Taking flak for off-label prescribing


I was still wet behind the ears, in my 3-year as a neurology registrar in Johannesburg, when I first used an off-label DMT in MS.

I manage to convince Vivian Fritz, my professor of neurology, to allow us to treat one of her patients with MS with mitoxantrone. This was shortly after the first case series had emerged from Germany.

The patient concerned was a young woman with malignant MS who had one relapse after another and was in our ward for steroids and neurorehabilitation. She had just had a severe spinal cord relapse. She had an EDSS of 8.5 (bed bound with partial loss of hand and arm function). She had had MS for just 2 years. I proposed that she would likely die from her MS if we did nothing to stop her attacks. What had she, and her family, to lose by trying a course of mitoxantrone?

Viv Fritz listened and read the case series. After some reflection, she finally agreed to us trying mitoxantrone in her patient. We went ahead with a course of infusions as per the case series. The patient did so-so; i.e. we managed to stop her having more attacks, but she never got out of a wheelchair. I heard later that she sadly died about 2 years later after she developed septicaemia from an infected pressure sore.

The point I am making about this case is that as a neurology trainee in South Africa I was able to read about a potential innovation in Europe, suggest it to my Professor, argue the case and change our unit’s practice. There were other examples of OLP in SA; it was common in Johannesburg and I suspect it is still happening.

In comparison, OLP is not universal. I have just returned from a short visit to Japan where I found the culture amongst Japanese neurologists to be very similar to parts of the UK in relation to OLP. Very few Japanese neurologists are prepared to stick their heads above the parapet and prescribe off-label DMTs. Why? And what are the potential consequences of not adopting OLP for their patients?

With regards to why I think it is cultural. OLP seems to be more common in cultures that allow individuals to express themselves and challenge the status quo. Japanese neurologists are very deferential and respect their superiors. The same applies to trainees in the UK. For OLP to be widely adopted in Japan and the UK, heads of department, or the ‘neurology establishment’, will have to lead the way.  

I am personally in favour of OLP as an engine of innovation. So many of our DMTs in MS have been developed from the insights and actions of individual neurologists who were brave enough, yes brave enough, to give it a go. Larry Jacobs administered intrathecal interferon-beta to his patients based on the hypothesis that MS was due to a virus. Interferons are foremost antiviral agents hence their name. Professor Jacobs saw positive results in a few of his patients and the rest is history. Interestingly, we still don’t know exactly how interferon-beta works. It may be working in MS as an antiviral agent; we just don’t know. Nobody to my mind has disproved the antiviral hypothesis of interferon-beta’s mode of action.  

Professor Larry Jacobs; interferon-beta pioneer

Mauch and colleagues tried mitoxantrone, an anti-proliferative chemotherapy agent, on the basis that MS is an autoimmune disease. Mitoxantrone is cell depleting chemotherapy agent and was the first immune reconstitution therapy (IRT) to be licensed. The idea is to simply kill the autoimmune cells responsible for causing MS. It took more than a decade of wider adoption of off-label mitoxantrone prescribing and research before mitoxantrone was eventually licensed as a treatment for MS.

Cyclophosphamide was less fortunate. Cyclophosphamide had been tried in MS for similar reasons as mitoxantrone. Unfortunately, cyclophosphamide was trialled in an era when the MS community didn’t know how to do trials. Cyclophosphamide failed as it was tested in more advanced MS and all the trials were underpowered, i.e. the trials had too few patients to be definitive. I am prepared to bet that if cyclophosphamide was formally tested in early in MS and the trials were adequately powered that it would be shown to a highly-effective DMT.  

A more well-known example of OLP and innovation is Professor Alastair Compston’s off-label use of alemtuzumab. It started with Prof. Compston using it in a handful of patients in the early 1990s. Alemtuzumab was being tried in MS based on the same hypothesis as that for mitoxantrone and cyclophosphamide, i.e. MS is autoimmune and that to treat it and potentially cure MS you need to reboot the immune system killing off the autoimmune cells or at least regulating them when the immune system reconstituted itself.

I recall attending my first meeting in Cambridge, in late 1993 shortly after arriving in the UK to do my PhD, when Alastair presented the results of his first two patients. At the end of the meeting Professor Newsome-Davis, a senior and well-respected neuroimmunologist said to me that he didn’t agree with this approach. I recall him saying what we really needed was a pair of molecular tweezers and not a sledgehammer to treat autoimmunity. Unfortunately, the molecular tweezers are still the holy grail and without Alastair Compston’s perseverance, alemtuzumab would have never made it to the clinic.

Another example, is Prof. Jonathan Edwards, a rheumatologist at UCLH, who was brave enough to successfully try rituximab as a potential treatment for rheumatoid arthritis (RA). This was a very counterintuitive as the whole world at the time thought RA was a T-cell mediated autoimmune disease. The success of rituximab in RA led to senior executives at Genentech drawing up a list of other autoimmune diseases to try rituximab in. This and other factors subsequently led to Anne Cross trying rituximab in MS. Without a brave clinician trying OLP of an anti-CD20 in RA, we wouldn’t have ocrelizumab and several other me-too anti-CD20s in trials for treating MS.

There are similar stories for dimethyl fumarate, daclizumab, cladribine and some of the other emerging DMTs. Innovation in MS and other areas of healthcare emerge in an environment where OLP is championed and clinicians and their patients are brave enough to test the waters. What has changed?

It seems as if Barts-MS is being criticised, by some UK neurologists, for our compassionate use of off-label subcutaneous cladribine in more advanced MS. I don’t understand this as our position is no different from that of our predecessors mentioned above. We are simply building on a hypothesis that inflammation drives MS disease progression at all stages of the disease. We don’t agree with the 2-staged disease hypothesis of MS, i.e. that MS has an inflammatory phase that is followed by a neurodegenerative phase. The data overwhelming supports the parallel hypothesis that inflammation drives neurodegeneration throughout the course of the disease.

The implications of the parallel hypothesis of MS is that MS is potentially modifiable by anti-inflammatory therapies throughout its course; this even applies to advanced MS, which is why we will be formally testing DMTs in people who are already using wheelchairs for their mobility.

Another implication of the parallel hypothesis of MS, i.e. MS is always both inflammatory and neurodegenerative, is that we need to build a sandwich with an anti-inflammatory therapy, or a combination of anti-inflammatory therapies, at the base and to then use this as a platform on which to build the layers of the sandwich, which includes add-on neuroprotective, remyelination and neuro-restorative therapies.

At the same time we need a holistic approach and to focus on all the other factors that may impact on the health of the brain of someone with MS. This is why we need to proactively manage all of the things that are potentially associated with accelerated ageing in pwMS.  

For this reason, I have been proposing for some time that we adopt the marginal gains paradigm when treating MS. Dave Brailsford from the British cycling team is acknowledged as making the marginal gains approach mainstream.

“The whole principle came from the idea that if you broke down everything you could think of that goes into riding a bike, and then improved it by 1%, you will get a significant increase when you put them all together.” Sir Dave Brailsford.

Small changes in many things can have a massive impact on the overall outcome. Prior to Dave Brailsford taking over as head coach of the UK cycling the team, it was in the doldrums. In 1996, prior to adopting the marginal gains philosophy, Team GB was in 12th place in the Olympic Games medal table with two bronze cycling medals. In comparison at the Beijing games in 2008 Team GB won 12 medals from 10 events; 7 gold, 3 silver and 2 bronze medals.

Why can’t we apply marginal gains to the management of MS? If you have MS, you need to ask what you need to do across your disease course to maximise your chances of having a good outcome. This means not only focusing on optimising your MS DMTs but doing all the lifestyle things you can do and more.

For the naysayers, who are criticising Barts-MS for trying to treat people with advanced MS (wheelchair users) and/or active secondary and primary progressive MS, can you imagine what it is like to be told that ‘you are beyond hope and there is no treatment that can help you’? Or ‘there is nothing I can do you for you as you have progressive MS’? This is why it is important to learn how to spread hope and to try and improve everything you possibly can for your patients with MS.

Spreading the hope is why we are doing the #CHARIOT-MS and #ORATORIO-HAND studies, why we are planning the #SALVAGE-MS study and trying to optimise our MS service, within the confines of the NHS, to adopt a marginal gains approach to managing MS.

I would also like to remind the naysayers that they seem not to have noticed that progressive MS is now modifiable? Ocrelizumab is licensed for active PPMS and Siponimod is licensed for active SPMS in the US and is likely to get an SPMS label in Europe. In addition, there are several other progressive trials underway with a high likelihood of being positive. We are now in an era where progressive MS is treatable.

If you are a naysayer, can I suggest you take off your blinkers, buy a pair of rose-tinted spectacles and smell the roses?  Our compassionate use of off-label cladribine has allowed us to collect enough observational data to make the case for doing a trial of cladribine in more advanced MS. We would not have been able to get this point without OLP. For this, we would like to thank our patients and some of our colleagues for their ongoing support and to put DrK on a pedestal for his perseverance and resilience.

We won’t let the critics silence us and distract us from the job at hand; preventing MS (#PreventMS), treating MS early and effectively (#AttackMS, #ThinkCognition) and treating MS in the more advanced stages (#Proximus, #ThinkHand, #Over&Under, #ChariotMS, #OratorioHand, #SalvageMS).

As I write this post I wonder what our colleagues are going to say about our strategy of targeting the intrathecal plasma cell response with an add-on off-label therapy that is currently licensed to treat myeloma (#SIZOMUS)? I suspect the same naysayers will continue to advise their patients to stay away from our centre. At Barts-MS we are proud to practice experimental medicine. Without brave and bold scientists & clinicians and their patients, who are prepared to volunteer for clinical trials using off-label therapies, the innovation cycle, at least in the UK, will grind to halt.

Disclaimer: Please note that off-label prescribing is not a substitute for on-label prescribing unless it is the only way for people living with MS to access DMTs in resource-poor environments.

Jacobs et al. Intrathecal interferon reduces exacerbations of multiple sclerosis. Science. 1981 Nov 27;214(4524):1026-8. Ten patients with multiple sclerosis who were treated with human fibroblast interferon (IFN-B) for 6 months showed a significant reduction in their exacerbation rates compared with their rates before treatment (P < .01). The IFN-B was administered intrathecally by serial lumbar punctures. There was no significant change in the exacerbation rates of ten multiple sclerosis control patients before and during the period of observation. The IFN-B recipients have now been on the study a mean of 1.5 years, the controls, 1.2 years. The clinical condition of five of the IFN-B recipients and one of the control patients has improved, whereas the condition of five of the controls and one of the IFN-B recipients has deteriorated (P < .036). These findings warrant cautious optimism about the efficacy of intrathecal IFN-B in altering the course of multiple sclerosis and support concepts of a viral or dysimmune etiology of the disease.

Mauch et al. Treatment of multiple sclerosis with mitoxantrone. Eur Arch Psychiatry Clin Neurosci. 1992;242(2-3):96-102. Ten multiple sclerosis patients, all with a rapid deteriorating disease profile, were treated with 12 mg/m2 of the cytostatic agent mitoxantrone, administered every 3 months. This dosage is only 25% of what a patient with a solid tumour would normally receive during the same time period. In all treated patients the deterioration was stopped following the initial dosage; in four out of ten patients there was even an immediate improvement of the neurological status. Eight out of nine patients showed an improvement after 1 year as compared with their enrollment status; the other one remained stabile. In correlation with the clinical improvement, the mean P100 latencies of visual evoked potentials showed a reduction after 1 year. However, the changes identified through magnetic resonance imaging were even clearer than those seen clinically. At admission, this group of patients presented with a total of 169 gadolinium (Gd)-enhancing lesions. Only 10 lesions were enhancing in nine patients 12 months after the initiation of treatment. It appears that mitoxantrone accelerates the disappearance of Gd-enhancing lesions and prevents the development of new ones. Minimal side effects such as mild nausea and a slight faintness were evident in six patients and then for only 1-2 days.

Moreau et al. Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis. Lancet 1994 Jul 30;344(8918):298-301. The central nervous system lesions of multiple sclerosis (MS) can be detected by magnetic resonance imaging (MRI) and the initial perivascular inflammatory component is distinguished by the presence of gadolinium enhancement. To assess the effect of systemic lymphocyte depletion on disease activity, seven patients with MS received a 10-day intravenous course of the humanised monoclonal antibody CAMPATH-1H (anti-CDw52). With some variations in the protocol, enhanced cerebral MR images were obtained monthly for 3-4 months before and at least 6 months after treatment. 28 enhancing areas were detected on the first series of 7 scans; 51 additional active lesions were identified on 18 scans before treatment; 15 were detected on 20 scans done over the next 3 months, but only 2 active lesions were seen on 23 scans during follow-up beyond 3 months. The difference in lesion incidence rate before and after treatment varied and the rate ratio was significantly reduced in only three patients. Collectively, in a “meta-analysis”, the rate ratios were 0.15 [corrected] (95% CI 0.09-0.24) for all seven patients and 0.24 (0.14-0.42; p < 0.001) with exclusion of the patient whose scanning schedule differed. The effect of CAMPATH-1H on disease activity provides direct, but preliminary, evidence that disease activity in MS depends on the availability of circulating lymphocytes and can be prevented by lymphocyte depletion. It is too early to say anything about the clinical results of treatment with this agent.

Edwards et al. B-lymphocyte depletion therapy in rheumatoid arthritis and other autoimmune disorders. Biochem Soc Trans. 2002 Aug;30(4):824-8.
B-lymphocyte depletion therapy is being explored in a wide range of autoimmune disorders. In many, there is early evidence for efficacy, and immunosuppression has not been a major problem. The mechanism of action is unclear but appears to be consistent with the lowering of autoantibody levels, where relevant antibodies are quantifiable. An interesting finding is the persistence of clinical improvement for periods of 1 year or more after B-lymphocyte return, which supports the concept that stochastic generation of rare pathogenic B-lymphocyte subsets may be a rate-limiting step in pathogenesis.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Thank you BartsMS and Professor G. Without this type of off-label therapy use, where would we be in the treatment progressive MS? As someone that has been dealing with MS progression for a little over 14 years, I applaud any therapy that affects the potential course of disease progression. At the age of 57, I have not given up hope.

  • Thanks to all the innovators and risk-takers in MS research. I once saw a programme about MND and the patient’s partner asked the neuro about using a drug that had shown some promise in early research. The neuro said no as the drug could potentially have serious side effects! The patient died six weeks later.

    I only wish the innovation and risk taking could find their way into the way trials are planned and run. Trials take way too long. A promising agent identified today would probably not reach the market until 2030. 10-11 years in the life of a progressive patient can see a patient go from cane to bed bound.

    While I accept that there is now a licensed drug for PPMS and there is the possibility in the near future of a drug for SPMS, the efficacy of them are not that great and will only benefit a minority of patients. We should not big-up these treatment- there is still a lot more to do. Stopping worsening for patients should be the goal.

    • You should not underestimate the efficacy of ocrelizumab and/or siponimod in progressive MS. This is what you get. But is a start and the base of the pyramid or sandwich.

  • How angry and appalled at the nay-sayers do those of us with MS need to be?!
    How disempowered and helpless do we need to be when facing treatment apathy and rejection from neurologists with all the power over our lives?!

    Why do I feel we operate health provision that will take any risk to save life, but will tolerate the destruction of what it means to be a functioning human being due to a distorted focus on side effects!

    Please, please, please carry on being the Bart’s that evidences so much dynamic attention to OLP, quality treatment, studies and research, this site and also to patient empowerment and a holistic approach to MS provision.

    • I think clinicians and the practice of medicine have been battered by medical malpractice or the threat of malpractice that clinicians are retreating to the safety of the label. They are not prepared to take risks with their patients regardless of whether or not it makes scientific sense. They need to be reminded that a license from the regulators is simply a marketing authorisation, i.e. the can advertise and market their product for a specific indication.

  • As a patient I say yes to all this and thank you for all you do. Despite many options on DMTs patients continue to progress so obviously sticking to what’s approved isn’t enough. In cases where OLP and the risk/benefit makes sense please continue to help that patient and document the results for the benefit of all future patients. We deserve all the stops.

    • Please remember that the examples I have given you are positive; success stories. There are clearly negative examples of OLP that don’t work; one that comes to mind is anti-TNF-alpha therapies.

  • Brilliant post!
    Just look what we’ve learnt thanks to all the brave clinicians and patients trailblazing off-label. With humility challenge the dogma, record, learn and share.
    Keep up the good work 🙂

    Ps re Prof. Jo Edwards, a rheumatologist at UCLH, who was brave enough to successfully try rituximab as a treatment for rheumatoid arthritis. This was a very counterintuitive as the whole world at the time thought RA was a T-cell, mediated autoimmune disease.
    Thanks, had wondered who tried this first!

    • Yes, it was the RA results that made Genentech stand-up and listen. MS was then high-up on their list of diseases to try rituximab in. So when MS investigators such as Anne Cross and Stephen Hauser approached Genentech they were already primed internally to explore anti-CD20 therapies in MS. Anette Langer-Gould explained this all to me as she worked for Genentech at the time.

      • Wasn’t it Bernard Hemmer and Olaf Stuve who led the way…It was in their recent review, I remember seeing the RA stuff on Tele and thinking when MS….vagal nerve stimulation next?

      • “When they stopped Rituxan’s development, it was the main reason I left Genentech,” she said. “I told them ‘you’re just withholding a highly effective treatment for MS patients for another decade’–and that is exactly what happened.”

        Stop…Take off the Rose glasses…Langer is critical of the Ritux-Ocrevus business deal. But from his last 2 papers Hauser doesn’t call it highly effective anymore…now he says…more or less…..”It doesn’t work”…..only took him 20 years to finally realize it…better late than….not…

        “. We demonstrate complex patterns of clonal B cell persistence in CSF and blood, even in patients on immune-modulating therapy. Our findings support the concept that peripheral B cell activation and CNS-compartmentalized immune mechanisms can in part be therapy resistant.”


        • The problem with the view was most people where they were finding the b cells were in treatment failures saying the exact opposite of what they were implying

          • Huh…all patients fail or progress…In this paper they say over time…all patients lose brain…stable in rr is still losing brain….
            So back to hsct as only thing that normalizes brain loss.

            “Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up. Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability. ”


            “Moreover, as relapses and focal white matter lesions are brought under excellent control by disease‐modifying therapies for RRMS, the effectiveness of these agents against silent progression is likely to represent a key determinant of their relative value.”

  • I love your forward thinking your right it gives me hope and enables to challenge my ms team too offer me a treatment I have made so many lifestyle changes and feel I would welcome any opportunity to challenge ppms as you say what else can I do- thank you it has given me a real lift to read this

    • We are only beginning to explore combination therapies in MS and as usual, PPMS is not uppermost on the trial list, but it should be. It is clear that an anti-inflammatory is only the beginning of our journey to modify the course of PPMS.

  • “The data overwhelming supports the parallel hypothesis that inflammation drives neurodegeneration throughout the course of the disease. ”

    Yes..by doing progressive patients in Russia and Mexico…it’s been seen that some do respond
    to HSCT.
    How many is hard to say as they do not do trials and non-responders tend not to
    respond to survey follow-ups. But there is a Facebook group of PPMS who have all had HSCT done.

    • This post is not about HSCT, which we are now doing at Barts. Before opening the floodgates for HSCT in more advanced MS we need more data; this will come from real-world data and trials.

      • real-world data

        “In the Italian experience, at 15 years after aHSCT, almost 60% of 160 evaluated patients did not experience disability progression. This proportion was significantly higher for RRMS (82%) versus SPMS (38%) (p=0.003). At 10 years, 78% of patients was free of inflammatory MRI activity. The proportion of patients free of any disease activity (relapses, inflammatory MRI activity, disability progression) was almost 50% at 10 years. Transplant related mortality was 0.65% (n=1).”

        A meta-analysis of autologous haematopoietic stem cell transplantation in MS
        G. Mancardi; Genoa/IT


        Ean 2019 OSLO

        • That is not the experience of other units, Prague, Rotterdam, Cyprus, Chicago, etc. which is why most units have stopped doing HSCT in progressive patients. What is needed is randomised, controlled data with blinded assessors.

          • How are yoou randomised people on this procedure?

            This is not a pill people will know they are on treatment


          • Flip a coin. It is only the assessors that are blinded. It is called a single blind study. This is what we are doing in the UK.

          • “That is not the experience of other units Chicago, etc.”

            Actually not entirely true…Burt has and to this day does early sp patients to stop progression.
            He just treats them off-trial…Some ppms w/
            lesion enhancement got hsct in uk. recently.

          • “What is needed is randomised, controlled data with blinded assessors.”

            Ok..You’ve never been a hsct “early adopter”…
            but now on facebook I see recently diagnosed laugh at DMT/neuros who try to put them on DMT and go straight to hsct…The word is out. So naive if you
            can battle ms with a prescription for a pill.

            Has there ever been a single patient on DMT who stopped progressing…? If not
            why start…?

      • No…but it’s not worthless ….ALS and MS are such horrible diseases
        you don’t even need blind studies…..If someone w/ ALS is alive after 3 years…or someone w/ progressive ms is still walking….you know something is working….Someone on yahoo ALS news story said wow…you have a disease that will kill you in 3 years now we want you to take a sugar pill for 6 months.
        The head of UCSF ALS center got the disease and they thought it heroic that he did his own study like all the subjects…but no it was crazy…if you thought it worked would you want placebo.

  • Good job ProfG is a diplomat (read wuss) and won’t name names. I would hunt them down and put them on my naughty list..Frankly I am sometimes horrified by some of the things that ProfGs colleagues get up to. Knowledge is seemingly a dangerous thing..,sadly this is not shown by enough people.

    • I have been around long enough to know about and understand the adoption curve. Some people are simply slow adopters and will eventually come around once the majority do. Unfortunately, it is the laggards who are the problem, particularly if they are in a position of power.

  • This problem peaked in the oil industry a few years ago. Better now, but still not gone:

    “We need new better equipment that shall be lighter and cheaper. Delivery within one year ”
    Next requirement:
    “We will only accept tried and tested equipment with a field record of 5 years and more.”

    Go figure…..

    We are thankful for your effort!

      • Geoffrey More in his 1990’s book Crossing The Chasm (about IT sales, not medicine) has a superb explanation of the bell-curve as it applies to technology adoption/attitude to risk. He discusses strategies to overcome this.

        Quite ahead of its time in many ways, as it forced the IT sellers (and their teams) to look at their customers – IT purchasers – through an entirely new lens.

        The way they are identified and how they are managed formed a key part. Medicine, in my experience, along with much of academia does not ‘do’ inter-disciplinary. The US is often even more resistant than the UK and Europe.

        Seeing an addition – not substitution – of a more businesslike approach in some aspects is just reviled as if it will soil the noble purity of the practice of medicine.

        • Or showtime. It’s produced by George Clooney, based on the book of the same name. Disappointing if you ask me. MASH is better 😀

  • Brilliant post and discussion Prof. G, but I would say that as I came to St Barts some years ago with PPMS and optimism about being treated after my previous NHS-consultant had written me off. I’m now a patient receiving OLP sub-cutaneous Cladribine and remain a firm believer in what St Barts is doing – doing the right thing for patients. No problems or reservations at all, including the 300 mile commute to the hospital.

    Although I have yet to find out about and discuss my recent MRI scan results, I don’t feel that I’ve got any worse since I started OLP Cladribine. I remain utterly optimistic that it’s doing what its meant to do. OK – so I now use a wheelchair (on your advice, I seem to recall!) but thats because I was fed up with the fatigue and lingering spasticity after stubbornly walking too far on a regular basis. I can still walk but now make a concious decision – short distances, crutches and FES, longer distances or hills, its wheelchair time. Independance returns and is here to stay if things go to plan.

By Prof G



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