Off-Label Use of Drugs

O

I give you something that is not MS COVID (p.s. thats below).

Laurson-Doube J, Rijke N, Helme A, Baneke P, Banwell B, Viswanathan S, Hemmer B, Yamout B. Ethical use of off-label disease-modifying therapies for multiple sclerosis. Mult Scler. 2021 Jul 26:13524585211030207. doi: 10.1177/13524585211030207. Epub ahead of print. PMID: 34304636

Background: Off-label disease-modifying therapies (DMTs) for multiple sclerosis (MS) are used in at least 89 countries. There is a need for structured and transparent evidence-based guidelines to support clinical decision-making, pharmaceutical policies and reimbursement decisions for off-label DMTs.

Objectives/results: The authors put forward general principles for the ethical use of off-label DMTs for treating MS and a process to assess existing evidence and develop recommendations for their use.

Conclusion: The principles and process are endorsed by the World Federation of Neurology (WFN), American Academy of Neurology (AAN), European Academy of Neurology (EAN), Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Middle-East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) and Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS), and we have regularly consulted with the Brain Health Unit, Mental Health and Substance Use Department at the World Health Organization (WHO).

WHAT DO YOU THINK ABOUT THIS?

MSIF’s recent Atlas of MS survey showed that 72% of countries have major barriers for accessing DMTs. The countries were categorised according to the World Bank’s income groups for analysis: 70% of low-income countries and 60% of countries in the WHO Africa region report no on-label MS DMTs available for use.

A total of 89 countries (87%) use at least one off-label DMT to treat MS. Rituximab and azathioprine were
mentioned by most countries : 69% and 67%, respectively.

A) General principles for the ethical use of off-label DMTs for treating MS and long-term changes needed

  1. Off-label use of DMTs to treat MS should be driven by the need to protect the person’s health.
  2. Off-label use should be evidence-driven* and considered when on-label DMTs are not tolerated, unsuitable for the best clinical outcome, unavailable or unaffordable.
  3. Shared decision-making between persons with MS and their health care professional is especially important when off-label DMTs are considered.
  4. Appropriate information on health benefits and risks of the off-label DMT should be made available to persons with MS by their health care professional during the full disease management pathway.
  5. Outcomes, effectiveness and adverse events when using off-label DMTs to treat MS should be carefully monitored.

Long-term changes needed:

  1. To support evidence-driven clinical decision-making and reimbursement decisions, guidelines for the use of off-label DMTs to treat MS are needed. We outline in (B) a proposed process for evaluating the evidence-base for off-label DMTs and for developing recommendations.
  2. The regulation of off-label prescribing for MS should be further considered and developed both nationally and internationally to support best clinical practice.
  3. Regulatory agencies and other organisations should develop measures to facilitate official registration of off-label use of medicines with a positive benefit–harm balance based on adequate evidence.

*Please refer to point 1 in long-term changes needed for details on support for evidence-driven decision-making.

(B) Process for off-label DMT evaluation and recommendations

The evidence-base available for off-label DMTs is different from medicines that have been granted marketing authorisation, as large phase III trials for MS are often lacking. There is little economic incentive for the pharmaceutical industry to seek regulatory approval for these medicines as they are often off-patent and may compete with the approved DMTs to lower their economic value. The marketing of medicines for off-label use is illegal in many jurisdictions, while off-label prescribing is accepted as an essential part of normal medical practice. Availability and reimbursement of off-label medicines is often limited by health systems, deemed ‘experimental’ (lack of formal clinical trial evidence), or too expensive for the formularies (even if cheaper than on-label alternatives), irrespective of the health authority’s views on efficacy.

Guidelines are crucial for supporting the standardisation and improvement of care, and to inform policy and reimbursement decisions. MSIF, advised by its off-label treatment (MOLT) panel, puts forward the following process for developing guidelines.

Process

  • (a). The convening organisation needs to be committed to impartiality of the outcomes, and free from conflict of interest relating to the funding of the guidelines.
  • (b). A multidisciplinary and international guideline panel should be formed, as a large number of countries are using off-label DMTs. Conflicts of interest should be carefully assessed and managed throughout the process to avoid undue influence.
  • (c). Specific PICO (Population, Intervention, Comparator and Outcomes) questions should be selected to guide and support clinical practice, with consideration of relevant comparators in low-resource settings, for example, off-label use may be the only option available.
  • (d). All relevant evidence should be considered with an understanding of the limitations. An independent, systematic review using GRADE methodology is recommended. Additional considerations not captured in the systematic review may be collated, but considered separately in relation to source and quality.
  • (e). The development of recommendations needs to be structured and transparent. Considerations should also be given to values, equity, acceptability, feasibility and resource requirements (costs). The recommendations need to be clearly justified with emphasis on the criteria used, the importance of these criteria for the recommendations and the judgments made based on the evidence and additional considerations. The GRADE-DECIDE evidence-to-decision framework is recommended.
  • (f). Targeted feedback from key stakeholders and open comment to correct inaccuracies should be part of the process. The final guideline should be published in a peer-reviewed scientific journal with additional modes of dissemination subject to careful consideration. The guideline should be updated on a regular basis when new information becomes available.

In 2018, MSIF applied for three MS treatments to be added to the WHO EML, using a process that considered all on-label DMTs. This application was not successful and the WHO Expert Committee requested a review of all DMTs used for MS, specifically naming two off-label DMTs: azathioprine and rituximab. The WHO request further highlights the need to provide international guidance on whether these off-label DMTs are appropriate to use and under what circumstances.

Azathioprine, rituximab, cyclophosphamide, fludarabine and methotrexate are listed on the World Health Organization (WHO) Essential Medicines List (EML), a list that guides health ministries on the medicines that should be available in all health systems.

MSIF will use this publication, together with subsequent guidelines addressing specific off-label DMTs, to provide tools for national action for MS organisations and health care professionals to discuss off-label DMTs for MS with health authorities, budget holders and payers when making decisions on formularies, national EMLs, national guidelines, budgets and reimbursement systems. The ultimate aim should be for people with MS to have access to a range of safe, effective and affordable DMTs.

I am not going to really comment on this, I will let you have your say but I have to say one thing and that is “subcutaneous cladribine”….I can’t for the life of me fathom why this is not a go-to treatment option and why it is not on the WHO list? I can see the intravenous variant is there

What is the fear of using it? Maybe I should market it as a laxative for Neurologists after all it is the “Scary Drug”…and it must scare the Sh1 out of them:-)

Rituximab costs alot relative to generic cladribine despite similar efficacy. Maybe because the action is similar to fludarabine but not the same and subcutaneous has the same active ingredient to cladribine tablets. Azathiprine appears to be active in the level of beta interferon but we know cladribine is an IRT and has minimal monitoring requirements.

CoI: Multiple and I did waste about ten years of my life Championing Off-label cladribine..I guess people have a fear of this agent..But Now ProfK and I have seen the light:-)…

Remember to Sign up for ChariotMS trial if interested and you get the oral variant…none of this off label stuff:-).

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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MouseDoctor

6 comments

  • You’re reminding me how absolutely fortunate we are, to live in prosperous countries.
    Reality is hard to hear. Certainly testing and being realistic about resources is the adult thing to do.
    Hoping for a cure may not be realistic but I still do.

    • Luis was wondering about that. Isn’t it something to do with being considered a procedure not a drug?

  • Off label treatment is absolutely necessary as labels for DMTs all adhere to this falsely created designations of ms “subtypes” like rrms, spms and don’t conform fully to the reality of the disease and the fact that the shredder is always present regardless of your “classification “. If off label treatment were not allowed people would have really limited options.

    • I’m in agreement with msintheus that off label treatment options must be allowed at this time and I worry that MSIF’s good intentions will backfire . In the US private health insurers determine which drugs to cover in their formulary. Sometimes best options are drugs in formulary that are off label for ones condition. Will the panel’s guidelines make it harder to access these off label drugs? The ethical issue is caused by lack of evidence based data because of lack of drug trials when economic incentives wane. We all want pwms to “have access to a range of safe, effective and affordable DMTs”, But Is it asking too much of an assembled international multidisciplinary policy maker panel to synthesize available evidence and the multitude of the variables which impact each population to make a DMT guideline that is free from conflicts of interests? Am I too cynical because I feel that it will be impossible to free the panel’s guidelines from financial influences, leaving the ethical quandary we started with? Not rhetorical.

  • Fantastic paper by the team at MSIF 🙂 good to see this published and thanks for posting MD.

    Re
    Off-label use of DMTs to treat MS should be driven by the need to protect the person’s health.

    Absolutely! 🙂

    Great to see both rituximab and cladribine (iv) on WHO EML. Cladribine doesn’t even necessitate ongoing hospital visits, monitoring and cost.

    Ironically, a pwMS in a low to middle income country with no licensed dmts could have access to more effective treatment than someone in uk offered only so-called moderate efficacy dmt. How weird is that?

    MD you did not waste 10 years over sc cladribine, you spoke out for its availability, false cancer signal in Movectro trial and ultimately triggered future licensing of Mavenclad.

    I feel conflicted as am a very lucky mouse receiving off-label rituximab in the UK as my only licensed alternative is contra indicated ☹.

    I would work my tail off to speak out for access to effective treatments for pwMS worldwide, regardless of whether on or off-label.

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