Ensaios clínicos de pacientes únicos em homeopatia: aspectos técnicos, educacionais e éticos / Single-case studies in homeopathy: technical, educational and ethical aspects

ensaio clínico de pacientes únicos (ECPU/ensaio n-de-1) consiste na observação sistemática de condutas terapêuticas adotadas para otimizar o restabelecimento da saúde em um único paciente, com múltiplos cruzamentos ao longo do tratamento, podendo ter adicionalmente propósito de pesquisa clínica. Foi proposto há décadas e tem sido mais utilizado nas áreas de psicologia clínica, recebendo maior atenção em estudos médicos nos últimos anos. Embora seja considerado como o tipo de estudo com maior força para tomada de decisões terapêuticas, ainda são escassas as publicações sobre o seu emprego em medicina. Este artigo aborda as possibilidades dos ECPUs na avaliação dos resultados clínicos da homeopatia, explorando seus aspectos metodológicos, éticos e educacionais característicos em comparação aos ensaios clínicos randomizados tradicionais. Em pesquisa clínica, diferentemente dos ensaios convencionais, os ECPUs permitem a participação mais direta do paciente na escolha dos procedimentos e acompanhamento dos resultados, com possibilidade de alterações imediatas e sem que seja necessária sua exclusão do estudo, além de implicações de ordem econômica, política e ética. Podem ser utilizados no teste de medicamentos usados de modo off label, sem as restrições impostas à inclusão de pacientes vulneráveis nos estudos clínicos habituais, com excessiva artificialização no delineamento experimental. Poderiam ser ainda adotados nas diversas fases de teste clínico dos medicamentos, reduzindo a exposição de grande número de participantes aos riscos da pesquisa e baixa margem de extrapolação clínica dos resultados ao conjunto da população. Em homeopatia, podem ajudar a aprimorar o conhecimento dos medicamentos já em uso ou a melhor detectar os efeitos de novas substâncias testadas em ensaios patogenéticos homeopáticos. Em função do seu propósito principal de otimização do tratamento individual ­ e do alinhamento com os princípios éticos da autonomia e beneficência associados à prática da medicina centrada-no-paciente ou de precisão - podem ser desenvolvidos em conjunto com o paciente e familiares, sem a obrigatoriedade de aprovação prévia por Comissões de Ética Médica ou Comitês de Ética em Pesquisa.

The single-patient clinical trial (n-of-1 trial) is primarily designed to systematically observe outcomes from different therapeutic options to optimize the restoration of health in a single patient, with multiple crossovers throughout the treatment. They may additionally have a clinical research purpose. They have been proposed for decades and were mostly used in clinical psychology, receiving greater attention in medical studies in recent years. Although it is considered the type of study with the greatest strength for therapeutic decision-making, there are still few publications with its application in medicine. This article discusses the possibilities of single-patient clinical trials in assessing homeopathy outcomes, exploring their characteristic methodological, educational and ethical aspects compared to traditional randomized clinical trials. In clinical research, unlike conventional trials, single-patient clinical trials allow for more direct patient participation in choosing procedures and monitoring results, with the possibility of immediate changes without the need for their exclusion from the study, in addition to economic, political and ethical implications. They can be used in testing off-label drugs without the restrictions imposed on the inclusion of vulnerable patients in usual clinical studies, with excessive artificiality in the experimental design. They could also be adopted in the various clinical trial phases of drugs, reducing the exposure of many participants to the risks of research and low margin of clinical extrapolation of the results to the entire population. In homeopathy, they can help refine the knowledge of medications already in use or better detect the effects of new substances tested in homeopathic pathogenetic trials. Due to their purpose of optimizing individual treatment ­ and alignment with the principles of patient-centered or precision medicine ­ they can be developed jointly with the patient and her family without the mandatory prior approval by Medical Ethics Committees or Research Ethics Committees.

Evidence-Based Evaluation of the Ethics of Sham Surgery for Parkinson's Disease.

The stated purpose of sham or placebo surgery is to enable the implementation of surgical placebo-controlled trials (SPTs) for evaluating the safety and efficacy of surgical interventions. Exposing the participants to the burdens and harms of sham surgery has been justified on the grounds of the absolute necessity for controlling large placebo effects and observer bias, assumed to be associated with surgical procedures. In the present review, we argue that evidence obtained from SPTs of cellular therapies for the treatment of Parkinson's disease (PD) has failed to demonstrate either large and consistent placebo effects or decisive methodological advantages for relying on sham surgical controls. We outline several alternative assessment strategies and designs available to establish the efficacy of cellular therapies. It is concluded that the evidence evaluated in the present analysis indicated that use of sham surgery in the context of developing novel surgical procedures for PD is not necessary, and therefore, unethical under a utilitarian model.

Ethical tradeoffs in trial design: case study of an HPV vaccine trial in HIV-infected adolescent girls in lower income settings.

The Declaration of Helsinki and the Council of the International Organization of Medical Sciences provide guidance on standards of care and prevention in clinical trials. In the current and increasingly challenging research environment, the ethical status of a trial design depends not only on protection of participants, but also on social value, feasibility, and scientific validity. Using the example of a study assessing efficacy of a vaccine to prevent human papilloma virus in HIV-1 infected adolescent girls in low resource countries without access to the vaccine, we compare several trial designs which rank lower on some criteria and higher on others, giving rise to difficult trade-offs. This case demonstrates the need for developing more nuanced guidance documents to help researchers balance these often conflicting criteria.

Sham surgery trial controls: perspectives of patients and their relatives.

This study reports on qualitative research conducted in the UK with people with Parkinson's Disease and their relatives on the subject of "sham surgery." It explores attitudes toward sham surgery and reasoning about hypothetical participation in a sham-controlled trial. Results showed that attitudes toward sham surgery may not necessarily predict trial participation behavior. A small majority of interviewees deemed sham surgery ethically acceptable with certain provisos, but hypothetical participation was driven primarily by disease severity and a lack of standard treatment options, with a preference for receiving the real surgery over sham. Ethical implications for patient equipoise and the autonomy of patients' research participation decisions are discussed.

El uso de placebo en investigación clínica / The use of placebo in clinical research

A pesar de diversos cuestionamientos éticos, los estudios controlados con placebo siguen siendo frecuentemente utilizados en investigación clínica. Si bien existen circunstancias donde esta práctica puede ser aceptable, por ejemplo cuando no hay tratamiento para la patología en estudio, en la mayoría de los casos su uso debería ser considerado no ético, ya que nadie debería padecer dolor o enfermedad innecesaria debido a una investigación médica. En dermatología es frecuente leer sobre ensayos clínicos controlados con placebo en patologías que tienen tratamiento estándar eficaz. Todos aquellos involucrados: investigadores, patrocinadores, agencias regulatorias y comités institucionales de evaluación, son responsables de conducir cada estudio en forma tal que se respete la dignidad y el bienestar de los voluntarios incluidos por encima de cualquier otro interés.

[Methodological problems of controlled clinical trials in surgical subspecialties]. / A mutéti szakmákban folytatott kontrollcsoportos klinikai vizsgálatok metodikai problémái.

Surgical subspecialties are handicapped in classical drug development considering professional and ethical solutions to questions in relation to introduction of new methods. The experts of invasive procedures are challenged significantly to comply with evidence based medicine and answer questions of the national health fund and/or health insurance companies, which are responsible for resource allocation. Sham operation is one of the ways to carry out controlled clinical trials. It had been pursued less frequently in the past, but we can see it as an important tool of invasive clinical trials nowadays. The contemplation about the applicability of sham operation contributes to understand other important issues in the development of invasive procedures.

Questioning the methodologic superiority of 'placebo' over 'active' controlled trials.

A resilient issue in research ethics is whether and when a placebo-controlled trial (PCT) is justified if it deprives research subjects of a recognized treatment. The clinicians' moral duty to provide the best available care seems to require the use of 'active' controlled trials (ACTs) that use an established treatment as a control whenever such a therapy is available. In another regard, ACTs are supposedly methodologically inferior to PCTs. Hence, the moral duty of the clinical researcher to use the best methods will favor PCTs. In this target article, I analyze the three reasons for believing that ACTs are inferior to PCTs namely: 1) ACTs lack 'assay sensitivity'; 2) ACTs do not measure absolute effect size; and 3) ACTs require more participants; and I contend that none are acceptable. Consequently the tension between clinical and research ethics dissolves: the moral duty of the clinician to avoid PCTs is unopposed by methodological considerations.

Investigação científica em seres humanos: a experiência de voluntários nos ensaios clínicos de uma nova vacina / Scientific investigation in human beings: the experience of volunteers in the clinical experiments of a new vaccine

Este estudo tem como objetivo de analisar as experiências vivenciadas pelos voluntários nos ensaios clínicos de um nova vacina contra Ancilostomídeos, realizados em Americaninhas, zona rural donordeste de Minas Gerais. Este estudo se reporta a investigação científica em seres humanos. Os ensaios clínicos são pesquisas onde tecnologias biomédicas podem ser testadas, proporcionando novas descobertas e garantindo avanços na medicina e na qualidade de vida das pessoas. Esses estudosdespertam debates sobre a ética em pesquisa, em especial quando desenvolvidas em áreas devulnerabilidade social. No Brasil, a legislação regulamentada em 1996 evidencia a atualidade e a relevância do tema, visto que pouco se sabe sobre a participação de pessoas em ensaios clínicos e quais os aspectos que envolvem a experiência de ser um voluntário: a decisão e motivação de participar, percepções, sentimentos e atitudes. O Instituo SABIN (EUA) e a Fundação Oswaldo Cruzestão desenvolvendo uma nova vacina contra Ancilostomídeos na zona rural no nordeste de MinasGerais. Trata-se de uma região de população vulnerável onde a exclusão sócio econômica pode fazer com que os sujeitos, mesmo após as informações sobre a pesquisa por meio do Termo de Consentimento Livre e Esclarecido, decidam participar do estudo sem conhecer os verdadeiros riscos e benefícios.Trata-se de um estudo de abordagem qualitativa descritiva fundamentada nas Teorias Compreensivas. Os sujeitos pesquisados fazem parte do Coorte I – Fase I dos testes da nova vacina.Foram entrevistadas nove pessoas. Utilizamos, para a coleta de dados, a entrevista semi-estruturadacom utilização de imagens fotográficas como recurso de livre associação. Para a análise dos dados,optamos pela Análise de Conteúdo com o referencial teórico da Antropologia da Saúde. Os resultados evidenciam os diversos aspectos da experiência de ser um voluntário em ensaios clínicos: a certeza nadecisão de participar, uma decisão livre...

Ensaios clínicos com vacinas anti-HIV/AIDS: a rotina de incorporação de uma prática científica / Clinical trials in anti-HIV/AIDS vaccine: the routine of incorporating a scientific practice

O estudo acompanha a rotina de um ensaio clínico de vacinas experimentais anti-HIV/AIDS desenvolvido no Projeto Praça Onze, da UFRJ, em colaboração com a rede mundial de pesquisas de vacinas anti-HIV/AIDS, HVTN (HIV Vaccine Trials Network) e apoio financeiro dos NIH (National Institutes of Health), dos EUA. Focaliza os processos de recrutamento, seleção e seguimento dos voluntários, articulando os aspectos mais gerais àsparticularidades e demandas locais deste estudo realizado no Rio de Janeiro, Brasil. Do ponto de vista teórico-conceitual utiliza recursos oriundos das ciências sociais -história, sociologia da ciência e da corrente interacionista da sociologia. O estudo mostra que, como todo ensaio clínico, o experimento do Projeto Praça Onze é uma atividade coletiva,sustentada sobre múltiplos atores e instâncias, com diversas racionalidades, o que gera uma permanente tensão. Estuda a tensão que se coloca, principalmente entre a expectativa dosprofissionais envolvidos (aconselhadores, recrutadores, médicos, enfermeiros, farmacêuticos, gerentes e coordenadores de estudos) e a experiência vivenciada pelos voluntários, assim como as possíveis negociações propostas durante o desenvolvimento do protocolo, a partir do contexto sociopolítico onde o mesmo está inserido. Os profissionais, apesar de suas especificidades, articulam-se para incorporar do universo dos colegas suas linguagens e seus modos de agir, num processo de hibridização dos conhecimentos e práticas. Os voluntários do ensaio, por sua vez, submetem-se, por um lado a uma rotina de disciplina e compromisso, queimplica na entrega de seu corpo à medicina, implícita nesse papel. Por outro, apropriam-se da lógica do ensaio clínico para, em sua ótica, transformar-se em um co-adjuvante no descobrimento de uma nova biotecnologia, que neste caso, se coloca como uma questão de vida ou morte, para ele e para uma ampla comunidade de infectados pelo HIV...

[Medical and ethical considerations of sham operation]. / Az álmutét és annak orvosi és etikai kérdései.

The absolute refusal of sham surgery as control in clinical trials can not be justified from professional, ethical point of view. Introduction of any new surgical treatment should be evidence based in the form of sufficient scientific approval to support a novel method. It has to be decided whether sham surgery or any other control modality could be an optimal baseline reference for a clinical trial. The feasibility and the ethical acceptability of sham surgery controlled clinical trials should be approved individually. At the risk evaluation of any (sham) surgery controlled clinical trial, we should contemplate the outcome of the opposite scenario as well; that is, the consequences of not pursuing a "lege artis" controlled clinical project to estimate the efficacy and safety of the invasive procedure. It is possible and obligatory to reconcile two basic medical goals: the treatment of the individual patient and the need of the society for proven, safe and effective treatments.

British and Canadian views on the ethics of paediatric clinical trials.

BACKGROUND: Ethical problems are quoted as a reason not to perform clinical trials in children. Little is known about the views of researchers regarding ethics. OBJECTIVES: A pilot study was conducted to assess the applicability of a questionnaire design containing trial scenarios to examine views regarding the use of children in drug trials and to elicit possible international differences. SETTING: Paediatricians and researchers in the United Kingdom and Canada. METHODS: Responders were presented with a questionnaire containing direct questions and six trial scenarios, each containing an ethical dilemma. Responders were asked regarding their own approval and their perceived opinion of whether an ethical review board (ERB) would approve. RESULTS: One hundred questionnaires (50 each country) were received. Few responders had research ethics training (14% United Kingdom and 8% Canada). Most (80 and 88%) felt children could be harmed by participation in trials and half (47 and 59%) felt children should only participate if they receive direct benefit. Many (58 and 61%) disagreed with payments beyond travel expenses. In the trial scenarios, 34% of responders were willing to enter healthy children in a pharmacokinetics study of an antibiotic for cystic fibrosis and 22% considered their ERBs would approve. Only a third (33%) would enter children in an analgesia trial that was placebo-controlled. CONCLUSION: Using healthy children and placebos in trials caused concern. Similar views were found between the two countries. The majority had no training in research ethics. The study highlights the usefulness of a questionnaire with clinical trial scenarios to try to elicit views on the ethics of conducting research in children.

AIDS care and treatment in Sub-Saharan Africa: implementation ethics.

With the advent of new AIDS treatment initiatives such as the World Health Organization's "3 by 5" program and the United States' "President's Emergency Plan for AIDS Relief," the ethical questions about AIDS care in the developing world have changed. No longer are they fundamentally about the conduct of research; now, we must turn our attention to developing treatment programs. In particular, we must think about how to spread limited treatment resources among the vast reservoir of people who need them.

Ethics and equipoise: rationale for a placebo-controlled study design of platelet glycoprotein IIb/IIIa inhibition in coronary intervention.

Rarely is it straightforward to specify the design and parameters of a clinical trial investigating an alternative therapy where effective therapies already exist. If existing therapeutic interventions are highly efficacious, safe, inexpensive, and firmly entrenched, an active-control design becomes the logical first choice. Short of this absolute condition, however, the merits and realities of the scientific, clinical, corporate, and regulatory environments need to be weighed before determining the appropriate approach. A state of clinical equipoise with regard to the use of glycoprotein (GP) IIb/IIIa therapy in percutaneous coronary intervention (PCI) provided the unique opportunity to address the complexities in selecting a placebo-controlled design for the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Trial (ESPRIT). ESPRIT investigators assessed whether a high dose of eptifibatide would improve the outcomes of patients undergoing coronary stenting. By using the example of the ESPRIT trial, we examine factors warranting the need for this trial and evaluate the process whereby the United States Food and Drug Administration (FDA) gave approval for a placebo-controlled design. Although the focus of this trial is GP IIb/IIIa inhibition therapy, the issues pertaining to the trial and how they were resolved are general enough to be applied to the design and conduct of clinical trials across a broad spectrum of illnesses and therapeutic modalities.

Placebos that harm: sham surgery controls in clinical trials.

Recent debates over the use of sham surgery as a control for studies of fetal tissue transplantation for Parkinson's disease have focused primarily on rival interpretations of the US federal regulations governing human-subjects research. Using the core ethical and methodological considerations that underwrite the equipoise requirement, we find strong prima facie reasons against using sham surgery as a control in studies of cellular-based therapies for Parkinson's disease and more broadly in clinical research. Additionally, we believe that these reasons can be generalized to apply to the use of other placebo controls that carry significant risks of positive harms in and of themselves. As a result, our arguments are centrally relevant to the emerging drive to subject therapies with a surgical component to the same rigorous standards of evaluation as those governing the approval of new pharmaceuticals.