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by Ganesh Suntharalingam, Honorary Secretary, Intensive Care Society

On the morning of Monday 13 March 2006, six out of eight healthy male volunteers on a clinical trial received a first dose of a drug never before given to humans, in an independent commercially-run clinical trials unit within the grounds of Northwick Park Hospital.

This was planned and expected to be completely routine. However, all six men had a life-threatening reaction requiring an emergency response by the NHS, which not only had a lasting impact on them but also brought about changes in how higher-risk clinical trials are run and regulated in the UK, EU, and beyond.

Saving the lives of those volunteers once they were transferred to NHS care required a huge, co-ordinated effort from the intensive care unit team, senior colleagues from other specialities, and many other clinical and operational staff across Northwick Park Hospital, with support from neighbouring critical care units and assistance from other agencies including the London Ambulance Service and the Metropolitan Police.

The release of the BBC’s documentary – The Drugs Trial: Emergency at the Hospital – on Tuesday (21 Feb) makes this a good time to look back at what happened and at one example (among many) of the NHS responding to a crisis.

The way the drug affected the six men is described in clinical terms elsewhere and very strikingly by the volunteers themselves in this documentary. Each developed high fever and early signs of shock within a few hours; and then, after briefly rallying with initial treatment on the trials unit, progressed to life-threatening illness, some more quickly and devastatingly than others.

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fourteen hours after they all received the drug, the worst affected volunteer was in advanced multi-organ failure

By late Monday night, fourteen hours after they all received the drug, the worst affected volunteer was in advanced multi-organ failure, his condition deteriorating so rapidly that it took two hours for the duty intensive care consultant and team to stabilise and transfer him on full life support to the intensive care unit (ICU) at Northwick Park Hospital.
Doing so took up the last empty bed on ICU, and it was already clear that the five other young, previously healthy men who had received the trial drug were also visibly deteriorating. Some were becoming sicker faster than others, but they were all developing multiple organ failure and all needed to be in intensive care.

Bringing six people who needed immediate treatment at the same time into a fully-occupied ICU would seriously challenge any intensive care unit in any health system in the world – as many of them have since told us. Splitting the volunteers among several other hospitals would have put them at risk, not least in trying to co-ordinate their treatment in the days ahead in an already complex situation.

The reaction fitted the recognised label of a ‘cytokine storm’, an unintended dramatic release of inflammatory biological signals in response to an attempted treatment drug, causing a chain reaction in the immune system.

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this had to be treated to all intents and purposes as a potentially new disease process

In truth, the rapidly evolving and unpredictable clinical picture, triggered by a completely novel drug with unknown duration and severity of effect in humans, meant that this had to be treated to all intents and purposes as a potentially new disease process, affecting multiple patients at once. Its effects and impact only became clear as they happened to one patient then the next, hour by hour, and treatment plans had to be adjusted accordingly.

This was not only about ‘finding the cure’, although this has been an understandable media focus, treating the underlying cause is critical in all intensive care and so an important part of the challenge was indeed to dampen or stop the runaway immune reaction – assuming that this was the explanation, which was far from guaranteed at the time. But another crucial part was to manage the multiple organ failure and make all the men safe in the face of their simultaneous rapid deterioration. This posed significant challenges in itself.

Northwick Park Hospital’s ICU is immediately adjacent to the hospital’s theatres and recovery area, which is not the case in many hospitals. Day to day this layout allows complex surgical patients to benefit from easy access to critical care skills and equipment and a close working relationship that would be hard to replicate.

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Intensive care, recovery and theatre staff, as well as anaesthetic junior doctors worked together to create a new five bed unit from spare and borrowed equipment in the middle of the night, with no warning – and began receiving multiple patients within an hour of decision

On the night of 13 March, the recovery area took on vital importance as a critical care ‘lifeboat’ docked to the existing ICU. Intensive care, recovery and theatre staff, as well as anaesthetic junior doctors worked together to create a new five bed unit from spare and borrowed equipment in the middle of the night, with no warning – and began receiving multiple patients within an hour of decision. This was a huge achievement and only possible because of an exceptionally well-functioning team.

Meanwhile, hospital site managers co-ordinated essential services and diagnostics. Police vans and ambulances brought kidney support machines from other intensive care units in the North West London Critical Care Network, who also mobilised with offers of transfer beds and other help. Duty pharmacist called colleagues in teaching hospitals all over London to gather rarely-requested drugs. By 1am, the recovery area was an orderly bustle, resembling something between a (well-run) field hospital and the hangar deck of an aircraft carrier.

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ensuring that the families were kept informed of developments was always a priority

By this stage, families of the volunteers were beginning to arrive, understandably desperate to learn more. Their sons, partners and brothers had walked in completely healthy for a routine, paid clinical trial and were now critically ill in intensive care.
Reactions ranged from shocked but calm concern to outright anger, although not directed at us; everyone understood that we were the NHS team treating the aftermath of someone else’s trial. Over the hours and days that followed, ensuring that the families were kept informed of developments was always a priority among the blizzard of information and outside interest.

Over the next few days, things did not get any simpler. The patients remained very unstable, with some of them still in an extremely severe condition and the others continuing to hover in and out of further, life-threatening, deterioration.
There was a torrent of further information from the clinical trial and increasing volumes of patient data as test results accumulated, as well as close attention from EU, US, and Japanese regulatory authorities as the incident had repercussions for early-phase drug trials globally.

As is always the case in medical emergencies, collaboration and a buddy system was the key. We requisitioned a seminar room and set up a regular expert panel, meeting several times a day with internal and external colleagues to exchange ideas and weigh evidence.
Meanwhile, across the corridor in the intensive care unit itself, the usual minor comedies of everyday healthcare continued: one of the trial volunteers, a driving instructor, pulling off his mask to give some slightly hazy last-minute telephone advice to a panicky student about to take her test; half-eaten pizza boxes piling up in the break room; consultant colleagues running for 36 hours at a time on energy drinks and illicit smoking breaks (outside the grounds, of course); a senior operating theatre colleague roaming the hospital confiscating Motorola flip-phone batteries from junior doctors to keep mine refuelled until it snapped at the hinge 18 continuous hours later.

Media interest peaked early and remained very high. This was a dramatic human interest story of healthy volunteers injured by a new, genetically engineered antibody from the cutting edge of medicine. This was amplified by the fact that everyone who knew anything about it – the victims, the families, the clinical staff, and (very soon) the senior biotech and clinical trials company staff, were all in the same building.

Unlike most major incident stories, there was no accident site to film or bystanders to interview. The large traffic island on the hospital ring road became a forest of cameras, and the drug trial displaced Saddam Hussein’s court trial as the top story on global news bulletins. The media were sympathetic to the NHS, but speculative interviews with faraway experts showed on every TV, including those watched by families and in some cases predicting imminent death. An early lesson was that it was best to have regular, brief, credible hospital updates which guarded the patient’s privacy but minimised external speculation.

A comment from a distressed partner caught live on camera became the infamous ‘Elephant Man’ label. In truth, it was not a specific symptom or effect of the drug, or some kind of explosive growth of the head. Critically ill people develop leaky blood vessels and shock, and the large volume of fluid we give them in the first few hours causes temporary swelling – most noticeable in the face. It gets better as they recover, but can look understandably upsetting to their friends and family.

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there was suddenly a sense on the morning of Wednesday 15 March that something had peaked. Temperatures started coming down

After 48 hours, as constant monitoring, treatment and discussions continued, there was suddenly a sense on the morning of Wednesday 15 March that something had peaked. Temperatures started coming down, the patients who were still awake began feeling better and could be unstrapped from their high-pressure oxygen masks, and organ function began to improve. Infusion pumps and kidney machines began to be disconnected from the luckier, less severely-affected patients. But meanwhile some of the men remained desperately unwell on ventilators.

This made celebrations muted as the quickest to recover began to leave the unit by the Friday, but it was nevertheless emotional to see them leave unharmed. After a little over two weeks, all six had survived and left to recover in another ward, but not without cost. One patient had life-changing injuries, and all critically ill patients take a long time to get fully back to normal. The incident had a lasting impact on all the volunteers, and Tuesday’s documentary brings it out very well by focussing on the patients’ story, eleven years down the line. Having seen an early tape, it was a powerful experience to see some of the volunteers going about their lives and reflecting on what happened, which I think everyone involved at the time will share.

The unprecedented TGN1412 incident showed that the clinical trial protocols and regulatory safeguards in place in 2006 needed to be updated for new scenarios – such as, in this case, a new, highly engineered, monoclonal antibody targeting the immune system and designed to amplify the effects of part of it.quote2

the volunteers survived because they had immediate access to intensive care

The Department of Health Expert Scientific Group made 22 recommendations for identification of high-risk first-in-human trials and appropriate additional precautions. One recommendation was based on what Northwick Park Hospital was able to deliver: the volunteers survived because they had immediate access to intensive care, and such access is an important part of current recommendations for safe conduct of high-risk early phase trials. However, the deaths of volunteers in a French clinical trial last year, although in a different setting and with a drug which was no longer first-in-human, shows that clinical trials remain an an evolving field.

What remains true is that trials of potential new treatments are important. As emphasised in this editorial the care that we were able to give the volunteers, as well as every other treatment the NHS provides, is in itself reliant on clinical trials, the vast majority of which are carried out safely and without incident.

In the years since the incident, a somewhat unjustified shadow has hung over the hospital locally, as the place where something terrible happened. This was not the hospital’s own trial but pointing the finger at our own commercial tenants in response has never felt like an appropriate or professional answer, and in any case the hospital does very successfully run clinical trials itself via its thriving research and development department, even if TGN1412 was not one of them.

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Although this was not an NHS trial, the real story is that the volunteers survived precisely because the trial did take place in the grounds of a large acute hospital

Although this was not an NHS trial, the real story is that the volunteers survived precisely because the trial did take place in the grounds of a large acute hospital which was able to mount a rescue without delay, and what was learned has gone toward making all such higher-risk trials safer regardless of who is running them, in this country and others.
The incident also showed the NHS doing what it does best: a large, very busy, acute urban hospital responding rapidly, effectively, with excellent teamwork, networking and improvising to a situation previously seen nowhere else in the world. Not only the patients, but all of us involved in the NHS response owe a huge amount to the intensive care unit and many other clinical staff from across Northwick Park Hospital and others who rose to the occasion without hesitation.

Importantly, the greatest credit should of course go to the volunteers, who not only showed remarkable grace and courage at the height of their illness during what was clearly a frightening time, but who have also, without exception, always been very generous and clear from the outset that they wanted their experience and information shared where it could do the most good in advancing science, and especially to make clinical trials safer for others.

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Dr Ganesh Suntharalingam was Clinical Director of Critical Care at Northwick Park Hospital from 2006-2014

The Drugs Trial: Emergency at the Hospital aired on Tuesday 21st February 2017 at 9pm on BBC 2. http://www.bbc.co.uk/programmes/b08g8np3

Clinical Article: Ganesh Suntharalingam, F.R.C.A., Meghan R. Perry, M.R.C.P., Stephen Ward, F.R.C.A., Stephen J. Brett, M.D., Andrew Castello-Cortes, F.R.C.A., Michael D. Brunner, F.R.C.A., and Nicki Panoskaltsis, M.D., Ph.D. N Engl J Med 2006; 355:1018-1028, September 7, 2006 DOI: 10.1056/NEJMoa063842 http://www.nejm.org/doi/full/10.1056/NEJMoa063842

Editorial: Jeffrey M. Drazen, M.D., N Engl J Med 2006; 355:1060-1061, September 7, 2006 DOI: 10.1056/NEJMe068175 http://www.nejm.org/doi/full/10.1056/NEJMe068175

This article is reposted from the London North West Healthcare Trust Website where it was published 27th February 2017. See the original at: http://www.lnwh.nhs.uk/about-us/news-and-media/latest-news/the-tgn1412-drug-trial-a-personal-view/#sthash.yMhibPYt.dpuf

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