Intern Emerg Med (2014) 9:797–798 DOI 10.1007/s11739-014-1117-0
CE - COMMENTARY
Randomization, ethics and clinical research Giorgio Costantino • Giovanni Casazza
Received: 30 July 2014 / Accepted: 12 August 2014 / Published online: 29 August 2014 Ó SIMI 2014
The Ethical Committee of Fondazione Umberto Veronesi has recently published a document [1] that deals with randomization in clinical trials. In this document, although it is recognized that the methodology of clinical studies based on randomization provides undeniable benefits, some ethical concerns related to individuals participating in clinical studies are raised. After an excursus on the reasons of the wide diffusion of randomization in clinical studies, the authors of the document raise some concerns regarding the ethical aspects of randomization. The rationale is that a patient randomized to the control group would not, according to the authors of the document, benefit from the probably greater efficacy of the new treatment. For this reason, it should be an ethical obligation of researchers to reduce the number of patients who will be randomized to the control group, and consequently will not gain a benefit from the new treatment. By supporting this argument, the authors implicitly question the principle of clinical equipoise of the two tested treatments (the lack of evidence, before the study has begun, that one of the two interventions is superior to the other in its efficacy). Finally, in their ‘‘Conclusions and recommendations,’’ the authors provide some technical scientific advice directed to all the operators involved in clinical studies,
G. Costantino Dipartimento di Medicina Interna, Azienda Ospedaliera ‘‘L. Sacco’’, Medicina ad Indirizzo Fisiopatologico, Universita` degli Studi di Milano, Milan, Italy G. Casazza (&) Dipartimento di Scienze Biomediche e Cliniche ‘‘L. Sacco’’, Universita` degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy e-mail: [email protected]
with the aim of mitigating the mentioned ethical drawbacks of randomization. The proposed recommendations, if applied in clinical studies, would lead to a substantial reduction in the number of patients randomized to the control group, and, more in general, in the number of patients requested in a clinical study. In brief, they recommend: 1.
2.
3.
4. 5.
To use, as much as possible, existing and newly implemented clinical databases to derive data. They suggest using all the available data, previously collected for other purposes, and to analyze them using a Big Data approach to reduce the number of randomized controlled trials. The early termination of studies when the new treatment proves to be more effective, (or with the same effectiveness but with other additional benefits,) than the standard of care. The rationale for supporting this strategy is that a smaller number of patients will undergo the control treatment, reducing ethical concerns. The promotion of further research in the field of statistical models. In particular, they suggest setting the significance level at 0.1, rather than at the usual 0.05. In addition, they suggest that the results of studies could be classified as ‘‘fully statistically significant’’ or ‘‘marginally statistically significant’’. They also propose allowing patients to partially decide in which arm of the trial they will be enrolled. To improve communication with patients, and to monitor for potential discriminations. To reduce the number of placebo-controlled studies, and to use ‘standard care’ control groups whenever possible.
In this issue of Internal and Emergency Medicine, a paper by Colli and colleagues [2] discusses the ethical
123
798
problem of randomization starting from the proposals of the document of Fondazione Umberto Veronesi. They critically analyze the suggestions reported in that document, and highlight some other ethical issues to deal with when conducting a clinical study, such as sponsorship and conflict of interests. In conclusion, we believe that all the people involved in clinical studies (patients, researchers and clinicians) might benefit from an open discussion concerning all that can be done to improve the methodology of clinical studies, also taking into account ethical considerations. This paper represents one contribution to this discussion. The debate is now open and anyone can contribute.
123
Intern Emerg Med (2014) 9:797–798 Conflict of interest
None.
References 1. Comitato Etico della Fondazione Umberto Veronesi (2014) Orientamenti sull’utilizzo della randomizzazione nella sperimentazione clinica. https://fondazioneveronesi.it/files/1313/8997/2853/Parere_ Comitato_Etico_RANDOMIZZAZIONE_def17gennaio.pdf. Accessed 21 July 2014 2. Colli A, Pagliaro L, Duca P (2014) The ethical problem of randomization. Intern Emerg Med. doi:10.1007/s11739-014-1118-z
CE - COMMENTARY
Randomization, ethics and clinical research Giorgio Costantino • Giovanni Casazza
Received: 30 July 2014 / Accepted: 12 August 2014 / Published online: 29 August 2014 Ó SIMI 2014
The Ethical Committee of Fondazione Umberto Veronesi has recently published a document [1] that deals with randomization in clinical trials. In this document, although it is recognized that the methodology of clinical studies based on randomization provides undeniable benefits, some ethical concerns related to individuals participating in clinical studies are raised. After an excursus on the reasons of the wide diffusion of randomization in clinical studies, the authors of the document raise some concerns regarding the ethical aspects of randomization. The rationale is that a patient randomized to the control group would not, according to the authors of the document, benefit from the probably greater efficacy of the new treatment. For this reason, it should be an ethical obligation of researchers to reduce the number of patients who will be randomized to the control group, and consequently will not gain a benefit from the new treatment. By supporting this argument, the authors implicitly question the principle of clinical equipoise of the two tested treatments (the lack of evidence, before the study has begun, that one of the two interventions is superior to the other in its efficacy). Finally, in their ‘‘Conclusions and recommendations,’’ the authors provide some technical scientific advice directed to all the operators involved in clinical studies,
G. Costantino Dipartimento di Medicina Interna, Azienda Ospedaliera ‘‘L. Sacco’’, Medicina ad Indirizzo Fisiopatologico, Universita` degli Studi di Milano, Milan, Italy G. Casazza (&) Dipartimento di Scienze Biomediche e Cliniche ‘‘L. Sacco’’, Universita` degli Studi di Milano, Via G.B. Grassi 74, 20157 Milan, Italy e-mail: [email protected]
with the aim of mitigating the mentioned ethical drawbacks of randomization. The proposed recommendations, if applied in clinical studies, would lead to a substantial reduction in the number of patients randomized to the control group, and, more in general, in the number of patients requested in a clinical study. In brief, they recommend: 1.
2.
3.
4. 5.
To use, as much as possible, existing and newly implemented clinical databases to derive data. They suggest using all the available data, previously collected for other purposes, and to analyze them using a Big Data approach to reduce the number of randomized controlled trials. The early termination of studies when the new treatment proves to be more effective, (or with the same effectiveness but with other additional benefits,) than the standard of care. The rationale for supporting this strategy is that a smaller number of patients will undergo the control treatment, reducing ethical concerns. The promotion of further research in the field of statistical models. In particular, they suggest setting the significance level at 0.1, rather than at the usual 0.05. In addition, they suggest that the results of studies could be classified as ‘‘fully statistically significant’’ or ‘‘marginally statistically significant’’. They also propose allowing patients to partially decide in which arm of the trial they will be enrolled. To improve communication with patients, and to monitor for potential discriminations. To reduce the number of placebo-controlled studies, and to use ‘standard care’ control groups whenever possible.
In this issue of Internal and Emergency Medicine, a paper by Colli and colleagues [2] discusses the ethical
123
798
problem of randomization starting from the proposals of the document of Fondazione Umberto Veronesi. They critically analyze the suggestions reported in that document, and highlight some other ethical issues to deal with when conducting a clinical study, such as sponsorship and conflict of interests. In conclusion, we believe that all the people involved in clinical studies (patients, researchers and clinicians) might benefit from an open discussion concerning all that can be done to improve the methodology of clinical studies, also taking into account ethical considerations. This paper represents one contribution to this discussion. The debate is now open and anyone can contribute.
123
Intern Emerg Med (2014) 9:797–798 Conflict of interest
None.
References 1. Comitato Etico della Fondazione Umberto Veronesi (2014) Orientamenti sull’utilizzo della randomizzazione nella sperimentazione clinica. https://fondazioneveronesi.it/files/1313/8997/2853/Parere_ Comitato_Etico_RANDOMIZZAZIONE_def17gennaio.pdf. Accessed 21 July 2014 2. Colli A, Pagliaro L, Duca P (2014) The ethical problem of randomization. Intern Emerg Med. doi:10.1007/s11739-014-1118-z
