Willy Wonka & the drug discovery pathway
Oompah loompah, doopety doo, I've got another puzzle for you
I’m not one to shy away from hot button issues. Last week, I poked the hornet’s nest by asking about your favourite Batman. This week I’m doing the unthinkable in a piece of writing - referencing a classic novel, but I’m using the movie adaptation…gasp!
What’s even worse, the movie adaptation doesn’t even retain the original title.
Today we’re talking about Willy Wonka & the Chocolate Factory. The Gene Wilder classic. So unliterary it uses ‘&’ rather than ‘and’.
The purpose of a cinematic exploration this week is to delve into the drug discovery pathway; the step-wise process that leads to the release of new drugs into the market. You can see it illustrated in the figure below.
This drug discovery pathway has given rise to every new prescribed medicine since the mid twentieth century. It has real implications when it comes to the costs of medicines and their availability to the public. But it’s soooooooooo dry to talk about. And there are plenty of text-book style explanations about this around already. So let’s do something fun instead and compare it to Willy Wonka.
Sounds absurd? Perhaps, yes. And I’ll admit, some of the connections may be a little…tenuous. But I’m confident this will be something you’ve never read before, so stay with me and let’s see where this goes.
When it comes down to it, the drug discovery pathway and the plot of Willy Wonka both involve the same general steps:
Identify potential candidates
Screen potential candidates
Test the potential candidates
Identify the worthy candidate.
1. Identify potential candidates
So many Wonka customers, such a long set up
Like most movies with a linear narrative, Willy Wonka begins with the setup. In this case, it’s showing us the world outside the chocolate factory, where we see just how many people love to eat Wonka candy bars. Wonka customers everywhere. And not just kids - old people too. Strange old people who sleep four to a bed.
It wasn’t until I watched this movie recently that I realised how long the setup part of the movie takes. I’d completely wiped this hour(!) of story development from my memory. Including the song about the Candy Man which I’m thinking would come across as pretty creepy if someone were to pitch it today.
If you believe what the Candy Man tells you, you’ll think that Wonka candy exists to make the world taste good. Ahhhh. It’s an interesting thought exercise to view this through the lens of big pharma, an industry that on a superficial level exists to improve health. (I’m not drawing any conclusions here, just going to leave that hanging for you to think about as we work through this).
So many drug candidates, so much time and money
In the drug development world, the set up maps to the drug discovery phase of the pathway. This involves identifying drug compounds that can be manufactured at scale and might have a clinical use. In other words, it’s about identifying drug compounds that are worthy of investment.
How do they find these drug compounds? I don’t know all the methods they use, but here are a few that come to mind.
One way is to identify a substance traditionally known to have medicinal properties and refine it into a more specific drug compound. This method has given rise to a lot of drugs we use today. Drugs like aspirin, warfarin, and morphine all have origins in plant species1 and research continues to explore plants as sources of other drug compounds2.
Another way is to identify a substance that exists naturally within the body’s signalling pathways and try to make a compound that mimics it. Hormones like insulin, thyroxine, oestrogen, testosterone, desmopressin…and so on are all examples of this.
Drug companies also work from the drug target, backwards. Identify a receptor or other target within the body or pathogen (bacteria or virus) and try making a drug compound that interacts with it. There are heaps of examples of drugs discovered like this, and it’s the reason why basically every pharmaceutical company are now investing in a GLP-1 division. If your up for a deep dive on GLP-1As, check out this post from Teching it Apart:
And, of course, there’s always chance. Serendipity has always played a role in scientific discovery, and drug discovery is no different.
The drug discovery phase involves a lot of lab work and significant financial investment. And, just like the movie, this setup phase also takes a long time - around 3 to 5 years. Most of the drug compounds tested will end up on the cutting room floor. Of the 5,000 to 10,000 drug compounds tested, only around 250 will make it through to the next part of the pathway.
Back to Wonka.
2. Screen potential candidates
Let the scramble for the golden tickets begin
Offscreen, Wonka decides he needs to make a succession plan, so he comes up with the Golden Ticket scheme. Only people who buy a chocolate bar have the potential to get a ticket. So its not purely about candy consumption anymore, you’ve now got to be purchasing the right kind of candy. This is the very reason why Violet Beauregarde made the switch from gum to chocolate bars- to make sure she was in with a shot.
The golden ticket scheme effectively whittles down the number of potential candidates to something more manageable. It also introduces the opportunity for corruption, strong arming tactics and fraud. And we see examples of all three.
Firstly, the corrupt behaviours of Mr Salt, who transforms his peanut shelling factory into a sweat shop for golden ticket discovery. Was this legal? I assume, yes. Was it ethical? Not so sure.
Second are the strong-arming tactics demonstrated by the creepy man in the bowler hat with the scar - Slugworth. He’s seen every time someone finds a golden ticket, whispering in their ear. I know it’s not kind to judge, but one has to assume his motivations are sinister and he’s trying to bribe them into giving over their ticket to him or act as his spy, These kids know what’s up though, and all resist…we assume.
Finally, we see evidence of fraud. A fake golden ticket! While this specific case of fraud is the only one explicitly shown in the movie, it is possible that more was occurring off screen. There’s a whole fan theory about Wonka setting up the whole thing to favour Charlie (these posts take me to weird places on the internet).
Don’t put those drugs in humans, yet
Back to the drug development, this process of whittling down the potential drug candidates to a smaller number worthy of greater investment maps to the pre-clinical studies phase of the drug discovery process. This involves all the testing that occurs before putting the drugs into humans.
These pre-clinical studies tell us the basics of how the drug works (its pharmacokinetics and pharmacodynamics) and whether or not it’s safe to test in humans (toxicity). Some of these studies occur on the lab bench (in vitro) while others are conducted in small animals like mice and rats (in vivo).
For everyone’s sake (including the animals), its critical this testing aligns with professional and ethical standards. Corruption, strong-arming, and fraud are really bad news when it comes to drug development3.
3. Test the potential candidates
Oompa loompa, doompety doo
We’re now down to five potential candidates to take over Wonka’s factory, not that they know that. Augustus Gloop, Violet Beauregarde, Veruca Salt, Mike Teevee, and Charlie Bucket.
Before they’re allowed into the factory, some contract arrangements need to be put in place. No one reads the fine print.
Unknowingly, the candidates are put through a series of tests. Important to note that these tests are all conducted within the controlled conditions of the Wonka chocolate factory, not real life (we’ll come back to this later).
One by one, four of the potential candidates are eliminated with a musical send off from the Oompa Loompah’s.
By the end we’re left with Charlie as the only kid that hasn’t had the Oompah Loompah exit.
Time for the human studies - clinical trials
The testing of the children in the chocolate factory maps to the clinical trials phase of the drug discovery pathway. This begins once a drug company has established their potential drug molecule is safe to test in humans through clinical trials4. But, just like the movie, it’s important to remember that these are all conducted under controlled conditions, to varying degrees. They’re also heavily regulated for what I hope are obvious reasons.
Clinical trials start being conducted with a small number of participants, and gradually increase as there is greater assurance of safety. There are three phases of clinical trials that must occur prior to a drug being approved to go onto the market, as shown in the earlier diagram.
What’s not shown on the diagram are the pilot or first in human studies (sometimes called Phase 0). This is where an untested drug is given to a very small number of healthy volunteers to make sure nothing super bad happens…like death.
If it passes that hurdle, the drug compound can proceed to Phase I clinical trials. These are also conducted healthy volunteers, but this time there are more of them - usually somewhere between 20 to 80. They’re typically conducted in young males because there’s lower clinical risk and more predictable pharmacokinetics. The main purpose of these studies is to determine the safe dose range and identify the common side effects of the drug compound. Again, if something super bad happens, the drug company equivalent of the Oompah Loompahs roll in to send that drug compound packing.
Phase II clinical trials start to look at efficacy - whether or not the drug will elicit the desired effect in people who have the target condition or disease state. These still don’t involve huge numbers of people though; a few hundred or so. This limits how the knowledge gained from Phase II trials can be applied to the broader population. But by the end of Phase II there’s a pretty good idea about who to give the drug to, at what dose, and what to expect in terms of safety. If the drug compound passes this hurdle, its ok to move on to broader scale testing.
Phase III clinical trials are all about the randomised controlled trials (RCTs). This is the type of study that, if well designed5, provides the highest quality of evidence. These trials compare the new drug therapy to a control group - either a placebo or an existing treatment. RCTs involve hundreds or thousands of participants, depending on the condition or disease involved, and can take several years to complete. They also cost a lot of money to run. However, they still utilise controlled conditions - the population receiving the drug compound is not reflective of the general population, nor is the level of care they receive6.
Now, back to Wonka one last time…
4. Identify the worthy candidate
Charlie Bucket, the chosen successor
In the final act of the movie, we’re left with only Charlie remaining. It doesn’t start off so great for Charlie though- Wonka finally calls him out on the bubble burping incident and tells him he’s been disqualified like the other kids were. This pisses off Grandpa Joe who decides to steal a gobstopper for Slugworth. But it doesn’t sit right with Charlie and he fesses up to Wonka.
Now is the time for the big reveal that Charlie passed all the tests to meet Wonka’s undisclosed criteria. Even Slugworth was a plant, a Wonka employee. Charlie finds out he doesn’t just get a lifetime supply of chocolate, but has now been selected as the successor for Wonka himself.
Off they ride on the glass elevator, and that’s where the story ends.
Regulatory approval and post marketing surveillance
This is where the movie departs a bit from the drug discovery pathway. While it’s true that both result in identification of a worthy candidate, when it comes to the drug compound the story doesn’t end there. The journey has just begun.
At the conclusion of clinical trials, the drug company has a drug compound that has sufficient evidence of quality, efficacy and safety (remember The golden triad of drug products?). This process has likely taken around 12 years and cost hundreds of millions, perhaps even billions of dollars. Let’s just say, they’re going to be looking for a return on their investment.
The drug company will make a submission to the appropriate regulatory authority to bring their new drug compound to market, and it will be under a patent for a prescribed period of time. Following regulatory approval, the drug is available for use in the general population.
This is where the conditions start becoming much less controlled. Whilst some countries, like Australia, will have guiding constraints around how drugs are used in practice the use will always be broader than it was in the context of clinical trials. This is where the Phase IV studies come in - post marketing surveillance.
I’ll admit, that this is the bit that most interests me from a professional perspective. What happens when drugs are used in the wild? Do they produce adverse effects that didn’t show up in clinical trials? Do older people, or those who are medically frail respond differently to the tested population? What happens when the drug is used in combination with other products? Is it suitable to use in other conditions other than the ones studied?
We’ll save that for another day though.
Thanks so much for reading!
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Some of them remain close to the original plant form - like traditional or bush medicines, things you smoke like cannabis and nicotine, and food-type products like coffee and teas. Others are plants refined into powders or tinctures - like the herbal products from the pharmacy, morphine, digoxin, and cocaine. And others still are synthesised products that have their origins in plants like aspirin and warfarin, are synthesised chemical compounds with their origin story deriving from plants.
The research centre I work for does some pretty cool work trying to better understand Aboriginal traditional medicines.
The ethics and standards around clinical trials deserves a post of its own at some point. Thalidomide is the example that’s often used to illustrate the need for adequate testing, but there continue to be incidents of unnecessary harm. The Hopkins asthma study in 2001 resulted in the death of a 24 year old and permanent damage to healthy volunteers.
Most countries follow the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and have a designated body to regulate practice. This is an international ethical and scientific quality standard that sets out the requirements for all aspects of trials involving human participants - including the design, conduct, recording and reporting.
There are a lot of badly designed RCTs that are just as misleading as any other type of poor evidence. If you want to interpret this kind of evidence, it’s important to understand how to critically evaluate studies before drawing any conclusions about the findings.
Participants in clinical trials get more attention than they do if they’re receiving usual care, which can impact the generalisability of results. This is known as The Hawthorne effect which occurs when people behave differently because they know they are being watched.
I really loved this. Also, I do work in this industry, and I didn’t know all of this! Excellent primer. 👌🏻