Thursday, 13 September 2012

Using off-license drugs in MS

There has been a lot of discussion about off-license use of drugs in MS; in particular Rituximab. In general off-licensed drug use is discouraged for several reasons:

1. The evidence base of the drug's efficacy, or more importantly its safety, may not be adequate. This is a particular problem in paediatrics were you have to extrapolate data from adults to children.

2. Pharma themselves are not keen on off-license prescribing; they can't be involved in any decision making. It is illegal to promote off-license prescribing; you just have to look at the size of recent fines handed out to Pharma by the FDA.

3. Our General Medical Council guidelines are very clear and discourage off-label prescribing

When prescribing a medicine for use outside the terms of its licence you must:

a. Be satisfied that it would better serve the patient's needs than an appropriately licensed alternative

b. Be satisfied that there is a sufficient evidence base and/or experience of using the medicine to demonstrate its safety and efficacy. The manufacturer's information may be of limited help in which case the necessary information must be sought from other sources

c. Take responsibility for prescribing the medicine and for overseeing the patient's care, monitoring and any follow up treatment, or arrange for another doctor to do so (see also paragraphs 25-27 on prescribing for hospital outpatients)

d. Make a clear, accurate and legible record of all medicines prescribed and, where you are not following common practice, your reasons for prescribing the medicine.

4. It is also "technically illegal" in the EU for widespread off-label prescribing within a healthcare system; you simply need to read the legal implications for NHS Trusts in England allowing their ophthalmologists to use Avastin off-license, instead of the licensed Lucentis, for age-related macular degeneration. Another recent example is that of 3,4-diaminopyridine or 3,4-DAP that is used in neurology for a rare disease that causes muscle weakness called Lambert-Eaton Myasthenic syndrome. This drug was used for decades off-license at very little cost to the NHS (~£800-£1,000 per patient per year). However, once a trial was done and the drug licensed under the EU orphan-disease legislation the cost went up to between £40,000 and £70,000 per patient per year. Once a licensed drug was made available it became "illegal" to prescribe the off-license version. This issue could have arisen with the two formulations of Alemtuzumab, Campath and Lemtrada, which has been avoided by the withdrawal of Campath from the market by Genzyme. The reason for this EU legislation is to protect the incentives that has been created for Pharma to invest in R&D and recoup their investments.

If you are interested in these issue I suggest you read the open letter by British Neurologists to the Minister of Health that was published in the BMJ:

Nicholl et al. Open letter to prime minister David Cameron and health secretary Andrew Lansley. BMJ 2010; 341 doi: 10.1136/bmj.c6466 (Published 16 November 2010)

"At a personal level I am very concerned about this issue as it prevents clinicians testing licensed drugs for other indications. For example, cladribine, rituximab and alemtuzumab all emerged by some pioneering clinician who was prepared to take the risk of testing the drug in MS and the MSers who were prepared to take undefined risks. This kind of legal mindset, if taken literally, will inhibit innovation. It also makes it impossible for me as a clinician and opinion leader to recommend off-license use of a drug in MS. I hope you understand?"


Other relevant posts on this blog in relation this issue:

14 May 2012
The Novartis decision to sue several NHS trusts for using Avastin rather than the much more expensive (but no more effective, as recently shown) Lucentis for wet macular degeneration is in my view a HUGE mistake that will ...

05 Sep 2012
The graph below compares the search volume index of alemtuzumab to CCSVI. To make the graphs readable I had to do a log conversion of the search volumes, which are given by week. To do the log conversion I simply .

20 Aug 2012
This means that alemtuzumab will no longer be available as a licensed product in the UK once existing supplies run out. This action is not being taken for any reasons related to product safety, efficacy or supply, but as part of ...
21 Aug 2012
Alemtuzumab is being pulled in the US as well. (Reuters) - Sanofi's rare disease unit Genzyme is pulling leukaemia drug Campath to prepare for its launch under a different dosage and as a multiple sclerosis treatment that ...

20 comments:

  1. It is not illegal as suggested to prescribe off-label where other licensed drugs are available. It is potentially (the Avastin litigation has not been resolved) 'illegal' for NHS trusts to pay for off-licence drugs in those circumstances but that is a different issue. Ability to pay is different from legality of prescribing.

    I strongly believe this should be the well-informed patient's choice. The job of the neuro is to advise fully on all implications and then work with the patient on their preferred way forwards. MS can be a very disabling disease that is difficult to prognosticate and that is what needs to be weighed in the other side of the scale against potential safety issues. Patients should not be forced to wait until they are disabled to take extreme action to prevent becoming so.

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  2. My God, from reading the plethora of posts on this blog I think it's safe to say that the field of MS, in general, is in an absolute mess!

    No one seems to know what they are doing and cannot agree on the terms and conditions. It's a case of headless chickens. Drugs are developed and rejected, or existing compounds are reappropriated only to be swollowed up by Pharmas and re-released as something to expensive to justify.

    MS starts to ruin a person's life from the very moment it starts. The biological processes involved are vast and the disease will require different drugs for every phase of the attack (RRMS to SPMS). The disease is not static, it evolves, altering its cellular biology in ways man has been unable to fathom. MS is a disease that will always be 10 steps ahead of scientists because it simply exists to destroy. That is its only purpose in life: to degenerate and kill the individual suffering from it.

    It's cleal that we are many, many generations away from living in a world free of MS, and that is not only because of a lack of scientific progress, but also because the markets don't want to cure diseases unless they can make mass money.

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    1. Killjoy! Imagine what it was like living in 1992? I know. A lot has happened in 20 years. I don't want the disease, but I am hopeful that the advances that are being made will make a big difference. Imagine what it will be like in 2032? Prof G and Mouse Doctor will have retired and MS, will hopefully, be no more.

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    2. I entirely agree, compared to when I started working in MS related research more than 25 years ago the progress has been immense and if anything the pace of progress is accelerating. Though obviously there is never a "good" time to develop MS, the situation now is so much better than it has been in the past. Some people need to take a bit more of a balanced view.

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    3. Hmm, I have PPMS and am on nothing. Where is the progress in my case, other than MS progression?

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    4. As there is no licensed therapies for PPMS it is easier to make a case for using off-label rituximab. The PPMSers in the rituximab trial were those who were less than 50 years of age and/or had active MRI scans with gd-enhancing lesions. I have had a few PPMSers who fulfill these criteria in whom we have been given permission to give a trial of rituximab.

      The point I was making is that if you have a licensed therapy, as we do in RRMS, you have to use that rather than the unlicensed treatments.

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  3. It is wholly inaccurate to suggest that the state of MS treatment is in such a bad state. NHS funding for such treatment might be problematic in resource constrained ties, but the state of the 'industry' is light years ahead of where it once was. A newly diagnosed RRMSer properly treated by a competent neurologist with knowledge of - and where appropriate access to - new and emerging treatments, can expect his/her condition to be well managed for many years and has every chance of maintaining a mild disease course. There's no cure - just like there's no 'cure' for diabetes or other chronic bodily 'malfunctions' - but get treated early and effectively and you can do very, very well. Alemtuzumab patients had an ARR of just 0.11 after 5 years - that's just 1 relapse per decade and it may well, used early enough, if Prof G and some others are right, prevent/delay/mitigate the severity of any future SPMS. I'm certainly much more optimistic than the poster above and am just glad I was diagnosed in 2012 and not 1992 or even 2002 for that matter. And, as another poster pointed out, there are around 70 new drugs from pre-clinical to phase 3 currently in development.

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    1. Hoping that just ONE of the 70 new drugs will be effective in SPMS (with no relapses) - otherwise it's great but not so great news....

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    2. Agreed. It seems RRMSers only see things from their point of view. If you ever get to our stage then your platitudes will be rendered moot.

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    3. Yes, and it will be better to have MS in 2022 than 2012. While we're at it, it'll be better having MS in 2032 than 2022.

      You're argument is nothing but self-comforting. The reality is that stopping relapses and stopping progression are not the same thing. You cannot claim that everyone treated with Alemtuzumab has been prevented from developing SPMS. That is scientifically untrue.

      More than 90% of all drugs being trialled will fail. That's the reality. Get real.

      Once again, RRMSers only seeing things how they want to see it.

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    4. Re: "You cannot claim that everyone treated with Alemtuzumab has been prevented from developing SPMS."

      Who said that? Not me. We know that this is not true. I have personal experience; I have 2 patients who were treated with Alemtuzumab during the RRMS phase, albeit quite advanced disease, who mow have SPMS. What we are saying that if you want to delay, and possibly, prevent SPMS you need to treat aggressively very early on in the disease. Waiting for the disease to become advance before trying this strategy does not makes sense. This experiment is currently running with CARE-MS 1 trial, we will see how well these MSers do over the next 10 to 20 years.

      The 90% failure rate does not apply to phase 3 drugs. The failure rate in MS phase 3 trials is less than 50%.

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    5. How late is too late?
      Does it depend on how long you've had RRMS, or how advanced it is, or your age?

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    6. We don't know how late is too late. The CAREMS-1 trial recruited MSers with an EDSS of 3.0 or lower and early disease (mots MSers were with 2 years of onset). I don't think there is a magic cut-off; all we know is the sooner we treat the better. This is because we like to prevent any damage from occurring. You are correct in stating that age is important. A lot of people, including myself, believe that ageing or premature ageing is one of the factors underlying secondary progressive MS.

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    7. "Indeed, in secondary progressive MS the previous
      relapse history appears to have minimal influence on eventual disability." (Ebers
      2004, Confavreux 2003, Confavreux 2000).

      All those RRMSers that are gloating about Alemtuzumab should stop being so cocksure and expressing misleading information as one of the commentators has done above. There are several RRMSers that are not on drugs and by identifying treatments they cannot access, that perhaps you can, just creates further tension for them.

      Jack Osbourne has refused DMTs as he thinks the hype, such as "Alemtuzumab patients had an ARR of just 0.11 after 5 years - that's just 1 relapse per decade and it may well, used early enough, if Prof G and some others are right, prevent/delay/mitigate the severity of any future SPMS," is largely hogwash.

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    8. The view that number of relapses is not important to whether you develop SPMS as mentioned above is not from the age of DMT.
      The data showed that whilst number of relapses may not determine when SPMS occurs, if you have alot early in disease it does.

      If Jack Osbourne really believes it it all hype, then he is in my humble opinion abit of a fool to deny the value of DMT. Whilst there is always some hype about drugs, the data is there for all to see.
      However it is nice that he has a choice to refuse DMT others are not so fortunate to get the offer in the first place.

      I would have thought that Jack Osborne was risk-taker based on his adrenaline junky TV past I would have the thought that a risk-taker would consider Alemtuzumab or other highly active DMT given the potential benefit of early treatment. However being a new parent may change that view.

      In my mind each relapse causes damage and the less you have the better.

      Do nothing and your risks of relapse are worse than being on DMT
      The value of unproven benefits from life style changes and nutriceuticals over current or soon to be available DMT perhaps is the higher risk taking behaviour.

      However currently I do not have MS and so I am in a different decision making situation. There is a risk of being a denialist of modern medicine. Everyone has an opinion and this is jst one.

      Certainly in mices it is clear that the number of relapses does not necessarily influnece the ultimate level of disability either but relapses do create disability and the more you have the greater chance of disability occurs. Progression in some strains may occur after one attack, one or two in others in another maybe four but in males if you do certain things maybe two. However it is clear that if you stop relapses early then the chance of developing significant progressive disability is reduced or stopped.

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    9. I want to second MDs comments. You must be careful extrapolating natural history data from the pre-DMT era to the DMT era. You mustn't forget that the Eber's data set shows a very strong correlation between early relapse data (first 2 years) and outcome.

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    10. to Anon 4.44 and others:
      You may be right and alemtuzumab etc may fail to prevent SPMS. But you almost sound as if you don't want them to work.

      And it's not clear what you want from RRMSers - to keep quiet about treatments?

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    11. MD - would you take Alemtuzumab if you were diagnosed?

      Separate question - is it possible/likely that the number of relapses in the first two years is related to progression as it signifies the level of
      disease activity but artificially reducing the number has no impact on progression? Ie it is
      an association but not causative?

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    12. Yes I would be willing to take it.

      We do not know definatively what drives progression but based on my current view I would think it will make an impact on when and if progression develops, but only time will tell. We will need to follow people and see what happens.

      If immunity is the cause then maybe job done otherwise we will need something in addition.

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