In March 2006, six men were taken seriously ill whilst acting as ‘healthy volunteers’ in a clinical trial at an independent research facility run by American company Parexel on the site of Northwick Park Hospital, London. This episode of the documentary series Dispatches (Channel 4, 28th September 2006) tries to uncover what might have caused an apparently routine safety trial to go so dramatically wrong. As well as discussing the case with a number of experts on clinical trials, investigative journalist Brian Deer spends a lot of time talking with Ryan Wilson, the man most badly affected by the trials. In keeping with this genre of reporting, there is also the compulsory pursuit of a representative from Parexel, in the vain hope he might talk on camera.
Each volunteer was to be paid £2000 for their involvement in the trial and subsequent follow-up. Of eight volunteers in total, two received the placebo. Having received the trial drug TGN1412, a monoclonal antibody, all of the other six very quickly started to suffer serious side-effects, including pain, nausea and falling blood pressure. The victims were transferred to the NHS intensive care unit on the same site, where their treatment was complicated by the fact that the drug was, of course, unknown to them and hence there was no previous treatment regime with which they could compare. What was clear, however, was that their symptoms fitted with “cytokine release syndrome”, a set of responses already seen previously as a consequence of other antibody-based therapies such as Rituximab.
Although four of the ill men were able to go home 48 hours later, Ryan Wilson was in a coma for 16 days and spent a total of 140 days in the hospital. Loss of blood to his extremities during the ordeal resulted in “dry gangrene” or mumification of his toes and some fingers leaving them like stone.
TGN1412 was developed by a small German biotech company TeGenero (who were forced into bankrupcy after this trial went so wrong). Brian Deer discusses the situation with a former investor in the company, who (at 24:30) argues that the science of the trial was justified, but the administration of the drug was the serious flaw – it would have been better for each volunteer to have been given the medicine in turn rather than at the same time, thereby allowing for monitoring of potential side-effects before delivering the drug to the next volunteer.
Brian Deer then considers the merit, and adequacy, of animal testing before going on to interview Prof Terry Hamblin, an expert on monoclonal antibodies. At the behest of the programme, Prof Hamblin re-read the documentation that had been submitted to the Medicines and Healthcare-products Regulatory Authority (MHRA), the body overseeing clinical trials in the UK. Like the previous interviewee, he highlights problems with the administration of the drug. In this instance, the issue is not with the staggering of start times, but with the period of time over which the drug was infused into the patients. In the animal studies, delivery of the drug to the subject had been slow, carried out over a period of an hour. In the human trial, however, this was reduced to 3 to 6 minutes. Prof Hamblin describes this as “reckless” (28:02) although, as pointed out later, there is at least one monoclonal antibody in clinical use which is administered as a single injection (35:59). There was also, Hamblin notes, no evidence of side-by-side in vitro testing of the drug with monkey cells and human cells to compare the immune response in both cases – a necessary stage to validate the transfer from an animal model into a human context.
Biotech consultant Dr David Glover, adds his reservations about the design and adminstration of the trial. Questions he would have liked to have seen addressed in advance include issues about the potency of the drug, about dose calculation and the speed of delivery. He is concerned that the MHRA may lack necessary expertise to assess trials involving newer biomolecules (such as antibodies) rather than traditional chemical compounds.
Brian Deer puts these criticisms to Prof Kent Woods, Chief Executive of the MHRA. Prof Woods counters that by its very nature, any clinical trial is an experiment – the outcome cannot be known for certain. “There will always be an element of risk” he stated. The important questions about inadequate in vitro testing are put again, although Deer undermines his own position by coming across as rather smug and confrontational.
Towards the end of the programme, Ryan Wilson is shown after surgery, when doctors have managed to save rather more of his feet than he had believed possible. He still expects, however, that his damaged fingers will fall off and the extent to which the drug may have affected his immune system remains to be established.
Later on, Deer considers the potential impact of the TGN1412 incident on future investment in drug trials. His challenge that potential investors may be happy for volunteers to be collateral damage if it brings a swifter answer to safety questions (and hence saves them money) is sharply dismissed by Biotechnology Investment analyst Ibraheem Mahmood. Mahmood does, however, acknowledge that the more stringency that is put into the testing process as a result of disasters such as the one occurring at Northwick Park, the greater is the cost involved in developing any new drug and therefore a point may be reached when research into medicines for some important conditions may not be financially viable.
The final sections of interest involve discussion of the recruitment of volunteers, the adequacy of briefing they received and the actual management of the trial by Parexel. In accordance with the law, Ryan Wilson and the other volunteers were asked for “informed written consent” to participate. The documents do make reference to the possibility of cytokine release, but Wilson is adamant that this was not explained and that he was drawn to statements about nut and shellfish allergy from which he knew he didn’t suffer. Specific warnings about cytokine release syndrome were spelt out rather more fully in TeGenero’s briefing to Parexel but, the programme argues, the precautions were not heeded. In particular, the advice to have steroids on hand during the trial does not appear to have been followed and some five hours elapsed before any were administered. Prof Hamblin finds this response unacceptably tardy; even without a specific warning (as provided here), this treatment should have been a first response once the patients’ difficulties were evident.
The film closes with the pursuit and non-interview of the Director of Parexel, and with Ryan Wilson offering his reflections on the whole experience.
In terms of clips that might be used in teaching, the section from 03:49 to 06:10 might be shown with students as a vivid description of the symptoms shown by the volunteers, as witnessed by Raste Khan, who received the placebo. 10:30 to 11:59 includes an interview with Ganesh Suntharalingam (Clinical Director of Intensive Care at Northwick Park) and details what happened next, the difficulties caused by the lack of previous knowledge about the drug, and mention of cytokine release syndrome. There is some nice footage (25:00* to 26:30) of experimental monkeys, culminating in the question: “Was TeGenero acting reasonably when it assumed that tests on little guys like these [Macaque monkeys] would predict what would happen when they put their candidate drug into volunteers like Ryan Wilson and the others?” and, more broadly, whether these animal tests were sufficient to justify transferring to human volunteers. The interviews with Prof Hamblin about problems in the design and performance of the trial runs from 26:30* to 29:20, and with Dr David Glover from 29:58* to 31:04. Prof Woods rebuttal of the criticisms runs (with associated commentary) from 32:23* to 36:28. The section on recruitment and risks is 48:25* to 50:00 and is followed immediately by concerns about slow adminstration of steroids, until 51:20
For more background information on the TGN1412 trial, see this BBC News page (and follow links from the right of that page for earlier articles) and the Dispatches website for further details about the episode. A copy of the programme, TRILT code 005C50CD , can be obtained from the BUFVC. Those interested in a more thorough appraisal of the events might also like to read a presentation given to the Institute of Clinical Research which, at the time of writing, was available via this link.
* Timings after 15 minutes are inclusive of the advert breaks in the original transmission. The programme is 56 minutes in total and “includes some strong language”, but not within the recommended clips.