What happened to all the cowboys?

Innovation and Risk in Medicine

“Only those who will risk going too far can possibly find out how far it is possible to go” T.S. Eliot

I remember first being exposed to T.S. Eliot. It was at school. It was a classic story of ‘boy goes to class, boy is bombarded by fine literature ad nauseam, boy develops overwhelming hatred of said literature.’ However he was one of the few writers I was exposed to during school who, after the dust of adolescent academia had settled, I was still willing to tolerate and even enjoy. I remember one of the earliest poems of his which was inflicted on us was The Love Song of J. Alfred Prufrock. I can now say, with the reflection (or really refraction) of hindsight, that this is a great poem, however one line always bothered me:

“Like a patient etherized upon a table;”

What a strange line. This line stayed with me for many years, well into my tertiary and even medical education. The reason? Nothing substantive or emotional, no life altering epiphany, just a question. Why Ether?

Whilst the links here may seem convoluted, they are not without good reason. This poem was published in 1915, well past the golden age of Ether. So why use this term? Sure, it’s more poetic than ‘chloronized upon a table,’ but is that the entire reason. The fact is, the history of anesthesia in the 19th century shows us the potential for medicine to contort and change itself from one beast to a complete other in a relatively short time period. It shows the potential for innovation and change to race well ahead of contemporary understanding. Prior to the 1840s, when these initial general anaesthetics were being created, surgery was synonymous with butchery. So how did we go from butchery to restoration in under 100 years?

While the aim of this isn’t to give a detailed history of general anaesthesia, there is some utility in trying to describe the story of these medications. The fact is the clinical history of general anaesthesia began with the dentists. Granted, before the dentists got their hands on the giddy-gases of the 19th century, particularly nitrous oxide and ether, there had been others to find their intoxicating potentials even a few decades before. However, the dentists were the first ones brave enough to try utilising these new substances whilst actively inflicting maxofacial algesia on their beloved patients.

Unfortunately this famously back-fired with the Horace Wells demonstration of nitrous oxide at Massachusetts General Hospital, where the patient awoke mid-demonstration in catastrophic pain. This event he found so scarring he, somewhat ironically, became addicted to chloroform and eventually committed suicide. However the dentists redeemed themselves with the entrepreneurial William T.G. Morton’s demonstration of Ether at the same venue (now called the Ether Dome), for a surgeons removal of a tumour and here modern surgery was born. This later progressed to the discovery of the anaesthetic uses of chloroform by James Young Simpson and the refinement of dosing chloroform by John Snow (who luckily in this case, did know something).

So what do T.S. Eliot, general anesthesia and an unsubtle Game of Thrones joke have to do with risk and innovation in medicine? Not much. At best its a springboard case study into the topic and at worst a not particularly interesting anecdote, but anyway here we are. The truth is, if we look at medical innovations in the 19th century there’s a wholly different ethos around how advancement occurred. In the 19th century the approach was either ‘I wonder what this is going to do’ or ‘how can I do this better.’ Today the way we approach medical innovation is ‘dear God I hope this doesn’t kill anyone and/or I don’t get sued.’ Sure I’m being purposefully facetious, but is it really that far from the mark?

Whenever a new medical procedure or drugs looks to enter the market there are only two questions that need to be answered: ‘is it effective’ and ‘is it safe.’ The average cost of answering these two questions, however, is around $500 million.This is because the rate of innovation in medicine is a function of risk. Every intervention which occurs in medicine, whether procedural or pharmacological, carries an inherent risk to the patient. These can be a risk of harm, loss of function or death. This is obvious, however the key point is that there is an element of risk regardless of attempts to safeguard the intervention. The crux of the matter is that no matter how perfectly we investigate these interventions there’s always the chance that Newton’s apple won’t fall to the ground and that we’ll end up killing a patient. This is the nature of the complexity of human biology, the nature of medicine and to some extent the nature of the physical universe at large.

This is the understanding which has formed the current paradigm of medical innovation. This innovation occurs at a relatively fixed rate, stable from year to year, sometimes it goes up, sometimes down but nothing extreme. Our rate limiting factor in this system is medical regulation, our inverse proxy for risk. Essentially, when a new intervention is being investigated there are several (increasingly rigorous) stages it must get through in order to be approved. This process is very time consuming and enormously expensive, but we do it because this is our proxy of minimising risk inherent in the system. This showed us that by altering the level of risk we were willing to accept we could affect the rate at which medicine advanced.

Prior to the 1950s, when many of these systems were put in place, medical innovation occurred at a relatively accelerated rate, but also in a different pattern. Often innovations came in great leaps as opposed to gradual progression. However the cost of this wasn’t fiscal, it was physical. When new drugs showed promise, they were utilised very quickly, almost without a second thought. In many cases this resulted in hundreds or thousands of deaths. Why was this human cost more acceptable then? Because there was no safer alternative, in fact there was no alternative. In the 19th century medical professionals needed whatever advances they could get, because the alternative was often the death of their patient. This is significant because it changes the risk equation. Today if we develop a new drug, we compare it to the old drug or whatever the ‘gold standard’ intervention is and we expect an improvement in some domain. In the 19th century, comparing a new intervention to nothing makes for a relatively easy decision.

The crossover from one ethos to the other happened gradually over time, like most things in history do. However, also like many things in history, we like to pin it on ‘one defining moment’ and in this case that would be Thalidomide. The thalidomide case was one of a drug that caused horrible birth defects and its target market was pregnant woman. The bottom-line of this story was that the FDA, largely due to Frances Oldham Kelsey, refused to approve this drug based on concerns of safety when many other countries in the world approved it. Why is this the tipping point between old and new innovation? Because here we not only see a more institutionalised system of monitoring medical intervention, we also see how an unacceptable risk and concern for safety can stop an intervention.

For the sake of hyperbole we can say the old system was natural selection, we’ll accept everything and whatever seems to work we’ll take, everything that doesn’t work we’ll ignore and try and forget the people both options killed. The new system is slower and more methodical, like a helicopter parent. We’ll sit and watch every movement, we’ll ensure no expense is sparred and at the end of the day when we still end up with a violent rebellious teenager, we’ll look back and try to see if we could’ve done anything differently.

So now what? The grand finale of this analysis of poetry, dentistry and teratogenicity. The real question behind all of this is fairly simple, are we happy with the way medicine progresses today? On the face of it, watching the news, looking at facebook, etc it would seem that new and wonderous changes happen daily. And indeed they do, particularly in the world of science. But how about clinically? When do we see these wondrous change in practice? Later. Sometimes never. But that’s fine because at the end of the day we are trying to avoid unnecessarily ending someones life. That’s the key, and I have to stress that personally I’m not really on one side or other of this issue. But the question needs to be asked, does it take too long under the current system for scientific discovery to be transformed into clinical innovation? I don’t have an answer for this question, but the point is that the question should exist.

Currently our system requires us to spend vast sums of money in an attempt to achieve our perceived acceptable level of risk in developing a new drug or procedure. However, integrated into the system is an elaborate, if ominously named, network of post-marketing surveillance which reveals risks which were never previously identified and often could never have been predicted. So is this system we’ve constructed to microscopically analyse new medical interventions worth the enormous sum it costs to maintain? The generalised answer is ‘yes’, the more accurate answer is probably ‘sort of.’ The system is necessary, it allows us to trust a new medication given to us by a medical practitioner. We know that there is evidence this medication is safe and, in most cases, more effective than salt water or a sugar pill.

So finally, with this in mind, we have to consider if the system has been pushed too far. Have we decided that the process we are going to inflict on medical innovation requires a level of risk so low as to be unrealistic and too expensive. Would the general public be willing to accept slightly more risk in a new intervention, for the sake of having it earlier? Is it even fair to ask this, considering post-marketing surveillance suggests that in some cases we make false promises about exactly how safe a medication is even under the current system? This is going to be the key issue over the next century which determines whether we are going to revolutionise medicine with these miraculous discoveries of science. Will we be able to use these to help people? Are there still some cowboys out there willing to risk going too far? Should there be?

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