Resource-poor countries do not have the benefit of all the disease-modifying therapies (DMTs) available in the UK, Europe, and elsewhere. Here I discuss some of the alternative treatments for MS that can be used when the choice of licensed DMTs is limited; I also consider some global initiatives that have provided or could provide additional ways to access some essential DMTs.

Key points

• ‘Off-label’ prescribing describes the use of a drug for an unapproved clinical indication, where significant scientific evidence exists that it is effective; it also includes the use of a drug in a country where it does not have marketing authorisation from the local drug regulatory agencies, even though it is approved for use elsewhere.
• We present here a list of ‘essential off-label DMTs’ that may be used in some situations to treat MS when other DMTs are not available; many clinicians consider off-label use to be better than no treatment.
• Additional factors that limit access to some DMTs for MS include the cost of production, storage, distribution and/or clinical testing and monitoring.
• Since the early 1990s, when interferon-beta was approved for use in relapsing ̶ remitting MS, more than 15 MS DMTs have been licensed and still more are in development.
• In 2023, the World Health Organisation (WHO) added cladribine, glatiramer acetate and rituximab to its essential off-label DMT list; this is a step in the right direction, but there is still a long way to go in ensuring effective, accessible treatment for many people with MS.

What is ‘off-label’ prescribing?

Before a drug is licensed for medical use, it undergoes a series of clinical studies designed to test its efficacy and safety for a named condition. The clinical studies will also determine factors such as the recommended dose, who can or cannot take the drug (e.g. not children or elderly people) and any contraindications (warnings and exclusions) associated with its use in that setting. Following satisfactory completion of the necessary clinical studies, the drug manufacturer may seek a marketing authorisation from the drug regulatory agencies to promote their product for the specific ‘indication’ or indications defined by those studies.  

Drug manufacturers are not legally permitted to encourage off-label prescribing, i.e. the use of regulated drugs for any indications that a country’s government has not formally approved. However, where significant scientific evidence exists that a drug is effective for an unapproved indication, clinicians will not uncommonly prescribe it ‘off-label’ if they believe that using that treatment confers more benefit than no treatment. Off-label use is generally legal unless it violates ethical guidelines or safety regulations. In the case of MS, off-label treatments may be the only option for patients in resource-poor countries or settings, for example, refugees or illegal immigrants without healthcare coverage in high-income countries.

I firmly believe that treating MS with an off-label medication is better than no treatment. The drugs listed in the table below are the options I have recommended in the past for people with MS from resource-poor countries. I call this my ‘essential off-label DMT list’, and it consists of drugs that are not licensed to treat MS but have a sufficient evidence base to give neurologists the confidence that they work. Not all of these will be available or appropriate for your county.

Drugs that are not currently licensed for the treatment of MS but are used in some situations to treat it ‘off label’. Please note that the DMTs included in this list are those recommended by Professor Giovannoni. Cladribine and rituximab are recommended for MS by the World Health Organisation as part of their Essential Medicines List.
HSCT, haematopoietic stem cell transplantation; IRT, immune reconstitution therapy.
* Included in the 23rd WHO Model List of Essential Medicines; **Converted to teriflunomide; ‡ Licensed for MS in some countries but not the UK.

Please note that cladribine in tablet form is licensed for MS in the UK and elsewhere and has recently been added to the list of essential medicines recommended by WHO (see later). Though not licensed for MS, administration by injection or infusion probably has similar efficacy and side effects to the tablet formulations, but this has not yet been established in large phase 3 clinical trials. However, the alternative parenteral formulations may be more accessible in resource-poor countries for oncological indications.

The MS-Selfie InfoCards on our website provide additional information about each drug listed above, including duration and frequency of dosing, assessment of their effectiveness in preventing relapses and long-term disability, and the likely frequency of short-term and long-term side effects.

Access to effective DMTs varies widely

Another factor that restricts availability is cost. Many of the DMTs available in the UK, Europe and other ‘first-world’ countries are simply too expensive for low- or middle-income countries, so their access is limited in those regions. Many newly licensed DMTs fall into this category; once their patents expire, the costs will likely come down because of competition from other companies that can make unbranded, generic copies or biosimilar formulations. This takes time, however.

In some countries, though, even the older, less expensive DMTs are unavailable. The requirements for storing, distributing, administering or monitoring them may be prohibitive, even if the cost of the drugs is not. Below are some case examples of people with MS who have contacted me for advice on how to obtain a treatment for their MS; in such situations, an unlicensed treatment may be the only option.

Access problems are not only experienced in low- or middle-income countries; they can also affect people with limited means living in ‘first-world’ countries.

Advent of effective MS treatments

Shortly after I arrived in London in 1993, the pivotal trial results for interferon-beta-1b in relapsing ̶ remitting MS were announced. Interferon-beta was not the first therapy to be shown to modify the course of MS, but it was the first treatment to be licensed.

Interferon-beta catalysed a remarkable era in MS treatment, transforming the clinical course of the disease. In the past, patients were admitted to the hospital for management of a relapse, a diagnostic work-up or to treat complications of MS, such as pressure sores. Nowadays it is rare for someone with MS to be an inpatient on a neurology ward because current DMTs are so effective at managing the disease. We now have more than 15 products licensed for MS, and more in development. 

Identification of essential ‘off-label’ DMTs

In 2014, I took a 6-month sabbatical and travelled to see how MS was managed globally; I visited MS centres in the US, Canada, Europe, Australia, South America, India, Egypt, the Middle East and South Africa. The situation in India and South Africa shocked me the most. In India, for example, fewer than 2% of people with MS were on DMTs. Unless you were wealthy and had private health insurance your MS was essentially left to run its natural course. This was what prompted me to start my essential off-label DMT list of drugs not licensed to treat MS but with strong evidence that they are effective (see back). <add hyperlink to table p2>

Did this list change things? Almost certainly. When I visited India recently, a leading MS neurologist thanked me for nudging the Indian neurologists to start using off-label rituximab. I was told that around 30 ̶ 40% of people with MS were now receiving a DMT – a considerable increase from 2% in 2014. Moreover, many middle-income countries have implemented state-funded MS treatment programmes. Things do change; it just takes time. 

World Health Organisation’s Essential Medicines List

The World Health Organization (WHO) publishes a biennial Essential Medicines List (EML) to assist governments in low-resource settings to prioritize their spending on medicines. In 2015, I began a collaboration with MSIF (Multiple Sclerosis International Federation) to campaign for better access to MS DMTs worldwide. The MSIF Off-Label Treatments (MOLT) initiative resulted in two submissions to the WHO to get MS DMTs onto the WHO Model List of Essential Medicines.

For the first EML submission (the 2019 list), the MSIF taskforce categorized 15 DMTs according to their efficacy and risk profiles to ensure maximum clinical versatility. Three DMTs were selected: glatiramer acetate, fingolimod and ocrelizumab. The WHO Expert Committee declined to add any of these to the EML but requested a revised application. The subsequent application included cladribine, glatiramer acetate and rituximab. In 2023, the WHO green-lighted these three drugs, and they are now on the EML for treating MS.²    

Rituximab is the first-generation anti-CD20 therapy that depletes peripheral B-cells and was the forerunner of ocrelizumab, a more humanised monoclonal anti-CD20 therapy. A phase 2 trial of rituximab showed that it is a very effective treatment for relapsing MS and was subsequently widely used off-label to treat MS. The wide availability of affordable rituximab biosimilars, real-world evidence of its effectiveness in MS, were the main reasons for the WHO to prioritise rituximab over ocrelizumab and other anti-CD20 therapies.

DMTs for MS now included in the 23rd WHO Model List of Essential Medicines since 2023.

Glatiramer acetate (GA) was chosen because of its safety profile, absence of monitoring requirements and good track record during pregnancy. However, it is a complex therapy with high manufacturing requirements, and therefore not particularly cheap. The cold-chain storage and distribution requirements for GA may be problematic in certain healthcare environments. 

Rituximab may prove the most controversial DMT on the WHO’s EML. Although it is widely used, we still don’t know the optimal dose. Rituximab also has cold-chain and several logistical delivery requirements. There is an issue around anti-drug antibodies (ADAs), which the body produces against a drug, that can potentially interfere with its effectiveness or cause adverse reactions; for further information, see section on anti-CD20 therapies. Assays for ADAs are challenging to access in resource-poor settings. Finally, rituximab is a biological therapy, and the costs remain relatively high. Once ocrelizumab comes off-patent, and biosimilars enter the market, the WHO may wish to consider replacing rituximab with ocrelizumab. The evidence base for ocrelizumab for both relapsing and primary progressive MS is superior to that for rituximab, ADAs are less of a problem and the dose is well established. 

Cladribine was chosen because it is a tablet with a good safety profile, low monitoring requirements and good efficacy as an immune reconstitution therapy. Oral cladribine is still protected by a patent, but when this expires the price will plummet. In the interim, the parenteral formulation can be used by injection or infusion. Cladribine will be the real game-changer.

I can’t overstress the importance of WHO’s decision to include three MS DMTs in the EML. Firstly, the WHO now acknowledges that MS and its treatment are global-level problems. Secondly, low- and low-middle-income countries will now have to recognise that MS is a treatable condition, and they will hopefully now be forced to include the diagnosis and management of MS as part of their healthcare plans.

Other ways to increase access to effective DMTs

Neurologists in resource-poor environments must act locally and start grass-roots movements in their own countries to get MS diagnosed, managed and cared for properly, including off-label prescribing. Patient organisations can participate in this too. Many patient organisations support compassionate access schemes even if they oppose off-label prescribing as a solution to the management of MS.

The Medicines Patent Pool (MPP), a United Nations-backed public health organisation, is exploring another avenue. This is a market solution, whereby the MPP licenses patents of high-cost drugs from pharmaceutical companies 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 hepatitis C. Although the MPP does excellent work, it takes time for things to happen and does not address this patient’s unmet need in the present. 

Conclusions

I have outlined my rationale for using off-label DMTs in situations where licensed options are not available or are hard to access. Let’s suppose that limited access to an effective DMT affects you, as a person with MS. In that case, I recommend approaching your neurologist or other healthcare professional with this information and discussing the possibility of being treated with one of these agents. No one drug is ideal for everyone. The attributes of each treatment vary, as does their availability. Therefore, what is available in one country or healthcare environment may not be available in another. In general, if you have active MS, it is better to be treated than not to be treated. Off-label DMTs should be used in the same way as licensed therapies, based on a treat-to-target of no inflammatory disease activity. If there is breakthrough disease activity, the treatment must be escalated to another more effective treatment.

References

1. McDonell J. et al. World Health Organization Essential Medicines List: Multiple sclerosis disease-modifying therapies application. Mult Scler 2020;26:153 ̶ 8.
2. WHO endorses landmark public health decisions on Essential Medicines for Multiple Sclerosis. WHO Press Release, 26 July 2023.