Are women appropriately represented and assessed in clinical trials submitted for marketing authorization? A review of the database of the European Medicines Agency.

OBJECTIVE: There is concern that patients included in trials do not represent the true patient population and women in particular may selectively be excluded. We looked at trial data submitted to the European Medicines Agency (EMEA) by drug companies to achieve marketing authorization in Europe between 2000 and 2003. METHODS: We reviewed the EMEA database and included the main studies for the risk/benefit assessment (pivotal trials) submitted between 2000 and 2003. RESULTS: In pivotal trials submitted to the EMEA there was no, or generally clinically negligible, evidence for gender bias; however, women were underrepresented in hypertension, diabetes and hepatitis B trials, and overrepresented in rheumatoid arthritis and allergic conjunctivitis. CONCLUSIONS: In trials submitted for marketing authorization to the EMEA gender bias was not a serious problem.

[Severe adverse reactions after the use of sulphur hexafluoride (SonoVue) as an ultrasonographic contrast agent]. / Ernstige bijwerkingen bij gebruik van zwavelhexafluoride (SonoVue) als echografisch contrastmiddel.

European Medicines Agency (EMEA) recently took precautionary measures to limit the use of the ultrasonographic contrast agent sulphur hexafluoride (SonoVue) in patients with cardiac disease. Throughout Europe a number of serious allergic reactions with probable secondary cardiovascular problems have been reported. In addition to this, there have been 3 reports of a fatal outcome soon after the administration of SonoVue. For all of these patients there was a risk of serious cardiac complications as a consequence of underlying cardiac problems. In The Netherlands 3 anaphylactic reactions have been reported, two in women aged 59 and 70 years respectively, and one in a man aged 80 years.

[Clinical evaluation of efficacy and adverse effects in the (European) registration of drugs: what does it mean for the doctor and patient?]. / De klinische beoordeling van werkzaamheid en schadelijkheid bij de (Europese) registratie van geneesmiddelen: wat betekent dit voor de dokter en de patiënt?

The clinical criteria for admission of new drugs to the European common market have become more stringent in recent years. Increasingly often, the manufacturer is required to demonstrate that the new drug offers a clinically visible and relevant benefit to the patient. Efficacy and adverse effects should not only be studied by comparative trials with placebo, the registration authorities also expect the drug to be compared with the standard treatment already available. Such trials should prove that the balance between efficacy and adverse effects of the drug is better than that of placebo and at least as good as the standard treatment, as regards not only statistical significance but also clinical relevance. Therefore, Dutch and European assessment reports and product information may be increasingly useful to prescribers, patients and insurers in determining the role and therapeutic value of new drugs within the existing therapeutic possibilities concerning certain diseases.

Absence of a 'cholinergic link' in the apomorphine-induced feedback inhibition of dopamine synthesis in rat striatum.

The blocking effect of apomorphine on the rise in striatal dopamine (DA) content, induced by 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) was taken as a measure for the intrastriatal feedback inhibition of DA synthesis. The effects of cholinergic drugs on this feedback system were assessed in order to verify the hypothesis that this mechanism is mediated via an intrastriatal cholinergic link. We presumed that DA receptors were located on a cholinergic neuron, while the cholinergic terminals in turn made direct or indirect axon-axonal contact with the dopaminergic nigro-striatal pathway (N.S.P.). Although cholinergic agents could modify the effect of HA-966 on striatal DA content, it proved to be impossible to counteract the blocking effect of apomorphine with cholinergic drugs as was to be expected. Therefore we concluded that the effect of apomorphine was not brought about in the way which had been postulated.

The effect of blocking dopamine release on synthesis rate of dopamine in the striatum of the rat.

Two experiments were carried out in rats to investigate the mechanisms by which dopamine (DA) synthesis is regulated. First, a unilateral lesion was made in the substantia nigra, thus interrupting the nervous impulse flow of the nigro-striatal pathway. Secondly, the release of DA in the striatum was blocked by means of 1-hydroxy-3-amino-pyrrolidone-2 (HA-966). In both experiments the synthesis rate of DA was accelerated as was shown by analysing the time course of the specific activity of striatal DA after an i.v. injection of 3,5-3H-tyrosine. Furthermore the influence of apomorphine on the rate of DA synthesis, accelerated by HA-966 or by lesion, was investigated. Apomorphine appeared to block the increase of DA synthesis. The results are discussed in the light of a transsynaptic feedback mechanism.