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Most people would agree that pharmaceutical companies have a moral
obligation to report information about the adverse effects of drugs to
the regulatory
authorities as they arise.
However, it seems that this obligation cannot
be relied upon and new legislation will now be passed to insist that
companies disclose any information that could affect patient safety,
regardless of its source.
The move follows a four-year criminal investigation into whether GlaxoSmithKline
failed to inform the Medicines and Healthcare products Regulatory Agency
of information it had
on the safety of Seroxat in under 18-year-olds in a timely manner
(see p297).
The MHRA’s investigation is the largest of its kind in the UK,
with 103 requests for documentation resulting in scrutiny of over one
million pages of evidence.
The allegations against GSK were that it failed to comply with legislation
requiring it to report adverse events occurring in clinical trials in
which Seroxat was given to children, and that it failed to report a safety
issue promptly once it was aware of its existence (see Panel 1).
Panel 1: The data in question
1998 — GSK completed two trials involving the use of Seroxat
in children, which failed to demonstrate that it was effective at
treating major depression in children.
September 2002 — In a further seven trials, the last of which
ended in September 2002, Seroxat’s efficacy for treating children
with major depression was not demonstrated.
November 2002 — The MHRA asked GSK about the status of clinical
trials in children and the company indicated that it intended to
submit an application for paediatric indications. It did not raise
any concerns about a lack of efficacy or adverse reactions during
clinical trials.
February 2003 — Unprompted, GSK sent an update to the MHRA
on clinical trial data it held in relation to suicidal behaviour.
However, adult and paediatric data were not differentiated and any
safety signal from the paediatric studies was lost when the two populations
were mixed since the adult population was much larger.
May 2003 — At the end of a meeting with the MHRA to discuss
the safety of Seroxat, GSK handed out a briefing document relating
to an application to extend indications for Seroxat to include children.
In it a safety concern related to suicidal behaviour among depressed
children taking Seroxat was highlighted. The MHRA subsequently requested
full clinical trial data from GSK, which showed that the safety concern
became apparent after a meta-analysis of the trials was conducted.
June 2003 — The lack of efficacy together with evidence of
a causal association between Seroxat and suicidal behaviour in children
led the MHRA to advise that it should not be used in the treatment
of depressive illness in the under 18s. |
After reviewing the investigation, Government lawyers have decided
that there is no realistic prospect of a conviction in the case and that
it
should not proceed to criminal prosecution. “The legislation in
force at the time was not sufficiently strong or comprehensive as to
require companies to inform the regulator of safety information when
the drug was being used, or tested outside its licensed indications,” said
the MHRA in a press release.
Although GSK has been spared prosecution, the MHRA believes that it should
have disclosed vital safety data earlier. Commenting on the investigation,
Kent Woods, the agency’s chief executive, said: “I remain
concerned that GSK could and should have reported this information earlier
than they did. All companies have a responsibility to patients, and should
report any adverse data signals to us as soon as they discover them.”
GSK rejects any suggestion that it withheld information saying that it
was only when a meta-analysis was conducted in late 2002 and further
analyses in early 2003 that the increased risk of suicidal behaviour
with Seroxat became evident. Alastair Benbow, medical director for GSK
Europe, said: “We firmly believe we acted properly and responsibly
in first carrying out this important clinical trials programme and then
informing the regulatory agencies when we identified a potential increased
risk of suicidal thinking and behaviour in patients under 18.”
The
MHRA acknowledges that the investigation has revealed significant weaknesses
in the drug safety legislation in force at the time.
Panel 2: Recent legislation
Since 2003, an EU directive governing the conduct
of clinical trials has been passed that introduced a criminal
offence for failure to report adverse events.
However, the directive
does not apply to trials conducted outside the EEA. In addition,
amendments to EU medicines legislation has clarified the obligation
to report safety information from clinical trials using products
outside their licensed indications, including an obligation
to report the information promptly. |
“Subsequent
legislation [see Panel 2] has partially addressed the problem, but we
will take immediate steps to ensure the law is strengthened further,
so that there can be no doubt as to companies’ obligations to report
safety issues,” he promised.
The MHRA has written to the Association of the British Pharmaceutical
Industry to ask it to remind its members of their responsibilities in
advance of any changes to the legislation:
“The public would undoubtedly
expect that any information shedding new light on the risk:benefit relationship
of a marketed medicine would be promptly communicated to the regulatory
authority so that, if necessary, further advice could be provided to
prescribers and users. This would apply equally whether or not that information
emerged from use in a licensed indication.”
The MHRA will be recommending that amendments to legislation are included
in the forthcoming EU pharmacovigilance regulations. However, given the
time it may take for EU legislation to be negotiated and come into force,
proposals to amend UK law will shortly be put out for consultation.
The agency wants to see absolute clarity in the legislation as to the
information that must be supplied to the regulator, regardless of its
source (arising from inside or outside the UK, as a result of any use,
eg, licensed, unlicensed or within clinical trials) and clear timescales
within which such information must be supplied as well as sanctions for
failing to comply.
The ABPI said that it welcomes the introduction of any new legislation
that provides further genuine protection for the patient, without simply
adding unnecessary bureaucracy. It added that, since 2005, the international
pharmaceutical industry has committed to the registration and publication
of its clinical trials involving patients whether the outcomes are
positive or negative.
A spokeswoman for the MHRA told The Journal that the investigation
has by no means been wasted. “The investigation scrutinised questionable
actions by one pharmaceutical company, but there are much wider lessons
for the whole pharmaceutical industry about the importance of working
within the spirit as well as the letter of the law,” she said. |
The
Pharmaceutical Journal