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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

The issue of contraception and pregnancy tests among minor adolescent women participating in clinical trials, whether healthy or suffering from a disease, represents a challenging issue for paediatricians and researchers, given the potential harmful effect of various therapeutic procedures being tested. First, they need to gauge at what age or developmental stage they need to impose pregnancy tests and contraception. Second, if the adolescent denies any sexual activity, it may be ethically questionable to impose such procedures. Third, these professionals must deal with the issue of confidentiality, taking into account the fact that some adolescents engage in penetrative sexual intercourse without their parents or caregivers knowing. Fourth, in such cases, they must assess the extent to which a minor adolescent can be considered as competent (capable of making autonomous decisions) and deserves privacy and confidentiality. There is indeed a legal obligation for the provider to check that sexual experiences and intercourse take place within a safe relationship. Fifth, if the prescription of contraception is warranted, they have to decide who should assist the adolescent in choosing the method. Finally, with the occurrence of a positive pregnancy test, they may face the rare instance of a competent minor adolescent who refuses to inform her parents. This article has been developed by a group of experts under the auspices of swissethics, the Swiss Association of Research Ethics Committees and SwissPedNet, the umbrella organisation that coordinates the paediatric research in Switzerland. The paper reviews how to address practical and ethical questions regarding minor adolescents of childbearing potential enrolled in a clinical trial that may involve teratogenic medication and offers a series of concrete advice and tools for dealing with problematic situations. Most paediatric protocols stipulate that adolescents included in clinical trials involving potentially teratogenic drugs should undergo pregnancy tests and use contraception. The circumstances in which such requirements are undertaken, however, has not been sufficiently addressed. The recommendations presented in this article will assist researchers in assessing which circumstances apply when considering minor adolescents as individuals with childbearing potentials. It also offers concrete suggestions for tackling such situations.

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.

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.

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.