Some recent news about a(nother) scandal in the pharmaceutical industry has led me to post on something that is critical to the future of medicine and science.
Let me start off by saying that I believe strongly in most medicines. I think the data behind their safety is incontrovertible. But for medicines that were invented recently, that same data would still leave me quite suspicious.
Here's why.
Let me start off by saying that I believe strongly in most medicines. I think the data behind their safety is incontrovertible. But for medicines that were invented recently, that same data would still leave me quite suspicious.
Here's why.
A Glorious History of Selfless Work
During the dawn of the modern era of medicine, Edward Jenner[Note 1], Louis Pasteur [Note 2], and Jonas Salk [Note 3] worked selflessly to bring medicine to the masses. These three great scientists and many others conquered modern plagues- smallpox, rabies, polio- all are practically unknown today because of their work. Diptheria, tetanus, and hundreds more diseases are eradicated because of the students they trained. They did not profit significantly from their discoveries- but rather, gave them freely to the world. In doing so, they saved more lives than any other humans in history. In fact, when asked who owned the patent (on his polio vaccine that would go on to save 20,000 American children/year) Salk replied, "There is no patent. Could you patent the sun?" Their main reward was funding that let them keep on working. Salk, Pasteur, and Jenner all kept on trucking until they died or could no longer physically continue.The Current Era: Out with the Selflessness, In with the Bling
Now let us examine modern medical science. Gone are the days when lonely researchers made great discoveries and gave them freely to the world. Once upon a time, the government through the NIH funded the vast majority of trials for new drugs. In 2011, Pharmaceutical Companies spent more money on research than the NIH.
This has had good effects: A cure for Hepatitis C was recently discovered by a company called Gilead. They patented it, called it Sovaldi, and are charging $84,000 per person. And they're going to get paid that much money, because liver transplants are even more expensive. It just so happens that liver transplants are capped by availability of organs and come at a slow rate and after 30 years- while Sovaldi needs to be paid for now.
I actually don't have all that much of a problem with this. Sovaldi works- all the evidence suggests that it's really, really effective with few side effects. It does show however that there is A LOT of money at stake nowadays- gone is the time when a scientist would refuse to patent a vaccine for the good of humanity. Gilead made $3.5 Billion- in three months.
All that money hinges on one thing- does the drug work? The evidence is pretty objectively clear that it does. To determine whether or not someone has Hepatitis C, there are several tests, including an RNA PCR, that are very accurate in determining whether someone is sick and if they've been cured. There isn't a lot of wiggle room: give someone the drug for a set period of time, and then see if their test is clear. Then measure how many of the people who got the drug got cured- and the studies have come out to an 80% cure rate, which is pretty high.
Any drug that helps things would be great, no? Along comes a company called Merck. It had legions of scientists working in the best labs that billions of dollars of anticipated drug profits can buy. Around 2000, they discovered a compound, and called it rofecoxib. It was one of a new class of drugs called COX-2 Inhibitors, after the receptor it targets. It was found to be good at relieving pain and helping people live their lives with less disability- and was also pretty good at not causing GI bleeding- a bad side effect of other drugs used for the same purpose. This was announced in a major medical journal- the New England Journal of Medicine, and Merck decided on Vioxx as a trendy trade name. Merck went on to do sales of $2.5 Billion on the drug.
The only problem? The sales were built on bad science. It was found that Merck had concealed critical data from the medical community that showed that the risk of heart attacks in patients who took Vioxx was more than five times that of the baseline, and risk of strokes more than double. Merck may have caused or contributed to 100,000 deaths before it's actions were exposed and the drug withdrawn from the market.
Around 2006, GlaxoSmithKline had a drug they decided to call Avandia. It was designed to treat Diabetes, another disease that costs 10s of billions of dollars each year. Avandia went on to do $1.3 Billion in sales per year- before the company was found to have concealed data that showed that Avandia too killed people with heart attacks. The company settled and agreed to be fined more than $3 Billion. Why did they agree to such a massive fine? Perhaps because emails like this turned up, "Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK". There was evidence that GlaxoSmithKline found out about a major article raising concerns about heart attack risk ahead of time, and got a response ready which they knew to be false. Their actions bought three more years of sales- and three more years of killing patients. GlaxoSmithKline knew their drug would kill people, and sold it on the market anyway. The drug did what it was supposed to do- control blood sugar levels. But the side effects were so terrible that it killed far more people than it helped.
I actually don't have all that much of a problem with this. Sovaldi works- all the evidence suggests that it's really, really effective with few side effects. It does show however that there is A LOT of money at stake nowadays- gone is the time when a scientist would refuse to patent a vaccine for the good of humanity. Gilead made $3.5 Billion- in three months.
All that money hinges on one thing- does the drug work? The evidence is pretty objectively clear that it does. To determine whether or not someone has Hepatitis C, there are several tests, including an RNA PCR, that are very accurate in determining whether someone is sick and if they've been cured. There isn't a lot of wiggle room: give someone the drug for a set period of time, and then see if their test is clear. Then measure how many of the people who got the drug got cured- and the studies have come out to an 80% cure rate, which is pretty high.
The First Scandal
Imagine another drug. What if the disease was harder to measure? And the outcomes more nebulous? And what about side effects that have nothing to do with the primary aim of the drug? Let's take arthritis as an example. Osteoarthritis is a debilitating disease that attacks the middle aged and the elderly- 27 Million in the United States alone. It is the most common cause of chronic disability in the United States. It costs hospitals ALONE $14 Billion per year to treat, the second highest of any category- let alone outpatient treatment.Any drug that helps things would be great, no? Along comes a company called Merck. It had legions of scientists working in the best labs that billions of dollars of anticipated drug profits can buy. Around 2000, they discovered a compound, and called it rofecoxib. It was one of a new class of drugs called COX-2 Inhibitors, after the receptor it targets. It was found to be good at relieving pain and helping people live their lives with less disability- and was also pretty good at not causing GI bleeding- a bad side effect of other drugs used for the same purpose. This was announced in a major medical journal- the New England Journal of Medicine, and Merck decided on Vioxx as a trendy trade name. Merck went on to do sales of $2.5 Billion on the drug.
The only problem? The sales were built on bad science. It was found that Merck had concealed critical data from the medical community that showed that the risk of heart attacks in patients who took Vioxx was more than five times that of the baseline, and risk of strokes more than double. Merck may have caused or contributed to 100,000 deaths before it's actions were exposed and the drug withdrawn from the market.
Fool me Once, Shame on You. Fool me Four Times, Shame on Who?
Was Merck just a bad actor? One bad company making one bad decision?Around 2006, GlaxoSmithKline had a drug they decided to call Avandia. It was designed to treat Diabetes, another disease that costs 10s of billions of dollars each year. Avandia went on to do $1.3 Billion in sales per year- before the company was found to have concealed data that showed that Avandia too killed people with heart attacks. The company settled and agreed to be fined more than $3 Billion. Why did they agree to such a massive fine? Perhaps because emails like this turned up, "Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK". There was evidence that GlaxoSmithKline found out about a major article raising concerns about heart attack risk ahead of time, and got a response ready which they knew to be false. Their actions bought three more years of sales- and three more years of killing patients. GlaxoSmithKline knew their drug would kill people, and sold it on the market anyway. The drug did what it was supposed to do- control blood sugar levels. But the side effects were so terrible that it killed far more people than it helped.
There is no test that can detect heart attack risk- the only way to measure it is to give it to a lot of people and watch what happens. Even then, if you have a lot of elderly people, or a lot of meat-eaters, or African-Americans, or Indian-Americans, or any group more prone to heart attacks your data may be thrown off significantly. These scientific difficulties are what Merck and GlaxoSmithKline hid behind and used to kill hundreds of thousands before they were found out.
But, that's not all. In 2013, Novartis- another company- didn't even hide behind scientific ambiguity. They straight up tried to fake the data by inserting one of their paid employees into a research project as a statistician without disclosing it. The worker blatantly invented data out of thin air showing valsartan to be more efficacious. Somehow, the Lancet (another prominent medical journal, based in Great Britain) found out about the fraud, and retracted the paper.
NOTE 1
Dr. Edward Jenner, Fellow of the Royal Society, was an English Physician who pioneered work in vaccines. It was he who ran trials, purposefully infecting boys with cowpox, and then exposing them to smallpox, proving that they wouldn't get sick (vaccination at the time was already known-Jenner's contribution was to find scientific proof). His actions resulted in the first vaccination campaign and overall is reputed to have, "saved more lives than the work of any other human". It must be noted that his methods (cutting boys' skins and putting smallpox pus into them to prove it wouldn't infect them) wouldn't pass ethical muster today, but at the time it was remarkably effective. He received no payment for this discovery, but the British Parliament did support his future work.
NOTE 2
Next up, Louis Pasteur, a Frenchmen. Pasteur is even more famous for this quote: "One does not ask of one who suffers: What is your country and what is your religion? One merely says: You suffer, that is enough for me..." His work too would be renowned for bringing pasteurization to milk, making it safe to drink. He created the first cure for rabies, and developed the germ theory of disease. He too received many government honors, and was supported by the government and private contributions- but did not become particularly rich. The fame of the institute he founded was so great that the Nazis left it alone even after they occupied the rest of France during World War 2.
NOTE 3
Jonas Salk, an American hero. In the 1950s, Americans were scared of two things: nuclear warfare, and polio. Polio had struck over 58,000 people, of which 22,000 were somewhat paralyzed and 3000 died. Salk turned down a lucrative practice in medicine to become a medical researcher instead, and with single-minded devotion spent 7 years of his life studying polio, finally discovering a vaccine in 1955. He was hailed as a savior. 220,000 people volunteered to test the vaccine. Soon, 1,800,000 school children also were recruited. It was a resounding success. He went on to receive support for his work, but also did not achieve a large fortune. In 1985, when the government turned their backs on gay men everywhere as HIV and AIDS destroyed their communities, Salk took up the crusade for a vaccine. He died a decade later, at the age of 80, still working to find one.
And now we come to what triggered me to write about this. This month, A FOURTH company was found to have concealed data about drug safety. An investigation by the British Medical Journal found that a drug company called Boehringer Ingelheim withheld data that showed that Dabigatran, their new anti-coagulant drug designed to prevent strokes, would be much safer if it's levels in the blood were monitored. Dabigatran's main selling point was that it was as safe as an old, cheap, and un-patented drug called warfarin- but unlike warfarin didn't need constant monitoring and blood draws. So the company hid the data, until now. This wasn't all- the slow motion train wreck that was Dabigatran is well documented by one EM Physician blogger- but the rest of it is outside the scope of this article.
Year after year, we have evidence of drug companies systematically hiding and falsifying science- for the sake of profit. This phenomenon itself has been scientifically documented: a study published in the Journal of the American Medical Association found that industry-funded studies were 3.6 times more likely to publish positive results about a drug than a study sponsored by the government or a university.
The Hardest Question: Why?
The causes of this corruption of medical science are many.
You might think that the reason companies have consistently committed scientific fraud or misled the public is obvious: money. But the answer is more complex: after all, in each of these four cases these companies are paying billions of dollars in fines and lawsuits- far more than they made from the drug. The companies all had to have known the information was going to come out. They had to have known that sooner or later, someone would discover how many people were dying on the drug, and that their company would become target number one for every trial lawyer in the country. Why would they do this anyway?
The answer lies in intra-corporate dynamics. The real question here is not "Why would a company do this?" but rather "Why would the executives in charge of units at a pharmaceutical company do this?" That executive isn't planning on staying with his or her unit long-term. They want short-term success to show their ability, before they move up at their company or another. These executives don't plan on being around to stand on the chopping block and take the ax when it's found out that they killed 100,000 people; they'll be long gone in 5 years when the butcher's bill comes back to their company. Thus, even though the company as a whole has a strong incentive to be sure about the science, the individual units and managers have an incentive to lie and fake it.
The answer lies in intra-corporate dynamics. The real question here is not "Why would a company do this?" but rather "Why would the executives in charge of units at a pharmaceutical company do this?" That executive isn't planning on staying with his or her unit long-term. They want short-term success to show their ability, before they move up at their company or another. These executives don't plan on being around to stand on the chopping block and take the ax when it's found out that they killed 100,000 people; they'll be long gone in 5 years when the butcher's bill comes back to their company. Thus, even though the company as a whole has a strong incentive to be sure about the science, the individual units and managers have an incentive to lie and fake it.
But, they don't even have to do the dirty work themselves- all they have to do is select researchers that are more likely to give them positive results.
On the researcher side: said scientists are desperate for funding as the US Government puts less and less money towards biomedical research. If they publish bad news about a drug, or fail to spin ambiguous results in the drug's favor, they fear being cut out of future work. So what do they do? Ambiguous results can be interpreted with maximum deference to the pharma company's point of view. Side effects can be blamed on other medications or simply not analyzed. Patient deaths can be hidden by finding that the patients didn't meet the original study criteria after all. All kinds of statistical tricks can be employed- like using five different quality-of-life measures until you find one that shows the drug has a good effect.
How does this show up in practice? The scientists that worked on the Vioxx study saw that 5-fold increase in heart attacks, and told the FDA that the numbers were because of a five-fold protective effect of the drug Vioxx was being compared with, Naproxen. The FDA saw right through this, but not in time to protect a lot of people. Researchers know- if they don't play ball with pharma and interpret every finding with the assumption that the drug is safe and effective, their livelihoods are at stake.
Meanwhile, the medical journals that were relied upon to police science through peer review, and protect the public by preventing bad studies from being published have some conflicts of interest as well. A study found that almost half the money that goes into some prominent journals such as the New England Journal of Medicine and the Lancet come from drug companies- they buy reprints of the Lancet, NEJM, and BMJ articles that their salesmen use to convince doctors to prescribe patients their company's drugs. To their credit however, as documented above this hasn't stopped medical journals from acting as occasional watchdogs- publishing retractions and investigations. One wishes that they would do a better job of it and keep 100,000 people from dying.
These three factors have combined to make doctors understandably suspicious of drug company sponsored trials. Another recent paper found that less than half of doctors would prescribe a new drug based on a trial sponsored by a drug company as opposed to a trial funded by the government. This is a good thing in protecting patients, but also results in doctors using decades-old drugs in place of modern ones that may well actually be safer and more efficacious. All drugs are tarred and feathered by the corruption of modern science- not just the bad ones. The NEJM had the audacity at the time to call upon doctors to "just believe the data" and trust the trials as long as they are of high quality regardless of funding. If you aren't already convinced of just how bad an idea this is, here is a very good takedown of this sentiment.
Solutions
What does this all mean? That medicine, and science, is in a serious mess. The evidence we rely upon to prescribe new drugs, to drive things forward, is fundamentally broken. I have no problem with a drug company paying for research to be done on it's new drug. I think the world needs to have a major problem with companies paying for the results of that research.
So, how do we fix things? Rather simply actually.
We establish a policy: no medical journal will accept a trial for study, unless it has been funded by an independent funding direction panel.
What does this mean? Currently, a drug company will develop a drug. Then, they'll have to find a researcher to carry out a trial: give 50 people the drug, give another 50 a placebo, and see who does better. The opportunities for influence here are rife, as detailed above. So, what do we do? We require a company that wishes to trial a drug in humans to go through a neutral third party.
This neutral third party would be the independent funding direction panel. Such panels could be set up by the NIH, as well as non-profit organizations such as the American Medical Association. These panels would take the money and the drug from the company, and then in a neutral and un-biased manner pick a researcher to run a trial of the drug. The researcher would know: no matter what they report, it will have no effect on the likelihood of them being picked again to do any other trial. This removes the strongest source of bias in the business.
Do you see the advantages of this system? We allow companies to buy the performance of research- but NOT the results of that research. All of a sudden, pharma funding effectively becomes non-profit funding, and doctors (and the public) can start to trust science again. It is my fervent hope that this becomes a national standard before it is too late. Right now, if a drug company declared that their data showed that they had a vaccine (or more accurately, a prophylactic drug) for autism, I would hesitate to trust that science enough to give it to any of my patients (let alone any future kids I might have).
What needs to happen to make this system a reality? Two possibilities. Congress could require that any studies used for FDA approval have to go through such a system. Since that is not likely to happen in this century, courtesy of the billions of dollars PhRMA sinks into political lobbying, there is an alternative.
Medical journals and organized medicine must band together, and give companies an ultimatum: use a system of independent funding panels to pay for research, or we will NOT prescribe any drugs based upon it. End of story. This is much more possible. The use of clinicaltrials.gov- a program that required companies to register trials and report negative and positive results- was implemented through just such an ultimatum by organized medicine, led by the New England Journal of Medicine.
There is a chance left to restore the integrity of medical science- let's just hope it happens before medicine loses the most valuable thing it has: the trust of the public.
NOTE 1
Dr. Edward Jenner, Fellow of the Royal Society, was an English Physician who pioneered work in vaccines. It was he who ran trials, purposefully infecting boys with cowpox, and then exposing them to smallpox, proving that they wouldn't get sick (vaccination at the time was already known-Jenner's contribution was to find scientific proof). His actions resulted in the first vaccination campaign and overall is reputed to have, "saved more lives than the work of any other human". It must be noted that his methods (cutting boys' skins and putting smallpox pus into them to prove it wouldn't infect them) wouldn't pass ethical muster today, but at the time it was remarkably effective. He received no payment for this discovery, but the British Parliament did support his future work.
NOTE 2
Next up, Louis Pasteur, a Frenchmen. Pasteur is even more famous for this quote: "One does not ask of one who suffers: What is your country and what is your religion? One merely says: You suffer, that is enough for me..." His work too would be renowned for bringing pasteurization to milk, making it safe to drink. He created the first cure for rabies, and developed the germ theory of disease. He too received many government honors, and was supported by the government and private contributions- but did not become particularly rich. The fame of the institute he founded was so great that the Nazis left it alone even after they occupied the rest of France during World War 2.
NOTE 3
Jonas Salk, an American hero. In the 1950s, Americans were scared of two things: nuclear warfare, and polio. Polio had struck over 58,000 people, of which 22,000 were somewhat paralyzed and 3000 died. Salk turned down a lucrative practice in medicine to become a medical researcher instead, and with single-minded devotion spent 7 years of his life studying polio, finally discovering a vaccine in 1955. He was hailed as a savior. 220,000 people volunteered to test the vaccine. Soon, 1,800,000 school children also were recruited. It was a resounding success. He went on to receive support for his work, but also did not achieve a large fortune. In 1985, when the government turned their backs on gay men everywhere as HIV and AIDS destroyed their communities, Salk took up the crusade for a vaccine. He died a decade later, at the age of 80, still working to find one.
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