La finalización anticipada de ensayos clínicos bajo la lupa

En el Annals of Oncology aparece un muy interesante trabajo de Trotta y col. quienes revisan los criterios y procedimientos para la suspensión anticipada de ensayos clínicos. En general se acepta que si en el transcurso de un protocolo el Comité de Monitoreo de Seguridad (DSMB) advierte que el medicamento o procedimiento evaluado es evidentemente muy bueno, o claramente perjudicial, se justifica suspender el desarrollo. Sin embargo la revisión de Trotta pone esto en debate, al mostrar que la suspensión muchas veces es injustificada, sobre todo si se postula que es porque el medicamente es claramente beneficioso. Esto está relacionado con el hecho de que muchos de esos protocolos son luego utilizados por la industria para gestionar el registro de los medicamentos evaluados.

Stopping a trial early in oncology: for patients or for industry? — Trotta et al., 10.1093/annonc/mdn042 — Annals of Oncology

En su conclusión Trotta et al plantean

Truncated RCTs reported as having been stopped early for benefit are becoming more frequent. Our findings highlight a consistent increase (>50%) in prematurely stopped trials in oncology during the last 3 years in comparison to whole period analysed (1997–2007).

Ethical reasons also play a role in the decision to stop a trial, since there is a responsibility to minimise the number of people given an unsafe, ineffective, or clearly inferior treatment. On the other hand, an interim analysis may also have drawbacks, since stopping trials early for apparent benefit will systematically overestimate treatment effects [32].

The studies analysed were formally well designed; all were randomised, controlled, on the basis of robust end points, and with a large sample size. Though criticism of the poor quality of oncological trials seems out of place, unfortunately early termination raises new important concerns. Our findings lead to a new awareness: oncological trials are now formally better designed than in the past, but they are too often stopped prematurely. This may cause harm resulting from unreliable findings prematurely translated into clinical practice. More than 85% of the RCTs published in the last 3 years with an interim analysis ending the trial were used for registration purposes. This suggests a commercial component in stopping trials prematurely.

Regarding the methodology used to conduct the interim analyses, sample sizes used to obtain the interim efficacy results varied widely. Substantial concern is raised by five studies which enrolled <40% of the sample planned for final analysis. It is obvious that the risk of overestimating treatment effects increases markedly when the sample is small. Therefore, it is very important to insist that a large number of events must occur before investigators or DSMCs examine interim data, although that cannot guarantee data reliability in any case. In addition, the heterogeneity in sample sizes indicates that these committees enjoy ample discretion in advising or deciding whether to stop a clinical trial early for benefit.

Statistical simulations have shown that RCTs can overestimate the magnitude of the treatment effect depending on the timing of the decision to stop (i.e. the fraction of the total planned sample size or expected number of events) [33]. Furthermore, repeated interim analyses at short intervals raise concern about data reliability: this strategy risks looking as though it is seeking the statistical significance necessary to stop a trial. In addition, repeated analyses on the same data pool often lead to statistically significant results only by chance [34, 35].

If a trial is evaluating the long-term efficacy of a treatment of conditions such as cancer, short-term benefits, no matter how significant statistically, may not justify early stopping. Data on disease recurrence and progression, drug resistance, metastasis, or adverse events, all factors that weight heavily in the benefit/risk balance, could easily be missed. An early stop may reduce the likelihood of detecting a difference in overall survival (the only relevant end point in this setting) because of the small sample, the possibility of crossing-over the experimental drugs, and contamination with other treatments.

Interim analysis data should always be evaluated by a DSMC, which should be independent in the sense that the members should have no interests in the study and should not directly participate in it. Although the majority of RCT reports stated there was a DSMC, we believe that its independence should always be reported. Stopping a trial after an interim analysis is often motivated by ethical considerations. The large number of patients spared (40%), as evidenced by our analysis, might support this. However, the relation between sparing patients and saving time and trial costs is also unquestionable and indicates that there is also a market-driven intent. Our findings show that only a very small percentage of trials (4%) were stopped early because of harm, i.e. serious adverse events, which is quite acceptable. Therefore, toxicity does not represent the main factor leading to early termination of trials.

Stopping a trial early does not guarantee that patients will receive the apparently beneficial treatment—assuming one believes they should—if study findings are not immediately publicly disseminated. We found long delays between study termination and published reports (2 years), possibly because of confidentiality concerns in light of the current regulatory process. If the trials had continued for these further 2 years, more efficacy and safety data could have been gathered. In addition, such delays further lengthen the time needed for translating trial findings into general practice.

The study suffers one main limitation: since there is no ‘standard’ for reporting interim analysis methodology in scientific journals, there may have been some heterogeneity in this respect and some information might have been missed, affecting the sensitivity of the analysis. This could be overcome if study protocols were publicly available and details of interim analysis were reported better in peer-reviewed journals, e.g. by adoption of the Consolidated Standards of Reporting Trials statement.

In conclusion, a decision whether to stop a clinical trial before its completion requires a complex of ethical, statistical, and practical considerations, indicating that results of RCTs stopped early for benefit should be viewed with criticism and need to be further confirmed. The main effect of such decisions is mainly to move forward to an earlier-than-ideal point along the drug approval path; this could jeopardise consumers’ health, leading to unsafe and ineffective drugs being marketed and prescribed. Even if well designed, truncated studies should not become routine. We believe that only untruncated trials can provide a full level of evidence which can be translated into clinical practice without further confirmative trials.

Como puede apreciarse, es necesario que un comité pueda evaluar no solo los puntos de corte propuestos para un ensayo (lo cual ya es bastante complejo), sino también los posibles términos de suspensión anticipada del mismo. Tanto la suspensión anticipada como la prolongación innecesaria o riesgosa son claras situaciónes problemáticas desde el punto de vista ético (y del bienestar de las personas que participan).

Los comités de ética en investigación ¿funcionan bien y sirven para algo?

Es una duda que nos plantean Carl Coleman y Marie-Charlotte Bouesseau, en el BMC Medical Ethics. En el trabajo How do we know that research ethics committees are really working? the neglected role of outcomes assessment in research ethics review intentan una aproximación a respuestas válidas.

Abstract

Background
Countries are increasingly devoting significant resources to creating or
strengthening research ethics committees, but there has been insufficient attention to assessing whether these committees are actually improving the protection of human research participants.

Discussion
Research ethics committees face numerous obstacles to achieving their goal of improving research participant protection. These include the inherently amorphous nature of ethics review, the tendency of regulatory systems to encourage a focus on form over substance, financial and resource constraints, and conflicts of interest. Auditing and
accreditation programs can improve the quality of ethics review by encouraging the development of standardized policies and procedures, promoting a common base of knowledge, and enhancing the status of research ethics committees within their own institutions. However, these mechanisms focus largely on questions of structure and
process and are therefore incapable of answering many critical questions about ethics committees’ actual impact on research practices.
The first step in determining whether research ethics committees are achieving their intended function is to identify what prospective research participants and their communities hope to get out of the ethics review process. Answers to this question can help guide the development of effective outcomes assessment measures. It is also important to determine whether research ethics committees’ guidance to investigators is actually being followed. Finally, the information developed through outcomes assessment must be disseminated to key decision-makers and incorporated into practice.
This article offers concrete suggestions for achieving these goals.

Conclusions
Outcomes assessment of research ethics committees should address the following questions: First, does research ethics committee review improve participants’ understanding of the risks and potential benefits of studies? Second, does the process affect prospective participants’ decisions about whether to participate in research? Third, does it change participants’ subjective experiences in studies or their attitudes about
research? Fourth, does it reduce the riskiness of research? Fifth, does it result in more research responsive to the local community’s self-identified needs? Sixth, is research ethics committees’ guidance to researchers actually being followed?

Ver en http://www.biomedcentral.com/1472-6939/9/6

LJ

Más ejemplos de ensayos clínicos antiéticos

En la misma página holandesa (del Centre for Research on Multinational Corporations, SOMO -en holandés-) hay un listado y análisis de ensayos clínicos antiéticos, incluyendo varios de América Latina.

Examples of unethical trials en:

http://www.somo.nl/index_eng.php

Buscar en las publicaciones del 2008

LJ

Las autoridades reguladoras estadounidenses y europeas exigen el uso de placebos y entonces…

…los ensayos clínicos se terminan haciendo en Europa Oriental, Asia y América Latina.  

Así lo demuestra el detallado estudio holandés “Ethics for Drug Testing in Low and Middle Income Countries”, hecho por Irene Schipper y Francis Weyzig, que resulta de lectura obligatoria para integrantes de comités de ética en investigación latinoamericanos.

Las conclusiones del resumen ejecutivo son:

Two overall conclusions are drawn from this research.
1) European authorities not only grants EU market authorisation based on unethical clinical trials, they actually induce the offshoring of unethical trials to countries outside Western Europe, by requiring trials that are rejected by the ethics committees in Western Europe, resulting in the fact that these trials mainly ends up in low and middle income countries like Central and Eastern Europe, Latin America and Asia (India and China). The research of SOMO shows that this is indeed the case with placebo-controlled studies in which stable patients and acutely ill patients diagnosed with schizophrenia and acute mania; these studies take place outside Western Europe almost exclusively.
2) The degree of transparency about clinical trials in low and middle income countries is low, both with regard to the number of trials covered in public databases and with regard to the amount of information on ethical considerations for each trial. Voluntary initiatives of the pharmaceutical industry to increase transparency about clinical trials
have clearly been insufficient in this respect. Information from national medicines agencies in EU member states is limited too, even though current EU legislation requires that all assessment reports be published without delay.

Se puede bajar de http://www.somo.nl/index_eng.php

LJ

No trataríamos a un animal así…

…dice Udo Schüklenk en su Ethx Blog

Wednesday, March 19, 2008

We would not treat an animal like that …

French woman Chantal Sebire died at the age of 52 at her home near Dijon. Sebire suffered from a rare form of cancer that disfigured her entire face, eventually robbing her of her eyesight, capacity to smell, and that left her in severe pain.
Sebire campaigned during her last months for her right to died a death with dignity, in other words, she requested that France permit her doctors to help her die. Voluntary euthanasia as well as any other form of euthanasia is illegal in France, hence her request was denied. As the court in Dijon, in rejecting her plea pointed out, ‘Even if the physical degeneration of Madame Sebire merits compassion, this request can only be rejected under French law.’
As Ms Sebire pointed out, ‘One would not allow an animal to go through what I have endured.’ The BBC reports, ‘Legislation adopted in 2005 allows families to request that life-support equipment for terminally ill patients be switched off, but does not allow a doctor to take action to end a patient’s life.’
Yet another example where zealot pro-life legislation trumps the decisions of competent individuals who make a voluntary decision to end their lives when they see fit. Sebire is right, we would not permit an animal to be treated as she was. She mentions that children eventually ran away from her when she walked in the streets of Dijon, while she was still capable of doing so. A truly tragic case.

Posted by Udo Schuklenk’s Ethx Blog at 7:21 PM

Gracias Udo, por la reflexión.

LJ

Una nueva estafa moral de la industria farmacéutica: los antidepresivos a la luz de los resultados no publicados de los estudios clínicos

Empresas farmacéuticas e investigadores suelen unirse en sus lamentos por la creciente dificultad al intentar reclutar pacientes para sus ensayos clínicos. Esto ha llevado a algunos autores a recomendar que participar en la investigación de nuevos productos debería ser obligatorio para los pacientes (Rhodes 2005, Orentlicher 2005) . Si la investigación clínica en la actualidad fuera un emprendimiento de la humanidad destinado a producir un conocimiento generalizable y útil para el conjunto de la sociedad, quizás (y con reservas), podría admitirse la obligación moral de participar en la misma, en la medida en el conjunto social se beneficiaría y, después de todo, los actuales enfermos reciben el beneficio de aquellos que anteriormente han aceptado solidariamente participar. Sin embargo, una mirada a las prácticas antiéticas de la industria farmacéutica, simbióticamente unida al sector académico y a la educación médica de posgrado, demuestra claramente que la desconfianza creciente de la población está ampliamente justificada. Agentes lúcidos del sistema de mercado como la consultora internacional Price, Waterhouse & Cooper indican los problemas que debería resolver el sector pharma para recupérar su “buen nombre”.

 

Fuente: Pharma 2020: The vision. Which path will you take? Página 25, PriceWaterhouseCoopers, 2007. Bajar de: http://tinyurl.com/2s93og

 

Entre las prácticas antiéticas figura la no publicación de los resultados de ensayos clínicos poco favorables, lo que tiene gravísimas consecuencias para la salud pública. El trabajo de Kirsch y col. demuestra como, cuando se incluyen TODOS los resultados de los ensayos clínicos, los que parecían medicamentos útiles para una enfermedad, en realidad no lo son, excepto en casos muy específicos. Uno no puede menos que preguntarse ¿para que sirve la FDA, si todos los casos de este tipo en los últimos años fueron descubiertos por académicos de afuera?

 

Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Irving Kirsch, Brett J. Deacon, Tania B. Huedo-Medina, Alan Scoboria, Thomas J. Moore, Blair T. Johnson

Background

Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.

El trabajo completo se puede bajar de http://tinyurl.com/2fxozc

LJ

El llanto farmacéutico

Las farmacéuticas suelen quejarse del “alto costo” de la investigación que hacen, e intentan justificar sus precios y las patentes en ese hecho. Sin embargo, esto es falso. Gastan el doble en marketing que en investigación. Pero además, los países “en desarrollo” son una muy pequeña parte de sus mercados (menos del 15%), por lo que sus presiones sobre los gobiernos que utilizan el mecanismo de introducción de genéricos por razones de salud pública no tiene ninguna justificación.
Para más datos leer lo siguiente, y ver el trabajo de Gagnon y Lexchin (cita 3), y el informe de Fortune 500 (cita 4) que ubica a las empresas en el segundo lugar en retorno (luego del petróleo).

Essential Action’s
Global Access to Medicines Bulletin
Issue No. 2, February 14, 2008

Whenever developing countries seek to improve access to essential medicines by hastening the introduction of generic competition and reducing prices, they invariably must confront a single overriding claim: their actions will undermine incentives for research and development (R&D) of important new drugs.

“PhRMA is deeply troubled by the recent trend toward the issuance of compulsory licenses for pharmaceutical products,” said Billy Tauzin, President and CEO of PhRMA, the U.S. pharmaceutical companies’ trade association, in 2007.Tauzin’s statement followed Thailand’s decision to import significantly cheaper generic versions of three life-saving drugs and Brazil’s decision to use the generic version of a key treatment for HIV/AIDS. “This misguided focus on short-term ‘budget fixes’ could come at a far greater long-term cost, potentially limiting important incentives for research and development that are necessary to positively impact the lives of millions of patients worldwide.”[1]

It is expensive to develop new drugs, but not nearly as costly as the pharmaceutical industry suggests.

Pharma R&D by the Numbers

Numerous independent studies and investigations[2] show that the world’s largest drug companies’ R&D spending claims are misleading and overblown, and that they spend much more on marketing than on R&D for new products. These findings undermine the pharmaceutical industry’s repeated assertion that high drug prices are justified by the cost of research, and that generic competition in the developing world will undermine the industry’s ability to develop new treatments.

Although PhRMA asserts that U.S. brand-name pharmaceutical companies invest more in R&D than marketing, independent investigators reach different conclusions. A January 2008 article, published in the peer-reviewed journal PLoS, concluded that U.S. drug companies spent almost twice as much on marketing as on R&D.[3] Researchers Marc-Andre Gagnon and Joel Lexchin of York University in Toronto, found that U.S. companies spent 24.4% of their U.S. sales on marketing and 13.4% on R&D in 2004. U.S. sales that year totaled US$235.4 billion. Gagnon and Lexchin based their findings on data and estimates drawn from industry sources.

“These numbers clearly show how much promotion predominates over R&D in the pharmaceutical industry, contrary to the industry’s claim,” wrote Gagnon and Lexchin. “[This] confirms the public image of a marketing-driven industry and provides an important argument to petition in favor of transforming the workings of the industry in the direction of more research and less promotion.”

And while companies argue that high drug prices are necessary to cover the cost of R&D - implying that companies make only modest profits after the cost of R&D is paid for - pharmaceuticals remain one of the world’s most profitable industries. The industry’s 2006 return on investment was 19.6 percent, according to Fortune, second only to the oil and mining industry.[4] Pharmaceuticals almost always rank in the top three industry sectors by this measure.

Current R&D incentives often result in limited health benefits as well as high prices

The investments that Big Pharma does make in R&D are driven by market demand, not public health need. One result is a surplus of “me-too” drugs, treatments that are similar to existing products and offer limited therapeutic benefits over existing medicines.

When new drugs are submitted to the U.S. Food and Drug Administration (FDA) for marketing approval, the agency classifies them as meriting either “priority review” (conferred for drugs that offer “major advances in treatment, or provide a treatment where no adequate therapy exists”) or “standard review” (applied to a drug that offers “at most, only minor improvement over existing marketed therapies”). Only about one third of FDA approvals are “priority.”[5]

Other reviews find that only about one in ten new drugs offer substantial therapeutic gains:

Between 1999 and 2004, 122 new active substances were introduced into Canada. Only 10 percent were designated as major therapeutic advances or breakthrough products, according to a report by the Patented Medicine Prices Review Board of Canada.[6]

Since 1981, Prescrire, a leading review offering independent comparative information on drugs and other therapeutic interventions has been evaluating new drugs and new indications for older drugs. By 2003, it had done almost 2900 such assessments and found that only 11 percent of medications constituted substantial advances.[7]

Developing country markets only a fraction of Pharma’s sales

Big Pharma is very concerned about developing country markets, where drug sales are growing at a faster clip than in rich countries. However, it remains the case that developing countries represent only a small fraction of Big Pharma’s revenues. Developing country markets account for less than 13 percent of global pharmaceutical sales, according to IMS Health. Slightly more than 1 percent of sales are attributed to Sub-Saharan Africa, the world’s poorest region.[8]

Any lost revenue from developing countries therefore by definition can only have a limited impact on Big Pharma’s capacity to undertake R&D.

The limited contribution that developing countries are now making to Pharma’s R&D budget opens the possibility of exploring new methods of funding R&D.[9] Developing countries should be able to pay a fair share of drug development costs through means other than high drug prices unaffordable to most people in those countries.

Web links:
[1]www.phrma.org/news_room/press_releases/phrma%3a_compulsory_licensing_trend_dangerous/
[2] www.cptech.org/ip/health/econ/rndcosts.html
[3]http://medicine.plosjournals.org/perlserv/?request=getdocument&doi=10.1371%2Fjournal.pmed.0050001&ct=1
[4]http://money.cnn.com/magazines/fortune/fortune500/2007/performers/industries/return_on_revenues/index.html
[5] www.fda.gov/oashi/fast.html
[6] www.pmprb-cepmb.gc.ca/english/view.asp?x=653&all=true
[7] www.prescrire.org/
[8] www.imshealth.com/ims/portal/front/articleC/0,2777,6599_80528184_80528215,00.html
[9] www.who.int/phi/en/

Published by Essential Action’s Access to Medicines Project
P.O. Box 19405, Washington, DC, 20036, USA
Tel: (1) (202) 387-8030
www.essentialaction.org/access/

Boletín Fármacos Vol 11, No 1, enero de 2008

Ética y Derecho

Investigaciones

- Investigación clínica en países en desarrollo
Emilio Pol Yanguas

América Latina
-Argentina: Un fallo judicial dictaminó que una empresa de medicina prepaga no podía sustituir un fármaco

-Bolivia: Salud multa a tres laboratorios por publicitar adelgazantes
-Chile, ¿tierra de conejillos de Indias?
-Puerto Rico: Cuestionan reclutamiento para uno de los ensayos por vacuna para el dengue

Europa

-Unión Europea: Plataforma contra la medicalización de la infancia

Estado Unidos

-Ejecutivos de compañías farmacéuticas ayudarán en la dirección de la Fundación Reagan-Udall ligada a la FDA
-FDA envía una advertencia a GlaxoSmithKline por publicidad engañosa de Tykerb
-Una práctica de la industria farmacéutica ante los tribunales
-Ensayos y tribulaciones ¿Cómo la FDA no consigue supervisar adecuadamente los experimentos en humanos?
-Ocultan que los antidepresivos no son tan eficaces
-El Congreso estudia los resultados de un ensayo con medicamentos para el colesterol (ezetimibe)
-Hoodia: El último de una serie de fraudes dietéticos

Asia y África
-Nigeria: Continúan las actuaciones contra Pfizer

-China: Continúan los procesamientos por sobornos y se estudian nuevas regulaciones

Generales
-Roche presentó su “Código de buenas prácticas en relación con las asociaciones de pacientes”

-La industria farmacéutica se apropió de las consultas públicas que realizó la OMS a través de la web
-La ética no entra al laboratorio
-Pacientes ignorados: La asignatura pendiente de los ensayos clínicos
-Ezetimibe: Cardiólogos cuestionan el atraso en la publicación de la información sobre hipocolesterolemiantes
-Un experto en diabetes acusa a una compañía farmacéutica de haberlo intimidado

Documentos y libros nuevos, y congresos / cursos

Revista de Revistas
-Medicamentos para la osteoporosis: ¿prevención o enfermedad inventada?
Ainhoa Iriberri, Exceso de fármacos para mujeres sanas, Publico.es (España), 17 de enero de 2008, que hace referencia al siguiente artículo: Alonso-Coello P et al., Drugs for pre-osteoporosis: prevention or disease mongering? BMJ 2008;336;126-129.
- Responsabilidad del patrocinador después de un ensayo clínico
Benites Estupiñán E, Acta bioeth 2006;12(2):251-255.
-Registro de ensayos clínicos: Una discusión internacional y las posiciones posibles para Brasil
Traducido por Boletín Fármacos de: da Rocha Carvalheiro J, Quental C, Registro de ensaios clínicos: a discussão internacional e os posicionamentos possíveis para o Brasil, R Eletr de Com Inf Inov Saúde (RECIIS) 2007;1(1):63-69.
- Publicación selectiva de ensayos clínicos con antidepresivos y su influencia en la eficacia aparente
Traducido por Boletín Fármacos de: Turner EH et al., Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252-60.

Ver acá

Nuestras miradas, nuestras realidades (IX)

Desde México Ricardo Páez y Javier García de Alba escriben un interesantísimo trabajo sobre la distribución de beneficios en la investigación internacional.

INTERNATIONAL RESEARCH AND JUST SHARING OF BENEFITS IN MEXICO
Developing World Bioethics (OnlineEarly Articles). 2008.

ABSTRACT

International research enrolling human subjects has raised an ethical concern regarding the just distribution of benefits between the countries that design the research and the host communities. Although several universal declarations have expressed this concern, a gap between theory and practice continues to exist, as well as a significant divergence between the design of the research protocol and the social context where it will be implemented. Although institutional review boards have made a valuable effort to evaluate international research, their sensitivity to the just sharing of research benefits as well as their attention to the social context must be evaluated. This article analyzes the distribution of benefits in a review of international research in Mexico and produces an ethical reflection based on the results.

La dirección para comunicarse es Ricardo Páez, MD, MS, Missionaires of the Holy Spirit Novitiate, Apdo. Postal 6, 76900 Corregidora, Querétaro, México. noviciadoqro@msps.org; ricardomsps@yahoo.com

El abstract se puede encontrar en www.blackwell-synergy.com/loi/dewb

LJ

Salió Medicina Social/Social Medicine Vol 3, No 1

Vol 3, No 1 (200

Ignaz Semmelweis y la Mortalidad Materna

Tabla de contenidos

Editoriales

“La nueva salud global”. La reversión de lógica, historia y principios
PDF

Alison Katz
1-4

Clásicos en Medicina Social

Reporte sobre la epidemia de tifo en Alta Silesia
PDF

Rudolf Virchow
5-20

La etiología, concepto y profilaxis de la fiebre puerperal
PDF

Ignaz Semmelweis
21-29

Medicina Social en la Práctica: Estudios de Casos de Activismo en Salud

MEDICC en Cuba: Una entrevista con C. William Keck y Gail Reed
PDF

Los Editores
30-36

Temas y Debates

De Alma Ata al Fondo Global: La historia de las políticas internacionales de salud
PDF

Observatorio Global de Salud Italiano
37-52

Lecciones de Ignaz Semmelweis. Una actualización epidemiológica y social para la maternidad segura
PDF

Julie Cwikel
53-73

Noticias y eventos

Declaración pública de la Asociación Latinoamericana de Medicina Sosical, ALAMES-Uruguay
PDF

Fernando Borgia
74-77

Rincón de los editores

Número especial sobre atención a la salud en Venezuela
PDF

Joan Paluzzi
78