Will volunteers still want to take part in research after the TGN1412 trial?
On March 13, eight men entered a clinical trials unit at Northwick Park Hospital in North London. They were each being paid a reported £2,000 to take part in a trial of TGN1412, an investigational substance which it was hoped might help treat leukaemia, rheumatoid arthritis and multiple sclerosis.
Within hours, however, news services all over the world were reporting the severe adverse reactions suffered by the six participants who had been given the active agent. In the months since, the intensive care doctors from Northwick Park Hospital have published their account of the clinical course of the participants who became patients (New England Journal of Medicine; 2006;355:1018; see Panel below), the Medicines and Healthcare products Regulatory Agency has issued a full report of the trial and the Government has set up an expert group to examine the future of clinical trials. In addition, the solicitor acting for four of the men, has described how the volunteers will have to live with a “dark cloud over their health for the remainder of their lives”. Yet, despite this catastrophe, clinical trial recruiters have seen surges of interest from would-be volunteers.
“All six patients survived” — how the intensive care team worked together to save the volunteers’ lives
Ganesh Suntharalingam, director of intensive care at Northwick Park Hospital, made frequent statements on the status of the volunteers during the initial critical stage of their treatment. However, it was not until the full account of the cytokine storm the patients suffered, and the treatment they were given was published this month that observers were able to assess the details of what had happened. The paper, “Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412” (New England Journal of Medicine; 2006;355:1018), describes how “despite evidence of the multiple cytokine-release syndrome, all six patients survived”.
TGN1412 produced a similar response in all six patients and in all the organ systems affected, the authors explain. “All six patients initially had clinical signs that fit the criteria for systemic inflammatory response syndrome. Subsequently, the most prominent clinical feature was the early appearance of respiratory distress and pulmonary infiltrates, accompanied by renal impairment and profound disseminated intravascular coagulation,” Dr Suntharalingam and colleagues say. The patients were initially treated at the clinical research unit where the trial was being carried out, which is on the hospital site.
In the BMJ this month, Dr Suntharalingam explains that when one of the volunteers became severely hypotensive it was decided that they should all be transferred to the intensive care unit of the hospital, because of the concern that all six participants would follow a similar course. “It was rather like treating the index case of an infective epidemic,” he says (BMJ 2006;333:570).
The intensive care unit’s central decision-making procedures and its ability to draw on outside advice were critical to its success in treating the patients, he added. The intensive care unit already had seven other patients when the men from the trial were admitted, but an incident plan had been draw up in response to the attacks in the US on 11 September 2001. “As we had planned, we expanded the intensive care unit into an adjoining post-operative recovery area. Many of the staff are cross trained and used to working with each other, so we had the ideal skill mix,” he said.
Nonetheless, as the patients’ symptoms developed, the clinical challenge facing the unit became clear. “We had patients in a very inflammatory state, with high temperatures and heart rates and falling blood pressures. We had a pattern of pathophysiology we were used to treating — similar to that seen in severe sepsis. But there was a very different underlying cause,” he says. “We had to make a quick decision on whether we thought the underlying cause was inflammation or infection, the possible cause of sepsis. It was possible that the drug had become contaminated in some way; at that stage we didn’t know.” It was decided, he explains, to treat the patients with high dose steroids and, for a time (before it was considered unnecessary), an anti-leukin 2 receptor antagonist antibody.
It was the ability of the unit to work as a team that enabled them to overcome the unprecedented clinical and logistical challenges that the incident posed, Dr Suntharalingam explained in the days after the participants were admitted. “I would like to praise the NHS staff at Northwick Park,” he said. “To bring six acutely deteriorating patients into critical care in the space of a few hours is almost unique and posed significant challenges. The staff in all our critical care areas responded superbly on the night and have continued to do so, and I am grateful to them all.”
The six participants have remained under close follow-up by other hospital specialists since they were discharged from the intensive care unit, to monitor their progress and to give further treatment as required.
Following the trial, clinical trial researchers speculated that participants may have been given a dose higher than intended, that the translation of the dose from the animal data had been misapplied or that the trial’s design and dose scheduling were inappropriate.
Many questions have been raised. Why were the volunteers given their doses in quick succession, rather than waiting to check no adverse effects were seen with each administration? Was the MHRA given all the information it needed and did it carry out all the relevant regulatory checks? Could the risk not have been predicted from previous studies? Should the smallest dose that produced a response in animals have been used as the basis for calculating the dose in humans, rather than the highest tolerable dose?
Also, this week, the Channel 4 television programme Dispatches, which was scheduled to be transmitted after The Journal went to press, claims that the dose was given to the patients too quickly — 15 times faster than it had been given to monkeys in the safety studies.
However, the MHRA’s interim report and, later, its full report (PJ, 8 April, p408 and 3 June, p649, respectively) both agreed that the most likely cause of the adverse reactions was “an unpredicted biological action of the drug in humans”. The product showed “a pharmacological effect in man which was not seen in pre-clinical tests in animals at much higher doses,” Kent Woods, chief executive of the MHRA said in the agency’s initial report.
Nonetheless, the full report levelled a number of criticisms at Parexel, the company which conducted the trial. Medical history documentation procedures were not adhered to, there was no formal system in place for 24-hour medical cover and the doctor charged with conducting medical tests when the participants first arrived at the clinical trials clinic did not have the necessary expertise, the MHRA said. However, it acknowledged that these inadequacies were not likely to have led to the adverse reactions seen in the participants.
In July, the expert scientific group established by health minister Lord Warner published its interim report (PJ, 29 July, p124), making 22 recommendations about the conduct of phase I trials of novel biological molecules.
The group will produce a final report in November and advise ministers on guidelines and regulations on the future authorisation of trials involving new types of biological drugs.
The group argued that: calculations of initial dose should consider all relevant factors, possibly using new statistical methods or computer modelling; decisions on whether to use healthy volunteers or patients should be made on a case-by-case basis for each drug; and drugs should be administered to each subject in sequence with an adequate time delay between each dose to allow observation of any adverse reaction.
In addition, the current system of approving clinical trials needs far greater flexibility, the group recommended — relying on guidelines developed from experience with existing medicines could lead to a false sense of security when dealing with new and fundamentally different medicines, so a science-based, case-by-case strategy is needed for the preclinical development of new medicines.
In addition, timescales should have more leeway, so that they could be extended for appraisals of great complexity, and consideration should be given to establishing specialist centres for phase I clinical trials of higher-risk medicines.
The foundation of the group’s recommendations was, though, that there should be frequent reappraisals of the regulatory process for first-in-man trials of “higher risk agents and advanced medicinal products based on innovative technologies”, as a system could not simply be relied upon to be appropriate for whatever future medicines may be developed. Nonetheless, given the current issues affecting clinical trials, the impact of the events surrounding the Northwick Park trial is likely to be much more far-reaching than these changes to regulations.
The brief surge of interest in clinical trials following in the wake of the TGN1412 trial appears to have been more than just a temporary blip (PJ, 25 March, p342). Chris Birch is the manager of medical services at Activity Benchmarking Ltd, which runs a subscription benchmarking service for pharmaceutical companies. Members of the service provide data on a variety of measures on a regular basis and the results are assembled into a report sent to members. “Surprisingly, member companies have reported an increase in interest in participation in phase I trials on the back of the incident at Northwick Park,” Mr Birch says.
“This has mainly come from people who did not know you could get paid for phase I health volunteer trials.” However, he adds, it remains to be seen whether this upsurge in interest will lead to increased recruitment.
In fact, lack of knowledge of studies may be a key factor in clinical trial recruitment. In a study of 5,196 adults, conducted last year by Harris Interactive Healthcare News in the UK, France, Germany, India, Italy, Poland, Spain, and the US, found that 49 per cent of respondents in the UK said they had been exposed to information about clinical research studies, compared to 55 per cent overall, 60 per cent in the US and 84 per cent in Poland.
Companies’ success at attaining their recruitment targets for individual studies varies widely, Mr Birch says, and can range from about 20 per cent to 100 per cent. “We are seeing more and more phase I and phase II trials undertaken in the UK, which require small numbers of patients, relative to later phase studies.
“These can be hugely expensive to recruit on a per patient basis, because of the reduction in the economy of scale relative to phase III trials. The cost per patient runs into thousands of pounds, although costs will vary widely from study to study,” he says.
In fact, US firm Cambridge Healthtech Associates surveyed over 50 clinical development professionals and found that 41 per cent ranked recruitment and retention of participants as the number one cause of developmental cost.
The solution to the increasing cost of recruiting participants is, Mr Birch says, to look at more innovative approaches.
One suggestion is to change the way patients decide whether to take part in research or not. A recent BMJ paper (2006;333:300) argues that a key problem for recruitment, in the UK at least, is that ethics committees now insist that participants opt in, rather than opt out, of research. Researchers have to ensure that they only contact people who approach them or who respond positively to letters from their GP or hospital clinician informing them about an opportunity to take part in research.
The authors of the BMJ paper argue that an opt-in approach results in lower response rates and a biased sample, particularly in terms of excluding patients who are socioeconomically disavantaged or from particular ethnic groups. The researchers’ solution is for all NHS users to give brief information about the potential use of personal information for research and for health care professionals to develop a strategy to inform individuals about how such research can contribute to improved health.
Another solution to the problem of patient recruitment might, however, be to widen the net of those providing information about trials to patients.
Mr Birch comments: “When I worked previously for a site management organisation and carried out research in primary care, we looked at the role of local community pharmacies in recruiting patients, especially for trials of products like fungal nail infection treatments.
“The pharmacist can ask people coming in for advice or to pick up a prescription whether they would be interested in taking part in a trial. We concluded that community pharmacies could be a valuable asset in terms of raising patient awareness of trials and supporting recruitment.”
Daljit Kaur, research manager of clinical trials at Cancer Research UK, agrees. “Community pharmacists could provide help with small local trials, such as asthma or diabetes studies being carried out at a local GP surgery,” she says.
“They could help inform patients that such trials are being carried out and, perhaps, when a patient collects asthma or diabetes medicine they could offer the patient a leaflet, some information or contact details about the trial and ask ‘Have you thought about this?’,” she adds.
If patients are interested in taking part in larger scale trials of therapeutic agents, or just finding out more about them, community pharmacists could always direct them to clinical trial websites, such as cancerhelp.
org.uk, where patients can register their interest in particular trials and nurses then pass information about the trials on to them, she says.
“If patients approach pharmacists to ask about participating in large clinical trials, they could easily pass on a list of similar websites,” she adds. “Maybe community pharmacists are an underused resource in that respect. They would not be able to have all the information, however, but they could certainly signpost those interested to the appropriate information resource.”
Citation: The Pharmaceutical Journal URI: 10002179
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