies
    1. Re: "Prof G you forget to mention the cost of marketing drugs."

      Yes, I agree. The amount of money spent on marketing of Pharma products is galling. I have posted on this before under the Red Queen Effect. I think banning advertising and marketing would not be feasible under the current market system; it would be too left-wing to pass muster. There are, however, other ways to reduce marketing budgets that are beginning to come into effect in both the US and Europe.

      I think the attitude of them (Pharma) vs. us (academia and the general public) is damaging and divisive. It is really a partnership; Pharma need academia to help them come up with new drug targets, to train their future staff and to help them run trials. We need Pharma to develop and market drugs. The idea that each can do without the other is ludicrous; I know this and politicians know this. The sooner we all realise this the better. I have yet to see evidence of a better system than one we have at present to innovate and develop treatments for people with MS.

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    2. I think as a rule of thumb, the budget for marketing etc is usually about twice the R&D budget (it may be more now, I don't know). I think that should be flipped round at the very least.
      I agree with Gavin that we have to work with what we have at the moment as there is no viable alternative.

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  5. Academics can get drugs to the phase 2 stage but after that maybe the FDA or other government entities need to take it to phase 3. After all, how much money does the government spend for Medicaid/NIH on these drugs?

    As a case in point, the Albuterol add on therapy has shown a dramatic decrease in relapse rate (0.09/year) as a add on therapy to Copaxone which only produces a relapse rate of 0.37/year. What current approved therapy for MS even comes close to reducing relapse rate to this extent?

    http://www.ncbi.nlm.nih.gov/pubmed/20837847

    The beta 2 adrenergic receptor agonist is known to stop EAE even after induction of the disease which seems to be a big complaint from people on this blog.

    http://www.ncbi.nlm.nih.gov/pubmed/7860715

    The role of this drug on regulation of the immune system has been know for a long time, but what can be done with it? Since it is a generic drug no pharmaceutical company is going to touch it but it has a lot of promise including other conditions such as Parkinsons:

    http://www.hindawi.com/journals/jir/2014/103780/

    So what do we do with this? I think the only option is to have a publicly funded trial to evaluate this. Why is this such an obstacle?

    ReplyDelete
    Replies
    1. simple answer is money.
      you are right that acedemics can do phase ii but they do this with government money the phase iii should be pharma. Government does not allocate enough money to do phase iiii properly.
      cladribine at ARR of 0.1 is drug that will tick your box as pivotal phase iii would cost in the order of 3-4 million but whole of UK budjet at anyone time is about 20 million so a trial over 2.5million is unlikely to be funded. For pharma to do it would cost 50-80 million easy. The systems need to change to allow academics to do phase iii and beyond but I think we are kidding ourselves at the moment if we think there is an alternative to pharma drug development I wish I was wrong ....please someone prove me wrong

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    2. Just get HSCT instead. No pharma required!
      Ah - it's been a while since we've had a bit of evangelism!

      On a serious note (you guys excluded) I think the field of haematology/ immunology is years ahead of neurology. I'd stick the funding with them.

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    3. HSCT is nothing but the ultimate in immune suppression therapy as your CD4+, T cells never recover to baseline. This may be fine in the short term but it is an experiment for things like cancer surveilance down the road.

      It has been discovered long ago that there is no difference in the autoreactive immune cell repertoire between healthy individuals and MSers, so damping down the adaptive immune system may not have an effect on chronic innate immune system activation which seems to be the case for pregressive MS:

      http://www.ncbi.nlm.nih.gov/pubmed/10686174

      I guess this is why HSCT is not very effective for progressive MS. Unless you try to understand the disease a cure will never be attained.

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  6. Ok mouses Prof G
    When you talk about treating off label, I had an episode of glandular fever as a child lasting months
    Just before christmas the same symptoms again, the sore throat when swallowing etc has stayed until now. In that time I've had a myriad of Ms symptoms including my first symptoms prompting investigations.
    If I wanted to pay privately to see you guys and fund Raltegravir etc myself would you treat me?
    I'm convinced The ebv link is there and even more in myself

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    Replies
    1. ProfG doesn't do private.maybe wait or the results o the trial

      Delete
  7. The problem we have is that the medial profession and pharma do drug trials vs interferon, as long as their drug is proven to be more efficient than interferon then it will get to market. We now have teriflunomide,glatiramer acetate, fingolimod, dimethyl fumarate etc. Why do you continue to bang the drum on cladribine and try and get it to market? Is it more effective than alemtuzumab or nataluzmab? If not and it just falls in line with the other half dozen drugs above, what's the point? The only real reason can be for the financial gain. Because why do I want another treatment option that is less effective than 2 that are already out there? We as patients need you to focus on making alemtuzumab/nataluzmab a safer drug to take or working on drugs that are more more efficient than the mabs.

    Relating to the earlier point, MS is still a massive unknown, and though I am not in a position to doubt what has happened over the last 30 years, an example, the recent post about BREMSO score, one search and I found another UK neuro who presents data that fundamentally disagrees with almost all of your criteria based on long term data. You guys here are convinced of the role that EBV plays in triggering MS, but one search on medscape shows that many people the EBV theory to be incorrect. There seems to be very little fact around MS and a lot of theories, which is what is so frustrating for MS sufferers.

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    1. Efficacy, safety, convenience and possibly cost.

      As effective or more effective than Alem and Nat look at the NEDA data-but far safer, more effective than the others. induction treatment so it is safer to have neuroprotective and repair on top for RR and PP/SP MSers.

      Merck Serono made a mistake to pull the plug as it has the potential to be a good drug...However the data says the generic works so.Cost in USA for alemtuzumab $158,000 verses possibly $350. In UK £80,000 (drug costs+ cost of dealing with autoimmunity) £1,500. At this price no post code lottery and DMT available for both PPMSers SPMsers and the world over.........shame it won't happen.

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    2. I read this about Cladribine - another chemo drug - and just think this really points back towards hsct. Ultimately, it seems, the more lymphoablative the treatment, the better the outcome.

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    3. It is selective lymphoablation and not a wipe out and cheaper and safer than HSCT

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  8. Matt where did you get HSCT?

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    Replies
    1. I went to Moscow. It's available (on trial) in the UK now though at Hallamshire hospital...

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  9. I wonder what Dr Dre thinks about Prof G's essential off-label list? Would he deny people with MS living in the developing world access to these therapies because they are immunosuppressive or off-label?

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  10. Matt is that trial not finished yet?
    Is it RRMS only?

    ReplyDelete

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