The Trouble with Trials

Rob Oldfield is 31-years-old. He’s an aspiring actor. He’s done lots of plays… and had some bit parts in TV shows… a couple of non-speaking roles in commercials. But, it’s a tough business.

Today, he’s lying in a hospital bed. He’s in a wing of Northwick Park Hospital in London England. But this isn’t an acting job. He’s found another way to make money.

He’s been up since before dawn … he had to be at the hospital at 6 am… so he closes his eyes, and tries to grab a nap.

After about 20 minutes a nurse comes into the room. She puts a needle into each person’s arm. See, Rob is just one of four young men in the room.

Each needle is connected to a machine that dispenses a new medicine: A miracle cure, hopefully. But it’s a cure for a disease… that Rob doesn’t have.

We do a lot of history stories on this show — but this is recent history…. 2006. March 13th, 2006. It’s a Monday.

This is a “phase one” clinical trial. Trials have three of these phases, each with their own specific question. Phase one asks: “Is it safe?”

By the time you get to phase one trials in humans, the medicine has already been tested on cell cultures in a petri dish, and on animals: mice or maybe pigs.

This particular drug – TGN-14-12 – had also been tested on monkeys. And everything looked great.

The medicine was created by a German company as a revolutionary treatment for leukaemia. It’s different from other cancer drugs. It doesn’t attack the cancerous cells itself… Instead, it teaches the immune system to attack them.

But these men — the four in Rob’s room and four others in a room across the hall – didn’t have leukaemia, they were just there to make sure the drug is safe. This was a ‘first in humans’ trial… So, they were given a dose 500 times smaller than what had been shown to be safe in the monkeys.

“A friend of mine had done trials. And he said I should sign up. They were offering two thousand pounds which I thought was OK.”

That’s Rob Oldfield. That clip is taken from a documentary the BBC did about him.

“I was interested, well just in the scientific contribution I could be making.”

If you’re Rob, it’s a pretty good pair of incentives… two-thousand British pounds, (that’s almost thirty-five hundred bucks US.) And you get to tell your friends at the pub that you’re helping to cure cancer.

And all it takes is three days of hanging around in a hospital.

“It’s a medicine being tested in a laboratory situation approved by the government. What could go wrong?”

It was a double blind, randomized trial – meaning some of the men were getting TGN-14-12, and some were getting a placebo (a dummy drug that has no effect.)

It was “double blind” because neither the subjects, nor the doctors knew who was getting the real stuff.

But it didn’t take long to figure that out.

The trial starts at 8am.

The four guys in the other room get theirs first. It takes about 10 minutes for each person… so around quarter to nine they move into Rob’s room.

But already, one guy – test subject #2 – starts getting a headache. Of course, they don’t want to give him anything for it… that would mess up the trial, so the nurse gives him a cold compress for his forehead and tells him to try to relax. He’s also feeling flushed. So he takes off his shirt.

Meanwhile the doctor administering the trial is now in the second room giving Rob and the other three men their doses.

Rob is test subject number seven… or as the sign over his bed says, “Double O Seven” — which is pretty cool if you’re a James Bond fan. It also means he’s second last to get his dose.

While Rob’s getting his injection, a nurse comes in and tells the doctor about the guy with the headache. The doctor checks his watch and quickly writes something on the pad he’s holding then moves on to the last subject…number 8.

OK Now it’s 9:30. All the men have had their injections and the doctor returns to the first room.

Patient 2 is now suffering from back pain. He still has a headache and now he also has a fever.

Then, another guy in that first room starts repeating the same three symptoms: Headache, backache, fever.

In the second room, where the men had gotten their medicine a little later, other symptoms are starting to show. Rob starts shivering. He isn’t cold… he’s just shaking involuntarily.

Then he throws up.

If you’ve ever been in a room where someone throws up… and you already aren’t feeling well… I think you can guess what happens next.

In his report afterwards the supervising doctor wrote “They started to fall like dominoes.”

In both rooms three of the four men are vomiting into big yellow plastic bio-hazard bags. The contents are tagged and saved. I mean this is a medical trial after all. Every piece of evidence has to be preserved.

Then patient three starts yelling. “I want to leave. I don’t want the money anymore – I just want to go home.”

Two of the men lose control of their bowels.

Then, two more.

Even as the clock approaches noon, nothing has stabilized. The symptoms aren’t plateauing… everything just keeps getting worse. The nurses close the curtains around each bed, so the subjects can’t see what the others are going through.

And in the midst of all this, two subjects, one in each room, are fine.

I mean, they are lying in a hospital bed in a room with three strangers who are screaming in pain… with doctors and nurses rushing around. One of them later described it as “complete chaos.” And all they could do was lie there and wonder “is this about to happen to me? Or did I get the placebo?”

Now at this point the doctor overseeing the trial says “OK we are done,” and breaks protocol. He tells the medical staff treating the men, and the men themselves, who’s who: He confirms that the two men who are feeling fine have indeed received a placebo. So those two men are sent home. They gather their things, and walk out of the hospital, not knowing if their fellow test subjects will survive.

In the mid-afternoon, the Intensive Care Unit is informed they have six patients in life threatening condition because of an experimental drug trial.

The men all have multiple organ failure.

Lungs, then Kidneys.

They’re put on ventilators and dialysis machines.

At 3:30 the men’s families are called… wives, girlfriends, parents… they’re told to come to the hospital immediately. All six men are in critical condition. The families are told this might be their last chance to say goodbye.

The men’s faces and bellies are swollen and disfigured. One woman even says her boyfriend looks like the Elephant Man. Well, that comment reaches the media and now the British press starts reporting on what was happening to these six men. And of course they call the incident “The Elephant Man trials.”

“Six men are in critical condition after a drug trial gone horribly wrong.”

“Doctors attending say they don’t really know what drug was being trialled.”

“Some of the patients are described as having swollen heads and bellies”

We know now, and I’m sure the doctors in the ICU knew then, that the swelling had nothing to do with the original drug being trialed… that was a reaction to the fluids and steroids the men were given to keep them alive. But at the time all the public knew was that an experiment had failed, and had turned these men into monsters.

What the drug had actually done was kick their immune system into high gear (which technically is exactly what it was supposed to do) – but then since there was no cancer to attack, it just went after healthy cells, destroying the muscles and internal organs. There’s a name for that. It’s called a Cytokine storm.

As the days went on, most of the men slowly recovered… the swelling went down, their organs resumed their normal functions.

But they still suffered from weakness and fatigue. And there were also a lot of unknowns.

• How would their immune systems behave in the future?
• Would they be susceptible to cancer?
• Could they have kids?

The worst off was patient double-o-6. The youngest of the participants… just 19 years old. Well after the other five had started recovering, he was still in intensive care needing a machine to breathe. The tips of his fingers had withered and blackened… they would eventually be amputated along with part of one foot and some of his toes.

He didn’t get out of the hospital for four months.

This was a high-profile case in Britain. Scotland Yard got involved. Their medical unit analyzed the drug and found that its contents and doses were exactly as listed. There had been no mistake… no human error… no deliberate sabotage.

The drug just caused a different reaction in humans than it did in animals. Four years later scientists figured out why: A tiny difference between how our immune systems work and those of macaque monkeys. One antibody – something called CD28 that we have, and monkeys don’t. That one molecule made all that difference.

There were inquests, lawsuits, and yes, the six men did receive financial settlements.

And there was also an independent professional review of the whole process.

One observation – something that is kind of obvious in hindsight – is that they shouldn’t have tested all eight men at once. Remember, the subjects were given the medicine one after the other, with the doctor moving bed to bed and room to room.

Why not wait an hour between each? Or even do one subject a day?

In all, 22 recommendations were adopted by the European Medicines Agency, making clinical trials, going forward, safer than ever.

“I’m glad to have been part of something that has reformed the whole industry,”

That’s Rob Oldfield – 007.

“and the trial has made me realize that life is quite precious and that we need to make the most of it really and have a healthy mindset about being alive.”

And the drug, TGN-14-12? The rights to it were acquired by a different company and they renamed it TAB-08. And get this, it’s back in use. Using a dose that is one one-thousandth as strong as what Rob got, the drug has passed phase one clinical trials. And now it’s being seen as a potential treatment for auto-immune diseases.

I’m Dan Riskin – and this is “Inside the Breakthrough – How Science Comes to Life” – an original podcast by SciMar.

In the first season we kind of bounced around the scientific universe… We looked at:

• how things get discovered…
• why some people make better scientists than others do…
• and what questions a researcher should ask.

We also played a lot of historical newsreels:

“In the study of science is found the most useful and satisfying knowledge.”

This season is going to be a little more granular. We’re going to dig into the world of clinical trials:

Not just ‘How’ and ‘Why’ things get tested… but the big questions…

• how we judge if a trial is a success… 
• why we call test subjects guinea pigs… 
• and why Marie Antoinette was drinking cocktails in a basement with one of Mozart’s best friends

The reason we’re focusing on clinical trials this season is that SciMar – the people who produce this show – are right in the middle of their own clinical trials right now. They’re testing the idea that you can use a hormone from the Liver – something they discovered and named “hepatalin” – to diagnose and treat type 2 diabetes. More on that later.

For now, I want to do what we do best…. Tell a story from history that shines some light on modern research.

This is episode 2 – The Trouble with Trials.

It’s late morning… just before lunch… A wave breaks over the starboard rail.

The water washes down the side deck and drains off the stern.

The bosun yells at the helmsman to keep the nose up and stop washing the crew.

There’s no real danger. This is HMS Salisbury – a 50-gun ‘ship of the line’ of the British Royal Navy. The ship is brand new – it was just launched last year. The swells of the Atlantic Ocean in spring are just minor inconveniences… I mean yes, the water is cold, but most of these men need a bath anyway.

The weather (and the occasional lapses in concentration by the man on the helm) are not what the crew is worried about.

There’s something much more dangerous … much more deadly… already on board…. lying in the forward hold.

The ship’s doctor is young – just 31 years old. He’s a Scotsman named James Lind.

He did his masters thesis on venereal diseases – which comes in handy on a ship full of sailors.

Lind also has a reputation for being well, a bit odd… for thinking differently. Medical experts of the day generally focused on curing illness, or in the case of the Royal Navy – removing musket balls and stitching up wounds. Their job was to “fix things” –

but Lind spoke loudly and often about preventing illness.

He campaigned for better conditions on ships:

• better ventilation
• clean blankets
• balanced nutrition

… all as a way to avoid the onset of diseases.

Now this seems like common sense now… but in the 18th century, that sort of approach was considered… well… just considered ridiculous.

But that’s not what made him famous. And it’s not what I want to talk about today.

You see, the reason James Lind is famous – is because of what he did on May 20th 1747.

That lurking danger in the forward hold, was a disease…

An illness that every sailor on board every ship in the world, knew and feared.

250 years earlier — Vasco da Gama lost 116 men from his crew of 170 (more than ⅔)

In 1520, Magellan lost 208 out of 230. 90%.

More than pirates, or storms, or even mythical sea monsters…. This was the thing sailors feared most.

Anyone stricken with it was placed in a separate part of the ship… supposedly for their own comfort… but everybody knew it was just so the other men on board didn’t have to watch them slowly die.

There was no cure. But Dr James Lind had an idea.

I selected twelve patients on board the Salisbury at sea. Their cases were as similar as I could have them. They all in general had putrid gums, the spots and lassitude, with weakness of the knees.

They received the same food as the rest of the crew: Gruel sweetened with sugar in the morning; mutton-broth at mid-day, and for supper, barley and raisins, occasionally with some rice.

But Lind added a little something to each man’s diet.

• Two of them were given a quart of cider to drink every day.
• Two others took twenty-five drops of “elixir vitriol,” three times each day – now “elixir vitriol” is a fancy way of saying sulphuric acid… so probably less pleasant than drinking cider.
• The next two got regular doses of vinegar.
• Another pair were forced to drink a pint of seawater every day.
• Patients 9 and 10 were given a lump of paste made of horseradish, mustard seed, and garlic.
• And the last two men — each had two oranges and one lemon every day.

This was the first controlled clinical trial of the modern era – and the goal was to find a cure… for scurvy.

Now today, we know that you can get scurvy from a lack of vitamin C – but at the time that was only anecdotal. Sailors had noticed that crews in the South Pacific who were allowed to bring fresh fruit on board from tropical islands rarely got it. But that was just sailors talk – not medical evidence.

Lind’s study had quick and clear results.

The most sudden and visible good effects were perceived from the use of oranges and lemons; one of those who had taken them, being at the end of six days fit for duty.

It was clear evidence – albeit in a very small sample size – but the Navy refused to take action.

The reason – no surprise here – was money.

I mean, getting lemons to all of Britain’s sailors? All around the world? Do you know how much that would cost?

Finally, in 1795, fifty years after Lind’s clinical trial, the Royal Navy made lemon juice a compulsory part of sailors’ diets.

Over the next two decades…. 1.6 million gallons of lemon juice were issued to British ships. They stored it in barrels with a layer of olive oil on top to keep it from spoiling. Over that time, the number of reported cases of scurvy fell from nearly fifteen hundred a year…. to two. Not two hundred. Two cases a year.

This is the point in the show where we pivot from the historical, to the modern. And for that I’m going to bring in Krista Coventry.

So I’m a director of Regulatory Affairs for a contract research organization. So that’s a private industry company that can, on a third-party basis, conduct clinical trials for an industry sponsor. 

Outsourcing your clinical trials to a CRO like Krista’s, is an increasingly popular approach.

It really adds that extra layer of integrity to your data because once you have your results it’s done through a third-party, it’s validated, and then the media report on that. It just gives it a little bit of extra integrity.

Right now, she’s running trials for SciMar – the people who produce this podcast.

They have all sorts of exciting irons in the fire right now.

New therapeutics in the race to control diabetes. They also have a really novel diagnostic technology, that we’re also in the process of testing, to help better identify individuals that are at risk for pre-diabetes and diabetes.

Her work includes trials in all three phases.

The first phase are phase I studies and those are where we want to look at the safety or the tolerability of the proposed product dosage. So we’ll look at what’s called the pharmacokinetics, which is: ‘how is it absorbed, and distributed, and metabolized, and excreted from our body?’ These studies are often small, we’re looking at anywhere from 10 to 50 people. And they’re always done in healthy individuals.

…That’s Rob Oldfield and the TGN-12-14 trials… you know the ones people would later call the “Elephant Man trials.” But that was a worst case scenario, very rare. Usually Phase I trials go off without any issues.

Provided that we’ve had no adverse events in phase I we want to confirm that the product does what it says it’s supposed to. So in phase II studies we’re looking at more participants, so anywhere from 20 to 100 participants on average.

Participants in this phase actually have the condition that is being treated… So think of Dr. Lind handing out lemons to dying men on board HMS Salisbury.

See, if Lind had been doing a “phase one” trial — he would have just handed lemons to healthy sailors to make sure they weren’t toxic… but you don’t really have to do that because everyone knows lemons are safe to eat.

Then we move onto a phase III study where we look at efficacy in a larger sample size, so here we’re looking at anywhere from 100 to 1,000 participants. And sometimes we’ll compare the investigational product to a standard treatment. When those results are favorable phase III studies can be considered a final confirmation of the investigational product’s safety and efficacy.

Krista suggested an ideal number of participants for each phase, but really, those numbers vary a lot.

How long it takes, is also a moving target.

The duration of the whole R&D process is often determined on how novel the technology is. So are you looking at something brand new or are you taking established ingredients and combining them in a new way? If you’re looking at a new molecule you’re really looking at anywhere up to a 10 to 13 year R&D process to really ensure, and discover, and document what that molecule does in the body.

One of SciMar’s trials is testing the effects of a hormone called hepatalin — one that had never been identified before — so those trials will be going on for quite a while yet.

But they’ve got two other products in trials that might move a lot more quicker because like Krista described, they are a combination of medications already getting used. Those trials are jumping straight to Phase 2.

One is for SciMar NuPa Test. It’s a new way to diagnose type-2 diabetes. I’ll have results from that trial by the end of this season… so 10 episodes from now.

The other trial is for something called: SciMar NuPa Renew. That one is a pill that SciMar thinks will reverse type 2 diabetes by “renewing” the body’s ability to produce hepatalin during a meal. If that trial produces the results they’re hoping… it has the potential to counteract obesity, type 2 diabetes, and heart disease in one fell swoop.

Now that is a bold claim… but… that’s why they do the trials.

I’m Dan Riskin. Thanks for joining me on “Inside the Breakthrough – How Science Comes to Life.”

One last thing … 

About 10 years after the Royal Navy made lemons mandatory, Britain found itself at  war with Napoleon.

The British Navy formed a blockade around the French coast… and if you know anything about naval blockades you know that you have to stay out at sea for long periods of time… and well…. that’s only possible if your crew isn’t dying from scurvy.

So, while it might not get mentioned in the history books… I’m a big believer that it was the curative powers of the lemon that defeated the Little General.

Sometimes when life hands you lemons…. things aren’t actually that bad.