Compassionate drug uses in Italy. Analysis of regional and local diffusion.

AIMS: Compassionate drugs are provided to patients with a specific disease and no further treatment option, most frequently via Early (or Expanded) Access Programs. In Italy, it often occurs that compassionate uses concern medicines whose price has not been negotiated yet (and therefore unavailable on the market), although their use has been approved in Europe. Thus, compassionate drug uses turn out to be a way to expedite the access to new innovative drugs with demonstrated efficacy. This study aims to investigate how widespread is the use of compassionate drugs throughout the Country. METHODS: We analyzed data from 20 early access programs implemented by 2 pharmaceutical companies in the last few years. Data were analyzed by the number of patients and centers in each Region and province, and a correlation was established between patients and centers in each Region and the resident population. A further analysis was carried out with the same criteria on the subpopulation of oncology patients, including more than 80% of total study population. RESULTS: In our sample, 7529 patients received compassionate drug treatments in 348 centers throughout Italy. A significant correlation exists between the resident population in each Region and the number of requesting centers (r2=0.877) and patients treated (r2=0.844) in the Region. Taking the value of the linear regression slope as the expected one, certain Regions show a better "performance", in terms of more patients treated than expected, namely Umbria, Emilia-Romagna, Lazio, Lombardy, Tuscany, Liguria and Friuli Venezia-Giulia. CONCLUSIONS: In this study we showed that the use of compassionate drugs in Italy is diffused in a manner closely related to the population of each Region. A number of Regions - mostly but not exclusively from the South and Island areas - show a performance below the expectations, in terms of patients treated.

Local Investigators Significantly Overestimate Overall Response Rates Compared to Blinded Independent Central Reviews in Phase 2 Oncology Trials.

The overall response rate (ORR) is a largely adopted outcome measure in early-phase oncology trials. ORR is highly relevant in cancer drug development at the time of deciding whether to move to confirmatory phase 3 trials; moreover, ORR is gaining increasing relevance in fast-track registration procedures. No systematic analysis has been conducted so far to investigate whether a discrepancy exists between ORR assessed by local investigators and those assessed by blinded reviewers in phase 2 oncology trials. In this study, we carried out a search in the clinicaltrials.gov and EudraCT databases, looking at the trials reporting the results of both investigator-assessed and independently-assessed ORR. A discrepancy index was obtained by calculating the ratio of each investigator-assessed ORR on the corresponding independently assessed ORR, so that a discrepancy index >1 indicates that the investigator was "more optimistic," whereas a discrepancy index <1 indicates the opposite. We also analyzed different subgroups (by tumor type, by drug type, by year). Twenty trials met the search criteria; in some cases, >1 comparison was conducted in the trial, so that the total number of comparisons analyzed was 33. The estimated mean discrepancy index was 1.175 (95% confidence interval, 1.083-1.264; n = 33). In conclusion, local investigators significantly overestimate ORR compared to paired blinded reviewers in phase 2 oncology trials. This may represent a risk in drug development, when deciding whether to move to confirmatory, more expensive phase 3 trials. Blinded independent central review should be used in ORR assessment if a more conservative estimate of treatment efficacy is required, as in the case of fast-track drug developments leading to accelerated approvals of cancer therapies.