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
- Azathioprine*
- Cladribine
- Cyclophosphamide*
- Fludarabine*
- Leflunomide
- Methotrexate*
- Mitoxantrone
- Rituximab*
- HSCT
*on the 19th WHO Model List of Essential Medicines (April 2015)
CoI: multiple
Are you really suggesting the FDA or the EMA compare rituximab to the new biologics in NMO?
Yes and no! If the FDA and EMA were independent of pharma funding and had a new brief to address off-label prescribing they could be asked to do due diligence of rituximab as a treatment of NMO. At level 1 this could be reviewing the evidence that rituximab is an effective treatment for NMO. If they were not satisfied they could then fund trials, via a grant call similar to PCORI, for the NMO community to compare rituximab to the new biologicals. These trials could be phase 3 head-2-head definitive trials or they could be pragmatic.
I must remind you that the EMA and FDA can’t do this at present as this is not their brief. I am arguing for to change their remit to look at off-label prescribing, i.e. drugs or biologicals that don’t have big pharma backing.
A brilliant article. I am shocked that Aubagio costs so much. I feel uncomfortable that the Dutch govt (via health insurance companies) has to pay so much for my medicine, (€135 a tablet). I think other models which encourage research and yet don’t potentially bankrupt the NHS are laudable. And are to be encouraged.