| The Government’s expert scientific group has, after over
a dozen meetings and two reports, now reached its final conclusions on
how phase
I clinical trials need to change in the wake of lessons learnt from the
TGN1412 trial at Northwick Park Hospital, London, in March.
The group, led by Gordon Duff, professor of molecular medicine at Sheffield
University, was established to examine trials of new types of drugs (see
Panel below). Its final report, issued last week, makes 22 recommendations
covering pre-clinical and early clinical development, the preparation
and review of applications, the clinical environment of trials, dosing,
and the expertise and training of staff conducting trials.
The TGN1412 trial and the
Government’s
response
In March six patients involved in a phase I
clinical trial of TGN1412, a drug being developed for leukaemia,
rheumatoid arthritis
and multiple sclerosis, were admitted
to critical care at Northwick
Park Hospital, London (PJ, 18 March, p307).
The Medicines
and Healthcare products Regulatory Agency immediately suspended
the trial and
established a moratorium on all new phase I trials of novel molecules
targeting the immune system and acting via a novel mechanism. It
also published two reports into the incident (PJ, 8 April,
p408, and 3 June, p649), concluding that “an unpredicted
biological action of the drug in humans is the most likely cause
of the adverse
reactions in the trial participants” and the doctors who
cared for the patients have also published accounts of the care
they gave to the response (New England Journal of Medicine 2006;355:1018 and BMJ 2006;333:570).
Looking to the future authorisation
of such trials, Secretary of State for Health Patricia Hewitt
established an expert group to look at the transition from pre-clinical
to
phase I trials and the design of these trials (PJ, 8 April, p408).
The group published an interim
report in July (PJ, 29 July, p124)
to which it invited comments ahead of its final report, as published
last week. |
Responses
Some of the recommendations, particularly those concerning dosing,
are clear responses to the particular circumstances of the TGN1412 trial.
In the immediate wake of the TGN1412 disaster, the fact that all the
participants’ doses in the trial were administered within a short
time — reportedly over less than six minutes — was widely
criticised. And the expert group now recommends that “new agents
should be administered sequentially to subjects with an appropriate
period of observation between dosing of individual subjects”.
In addition, the animal studies failed to alert the Medicines and Healthcare
products Regulatory Agency to the dangers TGN1412 could pose when administered
to humans. “The pre-clinical development studies that were performed
with TGN1412 did not predict a safe dose for use in humans, even though
current regulatory requirements were met,” the report concludes.
Therefore, it argues, when the primary pharmacological action for an
agent’s proposed therapeutic effect cannot be demonstrated in an
animal model, justification for the initial dose should include a clear
rationale for the proposed mechanism of action and for the safety and
efficacy of the substance in its intended use in humans.
Progress
Other recommendations in the report reflect the fact that science has
progressed to a point where a tick-box approach to approving first-in-man
trials is no longer appropriate — a reality illustrated so dramatically
at Northwick Park in March.
The report talks about how novel biological medicines, such as those
based on nucleic acids, pose difficult challenges for pre-clinical and
clinical development.
“It is now apparent that the pre-clinical development of such agents cannot
rely on methods that served well with smaller chemical molecules or previous
generations of biological medicines,” the report concludes. “Rigid
adherence to guidelines developed from experience with existing medicines
may carry the risk of creating a false sense of security when dealing
with new classes of medicines and there may be over-reliance on methods
that are not appropriate in specific cases.”
Decisions on the strategy for pre-clinical development of a medicine
should instead, the group recommends, be justified case by case and the
regulatory process should be subject to regular review. There should
be some flexibility in the time-scales for approvals to allow for particularly
complicated applications. Doses should be calculated using a broader
approach than “no observable effect level” — the group
champions the “minimal anticipated biological effect” (MABEL)
approach. And decisions about whether patients or healthy volunteers
should be the first to receive a new medicine must be fully justified.
For instance, the group argues, the balance of risks of harm and potential
benefits may be different for cancer medicines, where patients who experience
a beneficial response to a trial agent could continue using it.
As well as recommending changes to how trials are planned and carried
out, the report also makes suggestions about how communications between
the various parties involved in the development of new medicines should
be improved.
There should be more, and earlier, discussion between developers of medicines
and regulatory bodies. Developers of medicines, research funding bodies
and regulatory authorities should aid the collection of information from
unpublished pre-clinical studies and phase I trials with the aim of creating
an open-access database. And there should be pre-submission meetings
between sponsors and regulators, as there are in the US. Questions
Not all the group’s recommendations will necessarily become mandatory,
however. Health minister Andy Burnham welcomed the recommendations and
committed to review them. “We believe that implementing the wide-ranging
and comprehensive recommendations made in this report could make a significant
contribution to improving the safety of clinical trials of high risk
drugs such as TGN1412. We will be studying them carefully,” he
said. The Association of the British Pharmaceutical Industry has said
that it will revise industry guidelines in the wake of the report and “ensure
that all relevant points are included” in the new guidelines.
Even if the recommendations are all taken up, there are still many issues
thrown up by the TGN1412 trial that need to be examined and many unanswered
questions raised by the expert group’s recommendations. For instance,
if the UK tightens up its regulations, will trials not simply move elsewhere?
Would an open-access database stifle innovation or could competitive
advantages remain protected? Why should these rules apply only to new
types of drugs? Would they not help make other trials safer? How does
the MHRA need to change in the wake of the report?
The expert group’s report also acknowledges that many issues raised
in the consultation on the interim report were beyond the scope of its
investigation, including insurance cover, the continuing treatment of
trial subjects who experience adverse reactions, the process of informed
consent and the information given to volunteers.
“Although beyond our remit, we believe these wider concerns are all
extremely important, and recommend that they are taken up as a high priority
and
considered in detail,” the group says. All these issues, and many
more relating to clinical trials, need to be addressed and it is a sad
reality that it took such suffering for that to be learnt. |
The
Pharmaceutical Journal