A recent report in JAMA Oncology has espoused the hidden benefits of negative trials results – and this view seems to have been endorsed in new draft guidance from the EMA.
Negative results are understandably not usually greeted with the resounding fanfare given to more promising studies. However, far from being failures, the JAMA-published study argues that negative results can have at least as much scientific impact as more “successful” trials.
The researchers from the cancer research network, SWOG, analysed all of the randomized, Phase III cancer trial completed by the group between 1984 and 2014. Of the 94 studies, 26 were positive. Read more [here].
As you’d expect, the team found that the primary manuscripts first announcing these encouraging results were given far more prominence and cited more often. However, they found that the number of citations from all primary and secondary manuscripts did not differ between positive and negative trials.
This is partially important because of the wide debate on the ethics of full disclosure of trial results – especially negative ones.
According to one of the study authors - "Negative trials matter because they tell us what doesn't work - which can be as important as what does. Negative trials are also critical for secondary research, which mines existing trial data to answer new questions in cancer care and prevention. Negative trials are used frequently in secondary research, and add great value to the scientific community."
Draft oncology trial guidance…
The second potential shot in the arm for oncology research came in the new draft trial guidance published by the EMA (European Medicines Association). The guidance is available for comment until 15th September.
EMA calls on companies to submit data on overall survival “compatible with a trend towards favourable outcome” so as to capture possible negative effects on the activity of next-line therapies and also treatment-related fatalities.
“This has consequences with respect to interim analyses, other than for futility, and cross-over, which thus should be undertaken only when available survival data provide the information needed for a proper evaluation of benefit/risk,” EMA says.
Of course, a focus on negative results is only a small part of the measures proposed by the EMA. The main thrust is around the ways of facilitating the development of promise of new immune-modulating drugs and other non-cytotoxic agents.
The EMA believes that one of the reasons for the small proportion of new anti-cancer compounds that obtain marketing authorization is “due to poor activity or evidence of a detrimental safety profile. Until non-clinical models with good predictive properties have been defined, this situation is likely to remain essentially unchanged and the absence of such models is considered to constitute the greatest hurdle for efficient drug development within the foreseeable future.”
In addition to defining the proper dose(s) and schedule(s) of a cancer drug, EMA stresses the importance of identifying a target population with optimized benefit/risk in the section on exploratory studies.
Guidance is also provided on studies for combinations of drugs with minimal activity as monotherapies, but “synergistic effects when combined, as well as combinations of conventional cytotoxics.”
The full draft guidelines can be downloaded [here]