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Gene therapy orphan medicinal products constitute a unique group of new drugs which in case of hereditary diseases are usually administered only once at an early age, in the hope to provide sufficient gene product to last for the entire life of the patients. The combination of an exceptionally large single payment and the life-long clinical follow-up needed for understanding the long-term benefits and safety of gene therapy, represent new types of scientific, financial, social and ethical challenges for the pharmaceutical industry, regulators and society. With special consideration of the uniqueness and importance of gene therapy, the authors propose a three points plan for a close cooperation between the pharmaceutical industry and society to develop orphan gene therapy. (1) In fully transparent health technology negotiations a close and long-lasting, contractually fixed cooperation should be established between the manufacturers and local health-care stakeholders for sharing the medical and scientific benefits, the financial risks as well as the burdens of the post-authorization clinical and regulatory development. (2) The parties should agree on a fair, locally affordable drug price without the usually very high premium price calculated to compensate for the low number of patients. In case of high manufacturing costs, the companies should offer prolonged, 15–20 years long payment by installment with risk-sharing, especially considering that the late outcome of the treatment is unknown. Society should assist scientifically and financially organizing a specific patient registry, treatment in specialized hospitals and adequate long-term follow-up of patients, the coordinated management of financial transactions related to the risk sharing program. (3) The post-authorization treatment and prolonged observation of additional new cases coordinated by society should provide real world data needed for the modern complex regulatory evaluation of gene therapy products by the competent authorities. We assume that fair sharing of the benefits and risks as well as a well-organized cooperation of society with the industry in collecting real world evidence might result in better drug evaluation and improved accessibility due to lower prices. The outlined concept might support gene therapy more efficiently than the presently requested outstandingly high prices.

BACKGROUND A clinical research application must be submitted for approval by a competent ethics committee (EC) before a study can be executed. There is very limited information on how such submissions could be optimised, especially regarding research in children and adolescents, which requires particular caution and age-adapted patient information. METHODS We assessed all research applications from the University Children’s Hospital Zurich submitted to the EC of the Canton of Zurich in 2014–2015, i.e., in the first two years after Switzerland’s new Human Research Act came into effect. Moreover, we validated our findings by assessing a randomly selected sample of applications from the same hospital in 2018–2019. RESULTS We assessed a total of 86 applications from 2014–2015, originating from 29 departments and sub-specialties. The EC judged that it was not responsible for three applications and declined an assessment for another three because the studies had already been conducted. Thus, we included 80 applications in the present analysis (18 clinical trials, 52 research projects, 10 further use projects). Applicants withdrew four applications before the EC’s final decision and the EC rejected two after assessment. The EC had objections in 46 (62%) of the remaining 74 applications. Formal, including formal legal, objections (n = 503) and legal objections (n = 287) accounted for the vast majority of objections. There were also 71 ethical and 82 scientific objections. The most frequent formal and formal legal objections were incomplete or missing age-adapted patient information (49%) and incorrect templates for informed consent and signature forms (46%). A review of the 20 randomly selected applications from 2018–2019 confirmed that four out of the five most frequent deficiencies relating to informed consent were identical to those observed in the 2014–2015 applications. CONCLUSIONS Careful preparation of submission documents by the investigators and close adherence to formal and legal requirements have the potential to considerably optimise and expedite the EC review process, and thus the commencement of the clinical research. Keywords: age-adapted patient information, formal deficiencies, legal deficiencies, ethical deficiencies, scientific deficiencies

Composite endpoints are commonly used in randomised controlled clinical trials because they offer potential advantages, such as smaller sample sizes, shorter completion times and the summary measure for a treatment effect if more than one outcome is important. However, they are also associated with risks and pitfalls, particularly if basic clinical and statistical requirements are not adequately respected. This article focuses on time-to-event composite endpoints that combine fatal and nonfatal events and aim to demonstrate efficacy of a treatment in long-term trials. The most important issues with the selection of individual endpoint components — the trial conduct, data analysis, interpretation and reporting — are discussed. Composite endpoints should be clinically meaningful and the expected effects on each component should be similar, based on biological plausibility. Surrogates as endpoint components must have been validated, i.e. a correlation to a hard clinical outcome must have been confirmed. Patients need to be followed up on assigned treatment (clinical status permitting) until death or end of planned follow-up in the absence of events, and must not be regarded as ‘a trial completer’ after occurrence of the first component event. Difficulties in interpretation arise when the results on single components of the composite endpoint go in opposite directions, and when hard clinical outcomes are combined with soft endpoints, particularly if the latter occur much more frequently but are of inferior relevance. Accordingly, all individual components of the composite need to be analysed separately. In this review, several examples from recently published trials are used to illustrate both the principal needs and the inherent problems of using a composite endpoint. More specific regulatory guidelines and better reporting standards are needed. The ultimate goals of a trial with a composite endpoint should be to solve a medical problem and to support clinical decision making, rather than just to provide statistical convenience.

Es kann davon ausgegangen werden, dass 30 bis50% aller publizierten klinischen Studien Inkonsistenzen zwischen Studienplanung und Ergebnisprasentation aufweisen. Was wurde dagegen unternommen, wo sind Schwachstellen bisheriger Massnahmen, welche zukunftigen Optionen stehen zur Diskussion? Kurz vor Redaktionsschluss gab es noch eine positive Entwicklung, die am Ende des Beitrags noch kurz vorgestellt wird.

Die Europaische Kommission hat einen Vorschlag zur Neuregulierung der klinischen Arzneimittelforschung vorgelegt, der vor allem in Deutschland auf scharfe Kritik stosst. Auch der Gesundheitsausschuss des Bundestags hat sich gegen das Vorhaben ausgesprochen. hier die Grunde und ein Vergleich mit der Schweiz.

Biomarkers are becoming increasingly important in the process of development of new drugs. However, as they are often not able to reflect the actual clinical value and safety of a drug, their role in the framework of the licensing of drugs is limited. For the health authorities, proof of a positive benefit/risk ratio based on hard clinical end points is generally the decisive factor. Only in very few indications do validated surrogate end points exist that show a high predictive value for a relevant clinical end point – the granting of marketing authorization on the basis of a surrogate end point alone is therefore the exception. In principle, this is also true for drugs for the treatment of serious, life-threatening diseases, as the present accelerated approval procedures for the granting of a license on the basis of provisional data and without direct proof of a clinical benefit are used by the authorities only in isolated cases. Only if new biomarkers can be validated as surrogate end points for hard clinical end points can their value for the licensing of new drugs increase in the future.

Das Phanomen der Regression zum Mittelwert kommt in vielen Bereichen des praktischen Lebens vor und kann uns in die Irre leiten.

Within the framework of evidence-based medicine, meta-analyses represent a methodological tool to consolidate the state of knowledge on particular medical questions. However, meta-analyses per se already raise some fundamental problems. If quality criteria are not taken into account in the setting up of meta-analyses, this can result in methodological bias, so that in the final analysis, the intervention efficacy can be clearly underestimated or overestimated. Unfortunately, despite the existence of guidelines for their preparation, many published meta-analyses show considerable shortcomings as far as the methodology is concerned, and their value for the drawing up of diagnostic or therapeutic guidelines therefore has to be considered as questionable. Only a limited number of collaborative groups, for example the Cochrane Collaboration, set up meta-analyses with a high level of methodology. While their systematic reviews are to be recommended, the large number of published meta-analyses have to be viewed with scepticism, since often their results and conclusions cannot be comprehended objectively. In those areas of medicine where data and evidence are scanty, even meta-analyses cannot work wonders, because the value of a meta-analysis depends entirely on the value of the individual studies. Therefore, randomised, controlled studies will in future continue to play the decisive role in finding answers to the existing medical questions – and meta-analyses can help to formulate the right questions.

The use of a combined (composite) endpoint as a primary outcome in clinical studies offers many advantages, e.g., increased statistical efficiency, smaller sample sizes, shorter study completion times, and the possibility for a summary measure of different treatment effects. However, basic clinical and statistical requirements need to be respected in order to obtain valid results and to avoid difficulties in their interpretation later. Each component of a combined endpoint must be clinically meaningful. Patients must be followed up until death or to the planned end of the trial; these rules also apply to premature treatment withdrawal or after occurrence of the first pre-defined component event. All components of the composite endpoint need to be analysed separately in order to find out how they contribute to the overall result and to avoid the masking of negative effects on one or more components. Difficulties in interpretation may arise when the results for single components of the combined endpoint head in opposite directions, and when "hard" clinical outcomes are combined with "soft" endpoints, particularly if the latter occur much more frequently but are of minor clinical relevance.

Die Forderung nach konkreten Aktionen wird untermauert mit konkreten Vorschlagen, wie Massnahmen zur Qualitatssicherung und Forderung einer hochstehenden klinischen Forschung aussehen konnten. Vorbilder hierfur gibt es in der Aviatik.

Oxidative stress and endothelial dysfunction have been introduced as a unifying pathological mechanism for early atherosclerotic disease. They are caused by a variety of stimuli including cigarette smoking (environmental) and type 2 diabetes (disease factor). However, the role of hyperinsulinemia, a marker of insulin resistance, as a risk factor for atherosclerosis remains to be clarified.To study the relationship of smoking, hyperinsulinaemia and biochemical markers of oxidative stress and endothelial dysfunction, in patients with coronary artery disease.Case-control study of 5-year survivor status in smokers, former smokers and nonsmokers with angiographically documented stable coronary artery disease classified by self-reporting of smoking status together with plasma cotinine measurements.Cardiology and cardiac surgery unit of a tertiary care referral centre.Plasma levels of vitamins C, E and selenium, and the adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed in 214 patients at baseline together with the glucose and insulin response to an oral glucose challenge. Sixty known or newly diagnosed type 2 diabetic patients (28%) were identified and excluded from further analysis.E-selectin and ICAM-1, serving as markers of endothelial dysfunction, significantly correlated with hyperinsulinaemia (p0.05). Circulating immunoreactive insulin was elevated in active smokers and former smokers as compared to non-smokers after an oral glucose load (p0.05 for the area under the insulin time curve), despite a similar glucose response. Smoking was associated with a decrease in antioxidant vitamins C (p = 0.02) and E (p = 0.03), and an increase of E-selectin (p0.05) and ICAM-1 (p0.001). Low baseline ICAM-1 and high vitamin C levels emerged as the most significant multivariate predictors of 5-year survival (p0.001).Hyperinsulinaemia in smokers is linked with markers of endothelial dysfunction. Impaired vascular reactivity can thus be a new possible mechanism linking insulin resistance and smoking.

Der Autor ist Medizinischer Direktor von GlaxoSmithKline und setzt sich mit der im oben besprochenen Buch geausserten Kritik auseinander. Relativieren und dementieren ist dabei nicht sein Ansatz. Er sieht das Hauptproblem in fehlender Transparenz und findet, die Industrie tate gut daran, sich von eklatantem Fehlverhalten in ihren eigenen Reihen zu distanzieren anstatt es stillschweigend zu tolerieren.