Efforts to broaden the publication of clinical trial results, regardless of outcome, have made considerable progress in recent years. In general, though, Phase I trials have stayed out of bounds.
Last November, for example, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) approved an updated version of its Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases that widened the scope of mandatory disclosure for efficacy studies. At the same time, though, the revised position left the disclosure of Phase I trials to the discretion of IFPMA member companies.
Explaining the distinction, the federation’s director general, Alicia Greenidge, said disclosure of early safety trial information “cannot provide any useful insight into the potential efficacy of the compound trialled, but can make it easier for rival companies to gain an insight into the scientific approach of the company concerned”.
Now a retrospective cohort study published in the open-access journal PLoS Medicine has highlighted just how seldom Phase I trials see the light of day compared with other stages of clinical development.
Evelyne Decullier and colleagues from the University of Lyon, France and the Mayo Clinic in Rochester, US reviewed the protocols for a total of 444 clinical trials approved in France to determine whether and how the initiation, completion and publication of Phase I trials differed from the same outcomes with Phase II-IV trials.
The cohort was drawn from protocols cleared by a sample of 25 research ethics committees in France between 1 January and 31 December 1994. Principal investigators were contacted in January 2001 to determine whether the studies had been completed, what the outcomes were, whether the results had been published and, if not, why.
Low publication
By the time the data had been collected, just 17% of the 127 completed Phase I studies had been published in scientific journals, compared with 43% of the 218 completed Phase II-IV trials.
Even when the exercise was limited to trials with confirmatory results, only 25% or 18 of 71 Phase I trials had been published, versus 63% or 79 of 125 Phase II-IV studies. For around half of the Phase I trials, results were not made publicly available in any form, with confidentiality given as the main reason for sitting on the results.
This was despite the higher initiation (133 out of 140 studies versus 269 of 304 studies) and completion (127/133 versus 218/269) rates for Phase I trials compared with later stages of clinical development. Moreover, Phase I studies were more likely than Phases II-IV to produce confirmatory results (71/83 versus 125/175).
There is a strong ethical imperative for eliminating publication bias from Phase I trials, Decullier et al argue, commenting: “The testing of new pharmaceuticals on humans is approved by ethics committees based on the assumption that the inherent risks of trial participation are balanced by the benefit of new scientific knowledge for society. If this knowledge from Phase I remains hidden, then any potential risk incurred by trial participation is excessive and could endanger human lives”.
One third of research programmes for investigational drugs are abandoned mainly for reasons of economics rather than efficacy and safety, the authors note. This means even new drugs that show clinical promise are often discontinued and the associated knowledge “lost”.
Concerns about commercial or competitive advantage “should not obstruct transparency and do not outweigh the ethical and scientific responsibilities to disseminate knowledge gained by testing new therapies in humans”, they state.
