The case for screening in early life for 'non-treatable' disorders: ethics, evidence and proportionality. A report from the Health Council of the Netherlands.

In the Netherlands, the call to add 'non-treatable' disorders to the newborn bloodspot screening programme has found a sympathetic ear with the Government. In 2019, the Health Council of the Netherlands was formally asked for advice on the conditions under which bloodspot screening for such disorders might be offered. Here we present the reasoning and the recommendations of the resulting report, and briefly discuss its reception. The report holds on to the classical view that screening must benefit the child, but argues for a wider account of child benefit than only in terms of substantial health gains. However, screening for 'non-treatable' disorders would still require evidence of a favourable benefits to harm ratio. The report presents a framework for such screening, but concludes that apart perhaps from Duchenne Muscular Dystrophy (DMD), no or only very few 'non-treatable' disorders would at present meet its criteria. Setting up a screening programme that might benefit only a small percentage of families struggling with uncertainty about their child's diagnosis would not seem proportional. Instead, the Government is advised to invest in a better infrastructure for early referral, testing and care. The reaction to the report from proponents of such screening shows that the dividing line in the debate is not about whether screening neonates for 'non-treatable' disorders is acceptable in itself. It is rather whether such screening should be regarded as catering to a parental 'right to know', or as a public health service that should be subject to standards of evidence and proportionality.

Patients' and public views and attitudes towards the sharing of health data for research: a narrative review of the empirical evidence.

INTRODUCTION: International sharing of health data opens the door to the study of the so-called 'Big Data', which holds great promise for improving patient-centred care. Failure of recent data sharing initiatives indicates an urgent need to invest in societal trust in researchers and institutions. Key to an informed understanding of such a 'social license' is identifying the views patients and the public may hold with regard to data sharing for health research. METHODS: We performed a narrative review of the empirical evidence addressing patients' and public views and attitudes towards the use of health data for research purposes. The literature databases PubMed (MEDLINE), Embase, Scopus and Google Scholar were searched in April 2019 to identify relevant publications. Patients' and public attitudes were extracted from selected references and thematically categorised. RESULTS: Twenty-seven papers were included for review, including both qualitative and quantitative studies and systematic reviews. Results suggest widespread-though conditional-support among patients and the public for data sharing for health research. Despite the fact that participants recognise actual or potential benefits of data research, they expressed concerns about breaches of confidentiality and potential abuses of the data. Studies showed agreement on the following conditions: value, privacy, risk minimisation, data security, transparency, control, information, trust, responsibility and accountability. CONCLUSIONS: Our results indicate that a social license for data-intensive health research cannot simply be presumed. To strengthen the social license, identified conditions ought to be operationalised in a governance framework that incorporates the diverse patient and public values, needs and interests.

The social licence for data-intensive health research: towards co-creation, public value and trust.

BACKGROUND: The rise of Big Data-driven health research challenges the assumed contribution of medical research to the public good, raising questions about whether the status of such research as a common good should be taken for granted, and how public trust can be preserved. Scandals arising out of sharing data during medical research have pointed out that going beyond the requirements of law may be necessary for sustaining trust in data-intensive health research. We propose building upon the use of a social licence for achieving such ethical governance. MAIN TEXT: We performed a narrative review of the social licence as presented in the biomedical literature. We used a systematic search and selection process, followed by a critical conceptual analysis. The systematic search resulted in nine publications. Our conceptual analysis aims to clarify how societal permission can be granted to health research projects which rely upon the reuse and/or linkage of health data. These activities may be morally demanding. For these types of activities, a moral legitimation, beyond the limits of law, may need to be sought in order to preserve trust. Our analysis indicates that a social licence encourages us to recognise a broad range of stakeholder interests and perspectives in data-intensive health research. This is especially true for patients contributing data. Incorporating such a practice paves the way towards an ethical governance, based upon trust. Public engagement that involves patients from the start is called for to strengthen this social licence. CONCLUSIONS: There are several merits to using the concept of social licence as a guideline for ethical governance. Firstly, it fits the novel scale of data-related risks; secondly, it focuses attention on trustworthiness; and finally, it offers co-creation as a way forward. Greater trust can be achieved in the governance of data-intensive health research by highlighting strategic dialogue with both patients contributing the data, and the public in general. This should ultimately contribute to a more ethical practice of governance.

[The value of booster vaccination against COVID-19]. / Boostervaccinatie tegen covid-19.

The first vaccines against Covid-19 were approved in December 2020 and administered in the Netherlands from the beginning of January 2021. As of November 2021, The Dutch government has started its booster programme to administer an additional vaccine dose to the population.This paper discusses the current knowledge about the duration of protection of the Covid-19 vaccines that are used in the Netherlands, and the added value of booster vaccination.

Community-Based Healthcare for Migrants and Refugees: A Scoping Literature Review of Best Practices.

BACKGROUND: Strengthening community-based healthcare is a valuable strategy to reduce health inequalities and improve the integration of migrants and refugees into local communities in the European Union. However, little is known about how to effectively develop and run community-based healthcare models for migrants and refugees. Aiming at identifying the most-promising best practices, we performed a scoping review of the international academic literature into effective community-based healthcare models and interventions for migrants and refugees as part of the Mig-HealthCare project. METHODS: A systematic search in PubMed, EMBASE, and Scopus databases was conducted in March 2018 following the PRISMA methodology. Data extraction from eligible publications included information on general study characteristics, a brief description of the intervention/model, and reported outcomes in terms of effectiveness and challenges. Subsequently, we critically assessed the available evidence per type of healthcare service according to specific criteria to establish a shortlist of the most promising best practices. RESULTS: In total, 118 academic publications were critically reviewed and categorized in the thematic areas of mental health (n = 53), general health services (n = 36), noncommunicable diseases (n = 13), primary healthcare (n = 9), and women's maternal and child health (n = 7). CONCLUSION: A set of 15 of the most-promising best practices and tools in community-based healthcare for migrants and refugees were identified that include several intervention approaches per thematic category. The elements of good communication, the linguistic barriers and the cultural differences, played crucial roles in the effective application of the interventions. The close collaboration of the various stakeholders, the local communities, the migrant/refugee communities, and the partnerships is a key element in the successful implementation of primary healthcare provision.

In-Hospital Production of Medicines: Preparing for Disruption.

In-hospital production of affordable medicines holds potential to address problems of drug accessibility. However, expanding the scope of magistral preparation to include high-cost drugs and complex biologicals gives rise to new challenges. We discuss ethical and regulatory complexities faced by Dutch initiatives defying the current pharmaceutical system through magistral preparation.

Responsible data sharing in international health research: a systematic review of principles and norms.

BACKGROUND: Large-scale linkage of international clinical datasets could lead to unique insights into disease aetiology and facilitate treatment evaluation and drug development. Hereto, multi-stakeholder consortia are currently designing several disease-specific translational research platforms to enable international health data sharing. Despite the recent adoption of the EU General Data Protection Regulation (GDPR), the procedures for how to govern responsible data sharing in such projects are not at all spelled out yet. In search of a first, basic outline of an ethical governance framework, we set out to explore relevant ethical principles and norms. METHODS: We performed a systematic review of literature and ethical guidelines for principles and norms pertaining to data sharing for international health research. RESULTS: We observed an abundance of principles and norms with considerable convergence at the aggregate level of four overarching themes: societal benefits and value; distribution of risks, benefits and burdens; respect for individuals and groups; and public trust and engagement. However, at the level of principles and norms we identified substantial variation in the phrasing and level of detail, the number and content of norms considered necessary to protect a principle, and the contextual approaches in which principles and norms are used. CONCLUSIONS: While providing some helpful leads for further work on a coherent governance framework for data sharing, the current collection of principles and norms prompts important questions about how to streamline terminology regarding de-identification and how to harmonise the identified principles and norms into a coherent governance framework that promotes data sharing while securing public trust.

Assessment of HER2 status in breast cancer biopsies is not affected by accelerated tissue processing.

AIMS: To establish whether core needle biopsy (CNB) specimens processed with an accelerated processing method with short fixation time can be used to determine accurately the human epidermal growth factor receptor 2 (HER2) status of breast cancer. METHODS AND RESULTS: A consecutive case-series from two high-volume breast clinics was created. We compared routine HER2 immunohistochemistry (IHC) assessment between accelerated processing CNB specimens and routinely processed postoperative excision specimens. Additional amplification-based testing was performed in cases with equivocal results. The formalin fixation time was less than 2 h and between 6 and 72 h, respectively. Fluorescence in-situ hybridisation and multiplex ligation-dependent probe amplification were used for amplification testing. One hundred and forty-four cases were included, 15 of which were HER2-positive on the routinely processed excision specimens. On the CNB specimens, 44 were equivocal on IHC and required an amplification-based test. Correlation between the CNB specimens and the corresponding excision specimens was high for final HER2 status, with an accuracy of 97% and a kappa of 0.85. CONCLUSIONS: HER2 status can be determined reliably on CNB specimens with accelerated processing time using standard clinical testing methods. Using this accelerated technology the minimum 6 h of formalin fixation, which current guidelines consider necessary, can be decreased safely. This allows for a complete and expedited histology-based diagnosis of breast lesions in the setting of a one-stop-shop, same-day breast clinic.

Ethics of Informed Consent for Pragmatic Trials with New Interventions.

OBJECTIVES: Pragmatic trials evaluate the comparative benefits, risks, and burdens of health care interventions in real-world conditions. Such studies are now recognized as valuable to the perimarketing stage of drug development and evaluation, with early pragmatic trials (EPTs) being explored as a means to generate real-world evidence at the time of regulatory market approval. In this article, we present an analysis of the ethical issues involved in informed consent for EPTs, in light of the generally recognized concern that traditional ethical rules governing randomized clinical trials, such as lengthy informed consent procedures, could threaten the "real world" nature of such trials. Specifically, we examine to what extent modifications (waivers or alterations) to regulatory consent for EPTs would be ethical. METHODS: We first identify broadly accepted necessary conditions for modifications of informed consent (namely, the research involves no more than minimal risk of harm, the research is impracticable with regulatory consent, and the alternative to regulatory consent does not violate legitimate patient expectations) and then apply those criteria to the premarket and early postmarket contexts. RESULTS AND CONCLUSIONS: The analysis shows that neither waivers nor alterations of regulatory consent for premarket EPTs will be ethically permissible. For postmarket EPTs with newly approved interventions, waivers of consent will be ethically problematic, but some studies might be conducted in an ethical manner with alterations to regulatory consent.

Series: Pragmatic trials and real world evidence: Paper 3. Patient selection challenges and consequences.

This paper addresses challenges of identifying, enrolling, and retaining participants in a trial conducted within a routine care setting. All patients who are potential candidates for the treatments in routine clinical practice should be considered eligible for a pragmatic trial. To ensure generalizability, the recruited sample should have a similar distribution of the treatment effect modifiers as the target population. In practice, this can be best achieved by including-within the selected sites-all patients without further selection. If relevant heterogeneity between subgroups is expected, increasing the relative proportion of the subgroup of patients in the heterogeneous trial could be considered (oversampling) or a separate trial in this subgroup can be planned. Selection will nevertheless occur. Low enrollment and loss to follow-up can introduce selection and can jeopardize validity as well as generalizability. Pragmatic trials are conducted in clinical practice rather than in a dedicated research setting, which could reduce recruitment rates. However, if a trial poses a minimal burden to the physician and the patient and routine clinical practice is maximally adhered to, the participation rate may be high and loss to follow-up will not be a specific problem for pragmatic trials.

Series: Pragmatic trials and real world evidence: Paper 4. Informed consent.

The GetReal consortium of the Innovative Medicines Initiative aims to develop strategies to incorporate real-world evidence earlier into the drug life cycle to better inform health care decision makers on the comparative risks and benefits of new drugs. Pragmatic trials are currently explored as a means to generate such evidence in routine care settings. The traditional informed consent model for randomized clinical trials has been argued to pose substantial hurdles to the practicability of pragmatic trials: it would lead to recruitment difficulties, reduced generalizability of the results, and selection bias. The present article analyzes these challenges and discusses four proposed alternative informed consent models: integrated consent, targeted consent, broadcast consent, and a waiver of consent. These alternative consent models each aim at overcoming operational and methodological challenges, while still providing patients all the relevant information they need to make informed decisions. Each consent model, however, relies on different attitudes toward the principle of respect for persons and the related duty to inform patients as well as represents different views on whether the common good demands moral duties from patients. Such normative consequences of modifying consent requirements should be at least acknowledged and ought to be assessed in light of the validity of empirical claims.

The Social Value of Pragmatic Trials.

Pragmatic trials aim to directly inform health care decision-making through the collection of so-called 'real world data' from observations of comparative treatment effects in clinical practice. In order to ensure the applicability and feasibility of a pragmatic trial, design features may be necessary that deviate from standard research ethics requirements. Examples are traditional requirements to seek written informed consent and to perform extensive data and safety monitoring. Proposals for deviations from standard research ethics practice have resulted in controversy about their ethical acceptability. One of the justifications for altered procedures is the allegedly high social value of pragmatic trials. In order to properly operationalize the concept in the ethical assessment of pragmatic trial designs, specification is warranted. We identified three determinants from common claims about a pragmatic trial's social value: (1) the extent to which the research question has real world relevance, (2) the trial design's ability to generate a real world answer and (3) the probability of direct uptake of the results by decision-makers in practice. Subsequently, we discuss how these determinants should be applied to the practice of pragmatic trials, and to what extent they might be applicable to explanatory trials.

Stakeholders' views on the ethical challenges of pragmatic trials investigating pharmaceutical drugs.

BACKGROUND: We explored the views of key stakeholders to identify the ethical challenges of pragmatic trials investigating pharmaceutical drugs. A secondary aim was to capture stakeholders' attitudes towards the implementation of pragmatic trials in the drug development process. METHODS: We conducted semistructured, in-depth interviews among individuals from different key stakeholder groups (academia and independent research institutions, the pharmaceutical industry, regulators, Health Technology Assessment (HTA) agencies and patients' organizations) through telephone or face-to-face sessions. Interviews were structured around the question "what challenges were experienced or perceived during the design, conduct and/or review of pragmatic trials." Respondents were additionally asked about their views on implementation of pragmatic trials in the drug development process. Thematic analysis was used to identify the ethically relevant features across data sets. RESULTS: We interviewed 34 stakeholders in 25 individual sessions and four group sessions. The four perceived challenges of ethical relevance were: (1) less controlled conditions creating safety concerns, (2) comparison with usual care potentially compromising clinical equipoise, (3) tailored or waivers of informed consent affecting patient autonomy, and (4) minimal interference with "real-world" practice reducing the knowledge value of trial results. CONCLUSIONS: We identified stakeholder concerns regarding risk assessment, use of suboptimal usual care as a comparator, tailoring of informed consent procedures and ensuring the social value of pragmatic trials. These concerns increased when respondents were asked about pragmatic trials conducted before market authorization.

Survival after Perioperative Cardiopulmonary Resuscitation: Providing an Evidence Base for Ethical Management of Do-not-resuscitate Orders.

Automatic suspension of do-not-resuscitate (DNR) orders during general anesthesia does not sufficiently address a patient's right to self-determination and is a practice still observed among anesthesiologists today. To provide an evidence base for ethical management of DNR orders during anesthesia and surgery, the authors performed a systematic review of the literature to quantify the survival after perioperative cardiopulmonary resuscitation (CPR). Results show that the probability of surviving perioperative CPR ranged from 32.0 to 55.7% when measured within the first 24 h after arrest with a neurologically favorable outcome expectancy between 45.3 and 66.8% at follow-up, which suggests a viable survival of approximately 25%. Because CPR generally proves successful in less than 15% of out-of-hospital cardiac arrests, the altered outcome probabilities that the conditions in the operating room bring on warrant reevaluation of DNR orders during the perioperative period. By preoperatively communicating the evidence to patients, they can make better informed decisions while reducing the level of moral distress that anesthesiologists may experience when certain patients decide to retain their DNR orders.

Pragmatic randomized trials in drug development pose new ethical questions: a systematic review.

Implementation of pragmatic design elements in drug development could bridge the evidence gap that currently exists between the knowledge we have regarding the efficacy of a drug versus its true, comparative effectiveness in real life. We performed a review of the literature to identify the ethical challenges thus far related to pragmatic trials. The three central ethical questions identified for pragmatic trials are: (i) what level of oversight should pragmatic trials require; (ii) do randomized patients face additional risks; and (iii) is a waiver of informed consent ethically defensible? Despite the fact all reviewed publications dealt with post-launch pragmatic trials, these results could serve as an important starting point for conceptualizing which challenges could potentially arise in the pre-launch setting.