The British Journal of Psychiatry (2007) 190: 91-93. doi: 10.1192/bjp.bp.106.024794
© 2007 The Royal College of Psychiatrists
Regulatory policies on medicines for psychiatric disorders: is Europe on target?
CORRADO BARBUI
Department of Medicine and Public Health, University of Verona,
Verona
SILVIO GARATTINI
Institute of Pharmacological Research Mario Negri, Milan, Italy
Correspondence:
Dr Corrado Barbui, Department of Medicine and Public Health, Section of
Psychiatry and Clinical Psychology, Ospedale Policlinico, 37134 Verona, Italy.
Tel: +39 045 8076418; fax: +39 045 585871; email:
corrado.barbui{at}univr.it
Declaration of interest S.G. was a member of the Committee for
Proprietary Medicinal Products.
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ABSTRACT
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The European Medicines Agency (EMEA) is the regulatory body that provides
the institutions of the European Community with the best possible scientific
advice on the quality, safety and efficacy of medicinal products. Drugs
approved by the EMEA are automatically marketable in all the European member
states. Since the beginning of the EMEA’s activities a number of drugs
acting on the central nervous system obtained marketing authorisation. This
editorial highlights some aspects of the EMEA rules that may negatively affect
the evaluation of medicines for psychiatric disorders.
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INTRODUCTION
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The recent revision of the European pharmaceutical legislation has given
the European Medicines Agency (EMEA) new responsibilities. After more than 10
years of existence the EMEA has proved useful in ensuring member states shift
towards harmonisation of pharmaceutical procedures and simplification of the
process by which a central authorisation becomes valid in all the states
(Garattini & Bertele’,
2001). Any opinion expressed by the EMEA on old or new products,
relating to changes in therapeutic indications, approval, suspension or
withdrawal of a product, has to be accepted by all members of the European
Union. The system includes a centralised procedure, through the EMEA, and a
decentralised procedure, whereby a new drug approved by one member state is
accepted by the others after the procedure of mutual recognition. The recent
revision of the European legislation (Regulation EC No. 726/2004 of the
European Parliament and of the Council of 31 March 2004; Directive 2004/27/EC
of the Parliament and of the Council, 31 March 2004) has extended the list of
drugs that must go through the centralised procedure
(Garattini et al,
2003).
Since its establishment the EMEA has issued recommendations, notes for
guidance, conceptual papers and other official documents intended to guide the
design and reporting of randomised controlled trials conducted for regulatory
purposes. These official documents report the EMEA rules and criteria for
approval of new drugs. So far, nine products acting on the central nervous
system have been approved in line with these criteria, and in future years it
is expected that the increasing responsibilities of the EMEA will
progressively increase the number of products for psychiatric disorders
submitted for approval (Garattini &
Bertele’, 2003). In this still-evolving European scenario,
at least three technical aspects of the EMEA rules may negatively affect the
evaluation of medicines for psychiatric disorders.
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PROCEDURES FOR DRUG APPROVAL
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The centralised procedure is not compulsory for psychotropic drugs. In
addition to the fact that the dual system of approval – centralised and
decentralised – creates competition between the EMEA and the national
drug agencies, with financial implications, it generates heterogeneity between
countries in terms of approved indications (labels). Olanzapine, for example,
has been positively assessed by the EMEA through the centralised procedure and
released for marketing with the same label in all EU member states. However, a
decentralised route has been followed in the case of quetiapine, marketed
after 1995, and approved for the treatment of schizophrenia in the UK and for
the treatment of ‘acute and chronic psychoses, including
schizophrenia’, in Italy (Barbui
et al, 2003). Labels have a key role in regulating the
everyday prescribing and consumption of drugs: in Italy quetiapine is the only
atypical antipsychotic that can be prescribed in patients without a diagnosis
of schizophrenia or bipolar disorder. Off-label prescribing is not forbidden,
but implies that doctors take full responsibility for the prescription and
that patients give informed consent and pay the full price of the drug, as
reimbursement is usually restricted to disorders stated in the label.
Theoretically, approved labels should correspond to trial inclusion criteria,
and it seems rather contradictory that European regulatory authorities, while
strongly supporting the adoption of stringent inclusion criteria in clinical
trials, with rigorous and restrictive reference to diagnostic rules, permit
drugs to be licensed with generic and unspecific labels for use in clinical
practice. Probably, only the abolition of the decentralised procedure will
make the licensed indications of new drugs more consistent.
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CONTROLLED TRIALS
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At the EMEA new drugs can still be evaluated with no comparison with active
alternative treatments. This means that new drugs can be proved effective and
safe on their own, even though they might in fact be potentially less
effective or less safe than other drugs currently in use. Although in
situations where no (or only a few) active treatments are available this issue
may not be relevant, in the field of psychotropic drugs, where many effective
agents are available, this issue is crucial. Despite this, the demonstration
of a difference against placebo, and not against an active comparator, makes a
new psychotropic drug eligible for registration in Europe. If comparisons are
made, the industry usually relies on demonstrating therapeutic
‘equivalence’ or ‘non-inferiority’, because this is in
agreement with current EMEA requirements. This results in a high degree of
uncertainty about the therapeutic role of new drugs. Even the recent revision
of the European pharmaceutical legislation does not include the requirement
that, when feasible, clinical studies should be conducted in comparison with
reference drugs (in accordance with the Declaration of Helsinki) to establish
the relative benefit of a new drug. In terms of public health needs, the
concept of added value should be introduced into the legislation. This concept
has two positive consequences. First, it allows determination of whether a
drug is active. If comparative trials show that a new drug is more effective
than a standard one, it means that the new drug is active. Conversely, if a
new drug is not more effective than a standard one, it means that the new drug
is inactive or similarly active compared with the reference. In the latter
scenario there is no added value. Second, the concept of added value would
advance innovation in the development of drugs, because a higher threshold for
the entry of new drugs would force investigators towards the development of
innovative rather than ‘me too’ drugs. The current legislation,
allowing investigators to demonstrate a difference against placebo, has
encouraged the marketing of drugs with little degree of innovation.
Investigators should be induced to design and conduct clinical trials aimed at
discovering better activity, beneficial effects on different populations, and
less or different toxicity.
Methodological considerations also should be taken into account. Recent
data have shown that placebo-controlled trials, in comparison with
active-controlled trials, tend to overemphasise the occurrence of hard
outcomes, such as the rate of participants withdrawing from treatment
(‘dropouts’). In antipsychotic drug trials, for example, a
systematic review showed that the proportion of participants discontinuing
antipsychotics was substantially higher in placebo-controlled trials than in
active-control clinical trials (Kemmler
et al, 2005). In the field of psychotropic drugs, where
withdrawal rates approaching or exceeding 50% are not uncommon, this may
produce a problem of biased estimation of treatment effect, leading to
erroneous conclusions and poor generalisability. Future revisions of the
European pharmaceutical legislation should incorporate the requirement of
active-control clinical trials in the evaluation of psychotropic drugs, at
least in addition to placebo-controlled trials. Active-control clinical trials
should be designed and powered to generate evidence of superiority (added
value), providing physicians with clear indications on the therapeutic role of
new medicines, with respect to older medicines already on the market.
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OUTCOMES
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A third aspect, particularly relevant to the evaluation of psychotropic
drugs, is the choice of the outcome of interest. Whereas in other fields of
medicine the definition of outcome measures may be a relatively
straightforward task, in psychiatric disorders treatment efficacy may often be
an elusive concept, typically quantified by means of rating scales. The EMEA
guidance on this issue recognises that although improvement in symptoms should
be documented as a difference between baseline and post-treatment score, in
order to allow an estimate of clinical relevance the proportion of
‘responders’ or ‘remitters’ should be presented.
Cut-off points should be defined a priori in the protocol. From a
practical viewpoint this seems reasonable because it allows physicians to make
judgements in terms of proportion of patients (and not means and standard
deviations), absolute and relative risk differences and number needed to treat
(Barbui et al, 2001).
Unfortunately, this approach systematically magnifies the effect of new
medicines against placebo. A situation was hypothesised of a 1-point
difference in mean change in scores on the Hamilton Rating Scale for
Depression between drug and placebo, and it was shown that by defining
response as a minimum 12-point improvement on this scale a response rate of
50% in the drug condition and 32% in the placebo condition could be obtained
(Moncrieff & Kirsch,
2005). A small difference in symptom score can thus be translated
into a large and clinically relevant difference in proportions.
The EMEA rules should consider scores from rating scales and their
categorisation as secondary outcome measures. Randomised controlled trials
conducted for regulatory purposes should increasingly use, as primary
outcomes, hard and practical measures such as suicide attempts, treatment
switching, hospitalisation, school failure or truancy, job loss or even
withdrawal from the trial itself (Tansella
et al, 2006). The example provided by the Clinical
Anti-psychotic Trials of Intervention Effectiveness is paradigmatic in this
regard (Lieberman et al,
2005). This study, which randomly assigned a total of 1493
patients with schizophrenia to receive olanzapine, perphenazine, quetiapine or
risperidone for up to 18 months, employed as primary outcome the
discontinuation of treatment for any cause. This discrete outcome was selected
on the assumption that stopping or changing medication is a frequent
occurrence and a major problem in the treatment of schizophrenia. The finding
that 74% of patients discontinued the study medication within 18 months is a
clear confirmation of the relevance of this outcome
(Lieberman et al,
2005). A similar approach has been followed by the Bipolar
Affective Disorder Lithium Anticonvulsant Evaluation trial, where hospital
admission was defined as the primary outcome
(Geddes & Goodwin, 2001).
In these circumstances, the idea that hard outcome measures are suitable for
practical and pragmatic clinical trials, but not for randomised controlled
trials conducted for regulatory purposes, appears difficult to reconcile with
the principles of evidence-based medicine.
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CONCLUSION
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In Europe, current policies on medicines for psychiatric disorders need to
be further developed in order to fully comply with the EMEA mission statement
of promoting ‘the protection of human health... and of consumers
consumers of medicinal products’
(Council of the European Communities,
1993).
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ACKNOWLEDGMENTS
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The views presented in this editorial are those of the authors and should
not be understood or quoted as being made on behalf of the EMEA and/or its
scientific committees.
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Received for publication March 29, 2006.
Revision received July 24, 2006.
Accepted for publication September 1, 2006.
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- Peter Tyrer
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ABSTRACT
INTRODUCTION
