Registries or non-pharmacological observational studies? An operational attempt to draw the line and to provide some suggestions for the ethical evaluation of rare disease registries.

Originally established to evaluate the ethical aspects of clinical trials, Ethics Committees (ECs) are now requested to review different types of projects, including, among others, observational studies and disease registries. In Italy, clinical trials on medicinal products for human use and on medical devices are regulated by EU Regulation 536/2014, EU Regulation 2017/745, and 2017/746 while pharmacological observational studies are regulated by the Italian Medicines Agency guidelines of 2008 and by Ministerial Decree of November 30th, 2021. The other types of studies are not strictly regulated, causing discrepancies in their definition and assessment by the ECs, and slowdowns in the start of projects. The present contribution aims to propose definitions and distinctions between non-pharmacological observational studies and disease registries, which constitute different entities but are often assimilated by ECs, and to formulate suggestions for the evaluation of rare disease registries, which are an expanding research area of interest.

Ethical Problems of Observational Studies and Big Data Compared to Randomized Trials.

The temptation to use prospective observational studies (POS) instead of conducting difficult trials (RCTs) has always existed, but with the advent of powerful computers and large databases, it can become almost irresistible. We examine the potential consequences, were this to occur, by comparing two hypothetical studies of a new treatment: one RCT, and one POS. The POS inevitably submits more patients to inferior research methodology. In RCTs, patients are clearly informed of the research context, and 1:1 randomized allocation between experimental and validated treatment balances risks for each patient. In POS, for each patient, the risks of receiving inferior treatment are impossible to estimate. The research context and the uncertainty are down-played, and patients and clinicians are at risk of becoming passive research subjects in studies performed from an outsider's view, which potentially has extraneous objectives, and is conducted without their explicit, autonomous, and voluntary involvement and consent.

I. THE ROLE OF RESEARCH ETHICS COMMITTEES IN OBSERVATIONAL STUDIES: EPIDEMIOLOGICAL REGISTRIES, CASE REPORTS, INTERVIEWS, AND RETROSPECTIVE STUDIES.

It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

[Use of Electronic Medical Records for Research: New Ethical Challenges and Possible Solutions]. / Uso dos Registos Clínicos Eletrónicos para Investigação: Novos Desafios Éticos e Soluções Possíveis.

Some clinicians feel that Ethics Committees act as a blockade to observational clinical studies. In the case of retrospective studies some have tried to solve this problem by reducing this sensitive data to simple administrative data in the hands of the government. Others see the new European General Data Protection Regulation 2016/679 (European Union) as being more liberal than the Portuguese Law nº 21/2014, April 16th (Clinical Research Law). Both solutions presume participant consent from his / her silence, even if nobody truly tried to specifically inform him / her. Such views do collide with the guarantees of protection of patient's ethical rights. In this article we propose an ethical alternative to those positions.

Alguns investigadores entendem que as Comissões de Ética para a Saúde são um bloqueio aos estudos clínicos observacionais. No que toca aos estudos retrospetivos há quem proponha resolver este problema tratando os Dados Pessoais de Saúde como dados administrativos simples na posse do Estado e há quem interprete o novo Regulamento Geral de Proteção de Dados (União Europeia) 2016/679 de forma menos garantista que a Lei nº 21/2014, de 16 de abril (sobre a Investigação Clínica), resultando em ambos os casos na presunção que o silêncio do participante constitui consentimento, mesmo se ninguém tentar sequer informá-lo do novo usodos seus dados. Estas soluções colidem com garantias éticas de proteção dos direitos dos doentes. Propomos uma alternativa ética a estas propostas.

Huge variation in obtaining ethical permission for a non-interventional observational study in Europe.

BACKGROUND: Ethical approval (EA) must be obtained before medical research can start. We describe the differences in EA for an pseudonymous, non-interventional, observational European study. METHODS: Sixteen European national coordinators (NCs) of the international study on very old intensive care patients answered an online questionnaire concerning their experience getting EA. RESULTS: N = 8/16 of the NCs could apply at one single national ethical committee (EC), while the others had to apply to various regional ECs and/or individual hospital institutional research boards (IRBs). The time between applying for EA and the first decision varied between 7 days and 300 days. In 9/16 informed consent from the patient was not deemed necessary; in 7/16 informed consent was required from the patient or relatives. The upload of coded data to a central database required additional information in 14/16. In 4/16 the NCs had to ask separate approval to keep a subject identification code list to de-pseudonymize the patients if questions would occur. Only 2/16 of the NCs agreed that informed consent was necessary for this observational study. Overall, 6/16 of the NCs were satisfied with the entire process and 8/16 were (very) unsatisfied. 11/16 would welcome a European central EC that would judge observational studies for all European countries. DISCUSSION: Variations in the process and prolonged time needed to get EA for observational studies hampers inclusion of patients in some European countries. This might have a negative influence on the external validity. Further harmonization of ethical approval process across Europe is welcomed for low-risk observational studies. CONCLUSION: Getting ethical approval for low-risk, non-interventional, observational studies varies enormously across European countries.

I. The role of research ethics committees in observational studies: epidemiological registries, case reports, interviews, and retrospective studies

Abstract It is often unclear to the clinical investigator whether observational studies should be submitted to a research ethics committee (REC), mostly because, in general, no active or additional interventions are performed. Moreover, obtaining an informed consent under these circumstances may be challenging, either because these are very large epidemiological registries, or the subject may no longer be alive, is too ill to consent, or is impossible to contact after being discharged. Although observational studies do not involve interventions, they entail ethical concerns, including threats such as breaches in confidentiality and autonomy, and respect for basic rights of the research subjects according to the good clinical practices. In this context, in addition to their main function as evaluators from an ethical, methodological, and regulatory point of view, the RECs serve as mediators between the research subjects, looking after their basic rights, and the investigator or institution, safeguarding them from both legal and unethical perils that the investigation could engage, by ensuring that all procedures are performed following the international standards of care for research. The aim of this manuscript is to provide information on each type of study and its risks, along with actions to prevent such risks, and the function of RECs in each type of study.

Métodos estadísticos alternativos y su aplicación a la investigación en Cuidados Intensivos / Alternative statistical methods and their application to research in intensive care setting

En los estudios de casos y controles anidados, el muestreo de los controles se hace habitualmente por densidad de incidencia y mediante emparejamiento. Con respecto a los casos control clásicos, son más eficientes, permiten el cálculo de la incidencia de la enfermedad y cuentan con más validez interna por la menor presencia de sesgo. Las técnicas de riesgos competitivos pueden usarse si se estudian diferentes tipos de eventos y nos centramos en el tiempo y el tipo del primer evento. El particionamiento recursivo es un tipo de análisis multivariante cuyo propósito es la construcción de algoritmos de clasificación, especialmente útiles cuando hay un gran número de variables predictoras con relaciones complejas con el evento objeto de estudio

In nested case-control studies, sampling of controls is usually done by density of incidence and pairing. With regard to the classic control cases studies, nested ones are more efficient, allow the calculation of the incidence of the disease and they have more internal validity due to the lower presence of bias. Competitive risks techniques can be used if we study different types of events and focus on the time and type of the first event. Recursive partitioning is a type of multivariate analysis whose purpose is the construction of classification algorithms, and it is especially useful when there are a large number of predictive variables with complex relationships with the event

Observational health research in Europe: understanding the General Data Protection Regulation and underlying debate.

Insights into the incidence and survival of cancer, the influence of lifestyle and environmental factors and the interaction of treatment regimens with outcomes are hugely dependent on observational research, patient data derived from the healthcare system and from volunteers participating in cohort studies, often non-selective. Since 25th May 2018, the European General Data Protection Regulation (GDPR) applies to such data. The GDPR focusses on more individual control for data subjects of 'their' data. Yet, the GDPR was preceded by a long debate. The research community participated actively in that debate, and as a result, the GDPR has research exemptions as well. Some of those apply directly; other exemptions need to be implemented into national law. Those exemptions will be discussed together with a general outline of the GDPR. I propose a substantive definition of research-absent in the GDPR-which can warrant its special status in the GDPR. The debate is not over yet. Most legal texts exhibit ambiguity and are interpreted against a background of values. In this case, those could be subsumed under informational self-determination versus solidarity and the deeper meaning of autonomy. Values will also guide national implementation and their interpretation. The value of individual control or informational self-determination should be balanced by nuanced visions about our mutual dependency in healthcare, as an ever-learning system, especially in the European solidarity-based healthcare systems. Good research governance might be a way forward to escape the consent or anonymise dichotomy.

Alternative statistical methods and their application to research in intensive care setting. / Métodos estadísticos alternativos y su aplicación a la investigación en Cuidados Intensivos.

In nested case-control studies, sampling of controls is usually done by density of incidence and pairing. With regard to the classic control cases studies, nested ones are more efficient, allow the calculation of the incidence of the disease and they have more internal validity due to the lower presence of bias. Competitive risks techniques can be used if we study different types of events and focus on the time and type of the first event. Recursive partitioning is a type of multivariate analysis whose purpose is the construction of classification algorithms, and it is especially useful when there are a large number of predictive variables with complex relationships with the event.

Bridge the gap: The need for harmonized regulatory and ethical standards for postmarketing observational studies.

Drug safety issues do not respect national borders. Hence, addressing a safety question may necessitate globally coordinated efforts between regulatory authorities and market authorization holders (MAHs) to draw reliable conclusions. Regulatory authorities have shared responsibility with MAHs sponsoring postmarketing nonintervention studies in determining study goals and design. Their shared accountabilities include what will be investigated and how the data will be retrieved to ensure appropriate study quality required for regulatory decision making. The need for a harmonized framework and ethical standards for postmarketing observational studies is well recognized but has been lacking even among the United States, European Union, and Japan, which are so-called International Conference on Harmonisation (ICH) regions. A recent update of the Council for International Organizations of Medical Sciences International Ethical Guidelines for Health-Related Research Involving Humans provides further clarification on provisions for informed consent and the role of research ethics committees. However, without incorporation into legislative structures, the future impact of these guidelines is uncertain. This lack of harmonization leads to a complex and uncertain framework for ethical review and for participant informed consent, resulting in numerous inefficiencies in the regulatory postmarketing observational studies. The regulatory frameworks for postmarketing observational studies conducted under the auspices of regulatory agencies in the 3 regions are reviewed, with a focus on ethical requirements and opportunities for efficiencies.

Using observation to collect data in emergency research.

Research questions require specific data collection techniques to appropriately explore and understand the phenomena of interest. Observation as a term features commonly in the literature as a way to describe both the design of a study and methods deployed within procedures. Observation as a data collection method is a mode of inquiry to systematically collect information about different settings and groups. However, the objective of observation in data collection is to better understand the phenomena of interest situated in context. Specifically, observation data collection can improve understanding of practice, processes, knowledge, beliefs, and attitudes embedded in clinical work and social interactions. This pragmatic paper will assist emergency nurses and other clinicians to understand how observation can be used as a data collection method within clinical practice.

Some reflections on evaluating institutional review board effectiveness.

Most commentators agree that it is important to conduct empirical research on the effectiveness of institutional review board (IRB) review and oversight but the studies that have been published so far do not directly address this question because they do not attempt to measure the impact of the IRB on the welfare or rights of human subjects. Additional studies on IRB composition, staffing, review times, consistency, and so forth will not yield that evidence that is needed to measure IRB effectiveness if they do not also collect data on the welfare and rights of human research subjects. Researchers should consider developing studies, such as randomized, controlled trials, or prospective, cohort designs, which directly measure IRB effectiveness. Such studies could yield information that will be invaluable in improving IRB review and oversight and protecting human research subjects.

Adaptación y validación al español del cuestionario Aid to Capacity Evaluation (ACE), para la valoración de la capacidad del paciente en la toma de decisiones médicas / The adaptation and validation to Spanish of the questionnaire Aid to capacity evaluation (ACE), for the assessment of the ability of patients in medical decision-making

OBJETIVO: Adaptar al español y validar la escala Aid to Capacity Evaluation, diseñada para evaluar la capacidad del adulto para la toma de decisiones médicas, tanto en procesos de diagnóstico como de tratamiento para su enfermedad. DISEÑO: Observacional de validación prospectiva. Emplazamiento: Atención primaria y hospitalaria de la Zona Básica de Salud de Jaén. PARTICIPANTES: Ciento veintinueve pacientes. MEDICIONES PRINCIPALES: Cuestionario que incluía variables sociodemográficas, variables relativas a la decisión (ámbito, tipo de decisión, necesidad de consentimiento informado escrito), valoración de la capacidad con la escala Aid to Capacity Evaluation y otras relativas a la comorbilidad (hipoacusia, alcoholismo, nivel cognitivo con el Mini-Examen Cognoscitivo, y depresión mediante el test Goldberg o el Yesavage). RESULTADOS: La herramienta se considera viable. Las conclusiones del panel de expertos fueron favorables. El resultado de la validez de criterio, al comparar los resultados con la valoración de los expertos (forense y psiquiatra) fue muy satisfactorio (p < 0,001). La fiabilidad intraobservador fue baja, con un índice kappa de 0,135. La fiabilidad interobservador fue alta, con un índice kappa de 0,74. La consistencia interna obtuvo un α de Cronbach de 0,645 para el modelo reducido de 6 ítems. CONCLUSIONES: La adaptación al español de la escala Aid to Capacity Evaluation muestra una adecuada validez de constructo y consistencia interna. Su utilización contribuiría a la identificación de pacientes incapaces de tomar una determinada decisión médica y/o de otorgar un consentimiento informado

OBJECTIVE: To adapt and validate the Spanish version of the Aid to Capacity Evaluation scale, designed to assess the capacity of the adult in medical decision-making, both in diagnosis and treatment processes. DESIGN: Observational study of prospective validation. SETTING: Primary and hospital care of the basic health area of Jaen. PARTICIPANTS: One hundred twenty-nine PATIENTS: MAIN MEASUREMENTS: Questionnaire which included sociodemographic variables, concerning the decision (scope, type of decision, the need for written informed consent), assessment of the capacity to the Aid to Capacity Evaluation scale and other related comorbidity (hearing loss, alcoholism, cognitive level variables with the Mini-Mental State Examination and depression by Goldberg or Yesavage test). RESULTS: The tool is considered viable. The conclusions of the expert panel were favorable. The result of the criteria' validity, comparing the results with the assessment of the experts (forensic and psychiatrist) was very satisfying (P < .001). The intra-observer reliability was low (kappa = 0,135). Interobserver reliability remained high (kappa = 0.74). The internal consistency was awarded an alpha of Cronbach's 0,645 for the reduced model of 6 items. CONCLUSIONS: The Aid to Capacity Evaluation scale was adapted to Spanish, demonstrating adequate internal consistency and construct validity. Its use in clinical practice could contribute to the identification of patients unable to make a particular medical decision and/or to give an informed consent

Ethics of social media research: common concerns and practical considerations.

Social media Websites (SMWs) are increasingly popular research tools. These sites provide new opportunities for researchers, but raise new challenges for Institutional Review Boards (IRBs) that review these research protocols. As of yet, there is little-to-no guidance regarding how an IRB should review the studies involving SMWs. The purpose of this article was to review the common risks inherent in social media research and consider how researchers can consider these risks when writing research protocols. We focused this article on three common research approaches: observational research, interactive research, and survey/interview research. Concomitant with these research approaches, we gave particular attention to the issues pertinent to SMW research, including privacy, consent, and confidentiality. After considering these challenges, we outlined key considerations for both researchers and reviewers when creating or reviewing SMW IRB protocols. Our goal in this article was to provide a detailed examination of relevant ethics and regulatory issues for both researchers and those who review their protocols.