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Volunteers
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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. |
Fallout
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. Recommendations
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. Recruitment difficulties
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. Innovation
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.” |
The
Pharmaceutical Journal