#PolticalSpeak & #OffLabel: rituximab and the future of MS treatment

COMBAT-MS = COMparison Between All Treatments for MS #OffLabel #PoliticalSpeak

Ever since coming back from my sabbatical and witnessing the unmet need in resource poor countries for disease-modifying therapies for MS I have been promoting an Essential Off-Label DMT list for the treatment of MS. It has also become clear to me that this is not only a problem in resource-poor countries, but high-income countries as well.

The term flipping the pyramid refers to treating MS with the most active treatments first-line. In most countries the more effective treatments are only available 2nd or 3rd line mainly due to the costs of the treatments. In some countries, particularly in Sweden and the USA, they have overcome this problem by prescribing cheaper off-label options; rituximab and HSCT being the main off-label high-efficacy options available. To be frank rituximab (anti-CD20) is not really a cheap off-label option, but it is significantly cheaper than the licensed high-efficacy MS DMTs.

The issues around off-label prescribing when licensed therapies are available have been debated and discussed on this blog many times (search term OffLabel). These issues are rehearsed in an Editorial in last week’s BMJ (see below). Morales & Guthrie make the point ‘… off-label prescribing may need more explicit justification, the evidence supporting prescribing is actually more important than the presence or absence of a licence in itself…’. How do we get the necessary evidence to support clinicians and patients make the correct decision? One way is to do randomised controlled trials comparing say rituximab with one of the licensed DMTs. Who will pay for this? Fortunately, PCORI (Patient-Centered Outcomes Research Institute) has funded a pragmatic trial to generate evidence on the relative efficacy and safety of rituximab to other licensed DMTs. PCORI as an organisation was established to evaluate the benefit and harm of already existing methods and treatments used in health care in real world populations and where there is a decisional dilemma. PCORI was part of the 2010 Affordable Care Act (“Obamacare”) and is an independent non-profit trust-fund.

In July 2016 PCORI announced a $8.5 million study comparing the effectiveness of rituximab, a biologic drug, to other commonly used disease-modifying therapies in individuals with the relapsing-remitting form of the disease. The study will be based at Karolinska Institute in Sweden and conducted in collaboration with Kaiser Permanente Southern California. In particular, it will assess the comparative safety outcomes of medications.

I am privileged to have been invited to be a stakeholder on this important study. My role is advisory and to help with keeping the wider MS community engaged and up-to-date on the progress and the aims of the study. The good news is that we had our first meeting on the 9th February and have made good progress. It seems as if we have found an appropriate name for the study COMBAT-MS (COMparison Between All Treatments for MS). The term may be appropriate in that the results of this study may be very disruptive. Could these results be what is required to start and off-label prescribing revolution? I sincerely hope it does in resource poor environments where so many pwMS are being left without any DMTs and MS is simply allowed to run its natural course. In high-income countries the battle between off-label prescribing and licensed therapies will be more nuanced. On the one hand the politicians and the EMA want to support Pharma, and their innovation machines, and on the other cash-strapped healthcare systems will be looking to reduce their drug costs. Who will win? I sincerely hope our patients win; surely they deserve the choice of a flipped pyramid? I would therefore like to thank the COMBAT-MS team for trying to make a difference and generate the real-life evidence we need to assess the efficacy and safety of rituximab in the management of MS. 

The other good news is that rituximab is coming off patent and we can expect several, hopefully cheaper, biosimilars to emerge on the market in the next year or so. Some concerns remain about the future of PCORI under the new Trump administration. However, we all expect funded projects, such as COMBAT-MS, to be completed.

What this study highlights is the need to explore how to optimise the use of off-label rituximab in MS. What dose should be used? Could it be used as a PIRT (pulsed immune reconstitution therapy)? Will a response marker emerge that will allow us to use anti-CD20 therapies more intelligently? How will rituximab do in a head-2-head study against ocrelizumab? Will the fact that anti-drug antibodies are higher with rituximab, than ocrelizumab, make a difference long-term?

Morales & Guthrie. Off-label prescribing of antidepressants. BMJ 2017;356:j849 (Editorial)


….. Strength of evidence matters more than presence or absence of a specific licence

….. In most countries, medicines have a product licence that describes how they should be used. Licensing is intended to ensure that medicines meet acceptable standards of efficacy, safety, and quality for a particular indication in a particular group of patients.

….. “Off-label” use occurs when a drug is prescribed for an unlicensed indication, to an unlicensed patient group (such as children), and/or as an unlicensed dosage or formulation.

…. Clinicians can legally prescribe off-label, and professional licensing agencies recognise that off-label use is necessary if licensed medicines are ineffective, if they are associated with adverse effects, or if the licensed dose or formulation does not meet the patient’s needs.

….. Professional responsibility in these circumstances is fundamentally the same as for on-label prescribing. As the UK medical regulator says, “We expect you to carefully consider any treatment that you prescribe, and we expect you to be able to justify your decisions and actions when prescribing, administering and managing medicines regardless of whether they are licensed or unlicensed.”

…. Although off-label prescribing may need more explicit justification, the evidence supporting prescribing is actually more important than the presence or absence of a licence in itself.

….. These mismatches between licensing, evidence, and guidelines within countries complicate clinical and shared decision making, and variations in licensing and guidelines between countries add further confusion.

….. For all prescribing, patients (or their parents or carers) should be given enough information to allow them to make an informed decision whether to take a medicine. This should include whether the intended use is off-label, but more importantly prescribers should discuss the strength of the evidence base underlying their recommendation.

….. Off-label prescribing matters because it is usually (but not always) associated with substantial uncertainty about the balance of benefit and harm. Prescribers should therefore be cautious when they prescribe an off-label medicine on the basis of an extrapolation of evidence for a different indication, in a different patient group, or for a substantially different dose or formulation.

….. Equally, however, on-label prescribing also often involves extrapolation, most commonly because the patient needing treatment is very different from the patients included in trials.

CoI: multiple

11 thoughts on “#PolticalSpeak & #OffLabel: rituximab and the future of MS treatment”

    1. Yes, you can, but NHS England won't pay for it so you have to convince your NHS Trust to do so. Barts Health NHS Trust is in financial special measures and cannot take on the cost burden of high-cost off-label prescribing when there are licensed alternatives available via NHS England. Saying that some patients have elected to pay for it themselves, via the private access route. I have made the point before I am convinced the NHS does not want to undercut and affect the current Pharma model. NICE is in place to negotiate cost-effective prices for the NHS and Pharma is there to innovate and produce new drugs. Pharma is a big part of the UK economy so we need to support it. Economics is about the big picture, i.e. macro-economics. Saving money in one disease area may have unintended consequences elsewhere. NHS England and the Government understand this and don't want to rock the boat. Sweden has rocked the boat, which may yet have consequences for their healthcare system.

    2. Saying the above we need to rock the boat. Not all people with MS live in high-income countries that can afford high-cost drugs. We need an alternative model to get them access to effective DMTs. This is why we promote off-label prescribing.

    3. I think Sweden is beginning to row back on their rash decision(s). After saying NO to Daclizumab, they have just said YES and Swedish neurologists will now be able to prescribe daclizumab to their patients.

  1. Hm. Can't get it. How one could have generic MAB?Isn't it supposed to pass all trial stages that original rituximab passed to get licensed?

    1. That's the big question with biologicals such as monoclonal antibodies. Can't see pharma releasing the original hybridomas to generic companies so presumably they'd have to start from scrtach, so still an effective monopoly I guess, unless anyone knows different?

    2. We have been using cheaper copies of TNF alfa inhibitors for years now and they are just as good as the originals. Biotechnology has moved forward, scaling up techniques work better and the new drugs cost a fraction of what the original mabs were costing. BTW, pharma pricing is total confabulation. They will, of course, tell us elaborate stories about how much development costs ( yes it does), how many compounds bite the dust before they see the day's light (yes they do), and how expensive production is (it is NOT), but when the drug hits the market they have no shame whatsoever. It is pure cold-blooded extortion.

    3. The sequences of the antibodies are in the public domain and they are easy to make if you know how. I don't but I know a man and woman that does.In fact we have made commercial antibodies in a couple of weeks…what do we want it for?. That's secret.

  2. I do understand the huge cost of R&D and investment by Pharma but they can be sooo exasperating. So many me-too drugs, not exactly ground-breaking stuff! And HUGE profits! Thinking back, would we have Lemtrada if neuros hadn't started using off-label Campath 10+ years ago? As for the fiasco when Genzyme took it off the market and £££££ the cost :-(So rock away I say 😉 and the world thanks you for the Barts off-label list 🙂

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