III. The role of the Research Ethics Committees in the regulation of Pharma-Sponsored studies

Participants of Pharma-sponsored research are exposed to risks, benefits, and uncertainties that do not occur in other forms of clinical studies. Ethics committees represent the subjects’ first line of protection. This responsibility begins with the study review and ends after all study subjects finish the intervention. The objective of this paper is to review the most common controversial issues found in Pharma-sponsored studies. Potential solutions are proposed to prevent or resolve the polemical aspects. However, different challenges will be faced in the near future (e.g., when new therapies reach their late stage of development). All parties involved in research should work together to guarantee the protection of participants, the paramount principle on which clinical investigation is based. Pharma-sponsored research is a crucial driver to develop and implement innovative approaches to improve the informed consent process and the execution of the studies.

Ethical issues on the "synthetic" phosphoethanolamine clinical trial / Questões éticas sobre o ensaio clínico da fosfoetanolamina "sintética"

Summary Notwithstanding its approval by the National Committee for Ethics in Research (Conep) on April 19, 2016, a trial of the so-called "synthetic" phosphoethanolamine (syn-phospho) pill in cancer patients raises ethical concerns. An analysis by a laboratory contracted by the Ministry of Science, Technology and Innovation (MCTI) revealed that syn-phospho contained a great amount of impurities and did not meet standards of pharmaceutical quality required for an investigational drug. Cytotoxicity against human tumor cell lines and in vivo rodent xenograft tumor assays consistently failed to demonstrate a potential anticancer activity of syn-phospho. Preclinical safety studies of syn-phospho were also insufficient to support a trial of this investigational drug in cancer patients. Moreover, the ethical approval decision apparently overlooked two previous findings that suggested a possible enhancement of mammary carcinoma cell proliferation by phosphoethanolamine, and an apparent increase in lung metastases (rat implanted tumor assay) by syn-phospho. The syn-phospho risk-benefit ratio is clearly unfavorable and, thus, this trial in cancer patients does not fulfill a key requirement to make a clinical research ethical. There are also concerns regarding whether the study design is robust enough (scientific validity), and the social value of the trial of syn-phospho in cancer patients is questionable.

Resumo Não obstante a sua aprovação pela Comissão Nacional de Ética em Pesquisa (Conep) em 19 de abril de 2016, um ensaio da pílula de fosfoetanolamina "sintética" (sin-fosfo) em pacientes com câncer levanta preocupações éticas. Uma análise feita por um laboratório contratado pelo Ministério da Ciência, Tecnologia e Inovação (MCTI) revelou que a sin-fosfo continha grande quantidade de impurezas e não satisfazia os padrões de qualidade farmacêutica exigidos para um medicamento experimental. Os ensaios de citotoxicidade com linhagens de células originárias de tumores humanos e testes in vivo em roedores com tumores xeno-enxertados falharam consistentemente em demonstrar uma potencial atividade anticâncer da sin-fosfo. Os estudos pré-clínicos de segurança da sin-fosfo também foram insuficientes para apoiar a realização de um ensaio desse medicamento experimental em pacientes com câncer. Além disso, a aprovação ética aparentemente desconsiderou dois achados anteriores, sugerindo uma possível exacerbação da proliferação de células de carcinoma de mama pela fosfoetanolamina, e um aparente aumento de metástases pulmonares (ensaio de tumores implantados em ratos) pela sin-fosfo. A relação risco-benefício é claramente desfavorável para a sin-fosfo e, portanto, esse ensaio em pacientes com câncer não atende um requisito essencial para que uma pesquisa clínica seja ética. Há também preocupações quanto ao delineamento do estudo ser suficientemente robusto (validade interna), e o valor social do ensaio da sin-fosfo em pacientes com câncer é questionável.

La cara oculta del estudio 329 y la manipulación de la evidencia científica / Study's 329 hiddens face and scientifics evidence manipulation

El emblemático ensayo clínico 329, financiado por Smith Kline Beecham (actualmente GlaxoSmith-Kline) y publicado en2001, permitió posicionar a la paroxetina como un tratamiento efectivo y seguro para la depresión mayor en adolescentes. En la presente editorial el autor describe los sucesos ocurridos luego de su publicación, partiendo de los cuestionamientos iniciales respecto de su eficacia, hasta llegar a los resultados de su reciente reanálisis (llevando adelante por la iniciativa internacional RIAT), el cual concluyo que dicho fármaco no solo no provee un beneficio adicional al placebo para la condición y población utilizada, sino que además se asocia a efectos adversos sustanciales que no habían sido reportados en el informe original. Se exploran además las repercusiones de este suceso en la comunidad científica y se hace un señalamiento de la necesidad de permitir el acceso a las bases de datos originales que sustentan los resultados y conclusiones de las investigaciones publicadas, como mecanismo de transparencia superador a la revisión por pares. (AU)

The emblematic 329 study, funded by Smith Kline Beecham (now GlaxoSmith-Kline) and published in 2001, allowed to position paroxetine as an effective and safe treatment for major depression in adolescents. In this editorial, the author describes the events after its publication, from the initial concerns about its effectiveness, to the results of its recent reanalysis (accounted by the international RIAT initiative), which concluded that the drug not only does not provide an additional benefit than placebo, but is also associated with significant adverse effects that were not reported in the original report. It also explores the repercussions generated in the scientific community by this event, pointing out the need to allow access to original databases that support the findings and conclusions of published research, as an overcoming mechanism for transparency to the traditional peerreview. Agustín Ciapponi Study's 329 hiddens face and scientifics evidence manipulation. (AU)

Revisión de parámetros arrive, en artículos de revistas científicas chilenas, indexadas en Thomson Reuters, que utilizan animales de experimentación, in vivo, entre los años 2010 y 2012 / Revisão de parâmetros arrive em artigos de revistas científicas chilenas indexadas pela Thomson Reuters, que utilizam animais de experimentação in vivo, entre 2010 e 2012 / Guidelines arrive review, in chilean scientific journal articles, indexed in Thomson Reuters, that use animal experimentation, in vivo, between years 2010 and 2012

El artículo plantea conocer la situación de Chile respecto de las publicaciones científicas que informan utilizar animales de experimentación, basándose en las directrices ARRIVE (Animal Research: Reporting In Vivo Experiments), para la investigación con animales. Su objetivo es evaluar la metodología de un ensayo clínico a partir de la descripción detallada, con exactitud y con transparencia, de su diseño, ejecución, análisis y resultados. Se seleccionaron seis revistas chilenas que informan utilizar animales de experimentación y pertenecen a las ciencias biomédicas, con publicaciones desde enero de 2010, fecha en que se publicó la normativa ARRIVE, a diciembre de 2012, las que corresponden al 12,2 por ciento (6/49) del total de revistas chilenas indexadas en Thomson Reuters. De estas revistas se seleccionaron 110 artículos de un total de 1.567, que corresponden al 7 por ciento. De los artículos analizados, ninguno cumplió con el total de los parámetros de la normativa ARRIVE para el uso de animales de experimentación. Surgen desafíos para la investigación cientifica que utiliza animales, como también para aquellas revistas que difunden la información obtenida, con la finalidad de elevar la cantidad y calidad de este tipo de publicaciones.

We propose to know the national situation regarding scientific publishing using experimental animals, based on the guidelines ARRIVE (Animal Research: Reporting In Vivo Experiments) for animal research. It aims to evaluate the methodology of a clinical trial, from the detailed description, with accuracy and transparency, its design, execution, analysis and results. They selected six Chilean magazines, that use experimental animals and belong to the biomedical sciences, since January 2010, when it was published ARRIVE regulations, to December 2012. Corresponding to 12.2 percent (6/49) of total Chilean journals indexed in Thomson Reuters. Of these 110 articles were selected, from a total of 1567, corresponding to 7 percent. Of the articles analyzed, none fulfilled with the total ARRIVE regulation parameters for use of experimental animals. Challenges arise for scientific research that uses animals for research, as well as for those journals that disseminate information obtained from these investigations. With the purpose of increasing the quantity and quality of these publications.

O artigo propõe conhecer a situação do Chile a respeito das publicações científicas que informam utilizar animais de experimentação, baseandose nas diretrizes ARRIVE (Animal Research: Reporting In Vivo Experiments), para a investigação com animais. Seu objetivo é avaliar a metodologia de um ensaio clínico a partir da descrição detalhada, com exatidão e transparência de seu projeto, execução, análise e resultados. Foram selecionadas seis revistas chilenas que informam utilizar animais de experimentação e pertencem às ciências biomédicas, com publicações desde janeiro de 2010, data em que se publicou a normativa ARRIVE, a dezembro de 2012, as quais correspondem a 12,2 por cento (6/49) do total de revistas chilenas indexadas pela Thomson Reuters. Destas revistas foram selecionados 110 artigos de um total de 1.567, que correspondem a 7 por cento. Dos artigos analisados, nenhum cumpriu com o total dos parâmetros da normativa ARRIVE para o uso de animais de experimentação. Surgem desafios para a investigação cientifica que utiliza animais, como também para aquelas revistas que difundem a informação obtida, com a finalidade de elevar a quantidade e a qualidade deste tipo de publicações.

Reporting Results of Research Involving Human Subjects: An Ethical Obligation

Researchers have an ethical responsibility to report the results of research involving human subjects. Dissemination of results ensures that patient care is based on good science and that the field of medicine advances based on complete and accurate knowledge. However, current evidence suggests that publication is often neglected or substantially delayed, especially in the case of negative and inconclusive results. Researchers, editors and reviewers should value all high-quality research regardless of the conclusiveness of the results and ensure that all research involving human subjects is registered in a publicly accessible database.

Ticagrelor en el síndrome coronario agudo. Explicando lo inexplicable / [Ticagrelor in acute coronary syndrome. Explaining the inexplicable]

The PLATO study evaluated the efficacy of adding ticagrelor, instead of clopidogrel, to aspirin in patients with acute coronary syndrome, which showed surprisingly positive results making the drug acceptable to regulatory agencies and specialty societies worldwide. Notwithstanding the aforementioned success, contradictory information supplied by critical analysis was submitted by the sponsor. The controversial findings revealed several aspects that are difficult to explain, threatening the veracity of the study’s conclusions. Mortality rate pattern, excessive benefit not comparable to prior studies, unexplained loss of follow-up development and inconsistency in findings in accordance with the country, the type of events arbitrator and monitoring committee are some of the most questionable issues. Dubious reaction to this trial is based on the fact that the information could not be found in published articles. This complex situation poses a challenge to the critical analysis of the text and raises questions as to how far the conflicts of financial interest influenced the development of the study, the communication of its results and probably, acceptance of the drug for commercial use.

A nova declaração de Helsinque e o uso de placebo em estudos clínicos no Brasil: a polêmica continua / The new declaration of Helsinki and the use of placebo in brazilian clinical trials: controversy remains

Em 2000, dada a urgência de adequação à realidade científica vigente, iniciativas de revisão dos aspectos polêmicos da Declaração de Helsinque (DoH) à publicação de sua quinta versão na qual ficou estabelecido que o uso do placebo seria aceito apenas quando nenhum tratamento existisse. A Federal Drug Administration nos E.U.A., todavia, continuou a exigir controle-placebo, adotando o Guia de Boas Práticas Clínicas. Também a Agência ReguladoraEuropeia considerou tal proibição arbitrária e, junto a outras entidades, lançaram-se numa campanha contra a DoH. Em 2002 e 2004, Notas de Clarificação publicadas na DoH provocaram grande comoção mundial, culminando na versão de 2008. Apesarda divergência dentre vários grupos, sobretudo, quanto ao uso do placebo, o texto atual assumiu uma posição neutra, flexibilizando sua aplicação. Todavia, uma vez norma ética, a atual DoH fomentou o reinício das discussões sobre a necessidade de um documento mais ampla e uniformemente aceito. Hoje, esta polêmica ainda continua em alguns países, principalmente no Brasil, onde o Conselho Federal de Medicina (CFM) e a Comissão Nacional de Ética em Pesquisa (CONEP) proíbem o uso de placebo em estudos clínicos em território nacional, quando existir qualquer tratamento disponível. Este fato eliciou grande polêmica entre agências regulatórias e pesquisadores brasileiros. Assim, dado que, desde Nuremberg, a garantia do não enfraquecimento das normas de proteção dos sujeitos de pesquisa recrutados mundo afora é razão primordial de ser da DoH, a reabertura de diálogo em níveis nacional einternacional se faz premente perante a nova revisão comemorativa de seus 50 anos em 2014...

In 2000, given the urgency for the ethical guidelines adequacy to the present scientific standards, revision initiatives of the most controversial aspects of the Declaration of Helsinki (DoH). These efforts culminated with the publication of its fifth version stating that the use of placebo was acceptable when proven treatmentdoes not exist. The US Federal Drug Administration, however, continued demanding the placebo control and adopted the Good Clinical Practice Guidelines. The European regulatory agency also considered such prohibition arbitrary and, amongst other entities,started a campaign against the DoH. In 2002 and 2004, Clarification Notes published on the DoH promoted extensive controversy worldwide, concluded at its version of 2008. Despite the divergence amongst many groups, especially on placebo use, the current text assumed a more neutral positioning, flexibilising its application. Being an ethical norm, the current DoH re-started the discussions about thenecessity of a document of uniform worldwide acceptance. Today, the controversy still remains in a few countries, especially in Brazil, where governmental regulatory agencies – namely the Federal Council of Medicine and the National Commission for Research Ethics – posed a ban on the placebo use in clinical trials nationally,when there is available treatment, corroborating with the ongoingcontroversy amongst regulatory agencies and researchers in Brazil.Therefore, since Nuremberg, given the warranty of not weakening the protection of research subjects recruited throughout the worldconstitutes the DoH most desired aim, dialogue must be resumed both nationally and internationally, considering the upcoming revisionin 2014, at the DoH 50th anniversary...

El cumplimiento de la buena práctica de enfermería en los ensayos clínicos / O cumprimento da boa prática da enfermagem nos ensaios clínicos / Fulfillment of good nursing practices in clinical trials

La ejecución de ensayos clínicos exige dedicación y adherencia a un conjunto de procedimientos y normativas esenciales con el propósito de obtener resultados válidos para la evaluación y posible registro sanitario de un nuevo producto. En este artículo se muestra la propuesta cubana para el cumplimiento de altos estándares de calidad en las Buenas Prácticas Clínicas para la participación de enfermería en este tipo de estudios.

Clinical trial execution demands dedication and adherence to a group of procedures and essential rules, to obtain valid results to evaluate and the possible sanitary registry of a new product. In this article the Cuban proposal for high standard quality in Good Clinical Practices for the participation of nursing in this type of studies is shown.

A execução de ensaios clínicos exige dedicação e aderência a um conjunto de procedimentos e regulamentos essenciais com o propósito de obter resultados válidos para a avaliação e possível registro sanitário de um novo produto. Neste artigo se mostra a proposta cubana para o cumprimento de altos padrões de qualidade nas Boas Práticas Clínicas para a participação de enfermagem neste tipo de estudos.

Are You "Tilting at Windmills" or Undertaking a Valid Clinical Trial?

In this review, several aspects surrounding the choice of a therapeutic intervention and the conduct of clinical trials are discussed. Some of the background for why human studies have evolved to their current state is also included. Specifically, the following questions have been addressed: 1) What criteria should be used to determine whether a scientific discovery or invention is worthy of translation to human application? 2) What recent scientific advance warrants a deeper understanding of clinical trials by everyone? 3) What are the different types and phases of a clinical trial? 4) What characteristics of a human disorder should be noted, tracked, or stratified for a clinical trial and what inclusion /exclusion criteria are important to enrolling appropriate trial subjects? 5) What are the different study designs that can be used in a clinical trial program? 6) What confounding factors can alter the accurate interpretation of clinical trial outcomes? 7) What are the success rates of clinical trials and what can we learn from previous clinical trials? 8) What are the essential principles for the conduct of valid clinical trials?

Pesquisa clínica em seres humanos:o papel do coordenador de estudos clínicos / Clinical trial with human beings: the role of the study coordinator

O coordenador de estudos clínicos (CEC) é a pessoa responsável pelogerenciamento desse tipo de estudo. Poucos trabalhos científicos têm trazido dados a respeito do papel doCEC nas diferentes especialidades médicas. Este estudo tem como objetivo revisar a literatura e identificar a suafunção. Entre 1997 e 2008, identificaram-se 76 publicações sobre pesquisa clínica envolvendo CEC. Apenas16 referiam-se especificamente às atividades desse profissional. Foram descritos 19 tipos de habilidades, 25subcategorias e 128 diferentes funções de um CEC. Entre elas destacam-se: habilidades clínicas, psicossociais, decomunicação e organizacional e a responsabilidade pelo processo do termo de consentimento livre e esclarecido.Em alguns locais, o CEC escreve protocolos de pesquisas e faz avaliações estatísticas. Para esse trabalho, muitasvezes, há necessidade de disponibilidade em horário integral. A literatura disponível sobre as funções do CEC équase totalmente estrangeira e reduzida. No Brasil, a Sociedade Brasileira de Pesquisa Clínica é responsável porquase todas as publicações existentes. Todavia, muito do que se lê em publicações estrangeiras acerca do papeldo coordenador não corresponde à realidade brasileira.

The Study Coordinator (SC) is the person who is responsible for themanagement of clinical studies. Few scientific studies have shown data about the role of the SC in variousmedical specialties. This article aims to search for and identify the scientific literature regarding the role of theSC. Between 1977 and 2008, 76 publications on clinical research involving SC were identified. Only 13 werespecifically related to the functions of a SC. The activities described included 19 types of skills, 25 subcategoriesand 128 different functions of a SC. Among them, it is possible to mention: clinical, psychosocial, communicativeand organizational skills, as well as the responsibility for the whole process of the informed consent. In someplaces, the SC writes protocols of research and makes statistical evaluations. In order to accomplish this job, theSC often has to be available in full time. The literature that brings information on the role of the SC is almostcompletely foreign and in small number. In Brazil, the Brazilian Society of Clinical Research is responsible foralmost all the existing publication. However, much of what one reads in foreign publications about the role ofthe SC does not correspond to the Brazilian reality.

El uso de placebos en estudios clínicos y comunitarios: consideraciones éticas / The ethics of employing placebos in clinical and community research

El uso médico de placebos ha mostrado que no son sustancias inactivas, lo cual también es válido cuando se emplean en investigaciones clínicas. Dado sus efectos imprevisibles y variados, los placebos no pueden considerarse comparadores neutros frente a la droga en estudio, siendo preferidos por razones estratégicas –bajo costo, comparaciones fáciles–. No contribuyendo al rigor de los estudios, los placebos carecen de justificación ética ya que ponen a los probandos del grupo control en situación de orfandad terapéutica al no recibir el tratamiento de rutina que tenían o debían tener, además de no permitirles beneficiar del agente en estudio. Los estudios epidemiológicos, muchas veces “randomizados” con grupo control, se validan por su atingencia a los problemas y necesidades de la comunidad, por lo tanto se espera que sean de beneficio directo para la población, lo cual significa que sería una falencia ética marginar a la mitad de los afectados cuando son asignados a un grupo control. Los diversos estatutos que regulan la bioética de la investigación son tolerantes de los placebos, habiendo sido redactado so influidos por los mismos investigadores que favorecen su empleo. Es función indelegable de los Comités de Bioética en Investigación que, en aras de la protección de probandos, velen por restringir el uso de placebos a situaciones calificadamente excepcionales.

Placebos in clinical use show both subjective and provable objective effects. In research, placebos also retain a fair amount of activity, causing unpredictable and unreliable effects. Therefore, when used as comparators with a new drug, they should not be considered as inactive controls. If placebos are unreliable comparators, they have no further justification beyond serving as inexpensive agents that are simpler to both handle and compare than active therapies. Nevertheless, if they lack scientific justification, placebos should not be employed because all subjects falling in the control group will become therapeutic orphans, since patients under routine medication will be at risk of not receiving necessary treatment, at least for the duration of the trial. Studies in the area of public health, especially in epidemiology, are often encouraged to employ the randomized control technique, which includes using placebos in the control arm. Community based research is expected to be pertinent and beneficial to the host site, therefore inactive control arms will deny numerous subjects the benefit supposedly sought by the research. Placebos are tolerated by major research guidelines, in spite of heavy opposition by those bioethicists that believe them to put research subjects at unjustified risks. Local Bioethics Research Committees should protect research subjects by only accepting placebo protocols under exceptionally justified conditions.

Pesquisa clínica: aspectos éticos, científicos e regulatórios / Clinical research: ethical, scientific and regulatory issues

A pesquisa clínica constitui o principal meio para avaliação da eficácia e segurança de novos medicamentos e outras tecnologias médicas. Ainda que os ensaios clínicos estejam se desenvolvendo de maneira muito mais segura e ética do que se observava há décadas atrás, a eliminação de abusos grosseiros traz à tona alguns problemas éticos. Este artigo enfatiza dois grandes problemas éticos e desafios envolvidos na condução da pesquisa clínica: o conflito de interesses e a obtenção do consentimento informado. A maioria dos ensaios clínicos é financiada por indústrias farmacêuticas que apostam volumosas quantias nos produtos sendo avaliados. Além do mais, os cientistas que desenham, conduzem, analisam e publicam os resultados frequentemente recebem compensações financeiras pelas indústrias, tanto na forma de salário como taxas de aconselhamento. O consentimento é o processo pelo qual o paciente é informado e torna-se um participante nas decisões sobre seu manejo clínico. Argumenta-se, entretanto, que a obtenção da assinatura do participante no documento de consentimento informado adiciona muito pouco na qualidade do processo de consentimento. Este artigo também sugere medidas para assegurar a conduta científica e ética apropriada para ensaios clínicos.

Clinical trials are the primary means to evaluate the efficacy and safety of new drugs and other medical technologies. Although clinical trials are conducted far more ethically and safer now than they were some decades ago, the elimination of gross abuses has tended to highlight more subtle ethical problems. This review highlights two major ethical problems and challenges involved in the conduct of clinical trials: conflict of interest and consent process. Most clinical trials are funded by pharmaceutical companies with enormous financial stakes in the products being evaluated. Furthermore, the scientists who design, conduct, analyze, and report clinical trials often receive monetary compensation from drug companies, in the form of either salaries or consulting fees. Consent is a process by which a patient is informed and becomes a participant in decisions regarding their medical management. It is argued, however, that providing a signature to a form adds little to the quality of this process. This review also suggests measures to ensure scientifically and ethically sound clinical trials.

Responsabilidad del patrocinador después de un ensayo clínico / Responsability of sponsors after clinical trials are finished

Este artículo describe algunos problemas éticos derivados de los estudios multicéntricos en países en desarrollo, particularmente los referidos al rol de los patrocinadores luego de concluido un ensayo clínico. Luego de pasar revista a algunas normativas internacionales, propone un conjunto de obligaciones éticas para los patrocinadores de estos ensayos. Las evidencias mostradas hacia el final sugieren más bien pesimismo respecto de su cumplimiento.

This paper describes some ethical problems derived from multi center studies in developing countries, specifically those referred to the role of sponsors after the clinical trial is concluded. After reviewing some international norms, it proposes several ethical obligations fro sponsors of these trials. Finally, the evidence shows pessimism with respect to fulfilling them.

Este artigo descreve alguns problemas éticos derivados dos estudos muticêntricos nos países em desenvolvimento, particularmente os relacionados com o papel dos patrocinadores logo após a conclusão de um ensaio clínico. Após análise de algumas normas interaccionáis, propõe um conjunto de obrigações éticas para os patrocinadores destes ensaios. As evidências indicam um certo pessimismo quanto ao seu cumprimento.

Clinical trial practices: methodological and ethical aspects

The objective of this article is to review the methodology of controlled clinical trial, the protocol construction stages and their various ethical aspects. Controlled clinical trial is an experiment plant in which two contemporary groups of patients are compared in a forward-looking way, the first one is treated by the reference treatment [controlled group] and the other one if treated by the new treatment [tested group]. The allocation of treatments must be unpredictable and the follow-up of the patients makes blind with regard to the received treatment. These principles constitute the methodological frame of the controlled clinical trial which can not be approached under its only methodological or statistical angle. But also through an ethical serious reflexion worldwide especially with the fast progress of biologic sciences and medical techniques. In Morocco, the rule of the medicines is governed mainly by the Ministry of Health which has to assure security and the sanitary safety of the citizens. It is responsible for all the politics of medicines in Morocco and all their aspects. The realization of the bio equivalence and bio availability trials are two criteria which are darkened from the at present current texts. The accompanying measures of the implementation of these trials for example: universal principles in person's protection, the Good Practices of Medicine's manufacture, the Good Clinical Practices, the Good Practices of Laboratory are not foreseen either by the current rule