Abstract: We included four randomised controlled trials (RCTs). We found evidence of missing data and poor reporting. When bifeprunox 20 mg was compared with placebo for schizophrenia, the drug resulted in a reduction of the Positive and Negative Syndrome Scale (PANSS) positive subscale score regarding positive symptoms (n = 549, 2 RCTs, MD -1.89, 95% CI -2.85 to -0.92, low-quality evidence) and the PANSS negative subscale regarding negative symptoms (n = 549, 2 RCTs, MD -1.53, 95% CI -2.37 to -0.69, low-quality evidence). There was a clear improvement regarding deterioration in the bifeprunox 20 mg group (n = 231, 1 RCT, RR 0.71 95% CI, 0.54 to 0.93, very low-quality evidence). The total number of participants with equal to or greater than 7% weight increase was similar between bifeprunox and placebo (n = 483, 1 RCT, RR 1.02 95% CI 0.31 to 3.33 moderate-quality evidence). There were no useable data for quality of life, economic outcomes, and service use. Our results showed some positive effects and a favourable adverse effect profile for bifeprunox, although there were few data overall and none were of high quality. It would seem that these data alone would not have been enough for the FDA to decide to halt progress of the drug to market. We can only assume that we are missing important data. Both the FDA and the relevant pharmaceutical companies have not made all relevant data accessible. As some of these trials also involved an additional haloperidol, olanzapine, quetiapine, or risperidone arm, these data are not only relevant to evaluation of bifeprunox. In not making all data accessible, it is hard to see how the FDA and the drug companies have fulfilled their full obligations to people with schizophrenia or their clinicians.

Plain-language summary: The Information Specialist of the Cochrane Schizophrenia Group searched the specialised register in October 2015. He ran an electronic search for trials that randomised people with schizophrenia to receive either bifeprunox or placebo, finding 42 records. The review authors screened these for inclusion in the review. Only four trials provided useable data, and these were of poor quality with some evidence of missing data. Two trials are completed but not yet published; we could not obtain any information from these trials that we could use in this review. The data available to us showed that bifeprunox improved participants' scores on both positive and negative symptom scales. Weight increase was similar between those receiving bifeprunox and those allocated to placebo. Data regarding the effects of bifeprunox are scarce. The data we found, which were of poor quality, showed no real evidence that bifeprunox is unsafe or ineffective. Its effects do not seem significantly different to other drugs that are currently on the market. More data on this compound exists but is not publicly available. We believe that the licencing authority in the USA must have had more information on which to base their important decision. The drug company also seemed to lose the will to move forward with bifeprunox. Whether or not the decision to prohibit access to a potentially useful drug was taken because of clear evidence of adverse effects, market calculations, or biases, it would seem an omission that all information upon which this decision was made is not in the public domain.