Politics – Prof G's MS Blog Archive

Women

Barts-MS rose-tinted-odometer: zero ★s

As I gradually drift into health-related politics I realise that it is not enough just to measure something to trigger a change in behaviour. Information and data don’t change behaviour; carrots and sticks or incentives do. The US study below shows that women in academic medicine are no better off than they were 35 years ago. Women physicians are less likely than men to be promoted to the rank of associate or full professor or to be appointed to the department chair. I wouldn’t be surprised if the same situation exists in the UK and other high-income countries and it no doubt applies to academic neurology and the field of MS.

The discrimination against women and other segments of our population has a pernicious effect on outcomes. If there is no level playing field it affects motivation and performance in the workplace and ultimately the kind of research that gets done, MS services we provide and clinical outcomes of our patients with MS.

We have highlighted gender bias in relation to MS research activities many times before on this blog. In relation to the make-up of MS trial steering committees, speakers at conferences, authors on publications and the faculty of important MS conferences, etc. Unconscious bias is all around us and unless you have an active process in place to address gender imbalances they don’t go away.

My wife who is a feminist is adamant that nothing is going to change regarding gender inequality unless men start to engage and actively promote women in their spheres of influence. I agree with her and more importantly as a father-of-daughters, I have a vested interest in making this happen. In the UK we have the so-called Athen Swan initiative, by which academic institutions have to show that they are addressing the gender gap and depending on how well they are doing they get a rating. This rating was used by the funding agencies to effect change; to apply for research funding from the MRC and NHIR you had to have a gold or silver Athena Swan award, which meant that women were getting a better deal from these Institutions.

This Athena Swan policy was the stick and carrot to make change happen. However, the Athena Swan requirement for funding applications has now been dropped in the UK. As a result, I predict there will be a gradual slide back down the hill and the next generation of women in academic medicine will be let down. I hope I am wrong.

The cynics reading this blog post will ask what thas this got to do with MS? I would suggest you think about the answer to this question and make a comment. Discussing how broader societal issues impact on MS research, MS management and the MS workforce underpins what happens in the field.

Richter et al. Women Physicians and Promotion in Academic Medicine. N Engl J Med. 2020 Nov 26;383(22):2148-2157.

Background: In 2000, a landmark study showed that women who graduated from U.S. medical schools from 1979 through 1997 were less likely than their male counterparts to be promoted to upper faculty ranks in academic medical centers. It is unclear whether these differences persist.

Methods: We merged data from the Association of American Medical Colleges on all medical school graduates from 1979 through 2013 with faculty data through 2018, and we compared the percentages of women who would be expected to be promoted on the basis of the proportion of women in the graduating class with the actual percentages of women who were promoted. We calculated Kaplan-Meier curves and used adjusted Cox proportional-hazards models to examine the differences between the early cohorts (1979-1997) and the late cohorts (1998-2013).

Results: The sample included 559,098 graduates from 134 U.S. medical schools. In most of the cohorts, fewer women than expected were promoted to the rank of associate or full professor or appointed to the post of department chair. Findings were similar across basic science and clinical departments. In analyses that included all the cohorts, after adjustment for graduation year, race or ethnic group, and department type, women assistant professors were less likely than their male counterparts to be promoted to associate professor (hazard ratio, 0.76; 95% confidence interval [CI], 0.74 to 0.78). Similar sex disparities existed in promotions to full professor (hazard ratio, 0.77; 95% CI, 0.74 to 0.81) and appointments to department chair (hazard ratio, 0.46; 95% CI, 0.39 to 0.54). These sex differences in promotions and appointments did not diminish over time and were not smaller in the later cohorts than in the earlier cohorts. The sex differences were even larger in the later cohorts with respect to promotion to full professor.

Conclusions: Over a 35-year period, women physicians in academic medical centers were less likely than men to be promoted to the rank of associate or full professor or to be appointed to department chair, and there was no apparent narrowing in the gap over time. (Funded by the University of Kansas Medical Center Joy McCann Professorship for Women in Medicine and the American Association of University Women.).

Crowdfunding: Are you a supporter of Prof G’s ‘Bed-to-5km Challenge’ in support of MS research? The project being funded is being led by Dr Ruth Dobson; yes, a woman researching MS. So every pound raised will be addressing the gender issue indirectly.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

No patient with secondary progressive MS should be left behind

It was a privilege to be asked to write the foreword to a new policy document, “The Forgotten Many: A 2020 Vision for Secondary Progressive Multiple Sclerosis” dealing with more advanced MS. If you get a chance please read the document.

The ‘forgotten many’ is how people with secondary progressive or advanced multiple sclerosis (SPMS) describe themselves. SPMS has a significant impact on those with the disease, their families, the NHS and society overall.

The lack of efficacy of many of the licensed treatments for the relapsing forms of MS has left people with SPMS with the impression they have a second, different, untreatable disease. Telling someone they have SPMS is not too dissimilar to telling someone they have a terminal illness. For this reason, many healthcare professionals steer away from having this awkward conversation. For those people on a Disease-Modifying Therapy (DMT) for relapsing MS, disease progression conjures up fear that a diagnosis of SPMS will mean them having to stop their treatment.

A further issue is that many people with SPMS are discharged from regular neurological follow-up to local community-based services and their general practitioners to manage any problems. This is despite emerging evidence that aggressive management of MS-related comorbidities and lifestyle interventions can improve MS outcomes. So many people with progressive MS are smouldering away in the community thinking they have an untreatable, but relentlessly progressive disease.

A new report challenges this assumption and makes the case for actively managing and treating people with SPMS. However, to do this there is an urgent need to expand MS services and to develop new MS centres to accommodate these forgotten patients.

The emergence of treatments to treat and modify the course of progressive MS will require a retooling of MS centres and services; an increase in MS neurologists and specialist nurses, more dedicated MRI time for monitoring patients and additional ancillary services to address the massive unmet need associated with patients who have greater disabilities and associated comorbidities.

This report touches on the many facets of managing SPMS and the forgotten many and how we need to find them and offer them a holistic service to improve their quality of life, improve their neurological outcomes and at the same time reduce unnecessary and preventable utilisation of healthcare services. This report is a call to arms for parliamentarians, policy makers, NHS Providers, commissioners as well as the MS community to think differently, work differently and to now reconnect with the forgotten many.

No patient with secondary progressive MS should be left behind.

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

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

CoI: multiple