An incredible new document has been discovered and released on to the web. The document examines and reveals the background behind the failure of the MHRA and GSK to protect the public from the lethal effects of Seroxat. It is essentially a critique and it comes from the BMJ (British Medical Journal).It is quite revealing in nature; in that it asks some very tough questions in regards to the MHRA’s criminal investigation of GSK. Followers of the Seroxat Scandal will be aware that GSK were essentially let off the hook after a four and half year criminal investigation of the company. The original charge was in relation to GSK suppressing data about suicide in under-18’s prescribed Seroxat. The UK authorities claimed that there were “insufficiently robust laws” in place at the time so therefore GSK were not held accountable. Myself and others have long been dubious about the criminal investigation and its unjust outcome and with the release of the following document that belief and cynicism proves to have been completely justified. In this post I am going to paste the PDF in its entirety. Please read the following document and while doing so, ask yourself the question, what is the price of human life?
(for further reading and more issues raised , check out Bob Fiddaman’s blog)
http://fiddaman.blogspot.com/2009/02/mhra-did-they-fail-to-prosecute-gsk.html
doi:10.1136/jme.2008.025361 2009;35;107-112 J. Med. Ethics
L McGoey and E Jackson
regulatory failure and the uses of legal ambiguity
Seroxat and the suppression of clinical trial data:
http://jme.bmj.com/cgi/content/full/35/2/107Updated information and services can be found at:
Seroxat and the suppression of clinical trial data:
regulatory failure and the uses of legal ambiguity
L McGoey,1 E Jackson2
1
James Martin Institute, Saı ̈d
Business School, Oxford
University, Oxford, UK; 2 London
School of Economics and
Political Science, London, UK
Correspondence to:
Professor E Jackson, Law
Department, London School of
Economics and Political Science,
Houghton Street, London WC2A
2AE, UK; e.jackson@lse.ac.uk
Received 28 March 2008
Revised 28 July 2008
Accepted 14 August 2008
ABSTRACT
This article critically evaluates the Medicines and
Healthcare products Regulatory Agency’s announcement,
in March 2008, that GlaxoSmithKline would not face
prosecution for deliberately withholding trial data, which
revealed not only that Seroxat was ineffective at treating
childhood depression but also that it increased the risk of
suicidal behaviour in this patient group. The decision not
to prosecute followed a four and a half year investigation
and was taken on the grounds that the law at the relevant
time was insufficiently clear. This article assesses the
existence of significant gaps in the duty of candour which
had been assumed to exist between drugs companies
and the regulator, and reflects upon what this episode
tells us about the robustness, or otherwise, of the UK’s
regulation of medicines.
In October 2008, the Medicines and Healthcare
products Regulatory Agency (MHRA), the body
responsible for licensing medicines in the UK,
announced an amendment to the 1994 Medicines
for Human Use (Marketing Authorisations Etc)
Regulations which is intended to address one of the
gravest failures in pharmacovigilance since the
Medicines Act 1968 came into force nearly 40
years ago.
1
This amendment became necessary following
the MHRA’s revelation, on 6 March 2008, that
there would be no prosecution of GlaxoSmithKline
(GSK) for withholding clinical trial data, which
suggested not only that Seroxat was ineffective at
treating childhood depression, but also that it
increased the risk of suicidal behaviour in this
patient group.
The MHRA’s March announcement came at the
end of a four and half year investigation into
whether GSK had acted illegally by withholding
this data from the regulator. In a press release
published on 6 March, Professor Kent Woods,
MHRA 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. This
investigation has revealed important weaknesses
in the drug safety legislation in force at the time.
2
In the article, we examine the background to the
failure to prosecute GSK, and reflect upon what
this episode tells us about the robustness, or
otherwise, of the UK’s regulation of medicines. In
the first section, we provide a brief history of the
MHRA’s investigation into GSK’s failure to report
data which revealed safety concerns as well as a
lack of efficacy. Secondly, we examine the defects
in the legal framework which have enabled GSK to
avoid prosecution. Finally, we suggest that these
gaps in the law are not the only factor affecting the
MHRA’s ability to regulate effectively. We draw
attention to the role of the agency’s funding
structure, and in particular its need to compete
with other European regulators for licensing fees,
as well as its desire to avoid ‘‘reputational risk’’.
3
We conclude that the case of Seroxat and the
missing trial data casts doubt upon that MHRA’s
capacity to fulfil its own ‘‘mission statement’’:
We enhance and safeguard the health of the public
by ensuring that medicines and medical devices
work and are acceptably safe. … Underpinning all
our work lie robust and fact-based judgements to
ensure that the benefits to patients and the public
justify the risks.
4
Methodologically, the article draws on an
analysis of the relevant legislation and regulations,
and documents released by the MHRA, and Linsey
McGoey’s (LM) interviews with key individuals
such as Kent Woods.
5
THE MHRA’S INVESTIGATION INTO
GLAXOSMITHKLINE
The MHRA’s investigation into GSK was launched
in October 2003, following GSK’s submission, in
May 2003, of data from Studies 329 and 377,
clinical trials which tested the efficacy of parox-
etine (Seroxat/Paxil) in children and adolescents in
the mid-1990s in 11 countries. As soon as they
were received, the relevant data were analysed by
the Committee on the Safety of Medicines (CSM),
which found that they provided clear evidence (a)
that ‘‘there is no good evidence of efficacy in major
depressive disorder in the population studied’’,
6
and
(b) that there was ‘‘a clear increase in suicidal
behaviour versus placebo’’.
6
Following this CSM
review, the MHRA published advice to all doctors
that Seroxat should not be prescribed to under-18s,
and launched a criminal investigation into GSK’s
failure to submit this data in a timely manner.
In early 2004, suspicions of illegality were
bolstered by the leaking of a confidential, internal
GSK document that indicated that there had been
a deliberate decision to withhold Studies 329 and
377 from regulators. The GSK document, dated
October 1998 and entitled Seroxat/Paxil adolescent
depression—position piece on the phase III clinical
studies was first described in an article in the
Canadian Medical Association Journal,
7
and is now
widely available on the internet.
8
It stipulates that
company representatives should be cautious in
disseminating the results of Study 329 and 377,
stressing that ‘‘it would be commercially unacceptable to
include a statement that efficacy had not been demonstrated,
as this would undermine the profile of paroxetine’’, and that it was
necessary ‘‘to effectively manage the dissemination of these
data in order to minimise any potential negative commercial impact’’
(emphasis added).
8
It seems unarguable, then, that for five years, GSK
deliberately failed to disclose clinical trial data which provided
evidence that Seroxat should not be prescribed to under-18s.
Given that, in 1999 alone, 32 000 prescriptions for Seroxat had
been issued to children in the UK, it is clear that in the time-lag
between the completion of the relevant clinical trials (1998) and
the CSM’s warning notices (2003), tens of thousands of under-
18s were prescribed a drug that was unlikely to work, and
which carried an unacceptable risk of a serious, indeed fatal,
adverse reaction. We do not know how many, if any, under-18s
actually committed suicide between 1998 and 2003 as a result of
taking Seroxat, but given the large number of children involved,
it is certainly possible that deaths occurred which could have
been avoided by prompt disclosure of this information.
It was the understanding of MHRA staff that the Medicines
Act 1968 and Regulations which transpose a series of EU
Directives impose a legal duty on pharmaceutical companies to
give the regulator all clinical trial data which has a bearing on a
medicine’s safety and efficacy. This point was stressed by Kent
Woods (KW) during testimony before the House of Commons
Health Select Committee on 9 September 2004, as part of the
Select Committee’s 2004–2005 inquiry into the influence of the
pharmaceutical industry on UK health policy:
Q39: Siobhain McDonagh MP: How many clinical trials does the
MHRA examine before approving a drug application? Is the
MHRA confident that it completely reviews all the findings
necessary, both within and outside the public domain, before
licensing a drug?
KW: The legal responsibility is on the applicant to ensure that in
applying for a trial’s authorisation they do give us all the data,
whether or not it is in the public domain. That is clearly spelt out
in the medicines legislation, and, of course, it is fundamental to
our assessment of a product that we do have access to all the
available data. … If we have evidence that there has been a breach
of the regulations, then we have an inspection and enforcement
division which will take the necessary action to pursue
investigations; the legal framework is clear, that we must have for the
assessment process all the data which the applicant possesses
(emphasis added).
9
In practice, however, as John Abraham has pointed out, the
penalties for failing to submit clinical trial data, which include
fines and imprisonment, remain untested, as to date in the UK
no company has ever been prosecuted for withholding
information that has a bearing on a drug’s safety profile.
10
Woods confirmed this point during his interview with LM in
January 2007:
LM: While you were a witness before the Health Select
Committee, you noted there have been a number of instances
when the MHRA’s enforcement group has been called in to
assess whether there has been appropriate disclosure of data by
industry. [Observers suggest] there has never been a prosecution
of a company for suppression of data. Is that the case?
KW: I believe that’s the case. I’ve been in the agency for three
years. In fact, I’m pretty certain that that’s the case. I would
qualify that by saying firstly that our first stop is to achieve
compliance and prosecution is very much a long stop. And
secondly, industry has a very strong vested interest in not
actually stepping over the line. … The suppression of data would
particularly willing and able to take enforcement action. It is not
something which is in a company’s best interest to do.
Given Woods’ assertion that the MHRA is committed to
prosecuting breaches of the regulations, the Agency’s decision to
refer GSK’s suppression of trial data to the MHRA’s
Enforcement Group in October 2003 is not surprising. What is
perhaps surprising is the length of time it took the MHRA to
realise that prosecution would not be possible. Surely the five
year time-lag between GSK’s completion of trials which
revealed inefficacy and lack of safety, and their eventual
disclosure—not to mention the fact that the disclosure in
2003 came in the form of a briefing paper about a possible future
application to extend the indication for use of Seroxat in
children, as opposed to an urgent risk/benefit alert—spoke for
itself. It is hard to imagine any explanation of the non-
disclosure of this data that did not amount to a breach of
pharmacovigilance regulations. Yet, after a very long and
complex investigation, during which the MHRA ‘‘obtained
and examined over a million pages of documentation’’,i the final
decision was that the case could not proceed to prosecution.
Importantly, however, this decision was not taken because
the MHRA’s intensive investigation revealed that GSK had
acted properly in relation to the data in question. On the
contrary, as the leaked memo makes clear, GSK had deliberately
suppressed data which revealed that Seroxat should not be
prescribed to under-18s. Rather, once the evidence had been
gathered, Counsel’s advice was sought in order to determine
whether a prosecution should proceed, and the advice was ‘‘the
legislation was sufficiently unclear as to make a criminal
prosecution impossible’’.
11
BARRIERS AND LOOPHOLES WITHIN THE LEGISLATIVE
FRAMEWORK
This conclusion prompts a number of questions, the first and
most obvious of which is that if it is indeed true that the law
was insufficiently clear in March 2008, then it must also have
been insufficiently clear in October 2003, when the decision was
taken to launch a criminal investigation. Of course, if there was
a degree of ambiguity in the law, then it might be especially
important to spend time trying to assemble a clear-cut case of
illegal activity on the part of GSK. But the important point
about the MHRA’s March 2008 announcement was not that
there was some slight ambiguity which could have been ‘‘cured’’
by decisive evidence of wrongdoing. On the contrary, as we see
below, the defects in the law which were identified in 2008 are
potentially so broad that, regardless of the robustness of the
MHRA’s evidence of illegality, prosecution would be pointless.
The existence of gaps in the law which make prosecution futile
does not depend on the weight of evidence against GSK, rather
it is an independent fact which, if detected by a competent
lawyer in 2008, should have been detectable in 2003. If the law
as it existed between 1998–2003 made a successful prosecution
impossible ab initio, a four and a half year investigation into the
possibility of prosecution may have been a colossal waste of
time and money.
Secondly, was it, in fact, the case that the law at the relevant
time was insufficiently clear? It is certainly true that the
provisions which GSK were suspected of breaching consist, at
least in part, of a shifting set of Regulations—the Medicines
for Human Use (Marketing Authorisations Etc) Regulations
i
Linsey McGoey interview with Kent Woods, January 2007.
108 J Med Ethics 2009;35:107–112. doi:10.1136/jme.2008.025361
1994—which have, over the period in question, implemented a
number of new EU Directives. Without rehearsing every shift in
the content of the 1994 Regulations between 1998 and 2003,
two provisions are of particular importance.
From February 2002, para 8 of Schedule 3 of the Regulations
provided that: ‘‘Any person responsible for placing a relevant
medicinal produce on the market who fails to report to the
licensing authority any suspected adverse reaction, or to submit
to the licensing authority any records of suspected adverse
reactions… shall be guilty of an offence’’ (emphasis added).
More important still is para 10, which went further and
required the qualified person to provide ‘‘any other information
relevant to the evaluation of the benefits and risks afforded by a
medicinal product’’ (emphasis added). The regulations do not
apply retrospectively, so both these particular provisions applied
to GSK in the time period between February 2002 and May 2003
(when the data were eventually disclosed).
The MHRA’s view, which we share, was that ‘‘the informa-
tion eventually provided to the MHRA about adverse reactions
experienced in the trials of Seroxat in children was clearly …
relevant to the risks and benefits of the product’’.
11
On the face
of it, then, the provision that there is a duty to provide ‘‘any
information relevant to the evaluation of benefits and risks’’
does not look particularly vague or ambiguous, and would
appear to capture precisely the non-provision of data by GSK.
How then could the decision be taken that, contrary to
appearances, this provision is ‘‘insufficiently clear’’ to justify
prosecution?
In brief, the lawyers whose advice had been sought detected a
number of possible loopholes, described below, which would
have enabled GSK to avoid conviction, and this meant that a
prosecution would have represented a further waste of public
resources.
The first loophole relates to the duty to notify the MHRA of
adverse reactions. This, apparently, could be read to apply only
to adverse reactions ‘‘in the normal conditions of use of the
product’’. Though first licensed for adult use in the UK in 1990,
Seroxat had not been specifically licensed for use in under-18s
because enrolling children in clinical trials was not encouraged.
As a result, its prescription as a treatment for childhood
depression was effectively ‘‘off-label’’, albeit that GSK knew
that thousands of children were taking it, and had certainly not
advised doctors against prescribing it to children. It should be
noted that reluctance to enrol children in clinical trials means
that off-label prescription to children is the norm rather than
the exception, with obvious implications for patient safety.
Until the CSM issued their warning notices in 2003, being
under-18 was not listed as a contraindication to prescription of
Seroxat, and so it could be freely and lawfully prescribed as a
treatment for childhood depression.
Unusually then, GSK had conducted clinical trials of Seroxat
in under-18s. This fact, somewhat ironically, led to the second
legal loophole. Because the data which revealed an elevated risk
of suicide did not emerge ‘‘during normal conditions of use’’,
but instead from clinical trials, again they were not captured by
the regulations.
These two defects in the law might have been ‘‘cured’’ if
instead the MHRA could have invoked the duty to report
adverse reactions which occur during clinical trials, which is
contained in Section 31 of the Medicines Act 1968, and
governed by orders made under the Act. Yet, conveniently for
GSK, there are two further loopholes here in that this duty
applies only to trials conducted in the UK, and, at the relevant
time, failure to comply would not have been a criminal offence.
An EU Directive which came into force too late—in May 2004—
introduced a criminal offence for the failure to report adverse
reactions which occur during clinical trials, but again this
remains limited to trials which take place within the European
Economic Area (EEA).
It is worth noting that pharmaceutical companies have
always been entitled to rely on non-UK or now non-EEA trials
when submitting applications for marketing authorisations.
They have, in short, been able to benefit from the positive
results of trials conducted abroad, while at the same time, it
appears that they have not been under a corresponding duty to
reveal the negative results of non-UK, or non-EEA trials.ii
The existence of so many qualifications to what initially
looks like a clear and comprehensive duty to submit ‘‘any other
information relevant to the evaluation of the benefits and risks
afforded by a medicinal product’’ is perhaps surprising.
Certainly, two ordinary rules of statutory interpretation would
militate against this conclusion. First, the words used in
legislation are normally assumed to have their ‘‘ordinary
language meaning’’, unless otherwise specified. Use of the word
‘‘any’’, according to the Oxford English dictionary, captures the
idea of ‘‘indifference as to the particular one or ones that may be
selected’’, which would suggest that ‘‘any relevant information’’
should not, without a clear indication to the contrary, be
qualified to mean ‘‘only information gathered in a particular
setting’’.
The second rule of statutory interpretation which is at odds
with the existence of these legal loopholes is that, in the event
of statutory ambiguity, it is legitimate to ask what the
legislator’s intention was in drafting the provision in question.
Here the intention was evidently to create a duty to report all
relevant data, and in particular, to disclose suspected adverse
reactions and other information relevant to the regulator’s
evaluation of risks and benefits.
The interpretation of the law which has led to the decision
not to prosecute would seem to subvert the intention of the
creators of the regulatory regime, which was indubitably not to
provide a series of ‘‘get-out’’ clauses for drugs companies who
withhold, deliberately, evidence of lack of efficacy and serious
side effects for a group of patients who are routinely being
prescribed the drug in question.
Against this, it is of course true that there is a further rule of
statutory interpretation according to which, where there is any
ambiguity in the definition of a criminal offence, that ambiguity
has to be interpreted in the defendant’s favour, and so, if the
loopholes outlined above exist, the MHRA are clearly right that
the prosecution of GSK would be likely to fail, and so embarking
on it would be a further waste of time and money.
GAPS IN THE REGULATORY FRAMEWORK: NICE, MHRA AND
ACCESS TO DATA
It now seems likely, therefore, that the legal framework which
governs the licensing of medicines in the UK, set up by the 1968
Act in the light of the Thalidomide tragedy, has always been
seriously defective. The duty of candour owed to the regulator,
and referred to by Woods in his evidence to the Select
Committee, to provide ‘‘all the data which the applicant
possesses’’, backed up by the possibility of criminal sanctions
in the event of breach, has been revealed to be heavily qualified.
It does not exist where adverse reactions become apparent in
off-label use, even where that off-label use is both common and
well known, or where they occur in clinical trials that took place
ii
We are grateful to Catherine Will for this point.
J Med Ethics 2009;35:107–112. doi:10.1136/jme.2008.025361 109
outside the UK (or, since 2004, the EEA). These are significant
gaps in the regulatory scheme, which, as is apparent from the
Seroxat episode, subvert the purposes of regulation, and
undermine the powers of the regulator.
In short, there can be no sanctions despite clear evidence that
GSK withheld data which ensured that tens of thousands of
adolescents have been prescribed drugs which do not work, and
which may cause an elevated risk of suicide. In addition to the
implications for patient safety, this also represents a huge waste of
NHS resources: between 1998 and 2003, the NHS paid for hundreds
of thousands of prescriptions of Seroxat for under-18s, despite the
existence of (withheld) evidence proving (a) that it would not work,
and (b) that it might cause a serious adverse reaction.
This latter question raises important issues for the National
Institute for Health and Clinical Excellence (NICE). It might be
argued that not only should the MHRA have had access to this
evidence much earlier, on safety grounds, but that it would also
be relevant to any guidance NICE might issue on the treatment
of depression in children. Significantly, however, NICE does not
have the same rights as the MHRA has always been assumed to
have to require pharmaceutical manufacturers to supply clinical
trial data. According to Kent Woods, the two bodies are
exercising different functions. The MHRA decides whether a
drug is safe—using the powers it thought it had to require the
provision of ‘‘any relevant information’’, and NICE can then
rely upon that assessment in order to decide whether this safe
and efficacious drug is also sufficiently cost-effective to justify
prescription in the NHS. Woods elaborated on this point in his
interview with LM:
LM: Would you like to see it move to a system where NICE
policymakers had access to the same data as the MHRA?
KW: No.
LM: Why not?
KW: It’s important to understand firstly what NICE is there for.
NICE is an NHS organisation. And its job is to give advice and
guidance to the NHS. I mean, the NHS is just a very large health
maintenance organisation. We have a statutory responsibility to
the nation as a whole, and therefore our remits are somewhat
different… I think we need to keep separate in our minds the job
that this agency does, which is about weighing up risk and
benefit and quality, and what NICE does, which is about
effectiveness and cost-effectiveness.
Yet it is not clear that the roles of the MHRA and NICE can
be neatly separated in this way. If a drug does not work, then
that information is critical to a decision about cost-effectiveness,
since regardless of its cost, its lack of efficacy will make its
prescription in the NHS a waste of money. It is also critically
important that this two stage process for drug provision in the
UK means that any failure by the MHRA to gain access to
information about adverse reactions or lack of efficacy will be
magnified by NICE’s reliance on the robustness of the MHRA’s
conclusions on safety and efficacy. If the MHRA cannot detect
that a drug is unsafe and inefficacious, because a drug company
can withhold data without penalty, NICE’s dependence on
MHRA data analyses means that unsafe and inefficacious drugs
may subsequently be widely prescribed in the NHS.
A positive result of the Seroxat episode may be that the
inequality of access to data described by Woods may be
revisited. Indeed, we understand the MHRA is currently
negotiating with NICE about revising shared data arrange-
ments. But restructuring access to data alone may not solve
some of the problems that compounded the MHRA’s inability
to prosecute GSK. In the next section, we examine some further
structural factors that may be hindering effective drugs
regulation in the UK.
MHRA, INDUSTRY RELATIONSHIPS AND REPUTATIONAL RISK
Fallout from the MHRA’s decision not to prosecute GSK is not
the first time that the Agency has attracted criticism. John
Abraham
12 13
has consistently highlighted the existence of a
number of barriers that make it difficult for the UK regulator to
effectively monitor the safety of medicines.
14
The first is the
MHRA’s funding structure. The Medicines Control Agency
(MCA), which preceded the MHRA, was established in 1989
when the UK government decided to make the drugs regulator
semi-autonomous from the Department of Health. Unlike its
predecessor, the new MCA, like the MHRA today, became
entirely funded by fees paid by pharmaceutical companies in
exchange for drug licensing services. Within the EU, this model
of industry funding is becoming increasingly common.
15 16
In
comparison, the Food and Drug Administration (FDA), the US
equivalent of the MHRA, originally received no private funding
at all, and while its reliance on industry fees has grown, to
about 50%, it retains a degree of financial independence from
the pharmaceutical industry.
17 18
There is, as Breckenridge and Woods have pointed out, a
logical reason for the MHRA’s funding arrangements.
19
Why
should the UK taxpayer carry the burden of paying for the
licensing process, when private companies profit from drug
sales? And it is true that in many other sectors, the cost of
regulation is borne by the regulated, rather than by the
taxpayer. The particular problem industry-funded regulation
poses for the MHRA is that, unlike most other regulators, the
MHRA is effectively in competition for industry fees with other
EU regulators.
The reason for this is that drugs can be licensed throughout
the EU through what is known as the ‘‘mutual recognition
procedure’’.
20
Drugs companies choose to apply to a national
regulator, whose decision to grant a product licence will then be
recognised throughout Europe. Because the majority of licensing
fees go to the regulator to which the pharmaceutical company
first applied, an internal EU market has emerged, in which
national regulatory agencies compete for ‘‘regulatory business’’
by lightening the regulatory burden and speeding up approval
times. In the first nine years of this system’s existence, the
average assessment time for new drugs in the UK fell from 154
working days to 44.
21
While regulatory efficiency is, of course, to
be welcomed, making regulators compete with each other in
this way undoubtedly creates perverse incentives towards the
minimisation of regulatory oversight, or a ‘‘race to the bottom’’
in medicines regulation.
13 15
Another factor at stake may be what Michael Power has
described as the imperative to minimise ‘‘reputational risk’’.
3
The failure to gain access to Studies 377 and 329 is not the first
time the MHRA has found that its decisions have been based
upon inadequate or partial data analysis. During a 2003–4
investigation into the safety of all selective serotonin reuptake
inhibitor (SSRI) antidepressants (including Seroxat), the
MHRA’s expert working group discovered that daily doses of
SSRIs of more than 20 mg were no more effective at treating
depression, regardless of its severity, than doses of 20 mg or less.
At the time 17 000 individuals in Britain were receiving daily
doses of SSRIs at 30, 40 or 60 mg, thus increasing their risk of
suffering adverse effects,
22 23
and increasing the costs to the
NHS, without any improvement in efficacy. For our purposes,
the important point about the new advice about safe dosing
levels which resulted from this investigation was that it was not
110 J Med Ethics 2009;35:107–112. doi:10.1136/jme.2008.025361
prompted by newly submitted information, but following a
reanalysis of data which had been in the MHRA’s possession for
over 10 years.
14
Abraham has drawn attention to other examples of the
MHRA’s failure to act swiftly on evidence of the adverse effects
of licensed drugs, such as its handling of Halcion, a triazolo-
benzodiazepine (tranquiliser) manufactured by Upjohn.
24
First
licensed in 1978, the UK’s Committee on Safety of Medicines
began investigating reports of adverse effects as soon as the drug
was licensed for use in the UK. Despite the existence of data
dating back to the 1978 which proved that Halcion was not
safe, the drug was only removed from the market in 1991. Far
from being an aberration then, the MHRA’s inability to gain
access to all relevant trial data in relation to Seroxat indicates
that there was a failure to learn lessons following the Halcion
episode.
24 iii
This point resonates with recent work by David
Demortain, who has suggested that one of the reasons why
drug crises so often fail to produce any regulatory change is
because accountability is ‘‘determined by the action of a group
which, ironically, is likely to minimise the novelty of lessons
publicly drawn from the crisis in an attempt to defend its
ownership and minimise its responsibility’’.
25
It is worth noting that regulators in the US have a rather
different record. There are obvious similarities between GSK’s
withholding of the Seroxat trials and a case in the US, 20 years
ago, in which Eli Lilly had failed to report a number of fatal and
serious adverse reactions, in UK patients, to the drug
benoxaprofen (an anti-inflammatory drug marketed as Opren
in the UK and Oraflex in the US). According to the US
regulations, companies are required to report to the FDA any
‘‘unexpected side effect, injury or toxicity within 15 days’’ of
receiving notice of such an event. In the case of benoxaprofen,
because the adverse reactions had occurred in the UK rather
than the US, Eli Lilly’s lawyers argued that there was a lack of
clarity over whether the regulations required the company to
report them. Despite the existence of a degree of ambiguity, the
FDA successfully prosecuted Lilly for failing to report four
fatalities and six illnesses which were relevant to the safety of
benoxaprofen. As Abraham as pointed out, in the US, the
argument that non-US adverse reactions did not fall within the
word ‘‘any’’ was given short shrift, and the spirit behind the
regulations was decisive.
26
This episode is in sharp contrast to the MHRA’s compara-
tively lax treatment of GSK. In the absence of any serious threat
of sanctions for withholding data from the MHRA, have
companies in the UK, in fact, always been free to hide negative
trial results with impunity? Unlike the FDA, the MHRA has
never prosecuted a company for failing to submit relevant data.
As Tim Kendall, joint director of the UK’s National
Collaborating Centre for Mental Health, suggests in an inter-
view with LM:
The 1998 GlaxoSmithKline memo, which suggested suppressing
trial data on paroxetine use in children, is unlikely to be a lone
aberration. I think it is absolutely necessary for physicians,
psychiatrists and indeed the public, to publicly and forcefully say
that this is completely unacceptable. This threatens the
evidentiary basis of contemporary medicine. It’s nothing short of
a battle for the truth.
27
The failure to detect unsafe dosing levels; the failure to learn
the lessons from Halcion, and the failure to prosecute GSK
might all be said to cast doubt over the MHRA’s ability to
regulate effectively, raising the prospect of risks to its
reputation. For the regulator to reveal that it did not know of
the existence of evidence which casts serious doubt upon the
safety or efficacy of a widely prescribed drug immediately raises
an inference that the regulator, which is under a duty to
demand and analyse all such data, has not done its job properly.
In relation to their inability to gain access to GSK’s missing trial
data, perhaps fortuitously, the MHRA has been able to manage
this potential reputational risk by blaming the law itself.
CONCLUSIONS
We agree with the MHRA’s conclusion that the legislation and
regulations which cover drug safety in the UK have been
revealed to be insufficiently robust to ensure that companies
submit all data relevant to determining a drug’s risks and
benefits, and we would support measures, such as compulsory
pre-trial registration, to ensure that trials with inconvenient or
‘‘commercially unacceptable’’
7
results, such as Studies 329 and
377, cannot simply disappear. We are also pleased to see that the
Agency announced in October 2008 new amendments that aim
to close the gaps in the law described above. When the
Medicines for Human Use (Marketing Authorisations Etc)
Amendment Regulations 2008 come into force, there will be a
duty to provide ‘‘information arising from use of the product (a)
in a country or territory outside the European Economic Area;
and (b) outside the terms of the marketing authorisation,
including use in clinical trials’’. It is to be hoped that the law
will now be sufficiently clear to ensure that the duty of candour
which had always been assumed to attach to information about
a product’s risk/benefit profile has teeth.
Where our analysis diverges from the MHRA’s is with their
assumption that the only problem this incident has revealed is
the existence of loopholes in the legal framework. In our view,
there are other factors at stake, which create incentives towards
increasingly, and perhaps dangerously light-touch regulation of
medicines in the UK. Many of these were highlighted by the
House of Commons Health Select Committee in 2005, which
found that:
The regulator, the Medicines and Healthcare products
Regulatory Agency (MHRA), has failed to adequately scrutinise
licensing data and its post-marketing surveillance is inadequate.
The MHRA Chairman stated that trust was integral to effective
regulation, but trust, while convenient, may mean that the
regulatory process is not strict enough. The organisation has been
too close to the industry, a closeness underpinned by common
policy objectives, agreed processes, frequent contact, consultation
and interchange of staff.
9
Seen in this light, it could even be argued that defects in the
regulatory scheme were convenient for the regulator. Instead of
blaming its own structures and mechanisms, or, perhaps worse,
having to face a high-profile criminal trial in which GSK’s
lawyers would skilfully pick over documents, memos and
emails, in minute detail, in order to find fault with the regulator
and its processes, the MHRA has been able to avoid these
threats to its reputational status by blaming shoddy statutory
drafting.
Kent Woods’ letter to the CEO of GSK, Jean Pierre Garnier,
informing him of the decision not to proceed to prosecution,
suggests that a strengthening of the law ‘‘should be unnecessary
in an industry which relies so heavily on public trust and aspires
to high ethical standards’’.
28
The ‘‘moral responsibility’’ to
provide data, Woods goes on to say, ‘‘now needs to be insisted
upon by the unambiguous force of law’’ (emphasis added).iii See also McGoey 2007, p226 for further discussion of these points.
14
J Med Ethics 2009;35:107–112. doi:10.1136/jme.2008.025361 111
Deftly, therefore, Woods criticises GSK for failing to meet their
moral responsibilities, and the law for being too ambiguous. GSK
has avoided prosecution, and the MHRA has avoided the intense
negative scrutiny which would have been the inevitable con-
sequence of a criminal prosecution. For both, then, could this
almost be a win-win situation, four and half years in the making?
AUTHORS’ NOTE
Following its acceptance in August, this paper was amended to
include a reference to the announcement, in October 2008, that
the Medicines for Human Use (Marketing Authorisations Etc)
Regulations 1994 were to be amended.
Competing interests: None.
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