“We saw human guinea pigs explode”

Abstract

L Stobbart and colleagues examine newspaper coverage of adverse events in the TGN1412 trial

Media coverage has been shown to affect patient and public participation in medical services.¹ Following the publicity surrounding the TGN1412 trial at Northwick Park Hospital in 2006,^{2 3 4} we might expect heightened media interest to affect recruitment of patients and healthy volunteers to medical research. Public discussion and awareness of this incident may have implications for science as a whole, ultimately generating changes in legislation governing the conduct of phase 1 studies in particular and clinical research in general. Concerns regarding inducements for recruiting volunteers to trials may also precipitate changes to the level and nature of payment for involvement, which may in turn further affect recruitment.

The story

On 13 March 2006 eight men took part in a “first in man” phase 1 clinical trial of TGN1412, a humanised agonistic anti-CD28 monoclonal antibody being developed by TeGenero to treat various diseases in which T cells are involved, such as chronic inflammatory disorders or haematological malignancies. Within hours those receiving the drug experienced serious side effects caused by a severe inflammatory response, resulting in multiorgan failure due to a “cytokine storm,” for which they were managed in intensive care; some spent more than three months in hospital. Longer term effects for all of the volunteers remain unknown. The story broke in the printed media on 15 March, although radio news bulletins late the previous evening carried the first reports. Headlines were initially conservative but became more dramatic as the story quickly attained “scandal status.”⁵

The setting: print media

Journalists do not merely report news but actively “produce stories,” and in doing so they construct a representation of reality for public consumption.⁶ However, the public is not necessarily complicit. These representations can influence public opinion and action, but this involves an interactive, spiralling, and interchangeable process of both feeding the public and articulating the public's views, in which the public is no longer considered a passive recipient of information.⁷ It cannot be assumed that a story will be interpreted as intended or that all the interpretations of any one story will be the same.

Analysis of press coverage

We searched LexisNexis, a database of all UK newspapers, for the period 14 March to 21 April 2006, using the search term “drug trial.” We selected nine national newspapers for further exploration: the Daily Star; the Daily Mail, the Express; the Guardian; the Independent; the Daily Mirror; the Observer; the Sun; and the Times (including Sunday editions). We considered various formats including news reports, comment and editorials, and readers' published letters and emails.

The search yielded more than 200 articles referring to this phase 1 study. One researcher (LS) undertook a thematic analysis of the newspaper texts.⁸ This categorisation was reviewed and discussed with two other researchers (MM and TR).

Analysis of press coverage yielded three main themes: “human tragedy,” “good science, bad science,” and “engagement in science.” Representative quotes are shown in the boxes.

Box 1: Human tragedy

Detailed and emotive descriptions encouraging the reader to identify with the “victims” and their suffering:

Mr Wilson, from London, said the tips of most of his toes were “basically dead” and at least half of his big toe had already rotted away. A keen footballer, he also faces an agonising wait to see whether the infection will spread, forcing doctors to amputate his feet and hands.—Daily Mail

“His head had swollen to three times its normal size. His neck was the same. It was wider than his head and his skin had turned a dark purple. At first none of us recognised him. His nose was spread across his face like it had been squashed. He had tubes in his nose and mouth and was hooked up to a machine helping him breathe and to a kidney dialysis machine. His eyes had been taped up and he had been sedated. Our fear is that he may never wake up.”—Daily Star

The student . . . said that when he first asked the testers for help they gave him a paracetamol tablet. “An hour after the drug entered my body I was suddenly gripped by pain,” he said. “I felt my head swelling up like an elephant's. I thought my eyeballs were going to pop out. I screamed out, “Please, doctor, help me. Help me,” but he told me to lie down then came back with a single paracetamol tablet. It felt like a terrible nightmare. . . I started to think that these people were killing me and that I was going to die in this terrible place.”— Times

Box 2: Good science, bad science

Doctors and scientists presented as saviours and purveyors of medical miracles, while simultaneously vilified as irresponsible, uncaring and untrustworthy:

Miss Marshall, 35, called on the international scientific community for emergency assistance. Solicitor Ann Alexander, who is representing her critically ill boyfriend, said: “She wishes that there should be the widest possible attention to this tragedy in the hope that members of the scientific and medical community around the world will come forward with suggestions for treatment to help the doctors at Northwick Park who are doing a magnificent job.”—Daily Mail.

We should examine the extent to which the public can trust all the parties involved. Do we trust TeGenero whose chief scientific officer has been very open with the media, yet which has never brought a product to market before? Do we trust the research company Parexel, still recruiting healthy volunteers for other trials? Do we trust the research ethics committee that agreed this study could take place? And do we trust the motives of the NHS in allowing such a contract research organisation to exist on NHS premises—for gain?—Independent/Independent on Sunday

Box 3: Engagement in science

Discussions of the validity of informed consent and debate concerning level of payment, inducement, and coercion:

Parexel—which launched the trial on behalf of the German drug company TeGenero, the manufacturers of TGN1412—may have breached guidelines laid down by the Association of British Pharmaceutical Industries over the offering of inducements. “Neither payment, nor the level thereof, should be mentioned in a public notice,” these state. Yet Parexel”s website for enrolling volunteers to its TGN1412 trials clearly states that recruits would be “paid for your time and inconvenience.”—Observer

The unpleasant truth of phase one drug testing is that its point is to establish whether a drug is safe. The critical issue is whether those involved understand that by consenting to take part in a trial, they accept the possibility of a real risk to their health. Here is a recent advert for research: “Get paid for putting your feet up for a few days and contribute to medicine's research! You'll be well looked after . . . you can use our computer games, DVDs, wide-screen TV, digital channels and internet, and you'll get free meals. We'll pay for your time and inconvenience.” Giving informed consent is regulated at a national and international level. The documents are lengthy and filled with technical language. If you are a recent migrant with no job and language difficulties, would you pay attention to the adverts, or analyse the lengthy documents that constitute informed consent? Debate needs to focus on defining consent.—Guardian (reader's letter)

When he learned he would receive £2000 for just two days of his time, Nino jumped at the chance: the financial imperative quickly overcame any misgivings he would later have.—Daily Mail

Human tragedy

Initial headlines such as “Drug trial men in intensive care” and “Drug trial leaves six men seriously ill” (Daily Mail and Guardian, 15 March) introduced relatively brief accounts of the events but soon began to focus on the volunteers and their friends and families. Approximately 60% of articles reviewed carried a headline emphasising the “human tragedy,” such as the Sun's “We saw human guinea pigs explode.” The TGN1412 story fulfils many recognised criteria of “newsworthiness,” including frequency, threshold, unambiguity, meaningfulness, unexpectedness, continuity, personalisation, and negativity.^{9 10 11} Unfolding daily, the story lent itself to regular updates, and personalisation of the story was used to render it more meaningful to the reader. Volunteers were stereotypically identified as students or low paid staff, implying vulnerability, and our sympathy was sought by drawing attention to their motives in volunteering for this research. For example, Mohammed “wanted to set up his brother Mahmood in business and look after his father . . . and desperately ill mother” (Daily Mail, 20 March). Typically, the more innocent the “victim” the greater their newsworthiness—although children generally best fulfil this criterion, the implied vulnerability and volunteer status of these men carried similar weight.^{12 13}

TGN1412 was novel; its effects were unexpected and were described in horrific and lurid detail. Media representations suggested that death and disease had been “sequestered away from the majority of people's everyday experience.” Events such as this fulfil an element of voyeurism and schadenfreude, feeding readers' fascination with death and disfigurement. Science fiction or cinematic imagery is often used to add potency to detailed and gruesome descriptions—although no pictures were printed of the victims' deformities, references such as “his face now resembled that of the Elephant Man” (Daily Star, 16 March) were used with effect.¹⁴

Society places great store in superficial physical appearance and attributes as a means of presenting the self. These graphic accounts of despoilment may thus deter potential volunteers.

Good science, bad science

TGN1412 was being developed to treat conditions such as arthritis, leukaemia, and multiple sclerosis. In media descriptions of these conditions, the terms “chronic” and “devastating” were instrumental in emphasising the drug's potential value in eliminating suffering. By using these terms the media aimed to convince readers that the research was worthwhile and public involvement was vital.

If the volunteers are the “heroes” of this story then scientists and doctors may be seen as the “villains.”¹³ But conflicting and conflated images of these groups were juxtaposed throughout the coverage. Recent healthcare scandals such as those of Shipman and Alder Hey have led to media descriptions of an erosion of trust in medical and scientific authority. Doctors' and scientists' actions, advice, and opinions are no longer considered unimpeachable, but we still look to these professionals to develop treatments and cures.¹⁵ For example, while holding the medical and scientific communities responsible for her boyfriend's plight, Miss Marshall (box 2) appeals to them to “cure” him.

Experts were pitted against each other: a researcher defended his work, saying “I don't want to come across as a crazy scientist” but “we are not going to give up” (Mirror, 25 March). Others questioned his enthusiasm. The Sunday Times quoted an expert from a London research institute who claimed: “The danger is that they are messing around with T regulator cells and we don't know what all the T regulator subsets do.” A UK immunologist suggested that perhaps “they may have got carried away and didn't see the apparent dangers” (Observer, 19 March).

Placing the drug “at the heroic edge of medicine,” the Guardian (17March) echoed coverage of other medical and scientific advances hailed as “miracle cure” or “magic bullet,” bestowing the discoveries and their creators with supernatural or superhuman powers. Paradoxically, while “life” has become increasingly medicalised and expectations of science and medicine have increased, trust and respect for medical and scientific authority have allegedly diminished.¹⁵ When things go well doctors' lab coats and clinical detachment are a sign of professionalism and take on almost angelic symbolism, but with errors and setbacks they help convey a mad scientist image, with the sterility of the white coats suggesting something removed from humanity.

Engagement in science

Having gained the public's attention with lurid and dramatic headlines of a human and personal nature, the media soon said that there may be a “backlash after trials catastrophe” even though headlines simultaneously proclaimed: “Tests on humans vital for our safety” (Independent and Mirror, 16 March).

Much of the coverage focused on payments to volunteers and whether or not this represented inducement. Payments for participation in clinical trials are intended to compensate volunteers for their time rather than to induce them to participate or to minimise the significance of potential risk. Reports stated that volunteers could earn “anything between £100 and £3500 for taking part” and that the student and backpacking communities were a good source of volunteers, with some almost becoming career participants.

Conflicting reports emerged regarding the quality and quantity of information disclosed within the documents giving participants information. Several reports claimed that little or no information was given regarding the drug's novel status or the possibility of serious side effects. Others claimed that detailed information was provided, including the mention of the possibility of “cytokine storm.” Whether volunteers understood or appreciated the significance of the risks, and whether the promise of significant financial gain overshadowed any concerns they may have had, was debated. Whether fully informed consent had been obtained was questioned.

Implications for clinical research and “science”

Many of the newspaper reports that we examined constructed a reality in which science and scientists were out of control, the quest for scientific knowledge and progress may overshadow public safety, and our capacity for innovation increasingly outstrips the “know-how of the relevant experts” in dealing with associated risks.¹⁶ This media-constructed reality is also one in which innocent and vulnerable members of the public were coerced into risking their health, and possibly their lives, in irresponsibly conducted research, and where advances in scientific capabilities were not matched by new and safe means of testing.

Such coverage could result in a decline in the number of volunteers for clinical research. The Medical Research Council, the British Heart Foundation, and commercial clinical research organisations expressed this concern, and were reported as being surprised when inquiries about participation increased. It remains to be seen whether this surge in interest has translated to an actual increase in recruitment.

This incident has already taken on the qualities of an apocryphal event. It is referred to by patients both when framing questions about research involvement and as rationale for declining to participate. Organisations carrying out clinical trials have fielded inquiries from potential volunteers attracted by details of financial recompense; the incident is noted within ethical review of other, unrelated studies and is discussed at conferences, seminars, and research meetings. It is also referred to by clinicians when they explain the content of information documents, particularly the concept of potentially unforeseen side effects.

When the Medicines and Healthcare Products Regulatory Agency released its final report on 25 May 2006,¹⁷ press coverage of the report was limited. Following the interim report of the Expert Scientific Group in July, changes had already been made to the way in which “first in man” phase 1 studies are reviewed and conducted, effectively illustrating the effects of the “controversy machine” whereby crisis cases and “moral panic” precipitate regulatory change.^{17 18 19} Released on 7 December 2006, the final report of the Expert Scientific Group on Phase One Clinical Trials was published with 22 recommendations to increase the safety of future clinical trials involving first human exposure to agents with potential high risk.²⁰ Compared with media coverage of the trial itself, the report raised modest media interest. The full impact of the media coverage of the TGN1412 trial on volunteer and patient participation in other trials remains to be determined.