On the hunt for new ways to treat pain.
Where do the drugs we take every day come from? What journey do they take from the minds of scientists working in the pharmaceutical industry to the shelves in a dispensary?
The Pain Detective follows Colin Froy, a retired policeman living with cancer, chronic pain and a wry sense of humour, as he becomes our eyes and ears. Immersing himself in the world of pharmaceuticals, Colin traces a drug’s journey back from clinical trials to its beginnings as a concept in the minds of scientists.
Thrown into this alien landscape of modern science, Colin’s questions and humour allow us to experience science in an entirely unexpected light. Through him, we glimpse the personalities and the passion of the people behind the experiments and the harsh realities of trying to bring a new drug to market in the 21st century.
Ultimately, he helps us to capture a glimpse of the long, difficult journey it takes for every pill or medicine to make it to our pharmacy shelves. To clarify why pain, in particular, is such a difficult phenomenon to treat. To gain an insight into the machinations of how modern pharmaceutical companies operate and work together. To make the process of science that little bit more transparent and human to those who will never enter a lab.
Colin Froy: Well I retired August 2011, having been a policeman for 40 years in Hertfordshire Constabulary. In 2004 I went into Harefield Hospital to have a couple of stents put in, having had a, sort of, minor heart attack. But while I was in there the blood tests they’d done had shown that my creatinine levels were quite high, which is a sign that your kidneys are not working. It was that that showed I had this light chain deposition, which is a myeloma type cancer. The chemotherapy, I did it for about six months through a variety of tablets, but one of them after a month was thalidomide and the side-effects of thalidomide, they call it tingly toes. Because tingly toes, you think, you know, you get sort of tingle and it goes away, but it’s not like that [laughs], it’s painful toes. I mean, the nerve endings are all shot to pieces, like a dead tree. It gets worse and worse, and you just can’t walk as far as you used to. Now, if I’m lying in bed sometimes, I get this sensation as if someone’s just pushing a needle through the toes, and it lasts for four or five seconds and then it’s gone. They were doing a trial at Hammersmith Hospital with chilli pepper patches, and someone said, “That Colin Froy he’s got, you know, tingly toes.” And they said, “Oh yes,” you know, so I spent several sessions up there.
Doctor: Did you feel anything during the treatment last time round, did you feel any heat sensation or…?
Colin: No. But those nerve endings that have been damaged and frayed, when I had the trial they said what they did was that this would make them all drop off, the frayed bits, yeah, and new ones grow.
Colin: There’s a lot you don’t know in the world until you come across it. You think about medicines and you think this tiny little pill, yeah, and you think, “Yeah, that’s clever, who thought of that? Where do they come from? How do they make them? Where do these people work?” Think with the clinical trials, how many are done here in Hammersmith?
Praveen Anand: So there are maybe 15 to 20 trials that are taking place globally at any one time, particularly for neuropathic pain. In our own unit we are conducting two clinical trials at the present, and over the past five years we’ve conducted approximately four to five clinical trials, which means we have an idea that a drug is likely to work based on evidence we have before we give it to patients with, say, nerve pain. And then there are safety and tolerability studies that are done for the first time in man, called phase 1 trials. So this is when healthy volunteers take part in carefully controlled conditions in specialised units. We then have to seek approvals to see if they’re effective in patients. So these are called phase 2 studies, and if it works in those then we move to phase 3. And phase 3 studies involve several thousand patients and usually multi-centre, involve many different hospitals, indeed, many sites across the UK or around the world.
Doctor: This is aloe vera gel.
Doctor: So this just helps cool the skin after the treatment.
Colin: Oh, oh, that’s like winning the lottery, that is, oh.
So at the end of the trial, who writes it up in the end, is that you?
Praveen: Only at the later stages, when all the data has been collected, will the investigators and the sponsors, the company know whether the drug was effective and whether it was safe, comparing it to the placebo.
Doctor: And any concerns whatsoever, give us a call on that number.
Colin: Yeah, lovely. Yeah, thanks very much, I appreciate your help, cheers.
Barry (film maker): What are you thinking?
Colin: I’m thinking how sneaky you are that you’ve pressed that start button when we’re not looking.
Colin: Hi, how do you do?
Ruth: Nice to meet you, I’m Ruth.
Colin: Yeah, and you, yes, I’ve heard a lot about you.
Ruth: [Laughs] All good, I hope.
Colin: All good, every bit of it.
Ruth: Come and have a seat, hello Trish.
Trish: Hello, I’m Trish.
Ruth: Nice to meet you too.
Colin: Hi, Colin Froy, how are you?
Iain: Good to meet you, I’m Iain, very nice to meet you.
Iain: Hello, you must be Trish?
Iain: Hello, good to meet you. How are you?
Trish: Fine, thank you.
Iain: Good, pull up a chair.
Chronic persistent pain actually is very common, it’s difficult to treat and it is associated with very common illnesses like osteoarthritis or rheumatoid arthritis, or sometime diabetes. It’s enormously difficult to treat pain very effectively, and actually pain is the number one reason why people will go to their GP. A recent publication on the economic burden of pain revealed that the cost in the US alone is about $635 billion a year. So actually the cost of chronic pain is more than the cost of cancer and cardiovascular disease put together.
Ruth: Pain itself is actually a very complex phenomenon. And depending on how you injure yourself, the sort of pain that you’ll feel will be different. If you’ve got osteoarthritis, for example, or you fall over, you’ll get one type of pain, nociceptive pain, whereas if you injure your nerve and you get that horrible stabbing pain, like you can get sometimes with neuralgia or toothache, that could be neuropathic pain. And actually there are many different types beyond there.
So tell me about your pain, I’m very interested to hear about your pain.
Colin: Pain, well, five years, five and a half years ago when I got diagnosed with light chain deposition, which is a cancer in the blood, and thalidomide caused the tingly toes and fingers.
Ruth: Yes, so neuropathic pain is what you’ve got.
Colin: And then initially they prescribed pregabalin –
Ruth: Yeah, we make that.
Colin: Do you?
Ruth: We do.
Colin: But pregabalin, I mean, I’m still on that now but it gradually got worse and worse, so you had to assume –
Ruth: Yeah, either the drug doesn’t work so well or it’s got so bad that the drug can’t really cope with it.
Colin: That’s right.
Ruth: And you still take it now?
Colin: I still take it now.
Ruth: And you wouldn’t want to stop taking it just in case it gets worse, would you?
Colin: I don’t think it could get worse.
Iain: Right, I shall just go and find some lab coats and come back because Thursday is wash day, so they … .
Trish: Right, okay. I like the sound of that, wash day.
Colin: White first?
Iain: Yeah, white first. I’m just going to find some more lab specs because we need to have some specs on as well …
Colin: Specs? Are we going on a motorbike?
It’s a bit like doing the morning rounds in a hospital.
Iain: Each individual’s experience of pain is different from the next. So the challenge really that we have is identifying the mechanisms that are at play in a particular disease, and perhaps in a particular individual, and then trying to match a medicine to their symptoms to give them relief. And we call that personalised healthcare.
Colin from MedImmune: Right, let’s got through them, we have neurons, oligodendrocytes, microglia and astrocytes, these are the four main types in the brain. They all have slightly different roles but ultimately together they are what we are. That’s what –
Trish: Right, they work together?
Colin from MedImmune: Yeah, they work together to, you know, create consciousness, effectively.
Colin (Froy): Are they likely to be in the exam this afternoon?
John: My expertise is in electrophysiology, and what that is is the study of electrical impulses, or the measurement of electrical impulses, and how your nervous system talks to your brain. So if you’ve got pain in your hand then what happens is –
Colin: What about my feet where I’ve got it?
John: Okay. If you’ve got pain in your feet –
Colin: Tingling toes syndrome.
John: Yeah, then your nerves are going to become depolarised and fire action potentials, so that’s an electrical signal that goes from your foot, first of all to your spinal cord and then up to your brain, and that’s where your brain perceives it as pain. So what we can do with this piece of equipment, these are neurons which we can look at, just a single nerve cell, which is a model of what’s going on in your foot. And what we can do is measure those electrical impulses and try and understand the main mechanisms that are involved in, first of all, sensing that pain, and then, second, transmitting that pain to your spinal cord.
Ruth: We work in the very early parts of exploratory research, and actually the tools that we have to study pain are really very few. It’s only in the last few years that we’ve been able to look at the nerves that carry the pain impulses up to the brain. So most of the work we do is really targeted at the sensory nerves at the transduction system that goes from where the pain originates up to the brain. That’s where we start, and then actually it’s probably at least a five-year journey from when we pick our targets to having a molecule that is good enough to go into clinical trials.
Ruth: This is Eddy.
Colin: Hi, Colin Froy, hi.
Ruth: So Eddy’s one or our expert electrophysiologists.
Eddy: So this is a stem cell that’s been differentiated into a neuron, okay, which behaves like a pain fibre, okay? So –
Colin: Would that be similar to a stem cell that I’ve donated?
Eddy: Yeah, absolutely.
Colin: To medical science, if I don’t need it.
Eddy: Yeah, we could take one of your, we could take, yeah, one of your stem cells and differentiate it into a neuron like this, which is –
Colin: Right, if I see one lying about I’ll post it to you.
Eddy: And it’s an incredibly difficult technique this, because what we’re doing is we’re measuring the electrical activity of this neuron, okay?
Colin: Is that a, sort of, morning’s operation?
Eddy: Well, it’s a whole day, so probably in a day, if you’re lucky, you’ll get three or four recordings, that’s all. So it needs lot of patience and lots of skill.
Colin: Yeah, a deep breath when you get outside.
Eddy: Yeah, definitely, yeah. But it’s, you know, it’s exciting for us to be able to record proper human neurons. You know, so we’d be putting exploratory drugs on these neurons to understand whether they change the electrical activity of the neuron.
Colin: Yeah. It looks like an aerial photograph, isn’t it, with fields –
Eddy: It does, yeah.
Colin: Looking down.
What is, I mean, your role?
Iain: Yes, so my role here is to look after a group of neuroscientists who are looking for new drugs for the treatment of pain for Alzheimer’s disease and other neurodegenerative diseases like Parkinson’s, and a few others. And also we have an interest in some psychiatric disorders.
Colin: So with my tingly toes, would that be something that you would be looking to find something?
Iain: Yeah. So I think what you’re describing is a type of neuropathic pain, by the sound of it.
Iain: And that’s something that’s very much on our agenda to try and find new treatments for. We have several good ideas about how we might treat neuropathic pain.
Colin: So what sort of timeframe would that be then?
Iain: Typically, from having an idea to having a drug molecule which we could potentially test on humans, it could take anywhere between, sort of, two and four years. So it’s not a short time but it’s not a very long time.
The quest to try and untangle the mechanistic classification of pain has been going on for as long as I’ve been working in the area, you know, some 20-odd years. So I think in the last, you know, 10 or 20 years that the focus has really been into this, sort of, mechanistic classification. So to understand, in these individuals, what is causing the pain, where’s it coming from? So looking at what’s going on in these individuals and maybe doing some very careful quantitative testing with the new instrumentation that’s available now, perhaps some neuroimaging using MRI. So looking at what’s going on in their brain, perhaps in their spinal cord, and really understanding how their pain is being translated into their sensation. That’s really where the field is going, I think, from a mechanistic point of view.
Ruth: I think you’ve had every single type of painkiller that we have, the world has. So you’ve had the opiates, you’ve had capsaicin, you know, it’s quite rare that people would get that, it’s not that commonly used.
Colin: I had the patches put on and, again, I rang the lady doctor up a couple of days later and said, “Oh, you’re brilliant, this stuff is the dog’s biscuit, you know. I’m dancing, skateboarding, yeah,” and the pain just, whoosh, went. But again, about five weeks later, as quick as it went, it came back. Suddenly one morning I woke up and I thought, “Oh no,” it was a bit of a disappointment because I thought I’ve cracked it here.
Ruth: So do you still feel that we need better pain drugs?
Eddy: This is a recording of a human pain fibre, so this is incredibly rare to get this sort of tissue. You know, this is the ultimate to prove that your drug actually has an effect on a protein in the correct neuron. So it’s exciting, these are pretty much the first recordings we’ve ever got that have worked actually from this sort of tissue.
Colin: That’s a big old beast, isn’t it? So I’ve had this for three or four years now, but I live with it.
Iain: It’s a very challenging scientific area, not because we don’t understand the mechanisms particularly well, but because everyone’s pain is very different. And it’s everything from, you know, boring, aching, stabbing, tingling, burning, you name it, and all of those different descriptions of pain may have a slightly different mechanism underlying them. So it’s very difficult to come up with a drug that’s going to work for everyone. So the idea of doing trials in people that have their pain very well described and they can understand day to day what their pain’s going to feel like, that at least allows us to standardise the patient population with a particularly therapy, and hopefully match that therapy to the patients.
Colin: So the cells…
John: You have to look after them, these cells, yes.
Colin: David, George, I can see the names on the…
John: You’d be there a long time because we’re talking about millions of cells.
Colin: Oh, right.
John: It depends if you can come up with a million names.
Colin: And will it take all day to do what you want to do, or longer?
John: Yes, yes, well, these studies take years to understand really, the mechanisms that are involved in the generation of pain. Then we publish that data, if possible, in peer reviewed journals so they’re in the wider community, the wider community can see our scientific research and we can all learn from each other. So we try and share our research as much as we can.
Colin: You know, this magic pill that everyone talks about, you know, where you just take a pill and that cures everything, it certainly won’t be in my lifetime [laughs].
Ruth: Yeah, I’m not sure it’ll be in mine either, one magic pill that cures everything.
Colin: I think they say, well, you don’t know, do you, because the scientists and the people that looking at these things, they don’t tell you the whole truth.
Ruth: I will tell you the whole truth, as much as I can tell you, as much as I know.
Iain: I don’t think there’s a magic bullet that’s just going to work for everyone. I think, you know, each individual is going to have to have a drug given to them which is tailored to their experience, to their mechanisms that are going on to cause their pain. And that’ll be really good for them, you know, this isn’t rocket science, it’s much, much more difficult. Because, what we’re looking for is something that actually will have a beneficial effect in a very, very selective way, and actually have no bad side-effects.
Colin: Since all this happened, yeah, I only have positive vibes, yeah, because the news has gradually got worse and worse and worse for me, and you think, “Oh, right.” But, I think I’m only still here because of the positiveness that I’ve shown, you know, so I’ve had to sit down with my son and daughter out here, you know, and tell them what the damage is [laughs], and it could be tomorrow, whatever, that’s it, isn’t it? You know, but I don’t regret a day of it, because naturally you only remember the good times, don’t you?
John: What we’ve got now are automated systems that can, essentially robots that can run that experiment. Not only run that experiment, but they can run multiple experiments. This one can do 16 at one time, but there are also pieces of kit that can do 384 experiments in one go. So, you know, the equivalent of 384 people sat at 384 pieces of equipment like this.
Colin from MedImmune: Or a year of John’s work in a day.
John: Yeah, exactly, or a year’s work in one day.
Colin (Froy): And that writes up the notes at the end as well, does it? You just print them off?
John: You still need a scientist at the end to interpret the data, unfortunately…
Colin: A scientist to plug it in?
John: No, no.
Colin: It looks like a, one of those, previous life it was one of those things that goes up to the top of the mountain.
Eddy: Yeah, that’s right.
Colin: [Laughs] In its baby life. Hello, sorry, are you playing battleships there?
Eddy: When we look at this, these sorts of traces, you think, well, that’s pretty impressive, high-quality recording, not perfect but pretty good. And yet it’s coming out from just one well of a 384-well plate. So, you know, it’s not a million miles away from a recording from that rig there, but it’s been miniaturised into a 384-well plate, it’s really incredible.
Colin: So someone got a few brownie points.
Eddy: Yes. That’s why these new instruments are so important. We’re screening hundreds and thousands and millions of compounds – how do we do it faster and more effectively? And the answer is better-quality data using, you know, faster machines.
Iain: The important thing to realise is that we will screen through thousands and thousands of molecules before we find one that we that we think is worth progressing. And at every single stage there’s the opportunity to fail. We have to be realistic that, first and foremost, whatever drug we come up with has to be safe.
Colin: So the ideas come from…?
Iain: I don’t think anyone has a particularly, you know, they don’t, sort of, have a light bulb moment and think, “Oh, this is going to be a great idea.” Sometimes, but I think that’s rare. More often than not it’s from understanding the science, understanding the literature, talking to people, thinking things through, drawing out diagrams, thinking about points that we can intervene. But actually, the way science is done is not only experimental science, which is absolutely critical and absolutely core to everything we do, and high-quality experimental science makes or breaks everything that we try to do. But actually the development, the ideas development, the sharing of data, the what to do next, the strategies, it’s all about people talking to each other and having a good scientific community, a good closely knit scientific community like we have here at MedImmune, that’s what makes things work.
Ruth: My experience is to go from the idea, from when we start screening for small molecules, understanding the biology, to having a molecule that’s good enough to go into people. And that takes five years, and by the time we have a molecule that goes into clinical trials we’ve probably spent close on $30 million or $40 million. But that’s nothing compared with what it costs to run the clinical trials. If you can run clinical trials in human volunteers, if you can do that for less than $500 million you’ll be doing really well. And then of course when we make a drug the cost of success also has to include the cost of failure. So I think the latest data says that on average any new medicine that’s launched costs more than $1 billion.
Iain: We work on protein therapeutics and monoclonal antibodies, or biologics as they’re called now, biologic therapies. And think, you know, the evidence most recently of this monoclonal antibody to nerve growth factor and demonstrating that actually that looks very effective in some of the early studies in the clinic. I think that also tells us there could be a new wave of medicines that could come from biologic therapies here, that will be much, much more effective at treating pain than perhaps some of the more traditional approaches. So we’re hopeful.
Ruth: Something else we’re working on is what’s called a nerve growth factor antibody. I don’t know if you’ve heard of those.
Ruth: Now, that has been in development probably for more like 15 years and it’s certainly got a few years ahead of it still. Yeah, and the amount of money that –
Colin: Did you put it on the shelf for a couple of years?
Ruth: No, no, it’s been moving forward all the time. And sometimes, often, things don’t go well, you know, and you get bad news and… It’s like this morning, one of the drugs that we’re working on, actually this one’s for chronic lower back pain, it’s an early stage drug, we put it into the safety studies and it causes liver damage. Well, that’s the end of that. It happens all the time. So you’ve got to jump so many hurdles to get a drug to patients.
Colin: So is that really disappointing for you? All that work and time and money…
Ruth: Well, we, sort of, learn to live with it.
Colin: The main question is how big is the competition between companies?
Ruth: We live to make sure that the drug that we’re working on is going to really be good for people, I mean, that’s what we care about. The early biology, understanding which drug targets are on which nerves, or what really controls inflammatory pain, those sorts of things we collaborate a lot on. And towards the end of development, you know, when we’re doing phase 3 studies, where we might have a drug in thousands of patients, and at that point, you know, we could be in competition with another company. Or, actually more often these days we might join forces and, you know, co-develop at a late stage because it just costs so much money.
Colin: Does it go home with you?
John: It’s bit of a way of life being a scientist, and in your early career often you work very long hours, especially in academia, where you’re –
Colin: In where? What country’s that?
John: In academia, that’s not a country.
Colin: Oh, sorry [laughs].
John: It does sound like, something like Macedonia.
Colin from MedImmune: Your career is built up on the publications that you generate, as John mentioned earlier, you generate data, you write it up and send it out for peer review. And it’s that peer review, particularly in the quality of journal, which helps map out your path as a scientist and where your career goes.
Colin (Froy): What got you into thinking about doing this for a career?
John: It’s a bit of a mindset, isn’t it? It’s always questioning how things work and trying to understand how things work. And you get to do that every day as a scientist, which is quite rewarding, I think.
Iain: You know, transformational efficacy in pain will transform people’s lives, it’ll make so many people feel better, they can go back to work, they can go about their daily lives and have actually a much, much better quality of life. So although, you know, it sounds trite to say it’s not about the money, I mean, clearly the money for investment in the drugs has to come from somewhere. But actually all of us in the pharma industry, and here at MedImmune and AstraZeneca, it’s all about the patient. It’s all about trying to find new treatments that will make patients feel better.
Ruth: Controlling pain so that you’re aware of that sensation, you know that something’s going on but it’s not really painful. That would be something to aspire to, I think it will be quite a long time before we’ll be able to do that. But that’s what people here work on and that’s what we really care about.
Trish: You did really well…
Colin: Really, really interesting. I was in two minds whether it would be interesting, but it has been very interesting. I’ve learnt a lot. The next time I’m lying in a bed in Hammersmith Hospital and the bloke in the next bed says his tablets are useless, “Why don’t they find some that’ll cure my pain,” I’ll be able to explain to him the process and the amount of time it takes to get that tablet or medicine into the bottle. And say, “Look, it could be up to 12 years to get the tablet you want, or it could be 50 years to get the tablet known as the bullet, the all-singing, all-dancing tablet that cures all pain and any other illness that you’ve got.”
Ruth: Our goal is to know that it works, and when we get data back from the clinical trial that says something we’ve invented works. God, that’s the best day for us, absolutely the best day ever.
Iain: My view is the majority of people are doing this because they genuinely feel they can help people by dedicating their life’s work, as it were, to coming up with cures for diseases and treatments for diseases that affect individuals they may have come across or they may know.
Colin: If you ever go into a chemist do you stand there looking around the shelves and think, “Oh, that’s one of ours”?
Eddy: But it’s a dream to actually, you know, I mean, it is. So most people here in this building that’s what they want, they want to say, point at a drug and say, “I was part of that,” definitely, yeah.
Colin: Initially I’d thought of coming back as an ant, because ants, they’re very hard working, they’re good team players, but I actually read an article the other day which made me change my mind. And I’ve decided now that if I came back as an animal I would like to come back as a bull elephant wearing a permanent bulletproof jacket. Because the elephant is strong, it’s very intelligent, so that’s two of me… ticked, and it’s considered one of the smartest animals that we know about. I could go round kicking poachers in the bollocks, yeah, to prevent them shooting any more elephants for their tusks. So I’d be able to protect them and preserve lots of their lives.