PURPOSE:This paper describes the experience of the Ethics Committee of the Medical University of Vienna, Austria, while managing the workload of clinical study applications.METHODS:An expedited review process was introduced for initial review of study protocols regarded as minimal risk interventions in March 2004.RESULTS:A total of 504 study protocols were submitted for review in 2003 and this number has increased to 743 in 2007. Two hundred sixty eight studies were classified as minimal risk in 2007 and allocated to a subgroup of the Committee for review. The time to full approval was shorter for these studies as compared to other protocols.CONCLUSIONS:Implementation of initial expedited review can improve the performance of an Ethics Committee. A framework to achieve a single opinion for multisite research of minimal risk interventions should be considered to facilitate these low risk studies.

Introduction: Ethics committees have been an integral part of clinical research since 1975, when they were introduced through the amendment of the Declaration of Helsinki. Every proposal for clinical research on human subjects has to be submitted to an independent ethics committee for review and approval. The European Clinical Trials Directive 2001/20/EC was implemented in 2004 to harmonise the legislative framework for clinical research in Europe in order to make Europe more competitive in clinical research while at the same time improving the protection of research participants. Results: We have evaluated the situation of ethics committees in Europe five years after the implementation of the new law with special consideration of the number of Ethics Committees per European Member State and the number of members within the specific committees, including the selection of members, also in regard to gender aspects and training requirements, the remuneration or compensation of members in regard of their review obligations, and also issues of conflicts of interest. Conclusion: Inadequate remuneration for professional services and gender imbalance are universal concerns across Europe. As the position of ethics committees changes continuously towards greater responsibility, further guidance is needed to uniformly adapt their structures to those needs.

Decreased synaptic serotonin during depressive episodes is a central element of the monoamine hypothesis of depression. The serotonin transporter (5-HTT, SERT) is a key molecule for the control of synaptic serotonin levels. Here we aimed to detect state-related alterations in the efficiency of 5-HTT-mediated inward and outward transport in platelets of drug-free depressed patients suffering from seasonal affective disorder (SAD). 5-HTT turnover rate, a measure for the number of inward transport events per minute, and tyramine-induced, 5-HTT-mediated outward transport were assessed at baseline, after 4 weeks of bright light therapy, and in summer using a case–control design in a consecutive sample of 73 drug-free depressed patients with SAD and 70 nonseasonal healthy controls. Patients were drug-naive or medication-free for at least 6 months prior to study inclusion, females patients were studied in the follicular phase of the menstrual cycle. All participants were genotyped for a 5-HTT-promoter polymorphism (5-HTTLPR) to assess the influence of this polymorphism on 5-HTT parameters. Efficiency of 5-HTT-mediated inward (p=0.014) and outward (p=0.003) transport was enhanced in depressed patients. Both measures normalized toward control levels after therapy and in natural summer remission. Changes in outward transport showed a clear correlation with treatment response (ρ=0.421, p=0.001). Changes in inward transport were mediated by changes in 5-HTT transport efficiency rather than affinity or density. 5-HTTLPR was not associated with any of the 5-HTT parameters. In sum, we conclude that the 5-HTT is in a hyperfunctional state during depression in SAD and normalizes after light therapy and in natural summer remission.

The European Directive 2001/20/EC ("Clinical Trials Directive") was aimed at simplifying and harmonising European clinical research. The directive's attempt represents an important step because many European Member States lack national laws that specifically address details of research, but the goal has been only partly achieved. For academic investigators doing national or multi-national research the new European law and the requirements following its implementation are likely to have the opposite effect. Some areas seem to be of particular concern: trial sponsorship, the ethical review process, the participation of patients who are temporarily not able to consent in clinical trials, in particular the informed consent process, an accepted European registry for all clinical trials, insurance and pharmacovigilance. Furthermore there are fundamental problems of the conduct of clinical trials that could have been foreseen at the time of implementation of the new law, which are impeding academic basic clinical research. The bureaucratic burden for academic investigators has tremendously increased without representing any contribution to patients' safety or to the scientific value of research. Furthermore some large European academic trials cannot be conducted anymore due to the new regulations. This result in a reduction in the number of trials and additionally in a reduction in the number of patients enrolled in a study. European research and thus European patients will suffer from the loss of potential benefits of research. The Vienna Initiative to Save European Academic Research (VISEAR) brings together leading stakeholders from academic research groups and interested parties from industry, international organisations and regulatory authorities to focus on the issues of concern regarding the organisational and funding of academic clinical research in order to improve the development and use of medicines in Europe. The first step of the initiative was a meeting held on May 30, 2005 in Vienna. The resumés of the six parallel working groups are presented in this supplement of the Wiener Klinische Wochenschrift, a position paper with recommendations in relation to the EU Clinical Trials Directive and medical research involving incapacitated adults has been published separately.

Desmond Sheridan1Sheridan DJ Reversing the decline of academic medicine in Europe.Lancet. 2006; 367: 1698-1701Summary Full Text Full Text PDF PubMed Scopus (56) Google Scholar mentions several signs and solutions associated with academic medicine in Europe. I would like to call attention to the role of general practice in academic medicine and in medical research. During the past decade, changes in medical school curricula that put greater emphasis on early exposure to patients, clerkships with community-based clinicians,2Matthys J De Meyere M Mervielde I et al.Influence of the presence of doctors-in-training on the blood pressure of patients: a randomized controlled trial in 22 teaching practices.J Hum Hypertens. 2004; 18: 769-773Crossref PubMed Scopus (12) Google Scholar and longitudinal clinical experiences3Schroeder SA Primary care at a crossroads.Acad Med. 2003; 77: 767-773Crossref Scopus (29) Google Scholar were seen as ways to stimulate a renewed interest in primary-care practice. But is this sufficient for general practice to be an attractive academic discipline? There is growing evidence that absence of research in primary care could lead to overinvestigation of patients, inappropriate treatment, and diagnostic delay through wrong-track referral.4Mant D Del Mar C Glasziou P Knottnerus A Wallace P van Weel C The state of primary care research.Lancet. 2004; 364: 1004-1006Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar Four “evidence gaps” in primary care involve the effectiveness of interventions delivered mainly in primary care, the applicability of hospital-based research to primary care, the implementation of best evidence in primary-care practice, and the basic science of illness and its care in the community.4Mant D Del Mar C Glasziou P Knottnerus A Wallace P van Weel C The state of primary care research.Lancet. 2004; 364: 1004-1006Summary Full Text Full Text PDF PubMed Scopus (74) Google Scholar Despite changes in the health-care system and in education, students and residents encounter an atmosphere that is still chilly towards primary care. There has been further growth in specialisation, with differences in income and status between specialists and generalists.3Schroeder SA Primary care at a crossroads.Acad Med. 2003; 77: 767-773Crossref Scopus (29) Google Scholar There is a funding bias towards basic research and against clinical research.1Sheridan DJ Reversing the decline of academic medicine in Europe.Lancet. 2006; 367: 1698-1701Summary Full Text Full Text PDF PubMed Scopus (56) Google Scholar Furthermore, specialised and general medical journals are sometimes reluctant to publish general practice research. From the point of view of general practice, the extent to which research can influence clinical practice and the effect academic medicine might have on patients' wellbeing—intuitively relevant aspects—are not always taken into account. This stresses the future role of academic medicine and academic medical journals.5De Maeseneer J van Driel M Green L van Weel C The need for research in primary care.Lancet. 2003; 362: 1314-1319Summary Full Text Full Text PDF PubMed Scopus (151) Google Scholar I declare that I have no conflict of interest.

The physiological function of neurotransmitter transporter proteins like the serotonin transporter (SERT) is reuptake of neurotransmitter that terminates synaptic serotoninergic transmission. SERT can operate in reverse direction and be induced by SERT substrates including 5-HT, tyramine and the positively charged methyl-phenylpyridinium (MPP+), as well as the amphetamine derivatives para-chloroamphetamine (pCA) and methylene-dioxy-methamphetamine (MDMA). These substrates also induce inwardly directed sodium currents that are predominantly carried by sodium ions. Efflux via SERT depends on this sodium flux that is believed to be a prerequisite for outward transport. However, in recent studies, it has been suggested that substrates may be distinct in their properties to induce efflux. Therefore, the aim of the present study was a pharmacological characterization of different SERT substrates in uptake experiments, their abilities to induce transporter-mediated efflux and currents. In conclusion, the rank order of affinities in uptake and electrophysiological experiments correlate well, while the potencies of the amphetamine derivatives for the induction of efflux are clearly higher than those of the other substrates. These discrepancies can be only explained by mechanisms that can be induced by amphetamines. Therefore, based on our pharmacological observations, we conclude that amphetamines distinctly differ from non-amphetamine SERT substrates.

Despite numerous placebo-controlled clinical trials with antidepressants were conducted in humans and a large amount of data was already published in the last two decades, the members of the 4th European Expert Forum on Ethical Evaluation of Placebo-Controlled Studies in Depression were agreed that placebo-controlled trials with antidepressants also in the future are essential. Placebo-controlled studies measure the effect size in a reliable way and establish sensitivity and internal validity. They are scientifically sound and interpretable in terms of efficacy and are, therefore, clinically more relevant than non-placebo-controlled clinical trials. The "Note of Clarification" of the Declaration of Helsinki opens up where such trials are acceptable. This statement of the members of the 4th European Expert Forum is directed to academia, members of Ethic Committees, regulators, and industry to facilitate their decisions towards clinical studies with antidepressants. "Checklists" for the contents of patients information are given as well as for the investigator.Placebo-controlled clinical trials are scientifically necessary, ethical and feasible. The administration of the placebo is in itself a non-specific treatment and experts agree that there appears to be no increased suicidal risk in the placebo-group of carefully selected and monitored study patients.

The use of placebo in clinical trials has been repeatedly challenged as being unacceptable from an ethical point of view. The present paper responds to this criticism by taking up the issue in the light of the pertinent provisions of the Helsinki Declaration. Examples from different therapeutic areas are given that highlight the importance of placebo in situations in which its use is acceptable according to the Declaration. Particular emphasis is given to the question of active control trials, which, under conditions of low assay sensitivity, may become an ethically less acceptable approach than the use of a placebo control.

EDITOR—The merits of transparency of clinical research from the ethics point of view are not to be disputed. The request of the International Committee of Medical Editors for a publicly accessible registry seems exaggerated in its present form, and we agree with Abbasi's points.1 2 …

Today's clinical trials lead to the therapies of tomorrow; without these we would have no safe and efficient treatments.Conducting clinical trials involves adherence to a number of strict rules (established in the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use," E6), including the obligation to obtain informed consent from each participating individual.However, obviously there are several groups of patients who are not able to give consent.The European Directive 2001120/EC of 4 April2001 states that these subjects can be included in a clinical trial only if informed consent of the patient's legal representative can be obtained.This is especially relevant for patients in intensive or emergency care medicine.It is obvious that a legal representative cannot be produced or consulted in these patient groups.However, no proven diagnostic or therapeutic measures can be developed for these patients without clinical trials.Instead of setting up rules to protect these vulnerable patients and their special needs the Directive does the opposite: the law prohibits research, hinders therapeutic progress, and thereby violates the Helsinki Declaration (provision 6: " ... even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research ... ").With regard to Austria the EU Directive is the cherry on top of another irritating legislation.The Austrian Medical Device Act (Medizinproduktegesetz BGBl, 1997/21, Austrian Law on Medical Devices) states that clinical trials with medical devices can be performed only if the patient has given informed consent.There are no provisions for exceptions [1].This prevents any research being carried out in Austria that involves medical devices for emergency conditions or in the intensive care setting.It is truly disappointing that European legislation extends this unique Austrian peculiarity to drug research, neglecting values of solidarity.It is a very

1. Bi-directional GABA-transport was studied by performing uptake and superfusion experiments in human embryonic kidney 293 cells stably expressing the rat GABA transporter rGAT-1. 2. K(M) and V(max) values for [(3)H]-GABA uptake were 11.7+/-1.8 microM and 403+/-55 pmol min(-1) 10(-6) cells (n=9), respectively. 3. Kinetic analysis of outward transport was performed by pre-labelling the cells with increasing concentrations of [(3)H]-GABA and triggering outward transport with 333 microM GABA. Approximate apparent K(M) and V(max) values were 12 mM and 50 pmol min(-1) 10(-6) cells, respectively. 4. GABA re-uptake inhibitors (RI; e.g. tiagabine), as well as, substrates of the rGAT-1 (e.g. GABA, nipecotic acid) concentration dependently decreased [(3)H]-GABA uptake and increased efflux of [(3)H]-GABA from pre-labelled cells. The IC(50) values for inhibiting uptake and the EC(50) values for increasing efflux were significantly correlated (r(2)=0.99). 5. On superfusion, RI antagonized the efflux-enhancing effect of the substrates. The effect of the latter was markedly augmented in the presence of ouabain (100 microM), whereas the effect of RI remained unchanged. The most likely explanation for the release enhancing effect of RI is interruption of ongoing re-uptake. 6. The structural GABA-analogue 2,4-diamino-n-butyric acid (DABA) exhibited a bell-shaped concentration response curve on [(3)H]-GABA efflux with the maximum at 1 mM, and displayed a deviation from the sigmoidal inhibition curve in uptake experiments in the same concentration range. At concentrations below 1 mM, DABA inhibited [(3)H]-GABA uptake non-competitively, while at 1 mM and above the inhibition of uptake followed a competitive manner. 7. The results provide information of GABA inward and outward transport, and document a complex interaction of the rGAT-1 with its substrate DABA.

The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). Upon binding to this site, Zn2+ causes inhibition of [3H]1-methyl-4-phenylpyridinium ([3H]MPP+) uptake. We investigated the effect of Zn2+ on outward transport by superfusing hDAT-expressing HEK-293 cells preloaded with [3H]MPP+. Although Zn2+ inhibited uptake, Zn2+facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET). Mutation of the Zn2+coordinating residue His193 to Lys (the corresponding residue in hNET) eliminated the effect of Zn2+ on efflux. Conversely, the reciprocal mutation (K189H) conferred Zn2+sensitivity to hNET. The intracellular [3H]MPP+ concentration was varied to generate saturation isotherms; these showed that Zn2+ increasedVmax for efflux (rather than KM-Efflux-intracellular). Thus, blockage of inward transport by Zn2+ is not due to a simple inhibition of the transporter turnover rate. The observations provide evidence against the model of facilitated exchange-diffusion and support the concept that inward and outward transport represent discrete operational modes of the transporter. In addition, they indicate a physiological role of Zn2+, because Zn2+ also facilitated transport reversal of DAT in rat striatal slices.