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).


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