Ethical ethicals

Have you come across the word ‘ethicals’ before?

In some dictionaries, it’s merely listed as the plural of the word ‘ethical’, but the word has long been used to signify “prescription-only medicines”. I was once struck by the term “ethical ethicals”, which has a certain ring to it. I used to believe that, as a concept, “ethical ethicals” is viable. Now I’m not so sure.

There is empiric evidence that in the past, drug manufacture and distribution had a component of benevolence — ethical behaviour — that was not entirely centred on short-term profit taking.

Are you familiar with the disease ‘river blindness’? The condition seems distilled from the essence of science fiction horror movies. A fly bites you, injecting a nematode worm that invades and slowly destroys your eyes. The picture above — of children leading blind adults in Africa — is from the Wikipedia article on onchocerciasis, the other name for this condition. Millions of poor people were affected.

Now consider the actions of Dr P Roy Vagelos, the chairman of Merck. In 1987 he decided to release — free, forever — a new, effective drug for river blindness. I was hugely impressed by his comments:

“Dr. Vagelos said Merck decided to make the drug, Mectizan (known generically as ivermectin), available without charge because those who need it the most could not afford to pay for it.”

Ethical ethicals!

I would not be hugely impressed by such actions today — I would be utterly blown away; I would be convinced I’d been transported to a different universe. The focus, you see, has shifted. Studying how drug companies work today, it’s easy to extract the following themes:

1. Cater for the worried well. Promote ‘health’ rather than treatment of disease — nominally to support tropes like ‘prevent rather than treat’ but actually do so because it’s often well people who have the money.
2. Medicalise everyone. This is most clearly seen in the new US definition of ‘hypertension’ (high blood pressure) where the greater part of the adult population is now amenable to drug therapy.
3. Focus on drugs like monoclonals and gene therapy for high profits — it’s difficult to make knock-offs, and often you have to inject these repeatedly. Think ‘captive audience’.
4. But also put a lot of money into treatments that have no or marginal effectiveness — vitamin pills, cholesterol busters for people who are not actually ill, and so forth. Don’t worry if you have to treat 50–100 people for years to prevent one event — just advertise aggressively, and people will buy. Don’t worry if they don’t even work — or work in just 1% of people. Market well. Our bean-counters can always manufacture arguments of financial benefit.
5. Push the statistics to the limit. Take complete control over study design, analysis, publishing and marketing. Don’t treat disease, just market a product. Indulge in statistical legerdemain to “prove your point” rather than doing good, scientific studies.
6. Push ethics to the limit — Aww, what the heck. Abandon them completely. The starkest example is the marketing of opioids since the mid 90s, closely followed by gabapentin, yapping on the heels of Oxycontin.

7. Charge what the market will bear. Gouge as much as you can out of everything you control.

Mix several of the above, and exciting opportunities blossom. Take spinal muscular atrophy, an uncommon disease that affects children. Usually diagnosed in infancy or early childhood, ‘SMA’ leads to inexorably worsening weakness of voluntary muscles, ending with progressive inability to breath, and death from respiratory failure, or perhaps even worse than death, perpetual dependence on a machine for every breath you take. Or, it used to so lead. Perhaps there’s now something we can do for it?

SMA is a genetic defect — to get the condition, you need a defective gene from both parents. The SMN1 gene codes for the imaginatively named “survival of motor neuron” protein, an important housekeeping protein within cells. The details are complex, but if SMN goes bad, so do the nerve cells that control voluntary muscles. Many infants with the condition never even gain the ability to sit; those that do, deteriorate and soon end up as described above, dead or on perpetual mechanical ventilation. (The SMN2 gene likely influences severity).

Gene therapy provides a ray of hope. Perhaps we can use a virus vector like an adenovirus to insert a working copy of the gene into cells? Novartis seem to have quite deliberately called their offering “onasemnogene abeparvovec-xioi”, so that those who aren’t trained stunt linguists will resort to using the trade name ‘Zolgensma’. Administration of a one-off dose of 110 trillion virus genomes per kg of bodyweight does seem to help these children.

Let’s look a bit more deeply. We won’t dwell on the technical aspects, as you’re likely not that interested in how the SMN1 gene is combined with the beta-actin promoter from a chicken, and some may unwisely be put off by the “frankengene” vision that this conjures up. (Get over it, natural organisms have been seriously messing with genes for billions of years).

An important first question for me is “Where are the data?” In Early January 2021, I consult PubMed and obtain just 38 hits for the drug name. The first describes a case series of patients with thrombotic microangiopathy after receiving the drug, the second relevant article talks of liver toxicity, but let’s skip over these and look at more positive results. Surely there must be lots of these, because on 24 May 2019, the FDA approved the drug for use in all children under the age of two years who have SMA.

A report in late 2019 from Pediatric Neurology describes twelve cases from a phase-1 trial: eleven sat, two can stand and walk; “most remain free of respiratory supportive care”. Note that this is an uncontrolled, open-label trial, but it seems to have been the pivotal trial that garnered FDA approval. So much so, that the same cases have even been published twice! You see, this was an expedited FDA approval.

What more is there now? Waldrop and colleagues evaluated 21 children from Ohio who received the drug. Of the 19 with repeated outcome evaluations, two stabilised, and 17 improved during the initial period of evaluation. Others similarly report small numbers of cases. There are no controlled studies — nor will there likely ever be. Novartis has released preliminary results of 33 European patients in a “phase 3” study, claiming that “six could sit without assistance for more than 10 seconds and 20 could control their head movements”, and two thirds were able to eat without help, but full data are not get available.

Not all reports are even this glowing. Matesanz and colleagues describe a severe case, given not just Zolgensma but also an RNA-interfering therapy (nusinersen), who made “modest motor improvements” but still remains profoundly weak, with “continued systemic complications from her spinal muscular atrophy, including chronic respiratory failure, dysphagia, congenital heart malformation, digit necrosis, and diffuse macular rash.”

It turns out that Spinal Muscular Atrophy is poorly named. Apart from the nerves that power skeletal muscle, multiple other systems are affected, especially in severe cases. SMA can have severe effects on “heart, kidney, liver, pancreas, spleen, bone, connective tissues, and immune systems.” Even with this possibly near-magical therapy, patients may still remain severely afflicted, and may not, in fact, ever be ‘cured’, despite addition of drugs like nusinersen and risdiplam.

At this point, you might ask “How much does this therapy cost?”

But first, can you see that there are marketing opportunities here? “What price the life of a child?” A killing disease — distressed parents — a drug that seems to work, at least in the short term, at least in some children — and we have a winner.

Let’s see. The USA has a population of about 330 million, and this grows at 0.6% per year. That’s close to 2 million births per year. In most countries, SMA occurs at a rate greater than 1:10,000, so this translates to at least 200 new patients per year. Think “revenue stream”.

If we charge $2.1 million a dose, and there are just 200 patients, that’s nearly half a billion dollars per year from the USA alone — even more in the European Union. Actually, these numbers are conservative as there may be as many as 30 new patients per month in the US. Kaching! Rinse and repeat for other rare diseases, and we can bleed entire societies white.

With a World population approaching 8 billion, and a current rate of natural increase of about 1.5% per year, we’re looking at over 12,000 SMA cases worldwide, every year. The numbers then become quite eye-watering: a potential income of over 25 billion dollars per year. The catch, of course is that most countries around the world will balk at the price tag. But, no worries.

Fuck Asia! Fuck South America! Fuck Africa!

We might now ask “In any case, where did they get the $2.1 million price tag?” It seems that the drug company bean counters have done their numbers, at least retrospectively. Malone et al. have done a “cost-effectiveness analysis” that claims benefits for any price under $5M. Interestingly enough, the assumption here is that patients will live for “37.2 years” if given the drug. As the drug has only been around for a few years, even the gods may be a bit bemused by this analysis, however.

Let’s not even talk about evidence that there was extensive manipulation of Zolgensma data prior to FDA certification, as this just hurts too much. We now seem blind to the fact that there are indeed no “ethical ethicals”.

The counter-argument is of course something along the lines of: “But it costs a billion dollars to get a drug onto the market. Pharmaceutical companies invest huge amounts of cash in drug development, and not only do they need to recoup their investment, but they also need to make a living wage”.

This argument neglects a few more-than-minor considerations:

1. What many don’t realise is that most basic drug research is not funded by drug companies! It is funded by the NIH and other public (and beneficent) institutions. Drug companies surely do take risks in profiting from this research — but this has now degenerated into profiteering, which is a different thing altogether.

2. Drug companies are indeed hugely profitable, far more so than most other businesses. This profit is often on the back of the seven themes I listed up above, not simply ‘new drug development’.

I think we need to fix our mistake. But how can these powerful corporations and their leaders be introduced to the concept of “ethical ethicals”? Perhaps suffering children can lead us blind adults in the right direction? Or of course, their tiny, paralyzed hands can be used by drug companies to pluck at our heartstrings.

Dr Jo.