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20 hours ago
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Twenty miles outside Geneva, beneath the towering magnificence of a mountain called the Rock of Hell, is a long, pleasant road that runs past the Brocher mansion. Set in acres of gentle lawns and specimen trees, on the edge of the medieval village of Hermance, it is a blissful place. My friend Dominic Nutt and I have been trying to break in for years.
La Fondation Brocher is the world’s leading institute for research into “the ethical, social and legal implications of new medical developments”. It’s the bioethics equivalent of the Institute for Advanced Study in Princeton: only the admin staff and the cleaners are permanently employed here; academic fellowships last a maximum of four months. Billions of pounds’ worth of pharmaceuticals are influenced by the scholarly judgments that emerge from this idyllic lakeside building. Dom and I want to force entry because we’re advocates for patients, and we think we’ve solved a small corner of a major problem that’s holding back the discovery of new medicines. The trouble is, neither of us has a PhD – and in the rarefied world of academic medical ethics, that matters.
We’ve never been to the Fondation Brocher, but we’ve cased the joint on Google Maps. Between the bars of the security gates, you can see the glittering waters of Lake Geneva, beside which professors and postgraduates stroll about debating what is best for the world’s sick. Misty in the distance are the northern Alps and the vineyards of the Jura.
The problem we’ve solved is this: every year hundreds (perhaps thousands; nobody knows the real figure) of new, lab-tested drugs are abandoned. There’s often nothing obviously wrong with these potential medical treatments. In the laboratory, they have been shown to melt away tumours, make brain plaques disappear, puff up weakened bones with calcium, help mice and dogs live twice as long as usual. Of course, most of these treatments are likely to turn out to be useless (or even dangerous) in humans, but a few could save lives and ease the suffering of millions. We won’t know unless we do further research. But that research is not happening.
The trouble is financial. According to the Tufts Center for the Study of Drug Development, the leading reason for drugs to fail human safety tests (the earliest phase of human experimentation) has nothing to do with whether or not the drugs are safe; it’s because the scientists run out of cash and so cannot complete the early tests and move on to the next phase. Of the few drugs that get through to later experiments, in which researchers are starting to look for efficacy, almost a further third are dropped for financial reasons, not because they’re ineffective. In the brutal language of the pharmaceutical industry, this gap between lab discovery and the start of the large-scale, late-phase human experiments is called the “valley of death”.
The valley of death doesn’t cost much to cross. In many cases, between £2m and £5m is ample; without that money, no discovery stands a chance. £2m is the price of an Aston Martin Valiant. It’s what it costs to rent Richard Branson’s Necker Island for two and a half weeks. The solid gold toilet that those criminals stole from Blenheim Palace could pay for it twice over.
Industry and government policymakers are flummoxed by how to bridge the valley of death. There are only two broad ways to fund clinical trials: profit-making (venture capitalists, biotech, big pharma) or altruism (charities, government finance). For venture capitalists, the pressures of the market exclude ideas that require patience to investigate, or seem too risky because they’re unconventional. For the altruistic crowd – statutory and benevolent funders – money is tight; the focus must be on drugs that will benefit the most patients with the least risk of failure. Many brilliant potential medications are daring, crazily unfashionable, require decades of dull, careful nurture, or are out of patent and cheap as chips. Products like these don’t appeal to greed or cash-strapped benevolence.
Nobody knows what to do. Except (think Dom and I) me and Dom.
We’re not academics. I’m a biographer and illustrator. Dom’s a type 1 diabetic and a cancer patient in remission who does “comms” – communications. I’m still not sure what that is. (One day, he’s working for a fumbling university, trying to stop them imploding because they’ve got their sums wrong; the next, telling a London borough council how to publicise its garbage truck rota.)
If we’re correct, our idea could generate billions of pounds of money for research. It won’t get drugs all the way to market – the full process can cost anywhere from £50m to hundreds of millions of pounds – but it will help to pick out the products worth a punt. The list of drugs rescued from the valley of death by public intervention is already long: Kalydeco for cystic fibrosis; Gleevec for leukemia; Herceptin for breast cancer. As one researcher once said: “We’ve discovered the cure for cancer twice, but threw it away.”
We want to introduce a third financial force into drug development, alongside profit-making and benevolence – a wild force that everyone in medical research whispers about behind closed doors, but ignores in public with a rictus grin. As a motive to open up your wallet, there’s nothing to beat this force. It’s more powerful than greed and saintliness multiplied. It is desperation.
Our idea is to charge desperate sick people to take part in clinical research. In particular, desperate sick people who are very rich – and their loved ones.
It’s a repugnant suggestion.
Medical ethicists rightly howl at schemes in which participants have to pay to take part in clinical experiments. They’re called “pay to play” trials and, outside poorly regulated countries, they are expressly forbidden. Wretched and desolate patients drain their pension funds, bankrupt their families and sell their houses to join studies based on flimsy research for drugs that don’t work, and could kill. Charging patients to participate is the preferred finance technique for deluded zealots and quacks, because no respectable funding body will touch their sloppy research. The cost to the patient can be anywhere between £7,000 and £250,000. Ironically (as every con artist knows) this prohibitive cost is part of the appeal of pay to play. Something so valuable must be good, thinks the patient. (A few years ago, in the weirdness of Florida, the “young blood project” saw wealthy old people hooked up to blood extracted from teenagers, at a cost of $285,000 each.)
But there are several assumptions in this grim picture of pay-to-play clinical research, whereby desperate patients are fleeced by substandard operators. What if, thought Dom and I, you remove some of them? Take the assumption that pay-to-play trials charge all participants. Why not instead bill only one? Everyone else participates for free (as is usually the case in a respectable study), but this one patient is charged the most absurd sum of all: the cost of the entire caboodle, that £2m to £5m. If such a funding tactic were run by a well-regulated body, on peer-reviewed research, and it is impressed on all participants that new drugs carry huge risks as well as possible benefits, then the usual ethical objections to pay to play disappear. It would work best for small studies, for rare (and frequently underfunded) diseases.
But what sap is going to agree to pay the full cost of a clinical study just to ensure that nobody else has to pay a penny? Anyone who can afford it, say Dom and I. Approximately half a million people in the world are worth more than £10m. They don’t want to die. They have people they love, just like the rest of us; they don’t want them to die either. If these rich people could spend a measly 20% of their wealth to rescue a piece of quality research that may give them an outside chance to save their own lives, or the life of their mother, husband or daughter, they’d do it like a shot.
As for the poorer patients? That’s a quid pro quo: without them there could be no clinical study, because the research would have only one participant, which is statistically useless. To rescue lost drugs, the mega-rich and the poor have to work together, for the weal of all. The rich patient is shackled to benevolence.
I’ve called this idea the Plutocratic Proposal, after Jonathan Swift’s satirical essay A Modest Proposal, in which he suggested solving Ireland’s famine and overpopulation by allowing the poor to sell their children to the rich to be eaten. Dom the Comms doesn’t like the name. Plutocrats turn out not to like it either, especially if they know where it comes from. They think it objectifies them. But I think it’s important to be honest. In Swift’s essay, he suggested using the desperation of the poor to feed the rich; Dom and I want to use the desperation of the super-rich in order to treat the 99.5% of the world that is poorer.
We know the Plutocratic Proposal works, because we’ve tried it.
More than a decade ago, my best friend, editor and co-writer, Dido Davies, was dying from pancreatic neuroendocrine cancer (the same disease that killed Steve Jobs). I heard about a potential treatment in Sweden, flew out to meet the astonishingly open-minded and supportive Prof Magnus Essand, and got him to agree to a deal: if I secured the money that he needed to run a trial, he’d make Dido a participant. I didn’t have £200 to spare, let alone £2m, but I hunted it down. I found an oilman with the disease (living, as it happened, in a mansion just down the road from the Brocher, in Geneva) and got him to give more than two-thirds of the money, also in return for participation. The rest was raised, with considerably more effort and much more skill, by crowdfunding, through the tireless work of Dom and a third campaigner, Liz Scarff. We had successfully rescued a drug and started it on its precarious journey to market.
Dido died on the day our campaign announced it had secured the money. The oilman – a lovely person, called Vince Hamilton – also died before the study could begin. I lost interest in fundraising for stupid, boring life-saving ideas that don’t save lives in time. That was in 2013.
In the 12 years since, several researchers, trawling through the outer reaches of bioethics literature, have come across a paper about the Plutocratic Proposal that Dom and I published in the Journal of Medical Ethics, and got in touch to see if PP (as we initiates call it) could save their underfunded drug. These fleeting collaborations with expertise – sometimes no more than a Zoom call long – have enriched the idea. What began as one counterexample to the idea that all pay-to-play schemes are inherently unethical is now a set of five different proposals, covering early- and late-stage clinical studies, developed in cooperation with bioethicists, medical scientists and the odd biotech executive.
It’s all been done in our spare time. Dom and I are lousy at fundraising for ourselves. That’s because we want different things. Dom is keen to set up a business (“Not-for-profit, of course,” he says determinedly) that will promote high-quality, participant-funded studies and bring in vast sums of new research money. I can’t think of anything worse. I’m terrible at business. I long for a sharp-clawed medical entrepreneur to step in and exploit us, as long they’ll also pay us to go on working on these previously overlooked funding mechanisms.
One collaboration almost led to money. An Oxford don got in touch. He had a potential treatment for Stoneman syndrome, also known as fibrodysplasia ossificans progressiva, a disease in which muscle and connective tissue are gradually replaced by bone, causing the patient to grow a rigid second skeleton. A neglected treatment, a small proposed study, a heart-wrenching story that would make it easy to run a publicity campaign: perfect for the Plutocratic Proposal.
“But only 800 people in the world have it,” warned the scientist.
I did a back of the envelope calculation: 8 billion people on earth, 800 people ... so, one in 10 million ... Trial needs £2.5m … Donor needs assets of, say, £5m-plus … About 2.5 million people in the world are worth more than £5m. So, if you take the chance of having the condition (ie 1/10m) and multiply it by that number of eligible plutocrats, you get … one quarter of one plutocrat.
“More than enough!” I pronounced, delighted.
One of the advantages of PP’s use of desperation as a funding force is that you don’t have to worry too much about calculations like this. The super-rich don’t need to suffer from Stoneman syndrome themselves to feel desperate to finance research. It’s enough that a friend or family member has it, or a friend of a friend. Plutocrats have hearts, and the fact widens the catchment area considerably. A quarter of a plutocrat is as good as a whole.
Our most recent variant of PP is what made me finally get in touch with the Brocher and demand to be let in. It is the most demotic and captivating of our ideas so far and dispatches yet another assumption made by critics of pay-to-play schemes.
A few years ago, a second group of Oxford researchers from the university’s musculoskeletal department got in touch. They’d discovered a potential anti-ageing compound. “Analysis of data from decades of clinical research has shown that, with this drug, diabetes II, colon cancer, bowel cancer, dementia – all the comorbidities of ageing – go into statistical retreat,” Emeritus Prof Graham Russell told me in a disconcertingly matter-of-fact tone from his 17th-century farmhouse outside Sheffield. A recipient of the William F Neuman award for his outstanding contribution to science, Russell is considerably over 80, looks in his 70s, and wants the drug on the market yesterday.
The compound is a bisphosphonate – a small, simple molecule that (when I draw it as a cartoon) looks a bit like a person out gardening. Bisphosphonates have been used as industrial anti-corrosion agents for more than 100 years. If you’ve got an 18-metre cooling tower curdled with metal deposits, pour in a couple barrels of bisphosphonate and it’s clean by Tuesday. In the 1960s, Russell – then a young postdoc – was studying bisphosphonates when he made his first astonishing breakthrough. In that unsettling way nature has of connecting things that have no business being connected, he discovered that certain of these anti-corrosion agents also help with osteoporosis. Bisphosphonates are now one of the leading treatments for bone depletion, and millions of people have benefited from Russell’s work. Sixty years later, he and fellow researchers are proposing that at least one of these bisphosphonates – it goes by the splendid Thunderbirds-esque name of Zoledronate – may reduce the incidence of the diseases of old age.
“But no one will fund us,” says Russell.
Astonishing as that sounds, it isn’t unexpected. Metformin, usually used to treat diabetes, is another well-known drug that evidence suggests can prolong healthy life; it has also struggled for years to get the finance to test the evidence properly. Part of the trouble is that Zoledronate (like Metformin) is out of patent: anyone can make it. It’s difficult to see how big pharma could invest the hundreds of millions of pounds necessary to test its value as a longevity drug, and make money back on the investment.
A more serious difficulty, explains Russell, is the trial itself. Clinical trials are the keystone of medical research – because of them, and only because of them, we have a scientific way to determine whether a new intervention really works or is a delusion. But trials are also very limited. It’s hard to prise meaningful statistics out of the chaotic noise of a human being. Compare it to looking down a road in a thick snowstorm: is that dark shape in the distance a bush? A car? A deer? A stage 4 “comorbidity of ageing” being defeated by a barrel of my specially adapted anti-corrosion agent?
To help get round this problem of noise and complexity, trials operate under artificial conditions. They have to focus on one disease at time, using patients who don’t have a lot of other troubles that might confuse the data: no pregnant women, no children, no people with complex medical histories. But because Russell and his team believe that the comorbidities of ageing are in fact symptoms of underlying cell senescence, not independent conditions, they want to test Zoledronate on a huge clutch of illnesses, all at once, using the most physiologically muddled patients of all: the elderly. It’s an unorthodox idea and funders are orthodox; they have slammed the door in his face.
The first reaction of Dom and I was to think there is no way PP can help either. The Plutocratic Proposal is designed to rescue small-scale studies into treatments for rare diseases, not massive trials investigating the only universal human condition, ageing. But Prof Heather Draper, a bioethicist at the University of Warwick who has taken an invaluable, kindly interest in PP, had a better suggestion. She is an expert in clinical ethics, has writtenabout the Plutocratic Proposal in the British Medical Journal, and still pops up now and then to see how we’re getting on.
“Why not invert the original idea?” she said. “Instead of one patient paying a huge amount to join the study, suggest that everyone pay a tiny sum to participate – say, £5 or £10. It’s like crowdfunding but with an additional perk – participation – and it’s less than the cost of a hospital car park. This approach won’t fund the whole thing, but if the proposed experiment is big enough, and the drug cheap enough, it could help to get it started.”
It is a brilliant solution. Once again, this variety of PP dodges the obvious objections of the critics of participant-funded schemes.
Within the reach of all? Tick.
Beneficial to science? Tick.
Beneficial to society? Tick.
It will have to go through the usual quality checks and peer review, and if it needs to be a placebo-controlled trial, then half the participants will be getting an empty pill. But with proper public engagement (Dom the Comms’ department) I believe most people would still be prepared to take part in such a mass experiment, for a fiver, if in the end we can know whether the drug will help us in our old age or not.
“What shall we call this latest wonderful development in our growing family of ideas,” I say, “where instead of just one person paying a vast sum, we have everyone paying a tiny sum? I know! The Penurious Proposal.”
“No!” Dom and Heather cry out together.
There will be other worries to carefully address, such as data privacy; exploitation of people who think paying anything for a drug means it must be going to do them good; the fact that, in fact, not all people can afford £5.
That’s why we want the Fondation Brocher to drop its requirement that only academics be allowed to run workshops. Patients and advocates need to step in where scholars haven’t dared to go, so that we can polish up our proposed ways to help rescue possibly useless but perhaps world-changing drugs.
“There is one other problem with this potentially amazing pill,” says Prof Russell.
“What’s that?”
“It doesn’t exist.”
Stuck among the mess of blandly functionalist and Edwardian architecture of east Oxford is Britain’s leading research centre for musculoskeletal sciences, the Botnar Institute. Prof James Edwards is the man here in charge of Zoledronate research. A short, boisterous Welshman with a broad chest and his top shirt button undone, he believes that the trouble Zoledronate faces is that not only is it old news as a compound, it’s also inaccessible. At the moment it is available only as an intravenous drip for patients suffering from bone depletion, and costs about £500 a dose.
The evidence for Zoledronate diminishing major illnesses of old age that have nothing to do with bone mass has come in whispers – secondary observations in research papers that are primarily about osteoporosis or patients whose tumours have metastasised to the skeleton. To investigate its potential as a treatment for the “comorbidities of old age”, it needs first to be made cheap. It’s not a difficult or expensive process to turn the drug into pills costing a few pounds each, but the world is a busy place.
However, it is also a communal place and, like Profs Magnus Essand and Heather Draper, Edwards sits down to listen. Also like them, he is quick to make up his mind. He likes it. He enjoys the thought of patients and advocates working shoulder-to-shoulder with researchers to crack this irritating problem of the lack of small amounts of money holding up potentially huge discoveries.
“We can use the first version of the Plutocratic Proposal, to pay for the pill conversion and trial,” I say wildly, “then the Penurious Proposal could come in to kickstart the comorbidities trial: hundreds of thousands of participants paying a fiver each for a pill they’d take with their yearly flu jab.”
Anything he can do to help, count him in, says James. Then he needs to get back to work. In a room nearby, a researcher is watching a wall of TVs showing a live feed from the International Space Station: she is investigating the effects of zero gravity on joint tissues. In another room, a man is peering into a microscope: he has made drug-loaded bubbles, 500 times thinner than a human hair, that can repair bone fractures.
“How about an office between those two?” I call out to James. “And something better than my btinternet email address?” But he has gone.
I have written angry, pompous emails to the Brocher. I demand that “the extraordinary privilege and valuable environment the foundation offers be open to all who have important ideas to develop”, not just people with PhDs. I accuse them of valuing “acronyms” above “merits”.
I’m insufferable.
“Was Antonie van Leeuwenhoek, the discoverer of microbes, one of the greatest microbiologists of all time, an academic? No: a linen draper who never went to university. Mary Anning, discoverer of the first complete Ichthyosaurus skeleton, a guiding light of palaeontology? No, a schoolgirl. Henri Dunant, founder of the Red Cross, a giant in the history of bioethics, a man born in Geneva, in sight of your lakeside windows – an academic? Nope: a businessman who later went bankrupt.”
In the mornings, if we’re between jobs and have enough savings to keep us going, Dom and I start tinkering with our ideas again. At the moment, Zoledronate and the Penurious Proposal take up our spare time.
It is really important to make this clear: we are dealing with real science, not Hollywood stories, which means it is uncertain, unproven, quite possibly wrong. Zoledronate could extend patients’ healthy lives, saving them years of suffering (and the NHS billions of pounds) but equally it could not – and may, for at least a few people, because all drugs carry risks, do more harm than good. It’s precisely because its effects aren’t obvious that we need to stop it disappearing into the biohazard disposal bin and get it rigorously tested in a peer-reviewed trial.
Not everyone is convinced by our suggestions. I once got thrown off a campus in North America because the bioethics department hated the Plutocratic Proposal so much, on the grounds that it gave the rich one break too many. The security guards were called on me; I was escorted from the premises. It was delightful.
This is why Dom and I need to get to the tables of the Brocher and plonk down our grubby finds. We need the professional ethicists and patient advocates and biotech experts to clean these ideas up. “Why is it academics find it so hard to get out of their silos and do proper public engagement?” I pronounce grandiosely. “If we could only work together for the weal of all …”
“Hey,” interrupts Dom, who’s been checking his email, not listening. “They’ve accepted us.”
“Who has?”
“The Brocher. We got in!”
And it is true. On our third attempt, the Brocher convened a meeting of their scientific advisers and had the grace to change their minds – rather more grace than I’ve shown in my emails to them. They have decided to let us run a workshop at their institution this November. It is, as far as we’re aware, the first time non-academics have been allowed to do this.
I don’t blame academic institutions for trying to run from us: two middle-aged men with spare-bedroom email addresses. I’d run from us too. People like Dom and me demand patient guidance and time. We don’t keep to deadlines; we misspell the technical jargon, if we understand it at all; we are prone to fits of petulance, tub-thumping and undergraduate overstatement. In my experience, with certain wonderful exceptions such as Magnus, Heather and James, we have about a three-month shelf life with academics who agree to listen to us. After that, they stop answering emails. They are too busy on their own projects; they have ghastly teaching hours and those constant, robotic demands from their university management.
But Dom and I are not put off. That they open the door even slightly when we come calling – with our comically named funding ideas, and our talk of desperation as a financial force that they’ve all overlooked – is astonishing. But now we have a new fundraising problem: how do we find the money to fly our professors and patient advocates out to Geneva to debate these issues at our shiny three-day workshop by the lake?
