#ClinicSpeak: DOTS or no DOTS?

Should we trust our patients to take their oral cladribine tablets or should we make them come to the hospital to observe them doing it? #ClinicSpeak

Summary:  This post addresses the issue of adherence to oral cladribine tablets as prescribed. In addition, the post addresses some of the complexities of drug pricing. 

Wikipedia: DOTS (directly observed treatment, short-course), also known as TB-DOTS, is the name given to the tuberculosis control strategy recommended by the World Health Organization. According to WHO, “The most cost-effective way to stop the spread of TB in communities with a high incidence is by curing it.

The imminent UK launch of oral cladribine tablets (Mavenclad), at a list price of £2,047.24 per tablet, stimulated a debate amongst us at Barts-MS about whether, or not, we should trust our patients taking the tablets as prescribed or we should implement DOTS (directly observed treatment, short-course). One position is to trust our patients. Why? Firstly, if we allow them to collect their own prescriptions via a community pharmacy then the NHS does not have to pay VAT on the price (value-added tax). A DOTS programme will cost NHS England 20% more per tablet. Secondly, isn’t our relationship with our patients based on trust? If we don’t trust them to take their medication then we have failed as educators and as HCPs. The WHO DOTS programme was developed to solve the problem of poor long-term adherence to anti-TB drugs in resource-poor environments, which was selecting for drug-resistant TB strains. I, therefore, don’t think we can compare the treatment of MS with the treatment of TB. 

What would happen if one of our patients drops and loses one of the tablets? I am sure Merck would be understanding and provide a replacement tablet. You need to remember that the manufacturing price of a cladribine tablet is unlikely to be very high and hence it would be relatively cheap for Merck to provide a replacement tablet or pack. The price of pharmaceuticals is really very complex and includes intangibles such as intellectual property, the cost of the preclinical R&D, the costs of the clinical development programme, regulatory, marketing, sales, life-cycle management and the whatever else Pharma does (including paying academics to sit on steering committees, participate in advisory boards, give talks, etc.). 

Oral cladribine tablets have many advantages one of which is taking tablets, albeit for only 16-20 days over a 2 year period with the potential for the treatment effect to last years. Why would we then want patients to come to the hospital so that we can directly observe them taking their tablets? One person suggested that patients may be tempted to sell their tablets on eBay to the highest bidder? Do you think the prescribing of oral cladribine tablets will result in a secondary market? I suspect not in the UK, but I may yet be proved wrong. A potential solution to the latter is to use smart tablets, i.e. each tablet is labelled with a RIF (radio frequency identification) tag that is tracked by a wearable device, linked to your phone, to make sure each tablet is taken as prescribed. Or we can simply trust our patients. What do you think? 

CoI: multiple

29 thoughts on “#ClinicSpeak: DOTS or no DOTS?”

  1. Maybe ask the pharmacist to observe the consumption of the first tablet only? They might charge for this service. But I'm not sure what this would achieve other than the packet would be open. Could the first tablet cause any immediate physiological changes, such as change in heart rate? I might prefer to be at home when starting a new DMT, so I can relax. It's important to trust patients.

    1. Would pharmacist observation of consumption be considered DOT (and cost 20% more for the NHS)? If this is not considered DOT then perhaps pharmacist observation of consumption of all oral cladribine tablets. Rather than going to the hospital.Pharmacists do Observed Consumption for other medications.

    2. The drug causes apoptosis so it is a slow kill rather than a burst which ocrelizumab and alemtuzumab do so this explains the low administration reaction raye

    3. Observed Consumption at the pharmacy could be convenient for pwMS. As there are pharmacies in supermarkets, some open late and at weekends. Most areas have several pharmacies, near home or work.Is Cladribine a DMT that you can just carry on with your everyday routine on the days the tablets are taken? I.e go to work? Over the days when the tablets are taken would the pwMS be more vulnerable to infections?

    4. I suspect you will be more susceptible to infections as you are losing lymphocytes but DrK gives an anti-viral to limit this. Also depletion is not quick

  2. Cost of Ravenclad is like that of really expensive software. You lose the CD, it's easily replaced. CD no use to anyone else without your security key and maintenance/update subscription. Ravenclad no use to anyone else without blood tests and monitoring. Blackmarket would require involvement of corrupt neuro. As if!

    1. Mavenclad to Ravenclad could be auto correction. Please beware when using terms that are not in the dictionary.

  3. Do you know just how imminent for the launch of these tablets in the UK – next few months, end of next year or 2019? If I'm ever fortunate enough to have them as my next DMT, I'm sure I will feel rather nervous about taking them myself at home and guilty too when dear folks with MS in poor countries are having to be left untreated because of the price. How I wish I had the money to pay for your trial of off-label subcutaneous Cladribine.

    1. I was told by someone at the company that they can be got privately now but the official launch will be in 2018.Thanks for the support.Maybe in poor countries they will try the generic. Although "not for human use" science quality CLAD is $17 for 10mg or two and a half pills of the 25g oral…I guess it is similar action to alemtuzumab, therefore its alemtuzumab price.

    2. I didn't oral cladribine in 40 percent bioavailable meaning you only absorb 40 percent of what you eat and this compares to the intravenous or subcutaneous variants which are 100 percent bioavailable meaning 100 percent of what you inject gets into blood so if I inject 10 mg of my 17 dollar drug to get the same amount of cladribine I would have to eat 25mg of the oral version so two and a half pills costing about 5,000 pounds so that would be 6500 dollars.However the actual US price will be even higher if it gets licenced I think alemtuzumab is about 80,000 dollars but I may be wrong.However they did spend about 600-800,000,000 making the geñeric into a pill.

    3. "However they did spend about 600-800,000,000 making the geñeric into a pill"Are you serious?Obrigado

    4. This is the figure we saw on the web in an article, DrK can you remember the source.But when pharma do a trial and do a regulatory package there are lots of people involved and it takes years. The regulatory package was thousands upon thousands of pages for example I have just looked to see the level of lympopenia induced by cladribine that was 3,500 pages just for the lymphocytes now do the maths for each subset analysed and the rest hundreds of thousands of pages that someone has to type and check

  4. What's the difference with the other oral drugs that are pricy enough too? Are there any cases of black market selling before? Why should you doctors play the cops if cops don't at least ask you to because of such events?We should be really discussing about the pricing policy of the Pharma industry, not play hide and seek between us. Even if these events happen -which I think it will be quite impossible- it is still offensive and it is misleading.

    1. …If someone so sick prefers to sell his drugs to take the money, it is the welfare state that has failed, not the patient. And this is definitely not the way to protect the interests of NHS and its provisions.This is a recent research on the unjustified prices of cancer drugshttp://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2653012

    2. If you take the same drug give it to you cat it has one price, give it to someone with cancer it is another price ,rheumatoid arthritis another price and ms another price.I would bet there are a hole list of conditions whereas enclosed will work but I bet they won't be tested until it comes off patent.

  5. It may be available on the NHS in May 2018 according to the MS Trust website:"Cladribine will now need to be appraised by NICE and the SMC to determine NHS availability in the UK. NICE has started the process (link is external) and the MS Trust is contributing to the appraisal. A decision from NICE is expected to be published in February 2018, with the drug potentially available on the NHS in England and Wales three months later."

  6. I think that people should be observed, adherence sounds simple but having people show up and take a pill will ensure that they take it.

  7. I doubt the NHS will be pay the list price. I am sure they will negotiate a price that is much cheaper based on a NICE cost-effectiveness analysis.

  8. Trust the patient. Apart from anything else I couldn't afford the time off work to go to the hospital every day for weeks. Or the taxi fare cos there is no parking.

  9. If it's a short course like abs I think you can trust your patients. If the course is much longer it's very easy, even for a highly motivated patient, to forget/get distracted on the occasional day!

  10. It seems to me that the patients will be motivated, especially if they put some cash down. I've had the shots, and they're easy to tolerate. I think the drugs where you get a bad dose reaction make it much more likely to skip doses. Missed days shouldn't be a problem, given the mechanism.

  11. Wow, maybe I'm naive, never in a million years would I think of someone selling heir MS drugs for profit! Non compliance is another matter….

  12. Is there really a black market for these drugs? I think this needs to be established first and if there isn't then there are really only 2 reasons I can see for people not taking them1. They don't want to2. Cognitive impairment means they forget.If we assume 1 then it's an individuals choice to refuse treatment. Don't give them any more. If it's 2 and they forget to take their drugs then they are equally likely to forget to go to the hospital to take their drugs. Greater role for care givers? I'm on drugs for another condition which i will likely be on for the rest of my life (and we haven't started on MS drugs… Yet). I take them because I want to remain well and surely that's going to be the majority of patients?

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