I. EXECUTIVE SUMMARY The MRCT Center Post-trial Responsibilities: Continued Access to an Investigational Medicine Framework outlines a case-based, principled, stakeholder approach to evaluate and guide ethical responsibilities to provide continued access to an investigational medicine at the conclusion of a patient’s participation in a clinical trial. The Post-trial Responsibilities (PTR) Framework includes this Guidance Document as well as the accompanying Toolkit. A 41-member international multi-stakeholder Workgroup convened by the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard University (...) (MRCT Center) developed this Guidance and Toolkit. Project Motivation A number of international organizations have discussed the responsibilities stakeholders have to provide continued access to investigational medicines. The World Medical Association, for example, addressed post-trial access to medicines in Paragraph 34 of the Declaration of Helsinki (WMA, 2013): “In advance of a clinical trial, sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This information must also be disclosed to participants during the informed consent process.” This paragraph and other international guidance documents converge on several consensus points: • Post-trial access (hereafter referred to as “continued access” in this Framework [for terminology clarification – see definitions]) is the responsibility of sponsors, researchers, and host country governments; • The plan for continued access should be determined before the trial begins, and before any individual gives their informed consent; • The protocol should delineate continued access plans; and • The plan should be transparent to potential participants and explained during the informed consent process. -/- However, there is no guidance on how to fulfill these responsibilities (i.e., linking specific responsibilities with specific stakeholders, conditions, and duration). To fill this gap, the MRCT Center convened a working group in September of 2014 to develop a framework to guide stakeholders with identified responsibilities. This resultant Framework sets forth applicable principles, approaches, recommendations and ethical rationales for PTR regarding continued access to investigational medicines for research participants. (shrink)

Much new global genetic research employs whole genome sequencing, which provides researchers with large amounts of data. The quantity of data has led to the generation and discovery of more incidental or secondary findings and to vigorous theoretical discussions about the ethical obligations that follow from these incidental findings. After a decade of debate in the genetic research community, there is a growing consensus that researchers should, at the very least, offer to return incidental findings that provide high‐impact, medically relevant (...) information, when it is not unduly burdensome to the research enterprise to do so. Much as genetic research has been limited to U.S. and European settings, the incidental findings debate has primarily focused on research conducted in high‐income countries. In a 2015 paper, Alberto Ortiz‐Osorno, Linda Ehler, and Judith Brooks note salient differences between the circumstances of research participants in low‐ and high‐resource settings that alter the analysis of when and why incidental findings should be offered to research participants. In this article, we expand on their analysis and present a framework for thinking about how investigators’ obligations to return genomic data might change in low‐resource settings, particularly in settings where participants do not have access to the medical care needed to treat, assess, or monitor incidental findings that are actionable in settings with plentiful resources. (shrink)

Ethics guidance increasingly recognises that researchers and sponsors have obligations to consider provisions for post-trial access to interventions that are found to be beneficial in research. Yet, there is little information regarding whether and how such plans can actually be implemented. Understanding practical experiences of developing and implementing these plans is critical to both optimising their implementation and informing conceptual work related to PTA. This viewpoint is informed by experiences with developing and implementing PTA plans for six large-scale multicentre HIV (...) prevention trials supported by the HIV Prevention Trials Network. These experiences suggest that planning and implementing PTA often involve challenges of planning under uncertainty and confronting practical barriers to accessing healthcare systems. Even in relatively favourable circumstances where a tested intervention medication is approved and available in the local healthcare system, system-level barriers can threaten the viability of PTA plans. The aggregate experience across these HIV prevention trials suggests that simply referring participants to local healthcare systems for PTA will not necessarily result in continued access to beneficial interventions for trial participants. Serious commitments to PTA will require additional efforts to learn from future approaches, measuring the success of PTA plans with dedicated follow-up and further developing normative guidance to help research stakeholders navigate the complex practical challenges of realising PTA. (shrink)

There is growing interest among pharmaceutical policymakers in how to “disinvest” from subsidized medicines. This is due to both the rapidly rising costs of healthcare and the increasing use of accelerated and conditional reimbursement pathways which mean that medicines are being subsidized on the basis of less robust evidence of safety and efficacy. It is crucial that disinvestment decisions are morally sound and socially legitimate, but there is currently no framework to facilitate this. We therefore reviewed the bioethics literature in (...) order to identify ethical principles and concepts that might be relevant to pharmaceutical disinvestment decisions. This revealed a number of key ethical considerations—both procedural and substantive—that need to be considered when making pharmaceutical disinvestment decisions. These principles do not, however, provide practical guidance so we present a framework outlining how they might be applied to different types of disinvestment decisions. We also argue that, in this context, even the most rigorous ethical reasoning is likely to be overridden by moral intuitions and psychological biases and that disinvestment decisions will need to strike the right balance between respecting justifiable moral intuitions and overriding unjustifiable psychological impulses. (shrink)

The general aim of this article is to give a critical interpretation of post-trial obligations towards individual research participants in the Declaration of Helsinki 2013. Transitioning research participants to the appropriate health care when a research study ends is a global problem. The publication of a new version of the Declaration of Helsinki is a great opportunity to discuss it. In my view, the Declaration of Helsinki 2013 identifies at least two clearly different types of post-trial obligations, specifically, access to (...) care after research and access to information after research. The agents entitled to receive post-trial access are the individual participants in research studies. The Declaration identifies the sponsors, researchers and host country governments as the main agents responsible for complying with the post-trial obligations mentioned above. To justify this interpretation of post-trial obligations, I first introduce a classification of post-trial obligations and illustrate its application with examples from post-trial ethics literature. I then make a brief reconstruction of the formulations of post-trial obligations of the Declaration of Helsinki from 2000 to 2008 to correlate the changes with some of the most salient ethical arguments. Finally I advance a critical interpretation of the latest formulation of post-trial obligations. I defend the view that paragraph 34 of ‘Post-trial provisions’ is an improved formulation by comparison with earlier versions, especially for identifying responsible agents and abandoning ambiguous ‘fair benefit’ language. However, I criticize the disappearance of ‘access to other appropriate care’ present in the Declaration since 2004 and the narrow scope given to obligations of access to information after research. (shrink)

Increasing ethical attention and debate is focusing on whether individuals who take part in clinical trials should be given access to post-trial care. However, the main focus of this debate has been upon drug trials undertaken in low-income settings. To broaden this debate, we report findings from interviews with individuals (n = 24) who participated in a clinical trial of a closed-loop system, which is a medical device under development for people with type 1 diabetes that automatically adjusts blood glucose (...) to help keep it within clinically recommended ranges. Individuals were recruited from UK sites and interviewed following trial close-out, at which point the closed-loop had been withdrawn. While individuals were stoical and accepting of the requirement to return the closed-loop, they also conveyed varying degrees of distress. Many described having relaxed diabetes management practices while using the closed-loop and having become deskilled as a consequence, which made reverting back to pre-trial regimens challenging. Participants also described unanticipated consequences arising from using a closed-loop. As well as deskilling, these included experiencing psychological and emotional benefits that could not be sustained after the closed-loop had been withdrawn and participants reevaluating their pre- and post-trial life in light of having used a closed-loop and now perceiving this life much more negatively. Participants also voiced frustrations about experiencing better blood glucose control using a closed-loop and then having to revert to using what they now saw as antiquated and imprecise self-management tools. We use these findings to argue that ethical debates about post-trial provisioning need to be broadened to consider potential psychological and emotional harms, and not just clinical harms, that may result from withdrawal of investigated treatments. We also suggest that individuals may benefit from information about potential nonclinical harms to help make informed decisions about trial participation. (shrink)

The ethical value—and to some scholars, necessity—of providing trial patients with post-trial access (PTA) to an investigational drug has been subject to significant attention in the field of research ethics. Although no consensus has emerged, it seems clear that, in some trial contexts, various factors make PTA particularly appropriate. We outline the atypical aspects of psychedelic clinical trials that support the case for introducing the provision of PTA within research in this field, including the broader legal status of psychedelics, the (...) nature of the researcher-therapist/participant relationship, and the extended time-frame of the full therapeutic process. As is increasingly understood, the efficacy of psychedelic-assisted psychotherapy is driven as much by extrapharmacological elements and the cultural therapeutic container as by the drug itself. As such, we also advocate for a refocusing of attention from post-trial access to a broader concept encompassing other elements of post-trial care. We provide an overview of some of the potential post-trial care provisions that may be appropriate in psychedelic clinical trials. Although the World Medical Association’s Declaration of Helsinki calls on researchers, sponsors, and governments to make provisions for post-trial access, such provision may feel impracticable or out-of-reach within psychedelic trials that are already constrained by a high resource demand and significant bureaucratic burden. We show how conceiving of post-trial provision as an integral site of the research process, and an appropriate destination for research funding, will serve to develop the infrastructure necessary for the post-legalisation psychedelic medicine ecosystem. (shrink)

The principle of providing post-trial access for research participants to successful products of that research is widely accepted and has been enshrined in various declarations and guidelines. While recent ethical guidelines recognise that the responsibility to provide post-trial access extends to sponsors, regulators and government bodies as well as to researchers, it is the researchers who have the direct duty of care to participants. Researchers may thus need to act as advocates for trial participants, especially where government bodies, sponsors, and (...) regulatory bodies have complex interests vested in decisions about whether or not new interventions are made available, how, and to whom. This paper provides an empirical account of post-trial access in the context of HIV prevention research. It describes both access to the successful products of research and the provision antiretroviral drugs for trial participants who acquire HIV. First, we provide evidence that, in the current system, there is considerable variation in the duration and timeliness of access. We then argue that by analysing the difficulties faced by researchers to this point, and their efforts to meet this obligation, much can be learned about how to secure post-trial access in HIV biomedical preventions trials. While researchers alone have a limited obligation, their advocacy on behalf of trial participants may be necessary to call the other parties to account. (shrink)

In what sense, if any, are philosophers experts in their domain of research and what could philosophical expertise be? The above questions are particularly pressing given recent methodological disputes in philosophy. The so-called expertise defense recently proposed as a reply to experimental philosophers postulates that philosophers are experts qua having improved intuitions. However, this model of philosophical expertise has been challenged by studies suggesting that philosophers’ intuitions are no less prone to biases and distortions than intuitions of non-philosophers. Should we (...) then give up on the idea that philosophers possess some sort of expertise? In this paper, I argue that instead of focusing on intuitions, we may understand the relevant results of philosophical practice more broadly and investigate the other kind of expertise they would require. My proposal is inspired by a prominent approach to investigating expert performance from psychology and suggests where and how to look for expertise in the results characteristic of philosophical practice. In developing this model, I discuss the following three candidates for such results: arguments, theories, and distinctions. Whether philosophers could be shown to be expert intuiters or not, there are interesting domains where we could look for philosophical expertise, beyond intuitions. (shrink)

Objectives To analyse the perspective of clinical research stakeholders concerning post-trial access to study medication. Methods Questionnaires and informed consents were sent through e-mail to 599 ethics committee (EC) members, 290 clinical investigators (HIV/AIDS and Diabetes) and 53 sponsors in Brazil. Investigators were also asked to submit the questionnaire to their research patients. Two reminders were sent to participants. Results The response rate was 21%, 20% and 45% in EC, investigators and sponsors’ groups, respectively. 54 patients answered the questionnaire through (...) their doctors. The least informative item in the consent form was how to obtain the study medication after trial. If a benefit were demonstrated in the study, 60% of research participants and 35% of EC answered that all patients should continue receiving study medication after trial; 43% of investigators believed the medication should be given to participants, and 40% to subjects who participated and benefited from treatment. For 50% of the sponsors, study medication should be assured to participants who had benefited from treatment. The majority of responders answered that medication should be provided free by sponsors; investigators and sponsors believed the medication should be kept until available in the public health sector; EC members said that the patient should keep the benefit; patients answered that benefits should be assured for life. Conclusions Due to the study limitations, the results cannot be generalised; however, the data can contribute to discussion of this complex topic through analysing the views of stakeholders in clinical research in Brazil. (shrink)

This paper discusses the need to focus on the dignity of human participants as a legal and ethical basis for providing post-trial access to healthcare. Debate about post-trial benefits has mostly focused on access to products or interventions proven to be effective in clinical trials. However, such access may be modelled on a broad fair benefits framework that emphasises both collateral benefits and interventional products of research, instead of prescribed post-trial access alone. The wording of the current version of the (...) Declaration of Helsinki could in fact be interpreted to broaden the scope to include other collateral benefits by applying such a broad fair benefits framework. We argue that this possibility should be utilised by low and middle income countries’ health research ethics committees in order to ensure that research participants who enrol in clinical trials so as to receive medical care continue to access care after the trial is concluded, as befits their dignity. Although each LMIC has unique concerns, nonetheless there are common challenges based especially on emerging issues, such as post-trial access to healthcare. Accordingly, the South African perspective is used to draw lessons that can benefit other LMICs. (shrink)

En este trabajo desarrollo un modelo normativo sobre la obligación de continuidad de tratamiento beneficioso hacia los sujetos de investigación desde la perspectiva de la justicia social o distributiva, inspirado en la teoría de la justicia de John Rawls. Llamo a esto, el modelo de reciprocidad democrática. La idea original del modelo de reciprocidad democrática es defender que la obligación de continuidad de tratamiento beneficioso tiene como derecho correlativo el derecho a la salud. Así, dentro del marco rawlsiano, argumento que (...) las razones morales que dan peso a la obligación de continuidad de tratamiento beneficioso son, indirectamente, el principio de igualdad equitativa de oportunidades y, directamente, el derecho de justicia y/o el principio de equidad que se aplican a los miembros de una sociedad entendida como un sistema de cooperación social. (shrink)

Todos los días se prueban nuevos psicofármacos, tratamientos para el VIH/SIDA o el cáncer, entre otras enfermedades. Algunos de esos tratamientos son lo suficientemente exitosos como para cronificar enfermedades antes consideradas mortales, como los antirretrovirales para el VIH/SIDA o el imatinib para la leucemia mieloide a principios del 2000. No obstante, antes de que puedan ser comercializados o estar disponibles en los sistemas de salud pública, deben pasar por una serie de rigurosas pruebas de calidad, seguridad y eficacia. Estas pruebas (...) implican el testeo de las drogas en animales y su estudio en seres humanos, sanos o enfermos. Estrictas normas de buenas prácticas científicas y éticas regulan todo el proceso de las investigaciones biomédicas. El problema de mi tesis se centra en el momento de la finalización de los estudios en seres humanos. Alguien podría preguntarse qué pasa con las personas si se benefician clínicamente del tratamiento experimental durante el estudio cuando este finaliza. La interrupción abrupta de un tratamiento beneficioso podría poner en peligro la salud de los sujetos. Y en el caso de sujetos de investigación afectados por enfermedades crónicas, es probable que deban continuar con el tratamiento beneficioso u otra atención adecuada por el resto de sus vidas. Un sujeto de investigación estadounidense sin seguro de salud que participó en un estudio de largo plazo de diabetes resume estas preocupaciones: "de repente cortan la cuerda, y uno está solo por su cuenta ... O conseguís trescientos o cuatrocientos dólares por mes para seguir con esto o simplemente seguís adelante y morís". Este tipo de casos me llevaron a preguntar si existe alguna obligación moral de proveer el tratamiento beneficioso a un sujeto de investigación que no puede pagárselo. Muchas personas podrían pensar que interrumpir el tratamiento beneficioso al sujeto de investigación que padece de diabetes y no tiene seguro para cubrir un tratamiento es incorrecto, porque nadie debería morir de una enfermedad o dedicar todos los recursos disponibles para sobrevivir, especialmente cuando se contribuyó a encontrar una cura o a obtener la evidencia científica necesaria para desarrollar un mejor tratamiento que el existente. Otras personas podrían pensar que lo correcto es ofrecer el tratamiento a un "precio justo", y si la persona no puede pagar por la continuidad de tratamiento es su responsabilidad. Mi intuición es que una sociedad democrática justa tiene una obligación moral de establecer un sistema de continuidad de tratamiento beneficioso para los sujetos de investigación. En esta tesis intento justificar filosóficamente esta última intuición básica utilizando el marco teórico de la teoría de la justicia de Rawls. Elijo utilizar la teoría rawlsiana, porque esta teoría me permite ubicar los problemas morales con respecto a la continuidad de tratamiento beneficioso en su contexto social adecuado y en el contexto de la búsqueda general de una sociedad más justa. En particular, la encuentro especialmente adecuada para explicar fenómenos complejos de responsabilidad social como los que creo que subyacen en el problema de la obligación de continuidad de tratamiento beneficioso hacia los sujetos de investigación. Como mostraré más adelante, es imposible tener en cuenta los aspectos morales de la continuidad de tratamiento beneficioso aislada de la sociedad en la que se realizan los estudios con seres humanos. En el capítulo 1 presento una introducción general al tema de la ética de la investigación y al problema de la continuidad de tratamiento beneficioso. En el capítulo 2 intento determinar el campo de estudio de la obligación de continuidad de tratamiento beneficioso hacia los sujetos de investigación. Para eso, mi estrategia es la siguiente. Primero, busco identificar los casos de estudios clínicos donde se daría la obligación de continuidad beneficiosa hacia los sujetos de investigación. Segundo, presento el problema de la justificación moral de la obligación de continuidad y la necesidad de discutir las justificaciones basadas en la idea de justicia como reciprocidad. Para esto, en la sección 2, identifico la obligación de continuidad de tratamiento a través de una selección de sus casos paradigmáticos en la literatura. Comienzo con el caso de los estudios clínicos con antirretrovirales llevados a cabo en Sudáfrica en personas con VIH/SIDA. Luego, introduzco el concepto teórico de sistema de continuidad de tratamiento beneficioso. Este concepto me permite evaluar y comparar teóricamente cómo diferentes sociedades hacen frente al problema de proveer la continuidad de tratamiento beneficioso a los sujetos de investigación. Por último, rastreo los casos ejemplares de obligación de continuidad de tratamiento beneficioso hacia los sujetos en países desarrollados, con énfasis especial en los Estados Unidos. En la sección 3, analizo algunos problemas de confusión o ambigüedad más importantes en torno a la obligación. Primero, analizo el nombre de la obligación. Luego, trato de distinguir la obligación de continuidad de tratamiento hacia los sujetos de investigación de la obligación de disponibilidad razonable, una confusión muy común en la literatura de la ética de la investigación. Finalmente, me detengo a analizar una posible ambigüedad en el concepto de "tratamiento beneficioso" y utilizo algunos de los casos paradigmáticos identificados para argumentar a favor de mi interpretación. Atacado el primer problema, en la sección 4 y 5 me vuelco a relevar el problema de la justificación moral de la obligación de continuidad. En la sección 4, reconstruyo lo que llamo la "versión simple" del concepto de obligación a partir de la discusión sobre las fuentes de la obligación de continuidad de tratamiento beneficioso. Luego, planteo la necesidad de investigar las justificaciones basadas en la idea de justicia como reciprocidad debido a las ambigüedades y la falta de un marco teórico claro dentro del campo de la ética de la investigación en seres humanos. Finalmente, en la sección 5, introduzco algunas distinciones clásicas con el fin de complejizar el marco teórico de las obligaciones, el cual será utilizado en la discusión de los próximos dos capítulos. En el capítulo 3 discuto la justificación de la obligación de continuidad de tratamiento que da el modelo económico de Alan Wertheimer. En la sección 1 del capítulo, debido a lo específico del tema y lo poco conocido del autor, introduzco a la persona y el contexto institucional de su obra. En la sección 2 del capítulo, distingo tres interpretaciones del concepto de justicia como reciprocidad e intento mostrar que Wertheimer utiliza una interpretación caracterizada por el uso mutuo y el intercambio de beneficios, a la cual llamo "reciprocidad de mercado". En la sección 3, presento el marco teórico del modelo económico. La pregunta fundamental de Wertheimer es la siguiente: ¿tienen los investigadores o patrocinadores una obligación supercontractual de proporcionar la continuidad de tratamiento u otros beneficios a los sujetos de investigación? Según el autor, el consenso en ética de la investigación responde de manera afirmativa a esta pregunta y como fundamento de esta obligación se encontraría lo que Wertheimer llama "el principio de interacción". Analizo este principio y presento las críticas que hace Wertheimer al mismo. En la sección 4, presento la respuesta a la pregunta fundamental que da Wertheimer mediante su "argumento estratégico". En la sección 5 analizo la solución dada por Wertheimer e intento explicar algunos de los supuestos principales del modelo, a saber, (i) la lógica del argumento estratégico, (ii) la fuerza moral de los conceptos de Pareto y (iii) el compromiso del modelo económico con la restricción de la información. Por último, en la sección 6 presento mis críticas al modelo económico. En el capítulo 4 presento el modelo de reciprocidad democrática, inspirado en la teoría de la justicia de Rawls. Este modelo se presenta como un marco teórico y una interpretación de la justicia como reciprocidad alternativos al modelo económico presentado en el capítulo anterior. En la sección 2 del presente capítulo, explicito los problemas del marco teórico relacionados con el concepto de justicia como reciprocidad que subyacen a la discusión sobre la obligación de continuidad de tratamiento beneficioso hacia los sujetos de investigación. Para esto, me centro en tres puntos: (i) la relación del principio de justicia como reciprocidad y el concepto de obligación; (ii) el problema del alcance del principio de reciprocidad, y (iii) la relación entre el principio de reciprocidad y el concepto de equidad, o lo que llamo "el problema de la medida de la reciprocidad". En la sección 3, defino con mayor claridad el enfoque rawlsiano de la justicia distributiva y expongo una crítica a los argumentos antirrawlsianos esgrimidos por los defensores del modelo económico que afirman que los principios de justicia política de Rawls no se aplican a los individuos. Si mi respuesta a los defensores del modelo económico es correcta, los principios de justicia política se aplican a los individuos de manera indirecta, mediante la asignación de obligaciones posicionales por parte de la estructura básica de instituciones de una sociedad democrática, y permiten garantizar igual justicia a todos los miembros de la sociedad. En la sección 4, presento mi propuesta original de cómo entender la obligación de continuidad de tratamiento beneficioso hacia los sujetos de investigación. Esta sería una obligación posicional perfecta correlativa con el derecho a la salud en sociedades democráticas justas o moderadamente injustas. En la sección 5, muestro de manera detallada el mecanismo apropiado para extender los principios de justicia política al caso de la obligación de continuidad de tratamiento beneficioso hacia los sujetos de investigación. Con este objetivo, introduzco la idea de secuencia en cuatro etapas, que permite evaluar y diseñar nuevos esquemas institucionales para dar contenido a la obligación de continuidad de tratamiento. Y presento los principios de obligaciones y deberes individuales, que cierran el sistema rawlsiano brindando razones morales a los individuos para extender los esquemas institucionales justos a nuevas situaciones, reformar los existentes y cumplir con las obligaciones posicionales asignadas por estos nuevos esquemas. Por último, en la sección 6, discuto las objeciones más importantes al modelo de justificación de reciprocidad democrática. Por último, en la conclusión general, hago un intento de aplicación del marco teórico del modelo de reciprocidad democrática al análisis de los sistemas de continuidad de tratamiento para países como Argentina o Brasil y presento las líneas más importantes para la investigación futura. (shrink)

This collection presents six case studies on the ethics of mental health research, written by scientific researchers and ethicists from around the world. We publish them here as a resource for teachers of research ethics and as a contribution to several ongoing ethical debates. Each consists of a description of a research study that was proposed or carried out and an in-depth analysis of the ethics of the study.