Tag: off-label

It’s a fine line

Barts-MS rose-tinted-odometer: ★★ (Monday feels like an orange day; an orange cocktail day)

“I can’t wait for the next MS breakthrough; it will take 10-15 years to reach the clinic. I have smouldering MS and I need to do something about it now. Tell me Gavin what would you do if you were in my situation ?” PwMS

I have just had a call with a person with MS who I know very well. This person is not a patient of mine but he was asking me honestly what should he do about maximising his chances of doing well. He has been reading my recent blog posts and feels he needs to do something about his MS. He said he doesn’t want to have any regrets. 

In summary, he is middle-aged (49 years of age) and was treated with dimethyl fumarate for 6 years and was switched to ocrelizumab shortly after it was licensed. The switch was not because of breakthrough disease activity; he just thought he needed to be treated with a more effective DMT and the private neurologist who he saw recommended against having HSCT or alemtuzumab. He remains relapse and MRI disease activity free but has noticed his left leg dragging after walking long distances. His memory is not as good as it was in the past and he suffers from cognitive fatigue. He just knows he is getting worse regardless of what his EDSS and MRIs are showing. He knows he has early SPMS or smouldering disease.

What should he do? 

In the past I have always told my patients I am an academic and I can’t recommend X or Y because the evidence is just not good enough that they will make a difference. I also don’t want to be viewed as the MS expert who is recommending off-label or unproven therapies. The line between being an evidence-based practitioner and a quack is a fine line. 

Do I tell him to hang in there and wait for an evidence-based therapy to emerge or do I give advice about things that may make a difference? If I did give him advice would a scientific rationale be enough (preclinical data) to support my position or should my advice be based on data from preliminary trials in people with MS? Do you think it is irresponsible to give generic advice on managing smouldering MS? Finally, do any of you have advice on how you are self-managing your smouldering MS? 

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Affordable DMTs

My post on the ‘Damp Squib’ has upset several close colleagues. I need to explain my reasons for doing it; the main one being is that I am very frustrated that change happens so slowly, whereas shit happens so quickly.

The catalyst for our Barts-MS off-label initiative was my sabbatical 5 years ago and kicked-off with a blog post I did on the 3rd October 2014. I am ashamed that it is now 5 years since our first activities in this space and nothing has really changed for people with MS living in resource-poor environments. I can count the number of centres on one hand (excluding rituximab users, which is really a high-cost DMT) that are using off-label DMTs and they are all in high-income countries. As a proponent of ‘Time is Brain’ in MS, and that includes the brains of pwMS living in resource-poor countries, I have to ask myself how many brains have been shredded whilst we procrastinate. We want this campaign to become urgent. 

A good analogy would be the anti-retroviral access campaign that was run to get people with HIV living in low- and middle-income countries onto treatment. Why can’t we do something similar for people with MS?

When I criticise my colleagues I want to make it clear that there is likely to be an unconscious bias against off-label prescribing of generics and biosimilars despite a robust evidence base. This is the invisible elephant in the room. Whenever I have attempted to shift this issue to the top of the agenda it gets watered down and put at the bottom of the list of solutions for treating people with MS in low- and middle-income countries. In addition, the term off-label tends to be avoided and replaced by euphemisms, for example, repurposed. 

I suggest we avoid off-label and use a neutral term that will be all-encompassing and acceptable to all parties. I, therefore, suggest referring to these treatments as “affordable DMTs”, which is counterbalanced by the term “high-cost DMTs”. Affordable captures everything we are trying to do without stating the obvious. The term ‘affordable DMT’ solves the issue as it not only refers to off-label DMTs, but includes generic, biosimilar, and bioequivalent DMTs, and unlicensed and compounded DMTs and any other variation that emerges. In addition, what is affordable may vary from one country to the next.

It is clear that a lot of people in the MS community don’t want to rock the boat when what we really need to do is capsize the boat. Many of my colleagues, including me, are so conflicted that we tend to toe the Pharma-line because we have been indoctrinated by the system, i.e. the only solution to treat and manage MS is with high-cost innovative DMTs. This is clearly not the case and we need to collect and summarise the evidence to make the MS community realise that there are other ways to manage this disease. 

So I want to rebrand this the GRAD Initiative (Grass-Roots Affordable DMT Initiative), which may be more acceptable to the wider community and potentially neutralise our cognitive biases. The plan that I am currently formulating is based on a simple grass-roots movement, starting small and local:

  1. Identifying local MS champions and creating an international network of these champions.
  2. Creating and disseminating an essential affordable DMT list with detailed protocols on how to use each agent.
  3. Modified diagnostic criteria for use in resource-poor environments; these will need to country-specific.
  4. Protocols for derisking and monitoring DMTs in these environments.
  5. Creating a platform to allow neurologists and other HCPs from these countries to share their experience.
  6. Putting in place the suitable infrastructure to collect real-world data to assess the effectiveness of using affordable DMTs in these environments.

We are hoping to try to do something small and local in Africa, India and Pakistan. We plan to visit all these countries/regions in 2020.

Please don’t be shy we need champions and wider engagement from the MS community to make this happen. Please get involved and register your interest.

CoI: multiple

Damp Squib

The Editors’ of The Lancet Neurology weigh-in with a commentary on the decision of the WHO committee not to recommend glatiramer acetate, fingolimod and ocrelizumab for the WHO EML (Essential Medicine List). 

The Editors’ reiterate the usual recommendations to address the challenge of treating MS in resource-poor countries. 

  1. They acknowledge that adequate funding is needed for national health-care systems in low-income settings. 
  2. They suggest treatment guidelines that consider the different resource levels available in each setting, are also essential.
  3. They make the point that easily accessible training and peer-support for neurological specialisation would enhance multiple sclerosis care worldwide. 
  4. They highlight that the cost of treatment could be tackled either through 
    1. negotiations with the pharmaceutical industry 
    2. differential pricing (ie, the drug price varies according to several parameters such as affordability)
    3. voluntary licensing through organisations such as the Medicines Patent Pool
    4. or by looking at the potential of repurposing medicines already available in low-income settings for other diseases

They conclude with the comment that “it is essential to ensure that people with multiple sclerosis have timely access to safe and effective treatments. Repeated strong global advocacy efforts through organisations such as the WHO are needed to reduce the global burden of multiple sclerosis”. 

Why didn’t the Editors call for a political campaign to challenge the WHO? In my opinion, their editorial is a damp squib; it is far too passive, it lacks energy and direction. I suspect it will not make an iota of difference for people living with MS in low- and middle-income countries. Do they really care?

What we need is for the MS community to learn from HIV-activists and Amnesty International. We need a start a letter-writing campaign targeting all WHO country representatives to move multiple sclerosis up the WHO agenda. The letters need to be country- and region-specific with hard data and emotional stories. For example, personal narratives of how hard it is to live with MS on the streets of Kibera in Nairobi or in Diepsloot on the outskirts of Johannesburg. The targets need to be wider than the WHO and include health ministries, politicians and other people of influence. 

Diepsloot, Johannesburg, South Africa; image from Wikipedia

The access campaign needs to be managed and run like a political campaign. It needs a public relations and multi-media plan. The question I am asking is why is this not happening already?  Who is responsible for making it happen? One of the problems is that organisations who are meant to be representing pwMS are conflicted and essentially in the pockets of big pharma. Their committees are stuffed full of representatives who are conflicted and will not rock the boat. If you are interested in how far the tentacles of Big Pharma extend you need to read Ben Goldacre’s book ‘Bad Pharma’ or the House of Commons Health Committee report on ‘The Influence of the Pharmaceutical Industry’. 

To the get to the bottom of this, I have briefed a journalist to investigate these conflicts to see if they may explain the apathy of the MS community to address access to DMTs in resource-poor environments. 

The plan that I am currently formulating is to come at this via a grass-roots movement. I suggest starting small and local:

  1. Identifying local MS champions and creating an international database.
  2. Creating and disseminating an essential off-label DMT list with detailed protocols on how to use each agent.
  3. Modified diagnostic criteria for use in resource-poor environments; these will need to country-specific.
  4. Protocols for derisking and monitoring DMTs in these environments.
  5. Creating a platform and network to allow neurologists and other HCPs from these countries to share their experience.
  6. Identifying countries with suitable infrastructure to collect real-world data to assess the effectiveness of off-label DMTs in these environments.

Barts-MS Essential Affordable DMT List

  1. Azathioprine*
  2. Cladribine
  3. Cyclophosphamide*
  4. Fludarabine*
  5. Leflunomide
  6. Methotrexate*
  7. Mitoxantrone
  8. Rituximab*
  9. Generic dimethyl fumarate (Skilarence)
  10. Compounded dimethyl fumarate
  11. HSCT

*on the 19th WHO Model List of Essential Medicines (April 2015)

If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments please sign-up to our Grass Roots Affordable DMT Initiative (GRAD Initiative)

The Lancet Neurology. Essential medicines for patients with multiple sclerosis. EDITORIAL| VOLUME 18, ISSUE 12, P1067, DECEMBER 01, 2019.

Compounding Pharmacies

“It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness, it was the epoch of belief, it was the epoch of incredulity, it was the season of Light, it was the season of Darkness, it was the spring of hope, it was the winter of despair, we had everything before us, we had nothing before us, we were all going direct to Heaven, we were all going direct the other way – in short, the period was so far like the present period, that some of its noisiest authorities insisted on its being received, for good or for evil, in the superlative degree of comparison only.”

A Tale of Two Cities (1859) is a historical novel by Charles Dickens. 

Although global inequality seems to be receding since its peak in 2016 we still live in a world of ‘the haves’ and ‘the have nots’. A stark reminder of this is for people living with MS and having to experience global inequality in access to effective MS therapies.

My memory of a relatively wealthy young woman with MS in Banglore, India, who I met back in 2014 when on sabbatical, reminds me that we have so much still to do. This woman was having to raise money from her extended family, and her social network, to purchase her weekly Avonex injection one syringe at a time. If she couldn’t raise the necessary money she would simply miss that week’s injection. Her neurologist informed me that since developing MS her family was facing financial ruin. The question I asked myself later was ‘Why wasn’t her neurologist treating her with an alternative DMT that she could afford?”. Therein lies the problem, i.e. how do we get the neurology community and wider MS community to accept that there are cheaper, effective, alternatives for managing MS in resource-poor environments. 

Please note that I prefer using the term resource-poor environments and try to avoid using the term resource-poor country. This is deliberate because even in rich countries there are pockets of disenfranchised people without access to healthcare, for example, refugees, immigrants and the medically uninsured.  Britain may soon be included. In the event of a no-deal Brexit, a large number of foreign EU nationals with MS living in this country may have their free-access to the NHS withdrawn. At present, there is no clarity on how the EU and the UK will deal with healthcare coverage in the event of a no-deal Brexit.

As an MSologist with a large number of EU nationals under my care, the prospect of a no-deal Brexit gives me sleepless nights. How will we respond to a scenario of a home office and/or NHS official demanding that we stop prescribing high-cost DMTs to some of our patients? Rebound MS disease activity on withdrawing natalizumab or fingolimod is potentially life-threatening. 

It is essential that the MS community seek solutions for treating people with MS in resource-poor environments. This is why we are exploring different solutions including prescribing low-cost off-label DMTs, developing compassionate access schemes, creating low-cost generics and buyers clubs. Another grass-roots solution is to use compounding pharmacies.  

In short, compounding refers to the process of creating a pharmaceutical preparation or drug by a licensed pharmacist to meet the needs of a community when a commercially available drug does not meet those needs or is too expensive. When you look at our list of essential off-label DMTs we could add dimethyl fumarate to that list. There will criticism from Pharma that compounded, or home-brew, DMF formulations are inferior. But when it comes down to a choice of either bankrupting your family due to the high-costs of innovative treatments or taking a chance on a compounded formulation of the drug I know which one I would choose. 

We have previously covered the topic of a DIY DMF formulation on this blog and you can read how to make your own DMF tablets via this website. I am not advocating that individual pwMS do their own compounding, but this could be done centrally via a licensed compounding pharmacy. The quality of the compounded formulations could then be tested using an international quality control laboratory. The latter could be funded by the global MS community (MSIF) or charities with a vested interest in finding solutions to this problem, for example, the Melinda and Bill Gates Foundation or the Wellcome Trust. 

How to make a DIY version of Tecfidera or DMF

Obviously, Pharma will object and produce papers such as the one below claiming their product is superior and that compounded formulations are inferior, but maybe this will nudge them to do something about the hundreds of thousands of untreated people living with MS in resource-poor environments. To be fair to Biogen they were the only Pharma company who responded to my call-to-arms a few years ago about trying to find a solution to treating MS in resource-poor environments and I note that one of their senior executives has already signed up to our Grass Roots Off-Label DMT Initiative (GROLDI). To do this is bold and I suspect brave, but their action shows you that even Pharma executives are prepared to acknowledge that access to DMTs is a global problem.

Please note our Barts-MS Essential Off-label DMT list has just been expanded to include compounded DMF and the generic version of DMF that is used to treat psoriasis. 

  1. Azathioprine*
  2. Cladribine
  3. Cyclophosphamide*
  4. Fludarabine*
  5. Leflunomide
  6. Methotrexate*
  7. Mitoxantrone
  8. Rituximab*
  9. Generic dimethyl fumarate (Skilarence)
  10. Compounded dimethyl fumarate
  11. HSCT

        *on the 19th WHO Model List of Essential Medicines (April 2015)

Compounding pharmacies could be one way of improving access to DMTs in low-income countries. Do you think compounding pharmacies will address the problem of access to DMTs in resource-poor environments? Let us know your thoughts. 

If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments post please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI). 

Thank you.

Boulas P (Biogen, Cambridge, MA, USA). Compounded Formulations of Dimethyl Fumarate Show Significant Variability in Product Characteristics. Drug Res (Stuttg). 2016 May;66(5):275-8.

BACKGROUND: Pharmacy compounded products are not regulated to the same standards as commercially available, approved products, increasing potential safety and efficacy risks to patients. This report describes an in vitro study examining consistency of content and release profile of compounded dimethyl fumarates.

METHODS: Samples of compounded dimethyl fumarate (cDMF-A, cDMF-B, cFumaderm) from separate Austrian compounding pharmacies were analyzed for drug content, uniformity of dosage, impurity, and in vitro release.

RESULTS: The average dimethyl fumarate (DMF) content ranged from 102.5 to 96.7% of the 120 mg content listed on the product labels. While the DMF capsule-to-capsule content of cDMF-A was somewhat uniform (~20% difference), there was greater variability amongst cDMF-B and cFumaderm capsules (> 30% difference). Impurity testing revealed 2 and 4 unknown components within cDMF-A and cDMF-B, respectively, with levels ranging from 0.05 to 0.81% of total drug content. In in vitro testing of cDMF-A,>10% (12 mg) of DMF was released after 120 min in simulated gastric fluid and 17% (20 mg) released in simulated intestinal fluid after 60 min. While minimal amount of DMF was released from cDMF-B in simulated gastric fluid, 50% (60 mg) of DMF was released after 60 min in simulated intestinal fluid. Similarly for cFumaderm, a fraction (< 20 mg) of the 120 mg target dose was released after several hours in simulated intestinal fluid. The uniformity of release rates across capsules varied significantly.

CONCLUSION: These results demonstrate that compounded fumarates are not equivalent to licensed products and may present unknown safety, efficacy, or quality risks.

CoI: multiple

Buyers Club

Have you seen the film Dallas Buyers Club? It is one of the movies that haunt me and keeps coming back to me in my thoughts and dreams. I now know why.

Dallas Buyers Club is a 2013 American biographical drama about a patient diagnosed with AIDS in the mid-1980s when there were no licensed treatments for HIV. It was in an era when HIV infection was highly stigmatizing. Out of desperation, the main character  Ron Woodroof, brilliantly played by an anorexic-looking Matthew McConaughey, establishes the Dallas Buyers Club, to smuggle unapproved pharmaceutical drugs into Texas for treating his symptoms and starts distributing them to fellow people with AIDS. As a result, he faces massive opposition from the Food and Drug Administration (FDA) and most sectors of the medical establishment. The movie is a monument to the human spirit and our desire to live and be treated as equals. 

McConaughey and Jared Leto, who played Rayon a transgender AIDS patient, received the Academy awards for Best Actor and for Best Supporting Actor, respectively in the film. The film also won the Academy Award for Best Makeup and Hairstyling and was nominated for Best Picture, Best Original Screenplay, and Best Editing.

If you haven’t seen the film it is a must, but be warned you won’t finish seeing the movie without shedding a tear.

So what has it got to do with MS? In the latest BMJ, there is an article on Buyers Clubs in general. They are now quite common in the UK and have evolved out of the desperation of patients and their families to access treatments for many conditions where there is a current lack of access to specific medications under the NHS. Interestingly, the London gay community have set-up a buyers club to purchase pre-exposure prophylaxis or PREP to prevent themselves from becoming infected with HIV. There is nothing like the gay community to show us how health activism should be done.

Matthew McConaughey and Jared Leto in Dallas Buyers Club.

Could buyers clubs be the solution for people with MS to access high-cost DMTs in resource-poor countries? Are there any local MS Champions in Kenya, Tanzania, Uganda, Zambia, etc. who are interested in setting-up a buyers club? We could explore the logistics and cost of purchasing generic equivalents of high-cost DMTs and biosimilars and shipping them into areas of greatest need. I am sure we could find some philanthropic neurologists in these areas who we be able to screen, monitor and look after these people with MS who need treatment? One successful buyer’s club could become a template on how to clone and reproduce them across the world.

Buyers clubs could even become a way of improving access to DMTs in middle-income countries with inadequate socialist healthcare systems; for example, many people with MS  in Eastern Europe can’t access DMTs or have limited access to newer generation high-efficacy DMTs. 

Do you think buyers clubs will address the problem of access to DMTs in resource-poor environments? Let us know your thoughts. 

If you are interested in helping address the issue of lack of access to MS DMTs in resource-poor countries and environments post please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI). 

Thank you.

CoI: multiple

Off-label methotrexate

Prior to interferon-beta being licensed, I used to manage several patients under Prof. W. Ian McDonald who were insistent on being on treated with some form of DMT. The rationale was better to be on something rather than nothing. At the time there was some evidence that methotrexate was effective in MS and as it was relatively safe, so Prof. McDonald acquiesced. In retrospect, I have no idea if these patients responded or not as we didn’t monitor them clinically nor with MRI. How things have changed since then. 

As you may be aware there is class 1 evidence that methotrexate works in RA and some evidence that it works in MS as well (see below). I suspect it works rather well and in an era of treat-2-target of NEDA (no evident disease activity) it would seem reasonable in resource-poor settings to try oral methotrexate and if there was breakthrough disease to switch to another agent.

T2T-NEDA changes the dynamic of how we use DMTs; instead of leaving someone on a suboptimal or ineffective therapy we move onto something else. However, T2T-NEDA does mean that resources need to be found to do annual MRI studies or potentially peripheral blood neurofilament levels to monitor for treatment response. This I suspect will be a problem in resource-poor countries, but even then clinicians could fall back onto clinical monitoring, which is better than nothing. 

What I am saying is yes, if I was working in a healthcare system with limited access to licensed high-cost therapies I would consider low dose oral methotrexate appropriate as one of the off-label first-line DMTs in active relapsing MS. This is why low dose oral methotrexate is on the Barts-MS essential off-label DMT list for treating MS. 

Interestingly, several US neurologists are still using low-dose oral methotrexate for patients in their care who don’t have medical insurance coverage. It is quite interesting to note that we all want to do the best for our patients and adapt our prescribing behaviour to achieve this aim. 

This is why when a neurologist in Venezuela recently asked me for advice about how to manage one of her patients with active MS we settled on low-dose methotrexate; in reality, it was the only immunosuppressive or immunomodulator available to her. There was no supply of azathioprine, leflunomide or parenteral cladribine the other 1st-line DMTs on our essential off-label DMT list.

I don’t expect methotrexate to be highly effective, but probably it will fit in the moderate efficacy zone. The important thing is that works in some patients without causing catastrophic health expenditure or ruinous poverty.

Please note the low-dose methotrexate trial in chronic progressive MS (SPMS & PPMS) is the one study that we use as an example to support our length-dependent axonopathy study. Approximately two-thirds of the subjects in this trial had already lost most of their lower limb function (EDSS 6.0 or 6.5), which is why the trial was positive in the upper limbs, but not the lower limbs. 

What is needed is for an MS champion to do a trial of low-dose methotrexate vs. an active comparator or to simply collect real-world data on the number of subjects rendered NEDA on the drug. The investigators should also include regular blood sampling to measure peripheral blood neurofilament levels. In fact, we may be able to use an area-under-the-curve analysis of peripheral blood NFL levels to see how effective methotrexate and other off-label DMTs are in the real world. 

If you are interested in using methotrexate or other off-label DMTs in resource-poor settings please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI).

Goodkin et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995 Jan;37(1):30-40.

Objectives: A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. 

Methods: Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients’ Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. 

Results: Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. 

Conclusion: We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

Goodkin et al. Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology. 1996 Nov;47(5):1153-7.

Background: Methotrexate is a platform therapy for managing patients with rheumatoid arthritis. There is anecdotal evidence that it may work in MS.

Methods: We monitored 56 patients with chronic progressive multiple sclerosis (MS) who participated in a clinical trial of weekly, low-dose oral methotrexate with annual gadolinium-enhanced MRIs of the brain (Gd + MRI). Not of these patients had clinical exacerbations during the 8 months preceding study entry. We also monitored 35 of the patients with serial Gd + MRIs every 6 weeks for 6 months. 

Results: We observed a treatment effect, measured by absolute change in T2-weighted total lesion area (T2W-TLA), in the cohort that completed 6-week scans. We found change in T2W-TLA in this cohort to be significantly related to sustained change in performance on the nine-hold peg test but not to sustained change on the Expanded Disability Status Scale. Gadolinium enhancement of lesions on 6-week and annual scans was uncommon. Prestudy exacerbation frequency appears to be an important consideration in designing future clinical trials in patients with secondary and primary progressive MS.

Currier et al. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry. 1993 Nov;56(11):1217-8.

An 18-month double-blind treatment of multiple sclerosis with low dose oral methotrexate showed it to be well tolerated and suggested effectiveness in exacerbating-remitting MS but not in the exacerbating progressive and chronic progressive stages.

CoI: multiple

Politician G

If I was a politician I would change the way drug regulation works to stimulate repurposing of off-label and unlicensed drugs.

The wider MS community thinks off-label prescribing is accepting second-best. This is not the case.  The fact that a drug has a license or a label for a certain indication is because a pharmaceutical company has submitted an application to one of the regulatory authorities and has been given a marketing authorisation. The marketing authorisation allows the pharmaceutical company to advertise and promote the drug in question for a particular indication. 

Getting a marketing authorisation is not a simple task; it requires a substantial investment in generating the necessary data, analysing it and submitting it in a form the regulatory authorities require. In fact, regulatory submissions are now so complex that a third-party consulting industry has emerged to help the pharmaceutical industry to do their submissions.

Once a marketing authorisation has been granted it often comes with several post-marketing commitments, in particular, a requirement to collect data on safety in the so-called post-marketing environment. There is no way a pharmaceutical company is going to take on a new drug application and the post-marketing obligations unless the financial incentives are there to do it. I was once told by a senior pharmaceutical representative to cover the regulatory costs and post-marketing commitments for an MS-related DMT, global sales would have to be greater than $150M just to break even. Therein lies the problem! 

The upshot of this is that for drugs that are off-patent, have a patent life that is too short for a return on investment or are unlicensed (never been submitted for a license before) there are simply no incentives to license them. These drugs could theoretically be more effective than licensed drugs for a particular disease indication, but without head-2-head studies we can’t tell. A good example of this is the off-label use of rituximab in neuromyelitis optica; it may be good as, or better than, the three new players in the field (eculizumab, satralizumab or inebilizumab) but we may never know. 

Another issue is that the regulatory authorities be it the MHRA in the UK, EMA in Europe or the FDA in the US, rely on the pharmaceutical companies for their funding; i.e. by pharma submitting licensing applications or requesting advice (consulting activities) they pay fees, which are used to run the show. This creates a perverse symbiotic relationship between the pharmaceutical industry and the regulatory authorities and explains why these parties work together to actively discourage off-label prescribing. 

Off-label prescribing undermines both the activities and survival of the regulatory agencies (turkeys’ don’t vote for Christmas) and challenges the current and very lucrative pharmaceutical business model.  

In an ideal world, the regulatory authorities should be funded by the government and be independent of pharmaceutical funding. Regulatory authorities could then be tasked with policing and regulating off-label prescribing; i.e. they could be asked to review the evidence in favour of these drugs and grant these drugs the equivalent of marketing authorisation to support their wider use.

For example, I would envisage the MS community submitting a request to the EMA to review the evidence that rituximab a potential DMT for treating relapsing forms of MS. The EMA would then review the evidence and make a decision whether or not to extend the license of rituximab to cover MS. This would be independent of any pharmaceutical company. I would even envisage the regulators having the power to give a provisional approval with guidance on what data gaps need to be filled for full approval. This would then allow funding agencies and/or healthcare organisations to put out specific calls to the MS community to do the necessary trials to address the regulatory requirements. This would stimulate a robust development path for ‘neglected’ or ‘forgotten’ drugs independent of the pharmaceutical industry. 

Even more radical idea would be to create a division within the regulatory authorities to actually review and address unmet medical problems, which off-patent and unlicensed drugs may address, i.e. for the regulators to actually administer grant funds to do drug-repurposing trials. The latter may even be linked to new legislation to tempt pharmaceutical companies to apply for these funds.

Governments could enact legislation to grant unique marketing authorisations for repurposed drugs, similar to the orphan drug act. In a modern economy, it would be relatively easy to police a system where two products of the same drug could be marketed to make sure that a specific product is being prescribed and used for the repurposed indication, but at different prices. In fact, this happened with pregabalin in the UK. The anticonvulsant patent for pregabalin expired earlier than its patent for pain. Pfizer made sure that the NHS prescriptions for pain were of the more expensive branded formulation Lyrica, and not the cheaper generic formulations. The motivation for policing indication-based pricing would be to incentivise the pharmaceutical industry to repurpose off-patent drugs. In other words, they would get their return on investment.

I think the economists, and possibly the pharmaceutical industry, would like the latter solution to the drug repurposing conundrum because it involves a market solution. Repurposing legislation of this type would open up the possibility of doing innovative combination therapy studies using off-patent medication. The latter is urgently needed in the MS space to address add-on neuroprotection trials.

With Brexit looming and the UK about to leave the EMA, I don’t envisage this sort of solution happening anytime soon. Like the orphan drug act, drug repurposing legislation would need to be done at scale, i.e. at an EU level and not a UK level. At the end of the day, the UK market is simply too small with not enough profit margins to make it worthwhile for Pharma to invest the required amount of money to ensure an adequate return on their investment for repurposing a off-patent drug. 

We can daydream and come up with many potential political solutions for the off-label repurposing issue, but this is not going to help MSers living in resource-poor settings access DMTs anytime soon. So I would please urge you to act local and to help us start our Grass Roots Off-Label DMT Initiative (GROLDI, please sign-up to help) and to remind you of our subcutaneous cladribine protocol, which you can download. There is no reason why we can’t treat MS early and effectively in resource-poor environments. 

Barts-MS Essential Off-Label DMT List

  1. Azathioprine*
  2. Cladribine
  3. Cyclophosphamide*
  4. Fludarabine*
  5. Leflunomide
  6. Methotrexate*
  7. Mitoxantrone
  8. Rituximab*
  9. HSCT

    *on the 19th WHO Model List of Essential Medicines (April 2015)

CoI: multiple

Resilience

Down, but definitely not out!

The WHO rejected our application to get glatiramer acetate, fingolimod and ocrelizumab/rituximab onto the Essential Medicined List. Why?

The following is the relevant section from Executive Summary:

“The Expert Committee recognized the public health need for effective and affordable treatments for multiple sclerosis (MS) but did not recommend the addition to the EML and EMLc of glatiramer acetate, fingolimod and ocrelizumab at this time. The Committee acknowledged the application’s approach to increasing access to MS treatments by prioritizing selected treatment options. However, the Committee noted that some relevant therapeutic options for MS were not included in the application (azathioprine and natalizumab) or were not given full consideration (rituximab). The superiority of presented medicines over other therapeutic options in the outcomes considered (benefits, harms, affordability) did not clearly emerge. The Committee would, therefore, welcome a revised application which comprehensively reviews the relative roles of relevant available medicines for MS. “

For the committee to recommend we look at azathioprine again, when the WHO themselves rejected azathioprine in 2015, is 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 is 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 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.

So we take the punch on the chin, get up and start working on the next application that will be due in 2021. We are a resilient group and we owe it to people with MS all over the world to get them access to effective DMTs.

The following is the MSIF’s press release and the agenda for their meeting in London this Thursday and Friday. Instead of a celebratory mood, I suspect the atmosphere will be more sombre.

We may have lost a battle, but we have not lost the war.

#OffLabel

I am speaking at the Multiple Sclerosis International Federation (MSIF) Access to Treatment and Healthcare meeting next week in London. My talk is on “Off-label opportunities, barriers and risks in availability and affordability”.

My journey to this point goes back 5-years and started when I was on sabbatical and was visiting countries all over the world and seeing how MS was managed. I soon realised that MSers living in resource-poor environments had poor access to MS disease-modifying therapies and other MS services. This led us to formulate an Essential Off-Label DMT list and to start a social media campaign using the hashtag #OffLabel to get people to adopt off-label prescribing of DMTs. We also developed a protocol for off-label cladribine use and have distributed it widely. 

These activities and other factors nudged the MSIF to make ‘access to treatment’ one of their priorities and led to the MSIF submitting an application to the WHO to get three DMTs, albeit licensed DMTs, onto the essential medicines list (EML). If successful (hopefully we will hear next week – fingers-crossed) we will be able to use this as a springboard to raise awareness of untreated or under-treated MS across the world. It will also raise awareness about MS in low prevalence areas and challenge the prevailing dogma that MS is a rich-world problem. 

Please note our essential off-label DMT list is ‘evidence-based’ or at least anchored to licensed DMTs. The following is a new version of the list.

  1. Azathioprine*
  2. Dimethyl fumarate (generic, licensed for psoriasis)
  3. Cladribine
  4. Cyclophosphamide*
  5. Fludarabine*
  6. Leflunomide
  7. Methotrexate*
  8. Mitoxantrone
  9. Rituximab* 
  10. HSCT

*drugs that are on the 19th WHO Model List of Essential Medicines (April 2015)

I am particularly interested to hear stories about off-label treatments in your countries and if any of you are receiving off-label treatments.

Apart from rituximab use, particularly in Sweden, off-label prescribing is simply not being adopted. Why? I think it takes more than a few people standing on a soap-box to make it happen; what is required is a systems change and a whole lot of nudges to get HCPs to start doing it. This is why I have become so interested in behavioural psychology and behavioural economics, which teaches us why information is simply not enough to change HCP behaviour.

CoI: multiple

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