In March 2006, six young healthy men participated in a clinical trial for the drug TGN1412; within 16 hours all had been transferred to the intensive care unit at Northwick Park Hospital for severe and life-threatening reactions.
The disastrous ‘Elephant Man Drug Trial’ caused shockwaves in the medical and pharmaceutical community. TGN1412, a novel monoclonal antibody drug developed by TeGenero, a German biotech company, was intended for the treatment of autoimmune diseases and leukaemia. The Phase I trial (first-in-human testing) was conducted by Paraxel at an independent clinical trials unit at the Northwick Park. Clinical and animal testing, including on non-human primates, had already been completed and reported not to indicate any safety issues.
TGN1412 was administered to the six men by intravenous infusion over the course of 3 to 6 minutes. Each patient received the experimental drug in quick succession. Within 60 minutes, the first participants suffered severe headaches, muscle pain, nausea, vomiting, diarrhoea, severe fever, restlessness, rash and rigors. After four hours, the volunteers developed hypotension, tachycardia and onset of respiratory failure.
- By the following day all of the recipients had been admitted to the ITU at Northwick Park. Their symptoms progressed to multi-organ failure. It was later established that the TGN1412 doses had caused a “cytokine storm” in the volunteers; an extreme and near fatal immune response. The participants were hospitalised for periods of three to six weeks. The long term effects on their immune systems remain unknown, though on discharge some were warned they may suffer an increased risk of cancers and auto-immune diseases.
Gene Matthews acted for Rob Oldfield, amongst other trial participants, in a successful compensation claim for the serious injuries he suffered.
Rob vividly remembers the events of 2006:
“I went into the trial partly for the money, and also to do something for the good of people. I thought it could have been a massive break-through in medical science. I don’t really remember the risks being spoken about; we were given a ten page information document which we didn’t really have time to read. Everything was played down a lot. I had no idea it altered the immune system.
Not long after I was injected I started to feel very cold. I remember being sick into a biohazard bag, and all of us being very ill. I was taken to ITU. The steroids masked the pain somewhat. I didn’t really realise how bad things were – my Mother received a call from medical staff the same night. It was like they were saying “this is your goodbye – this person could die”. My immune system crashed and my liver, kidneys and lungs were failing. Fluid seeped in to my lungs. Thankfully, after three weeks treatment I survived”.
TGN1412/ Northwick Park drug trial - What did we learn?
In the immediate aftermath of TGN1412/ Northwick Park drug trial, there was much discussion within the scientific, medical and regulatory community about what went wrong and the steps which could be taken to prevent a similar disaster in the future. The apparent unpredictability of the adverse events associated with the trial raised significant alarms.
The Medicines and Healthcare Regulatory Agency (MHRA) regulates clinical trials in the UK. In an interim report, of 5 April 2016, they identified the likely cause of the adverse reaction in the TGN1412 trial an “..unpredicted biological action of the drug in humans”. The ‘unpredictability’ raised serious concerns. Shortly after, the UK Secretary of State for Health established an “Expert Scientific Group” (ESG), to “review what could be learned from the TGN1412 trial”, and consider future recommendations for Phase I trials.
The ESG report was published on 7 December 2006. It found that preclinical studies performed with TGN1412 failed to consider what constituted a safe dose for use in humans. In addition, it made 22 recommendations for improving the safety for Phase I trials of higher risk medicines. These included:
- Changes in the calculations of the starting point for drug dosing;
- Early discussion between regulators and sponsors with much more scrutiny applied to novel agents and access to independent, specialist opinion;
- Sequential clinical testing – one person at a time – rather than simultaneous, with an appropriate period of monitoring for sudden ill effects;
- Careful consideration of the route and rate of administration – i.e. drugs should be administered by slow infusion rather than as an injection.
The MHRA tightened the UK clinical trial regulations. New guidelines were put in place for trials of certain categories of drugs which have never been tested in humans. The guidelines ranged from dosing protocols to training for investigates. Additionally, the MHRA established a voluntary accreditation scheme for companies running Phase I clinical trials in the UK.
Following the ESG Report, the European Medicines Agency (EMA) published “Guidelines to identify and mitigate risk for First–In-Human Clinical Trials” in 2007, improving European regulation.
What has changed?
A decade on, have lessons been learnt from Northwick Park? And has the risk of a repeat event been reduced?
The MHRA answers yes. They report that conduct in Phase I trials has moved on: the regulation of clinical trials has been simplified and streamlined and “additional provisions and guidance has been put in place for certain novel products to provide as much assurance on safety as possible”.
Some have voiced concern that a disproportionate regulatory burden may now have been imposed on those seeking to conduct Phase I Clinical Trials in Europe. Yet the recent tragic events in France throw this into question. One man died and several others were left seriously injured during the Phase 1 clinical trial of painkiller BIA 10-2474 in Rennes. ANSM, the French national drug safety agency, has confirmed that eight volunteers received the fifth of the highest dose escalation of the drug simultaneously – seemingly a direct contravention of the EMA 2007 recommendations. This raises serious concerns.
Regulatory transparency, and transparency of research data, was a critical concern for the TGN1412 victims. Following a protracted three year legal battle, the MHRA released the full information available to it at the time it authorised the TGN1412 trial. The information suggested that investigators should have been aware of the risk of trial participants suffering a cytokine storm and that the MHRA failed to appreciate the foreseeable risk of a cytokine storm. Thankfully, improvements have been made. Following various campaigns for greater transparency (including the AllTrials campaign), the European Parliament voted in April 2014 to adopt the EU Clinical Trials Regulation which will require that all drug trials conducted in Europe are registered with clinical study reports made publicly available following completion of the trial. However, the legislation does not require manufacturers to publish historical data.
Even with safe regulation and increased transparency, at some point a human will always have to be the first to test a new drug. Inevitably, there will always be risks associated with that stage. Figures released by the MHRA in 2015 suggest that, in the past five years, 7,187 participants in clinical trials had suffered serious and unexpected adverse reactions, 493 of which were immediately life-threatening and 197 resulted in significant disability or incapacity.
It is therefore critical that an appropriate compensatory scheme is in place for when things do go wrong. The Association of British Pharmaceutical Industry (ABPI) provides guidelines on the insurance and compensation for clinical trials. Those who have suffered ill health as a result of their participation may be entitled to compensation. Despite this, at the time of the TGN1412/ Northwick Park drug trial settlement, participants struggled to obtain adequate compensation, with no allowance at all for the risk of later development of illness; TeGenero, which went into insolvency, had insurance cover of only £2 million and the insurance policy permitted a single “once and for all” payment only.
Again, some improvements have been made. In 2012, the ABPI published new guidelines for Phase 1 clinical trials, requiring that individuals should have up to three years to notify insurers of potential claims, and trial conductors should have joint insurance protection of £5 million. Whilst a significant step, the limitations remain – for example, the insurance cap would be wholly inadequately to cover a single, let alone a group of, catastrophically injured (formerly healthy) volunteers.
The human cost
Clinical trials (and the safe drugs that hopefully emerge) benefit humanity; without them, numerous life-saving medicines would not exist. Yet when things go wrong the human cost can be very high- individuals suffer life-changing physical and psychological injuries.
“For around a year afterwards I had a short term memory loss. I struggled to remember everyday things. We were told to stay away from public transport, choose our food carefully, that sort of thing – because our immune systems might not be able to cope. It really affected my everyday life. Ten years on, I still get mouth ulcers more than I used to. I don’t know what the long term effects on my immune system will be.
Now, I feel quite cynical about clinical trials. I had thought it was a good thing – being an ambassador for science – but because of trial I feel like I was just equipment within a system, not a human being. It is hard to see that the corporations are interested in anything other than money.
The compensation helped me to rebuild my life. I hired a personal trainer who helped me to build my strength back up. It felt like a real fight against TeGenero to get it though; surely adequate compensation should be by right? ”
Thankfully, despite Northwick Park, there appears to be no reduction in interest in early stage clinical trials: the MHRA reports that the number of UK clinical trial authorisation applications has, since May 2004, remained stable at 900 - 1,000 per year.
It is for this reason that the fight for safe clinical trials, and adequate compensation, continues.