Several things often happen together for a reason and then make you sit up and think.
Firstly, I got a tragic email from a young woman, who lives in Los Angles, who was recently diagnosed with MS. Unfortunately, she is unable to get herself onto a DMT due to being uninsured. She describes having quite active MS and unless she is treated early and effectively will almost certainly be unable to continue working. She was desperate enough to ask about what would be required for her to move to the UK to live, work and have her MS treated in the UK. Although moving to the UK is possible she would need to have a work permit and a job. Instead of the latter, I put her in contact with a very compassionate neurologist in LA who I am sure will be able to weave some magic and help get this poor lady on one of the compassionate access programmes the Pharma companies run in the US.
Only weeks after receiving this email the BMJ has run a feature on US Healthcare focusing on the 27 million people who are uninsured. Jullie Rover, Chief Washington correspondent, Kaiser Health News, describes how healthcare is a partisan issue in the US and that is unlikely to be sorted out by the respective political parties in the near future. This is despite healthcare costs becoming a major political issue for Americans (see an excerpt from her article below).
Excerpt: “In 2003, according to the Kaiser Family Foundation, a non-partisan policy analysis group, 60% of Americans surveyed said insurance coverage was the most important health matter, with 33% saying the cost was the most important. In 2018, by contrast, that had almost exactly reversed, with 59% saying the cost was the most important health matter in their lives, and only 26% saying coverage. A separate poll by researchers from the Harvard TH Chan School of Public Health and elsewhere also found healthcare costs near the top of voter concerns, with 70% calling health affordability ‘a very big problem’. ” Julie Rovner. The complicated, political, expensive, seemingly eternal US healthcare debate explained. BMJ 2019;367:l5885 (Published 10 October 2019).
Now one could argue, and many do, that affordability and access to high-cost DMTs is a rich-world issue and has little relevance to middle- and low-income countries. However, you would be wrong.
I recently had an email from a neurologist in Venezuela asking for advice about how to manage one of her patients with active MS when there were almost no available DMTs in her country. After email ping-pong, we settled on low-dose methotrexate as being the only immunosuppressive or immunomodulator available to her. There was no supply of azathioprine, leflunomide or parenteral cladribine. In other words, Venezuelan neurologists and doctors have to make do with what was is available. Surely treatment with an off-label medication is better than no treatment?
What about the Syrian refugee with MS living in a refugee camp in Lebanon? The email I received from her sister, brought tears to my eyes. I have lost contact with them, but after speaking to a friend and colleague in Beirut I was led to believe that the Lebanese government and healthcare system would help them. However, the subsequent email exchange I had with this poor patient’s sister implied that they would have to pay for the DMT privately. I, therefore, recommended off-label parenteral cladribine or leflunomide (pro-drug for teriflunomide). I am not sure if this was ever taken up.
I could go on with case histories of this kind that I have been asked advice on either from the patients themselves, their families and friends, or their neurologists. A list of the countries that come to mind are Tunisia, Morroco, India, Pakistan, Chile, South Africa, Botswana, Tanzania, Egypt, Columbia, Brazil, Lithuania, Ukraine, Poland. Romania, Bulgaria, Serbia and Mexico.
The problem in low- and medium-income countries is access to high-quality MS services and affordable DMTs is highly variable. This is a problem that is not going to be solved easily. One solution we recently explored, unsuccessfully, was the WHO essential medicines list or EML. The MSIF coordinated a multi-stakeholder application, which I co-chaired with Brenda Banwell, to get glatiramer acetate, fingolimod and ocrelizumab/rituximab onto the WHO Essential Medicined List.
The WHO acknowledged our approach but noted that some relevant therapeutic options for MS were not included in the application (azathioprine and natalizumab) or were not given full consideration (rituximab). For the committee to recommend we look at azathioprine again, when they rejected azathioprine in 2015, was odd. To the best of my knowledge, nothing has changed in terms of new data since 2015 to change Azathioprines position as a potential off-label treatment for MS.
As for natalizumab, we did not add it to the EML application because it is still on patent, i.e. expensive, it needs to be given as a monthly infusion, which adds to its expense, and is associated with a high monitoring burden for PML. The latter would be very difficult in resource-poor environments. At the moment the PML JCV serology assay is controlled by Biogen so when natalizumab comes off-patent, and say natalizumab biosimilars emerge, what will happen to the international JCV serology monitoring system that currently exists? Would the WHO take it over from Biogen? Would it be distributed to national labs? Will resource-poor countries be able to incorporate this into their already over-stretched lab systems?
We went through all these factors in our deliberations and came to the conclusion that 6-monthly ocrelizumab, and rituximab if ocrelizumab is not available, would be a better alternative to natalizumab. Another factor was that ocrelizumab is now licensed to treat PPMS. If we excluded ocrelizumab from the list what message would this send out to PPMSers in the world? In addition, the monitoring requirements for anti-CD20 therapies are much less burdensome than natalizumab, although this may change as the long-term safety profile of anti-CD20 therapies changes with time.
So we can take the punch on the chin, get up and start working on the next application that will be due in 2021, or does the MS community need to do something else?
The question I have asked myself is “Do we really expect people with MS living in resource-poor environments to wait another 2-3 years for the WHO to deliberate and possibly add MS DMTs to the EML and then for countries to enact changes?” If the drugs are high-cost, and they are likely to be high-cost, then poorer countries will just ignore the WHO EML. This doesn’t help people living with MS now.
I think it is time to act local and to start a grass-roots movement based on local MS champions to get MS diagnosed, managed, and care for properly in these resource-poor environments and to get off-label prescribing high-up on the agenda.
If you are from a resource-poor country the following are the nine options that we at Barts-MS have supported in the past. Not all of these options will be available, or appropriate for your county. For example, rituximab biosimilars are still relatively expensive and require quite a sophisticated infrastructure to deliver them, but this is not insurmountable as many countries, in even high-income countries, have adopted off-label rituximab treatment for MS with gusto. In comparison, in very low-income countries drugs such as leflunomide (class 1 evidence), subcutaneous cladribine (class 1/2 evidence) and possibly azathioprine and methotrexate may be more appropriate.
*on the 19th WHO Model List of Essential Medicines (April 2015)
So what next? If you live and/or work in resource-poor environments and want to start a grassroots movement can you please register your interests using the google form below. We can then arrange a web-based meeting to formulate a strategy. I envisage us putting in place a simple diagnostic and management algorithms for resource-poor environments and writing detailed protocols for each of the drugs on our essential DMT list. This list is not exhaustive and we can add or even cull agents from this list if they are not appropriate for your country.
We may feel the need to get your local patient organisations behind this initiative, but unfortunately, many receive a lot of funding from Pharma, are openly conflicted, and hence tend to be against off-label prescribing as a solution to the management of MS. This is why patient organisations tend to prefer and support access schemes.
I have been down the access route. A few years ago I tried with Biogen to implement such a scheme as a test case in Zambia, but we failed to get it off the ground. There were too many hurdles, politically and logistically and there was a question mark about its long-term sustainability. It would have been unethical to provide the free drug to a patient with MS for say 3 or 4 years for the scheme to be discontinued because the local healthcare system couldn’t take over the prescribing and monitoring of the drug sometime in the future.
Another solution is a market solution, which the Medicines Patent Pool (MPP), a United Nations-backed public health organisation is exploring. The MPP licenses patents of high-cost drugs from Pharma and then sublicenses them to generic companies to produce a generic equivalent for low- and middle-income countries. This model has worked very well for HIV and more recently for hepatitis C. I am working with the MPP at present on MS. Although the MPP does great work it will take time for this to happen and does not address the unmet need now.
So if you want to join and help with a Grass Roots Off-Label DMT Initiative (GROLDI) please join by signing-up below. We were planning to start this almost 4 years ago but realised we couldn’t do this on our own. However, recent events, particularly around the WHO-EML debacle, have made it clear to me that we have let so many people living with MS down over the last 4 years that I feel guilty. However, it is not all bad news; in the interim, under the leadership of Prof K, we have developed our subcutaneous cladribine protocol that you can download and start using now (see below).
I have accepted several invitations over the next 12 months to speak about MS and its management in resource-poor countries. I will use these trips to raise off-label prescribing high-up on the agenda and to find as many GROLDI champions as possible.
Mao et al. Cladribine: Off-label disease modification for people with multiple sclerosis in resource-poor settings? Mult Scler J Exp Transl Clin. 2018 Jun 26;4(2):2055217318783767.
BACKGROUND: A considerable number of people with multiple sclerosis (pwMS) live in low- and middle-income countries (LMIC), where lack of resource adversely affects access to effective disease-modifying treatment.
OBJECTIVE: The objective of this commentary is to propose a useful cost-effective disease-modifying treatment option for pwMS in LMIC with potential high efficacy and high convenience to the pwMS and treating physician.Viewpoint: We propose using generic 2-chloro-2′-deoxyadenosine (cladribine), a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II and III trials to be a highly effective disease-modifying treatment for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high-income economies where an oral preparation has recently been licensed by the European Medicines Agency.
CONCLUSION: Our viewpoint takes into account experience we have gathered over the past three years in the use of generic cladribine to treat pwMS. Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.