PLoS Medicine - Communicating the Results of Clinical Research to Participants: Attitudes, Practices, and Future Directions

Communicating the Results of Clinical Research to Participants: Attitudes, Practices, and Future Directions

David I. Shalowitz*, Franklin G. Miller

Una interesante revisión del tema, con resultados no definitorios (lo que es razonable), y con buena bilbiografía para los interesados en el tema.

Shalowitz y Miller comienzan la discusión diciendo:
“As we have conducted a narrative review of studies concerning
communicating research results to participants, rather than a
systematic review, definitive conclusions about findings and their
ethical import cannot be drawn. Nevertheless, the data reviewed here
suggest several important implications. Available data consistently
indicate that research participants want aggregate and clinically
significant individual study results made available to them.
Participants’ desires do not necessarily determine policy, but respect
for participants requires taking their preferences seriously. Though
investigators appear to support the communication of aggregate study
results, less is known about investigators’ attitudes towards
communicating individual research results or about the costs and time
required to do so. Future research should focus on these issues,
including ways to facilitate communication of results by addressing
investigators’ concerns.”

Fuga de datos de millones de chilenos en internet

Fuga de datos de millones de chilenos en internet

SANTIAGO.- Los datos de unas seis millones de personas, incluidos teléfonos, direcciones personales y registro tributario, circulan en internet desde hace dos días; una fuga de información sensible que revela las vulnerabilidad del sistema chileno, según expertos.

Las planillas, filtradas en internet por un hacker que se identificó como “cobarde anónimo”, podían aún obtenerse ayer en la web.

Desde el momento en que la información fue divulgada hasta ser denunciada y levantada por los administradores de la página web utilizada por el pirata, muchos alcanzaron a retomarla y luego la han hecho circular por la web, explicó Leo Prieto, director de Fayerwayer, el sitio en cuestión. “Sí, los datos aún están disponibles en la web e incluso algunos medios han cometido el error de republicarlos”, señaló.

Las autoridades respectivas, indicaron que es posible que no haya habido una intromisión ilegal a un servidor -lo cual es un delito- sino que los datos pudieron haber sido comercializados por otra vía, lo cual no está penado por la ley chilena.

Por ejemplo, los datos del registro electoral pueden ser comercializados. “Si se entrega una información para un fin no se puede utilizar para otros. Eso es materia de ley. Hemos estado trabajando en esta iniciativa y en las próximas semanas esperamos mandarla al congreso”, dijo el Subsecretario de Telecomunicaciones, Pablo Bello. (AFP)

En entradas anteriores hemos alertado sobre los proyectos de bases de datos que circulan por nuestros países. Como se puede ver, además de poder constituirse en peligrosos mecanismos de control, son inseguros, de modo tal que es muy difícil el control de la confidencialidad de los datos que se incluyan.

LJ

…y solo exige que se cumpla con las GCP!

Ver: Integrity in Science Watch Week of 05/05/2008 en http://www.cspinet.org/integrity/watch/index.html#2

FDA Scraps Helsinki Declaration on Protecting Human Subjects

Drug companies got a green light last week to start using data from
foreign clinical trials in new drug applications even if the trials
only compare new products to placebos instead of best available
treatments. The change marks a sharp departure from the 1989
Declaration of Helsinki protecting human subjects in clinical research,
the Food and Drug Administration’s previous standard. The new rule,
which goes into effect next October, was pushed by drug and device
manufacturers, but opposed by numerous public interest, patient
advocacy, and consumer groups. The Declaration of Helsinki “is the
standard-bearer for international research ethics and enjoys particular
respect in the developing world,” said Peter Lurie, deputy director of
Public Citizen’s Health Research Group. Its rejection is “in line with
other U.S. efforts to flout international mores.”

The new
rule’s substitute standard says foreign trials should follow good
clinical practices (GCP) and include a review and approval by an
independent ethics committee. A major difference between the Helsinki
Declaration and GCP is the former’s insistence on using existing
treatments instead of placebos if they are available. The Helsinki
Declaration had the effect of extending existing treatments to people
in poor countries if they participated in clinical trials.

The
change is likely to push more clinical trials abroad, where an
estimated 35 percent of all trials submitted to the FDA in new drug
applications now take place. Unlike trials conducted in the U.S.,
companies do not have to submit an investigative new drug application
(IND) to the FDA before beginning research in foreign countries. The
FDA estimates about 575 of the foreign trials submitted to the agency
each year as part of new drug applications do not go through the IND
process. The FDA rejected the notion that adopting the self-regulating
GCP standard and eliminating references to the Helsinki Declaration
“will hurt subjects in developing countries or result in less
protection for subjects in foreign studies.” GCP requires trial
sponsors closely monitor trial behavior and report adverse events, the
agency noted.

Es de gran importancia para los Comités de Ética en Investigación de América Latina insistir en la protección de las personas en investigación a partir de la Declaración de Helsinki. El hecho de que la FDA (un organismo estadounidense bastante inefectivo para proteger a sus ciudadanos) no exija su cumplimiento es un buen indicio para reforzar la exigencia en nuestra región.

LJ

El uso del efecto placebo (diferente del uso de placebos en investigación clínica), es uno de los puntos más debatidos éticamente, pues se parte de que quien lo usa “no está usando nada”, y en realidad lo que se quiere decir es que no está utilizando ningún medicamento activo. La investigación sobre el tema parecería indicarnos que, en realidad, quien lo usa está utilizando algo que no sabemos exactamente como funciona, ni que “es”. Este trabajo de Kaptchuk y col en el British Medical Journal, arroja luz sobre el tema y vale la pena leerlo. Una de las conclusiones es que “These results indicate that such factors as warmth, empathy, duration of interaction, and the communication of positive expectation might indeed significantly affect clinical outcome.” Si esto es así, no brindárselo a los pacientes ¿es una conducta ética?

Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome — Kaptchuk et al. 336 (7651): 999 — BMJ

…pero que los hay, los hay.
Y sobre todo en el área de la redacción de artículos “científicos”, según publican Ross et al en JAMA, y parece que Pfizer y Parke-Davis lo saben muy bien.

Ver en JAMA, April 16, 2008—Vol 299, No. 15:
Guest Authorship and Ghostwriting in Publications Related to Rofecoxib
A Case Study of Industry Documents From Rofecoxib Litigation

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).

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

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

…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