Editorial Note: This post will be an easy and obvious read if you’re Irish. If you’re not, with Google or whatever it should be accessible and indeed the little bit of extra effort may make it a more rewarding read. There is a warning below in respect of one item you might choose to Google. There is also one made up word that won’t appear in Google – until after this post is published. A closely related word does appear – which is just fine.
Study 329 was the most famous Randomized Clinical Trial (RCT) in history. This study of paroxetine given to children and adolescents, who were supposedly depressed, led to a publication in 2001 in the Journal with the highest impact factor in Child and Adolescent Psychopharmacology. The paper had an authorship line to die for including Marty Keller, Neal Ryan, Stan Kutcher and others. Its claim that paroxetine worked well and was safe led to mass sales of the drug.
Turns out the study was ghostwritten, there was no evidence the drug worked and there were triple the number of suicidal events on paroxetine compared to placebo – along with other problems. It also became clear that several years before, in 1998, GSK had internally conceded their drug didn’t work for children but figured they would pick out the good bits of the study and publish them.
FDA were happy to overlook the fact the drug didn’t work, it would seem, but New York State weren’t and took a fraud action against GSK, the marketers of paroxetine.
One consequence of this fraud action, resolved in 2004, was that in 2014 a team got access to the data behind the trial and published a reanalysis of the data. Study 329 became the only trial in history for which there are two contradictory published articles. The restoration of 329, to something like what the original publication might more appropriately have said, was finally published in the BMJ in 2015.
The BMJ ordinarily publishes articles within weeks but in this case there was a year long extension to the 329 date. The British medical establishment essentially had a nervous breakdown over 329. The details of what happened can be found on Study 329.org and even more detail will be available in a racy pacy juicy book later this year – telling you who was sleeping with who behind the scenes.
After a referendum in 2016, Britain was supposed to leave the European Union on 329. 329 has come and gone. A process that was supposed to be efficient and smooth has led to a nervous breakdown. There are claims of fraud and lies, scaremongering and ghostwriting on all sides. What’s up?
A large poll of voters’ statements about why they voted the way they did, taken as they exited from referendum polling booths in 2016, found that sovereignty was the most commonly cited issue by leave voters.
If you’re Irish, you might wonder about this. Britain was still able to bomb Iraq, Libya and Syria without anyone in the EU stopping them. Sovereign to do what exactly?
Britain joined the EU on January 1 1973. This was the day the Chocolate Wars began. Other European countries argued British “chocolate” contained vegetable fats rather than just cocoa and couldn’t be called chocolate. A Thirty Years War followed that contributed to British perceptions that Europe meant rule by Brussels’s bureaucrats. European choclatistas on their side saw nation based artisanal enterprises threatened by multinationals bent on replacing wholefoods with processed foods.
Retrospectively, even if these moral high-ground arguments were being put forward by people who brought us the Mafia and other locally sourced movements, many people would probably concede European chocolate was just better.
But whatever you think of the chocolate, behind this War lay the role of regulation in modern life. When regulators license a drug, they apply criteria in just the same way as they apply criteria to butter or chocolate. Meet the criteria and you can claim your product is butter, chocolate, an analgesic or an anti-hypertensive.
Your product might kill people, be an inferior butter or bone-thickening drug but it’s not the role of the regulator to keep people alive (other than through any contribution banning egregiously false advertising claims might make), nor to mediate between artisanal and multinational sectors of the market, nor to do politics. The role of regulators is to apply criteria.
When trading blocs such as China, America or Europe rub up against each other now, the issues to be negotiated are rarely about politics, and all about achieving regulatory alignment. The criteria applied to feta cheese, diesel emissions and drugs determine the room to move an American, Chinese or European president has.
Where both liberals and communists in the 19th century envisaged the State withering away, by the time we hit the 1960s we had nuclear bomb proof regulatory systems that seem unlikely ever to wither away. America’s FDA is a good example of this. Having no regulations for food or drugs is no more an option than removing all signage from roads and junking driving codes.
While companies have preferential access to the regulatory apparatus through appeals and other processes, and regulators are encouraged to partner industry, and consider the impact of regulations on jobs, this is not a global capitalist conspiracy in the sense of deals that no-one else could support done behind closed doors and imposed on us. The initial drive to regulation came from us, the people, and our effort to control the power of the sovereign.
There is input from experts, including some representing consumer interests, to the regulatory process and the resulting regulations are publicly available, even if industry discussions with regulators are not. In the case of drugs, FDA advisory panels are composed mostly of notionally independent doctors and the meeting transcript is publicly available.
Somehow though in the case of recent antidepressants, everyone on FDA panels appraising Spravato and Brexitanalone, bar Kim Witczak, who is not a doctor, and Julie Zito, who is not a prescriber, voted in favour. Even though Brexitanalone is an ancient drug being hyped up 20 years ago as something that would transform Snow White into a bronzed, skinny, Libidy-chasing third millennium woman. Me too and three and four might have been her motto – at least that’s the way the pre-marketing hype was tending 20 years ago. (For Spravato see here and here).
Its not as though we don’t notionally have our guys on these panels. The panel was stuffed full of what you might imagine were our guys. Yet somehow….
Our guys never get to see the data. They depend on FDA to look over it, which at best FDA do literally – they look over it. If we got to see the data afterwards, or at least some scientists did – this after all is supposed to be science and science hinges on data – and our guys knew we could see it, they might man up, other than at those exceptional times that call for political maturity – when faced with a dwarf-eating Snow White.
Its the lack of access to the data that’s key and the myth that RCTs are a good way to evaluate drugs – they aren’t but they provide good boxes to tick. Clinically RCTs are useless.
With drugs and foods, industry score in another way. Once a drug is approved they can deploy armies of lawyers to work on possible meanings of “organic”, “artisanal”, “locally sourced”, “chemical imbalance” or “mood-stabilizer”.
In the 1980s, Pharma was among the first industries to push for a global harmonization of regulations. This underpinned a globalization of the industry. The general view was, and may still be, that any problems with this necessary feature of modernity are balanced in health, that most sensitive of areas, by the presence of physicians to act as a counter-weight to industry and as advocates for consumers.
The bottom line though is that even Europe is not sovereign. It does what America decides. FDA approved fluoxetine (Prozac) for kids despite recognising the trials showed it didn’t work and that it caused suicidality. The European Medicines Agency (EMA) and Britains MHRA followed suit and approved fluoxetine for kids. WHO included fluoxetine in its list of essential drugs for children. NICE and other guidelines recommended and recommend fluoxetine and other SSRIs for children despite there never having been a single positive trial.
Sovereignty would mean being able to say – look none of these (mostly chlorinated) drugs have been shown to work for children. That doesn’t mean they can’t be used but if we’re going to keep people safe, in this case children, we have to at least be able to call it as it is. Put like this, the idea that Britain is somehow going to regain some lost sovereignty by leaving Europe is clearly nuts.
It is probably unfair to say MHRA is about as craven as a regulator can be. Its not the job of a regulator to be brave. It is more accurate to say British physicians as about as craven as physicians can be – well at least as craven as European and American physicians. If physicians stood up to be counted they could make a difference – regulators would have to listen. But if British physicians did this, there’d be a lot less Sir’s around the place.
The British have a wonderful system to keep people in place – offer to give them letters after or before their name. Works a treat and costs nothing.
Back when Absolute Monarchs were still the in-thing, England invaded Ireland. A doctor, William Petty, was given the job of surveying Ireland and its people. Petty created the first GDP for any country anywhere, created the first public health and hints of Evidence Based Medicine and proposed the first Free Trade agreement between any two countries – Ireland and England. Given the Brexit mess now, and all the claims about Free Trade, this is an irony like no other.
Petty’s ideas gave rise to liberalism and public health. His influence came to head, as it were, with the decapitation of Louis XVI in the French Revolution and the replacement of absolute power by regulated power.
It once seemed that this regulated power could always be undone. There are no better illustrations of this than the 19th century interplay between Ireland, then Europe’s most destitute country, and England, the world’s most powerful. After Ireland was forcibly absorbed by Britain in 1800, Daniel O’Connell, realizing that power in this new world was constrained by laws, and boasting he could drive a Horse and Carriage through any English law, campaigned to get the Irish to hang together peaceably.
His campaign demonstrated a weakness inherent in England’s apparent strength and led to Catholic emancipation in Ireland (not yet in England) and on to a series of Irish inventions including the boycott, and the hunger strike that (give or take a little bit of violence) against the odds delivered freedom to the Irish to oppress themselves – even to the extent of handing over sovereignty to others. (Its probably not for nothing that the abbreviation for Ireland – IRL – also stands for In Real Life)
But since somewhere in the 1980s, in medicine anyway, the regulatory apparatus has become as it were a learned intermediary between us and industry. Just as companies invoke doctors as learned intermediaries when things go wrong, they now claim to have adhered to all the rules and regulations and that those who work in industry are more rule-abiding and ethical than the average doctor or regulator – just as German soldiers were at least as ethical and professional as American troops in 1944.
The more we drift toward Google cars and away from Horses and Carriages, the worry has to be that piercing this System will be harder and harder.
In terms of drug wrecks, the key factor has been losing access to the data from the RCTs in which we have participated. This data should be as inalienable as our vote. Industry power stems from its seizure of our data. If we take our data back so that our consent must be sought for its use, and we decide when and under what arrangements it is in our interests to co-operate, we take back not just data but power.
We need a medical version of that recent Irish invention – the backstop. Bottom line is doctors shouldn’t prescribe drugs for which they don’t have access to the data. There should be a hard border between us and chemicals like this. We have nothing to lose by getting our doctors to insist on this. Since the 1980s, there have been vanishingly few drugs that industry has produced that we need – Triple Therapy for AIDS, Gleevec for certain leukemias and maybe Solvadi for Hep C. As things stand there won’t be many more as industry have figured that making drugs that cure disease is bad business.
We could learn something from Study 329 and 329 a Study. Lets put a backstop in place and see who blinks first. We wouldn’t need to take the drastic cutting off their eyelids measures that DUP politicians contemplated in the build up to Brexit 329. Industry would blink first.
(Google “DUP cutting off eyelids” if this is not familiar to you. Make sure you put DUP in the search term – I take no responsibility for the consequences if you don’t. The DUP are a Northern Irish unionist party whom most English people think want a union with the South of Ireland. They are seen by most English people as causing them endless Troubles).