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INTRODUCTION
Compassionate drug use (CDU) is one of the manners to provide unauthorized treatments to patients with no further treatment options, along with the inclusion of patients in clinical trials, off-label prescriptions, or medicine import. Most often, compassionate drugs are given through the inclusion of patients into specific early access programs or expanded access programs (EAPs) managed by the companies producing the drug [1, 2]; this is especially true if the company has already applied, or is going to apply, to get the drug approved in a given indication. Less frequently, the compassionate drug is prescribed for individual use, outside any EAP. In both cases, the company scrutinizes the individual requests for approval, and provides the drug for free [1, 2].
In the European Community (EC) Regulation n. 726/2004, compassionate drugs are referred to as “unauthorized medicinal products” [3]. However, in Italy the notion of compassionate drug includes not only medicines that are not approved yet in the EC, but also medicines with one or more indications approved by European Medicines Agency (EMA)/EC, whose price has not been negotiated yet with the Italian drug agency (Agenzia Italiana del Farmaco, AIFA). As a matter of fact, the latter category is not available for use in the clinical practice even if approved in the EC.
In a previous study on the CDU requests processed in a big Italian academic hospital in the period 2018-2021 [4], we showed that more than 95% of the CDUs (i.e., 443 out of 463) was concerning drugs with at least one indication approved in the EC. Thus, CDUs (and EAPs) can be taken as an index of the access to approved innovative treatments in advance to their availability on the market. In this perspective, we have previously investigated how diffuse CDUs are in Italy by analyzing the databases of two pharmaceutical companies running several EAPs in the last few years in the country [5]. We analyzed the data by region and district, showing that the use of compassionate drugs is widespread, and is closely related to the population of each region. However, this analysis did not consider the relative weight of centers of excellence and/or large hospitals present into the region. For this reason, in the present study we re-analyzed the above database at single-center level, showing that, despite a good diffusion of CDUs in each region, the large majority of CDUs was managed by a relatively low number of centers.
MATERIALS AND METHODS
The databases were provided by Bristol Myers Squibb (BMS) Italia and Roche Italia SpA. The data from BMS included seven EAPs and two products, nivolumab and luspatercept, which accounted for five and two EAPs respectively. The data from Roche included ten products, which were provided as compassionate drugs through three (atezolizumab), or two (pralsertinib, risdiplam) or a single EAP (alectinib, emicizumab, entrectinib, glofitamab, ocrelizumab, polatuzumab vedotin and trastuzumab emtansine) respectively, to a total of 14 EAPs. Emicizumab was not included in our analysis since only one patient was treated within the EAP. Overall, twenty EAPs involving twelve products were included in our analysis.
The two databases had similar structure; BMS data were based on the physician requesting the drug, and each string of information included: 1) the name of the physician, 2) the clinical center and 3) the number of patients enrolled in that center.
Roche data were based on the center requesting the drug, and included: 1) the clinical center, 2) the region where the center is located and 3) the number of patients enrolled in that center. Our analysis did not include the physicians.
Twenty-one regions were considered in our analysis, according to the approach used by AIFA, which takes separate the “autonomous provinces” of Bolzano and Trento (actually belonging to the same region, Trentino-Alto Adige) [6]. For each of the 343 prescribing centers, the total number of dispensed CDUs was calculated. The centers were grouped per region and ordered per number of CDUs managed. All statistics used in the study were descriptive.
The number of centers dispensing CDUs in each region are reported from the region with the higher number of dispensing centers downward. Two cutoff thresholds were set at 75% and 90%, respectively.
RESULTS
Compared to our previous report, which showed 348 centers dispensing CDUs in Italy in the study period [5], in the present re-analysis we found 343 dispensing centers. Careful single-center analysis carried out here let emerge that a number of centers were counted twice in the previous study, accounting for the discrepancy. Likewise, here we counted a slightly lower number of patients (7508 vs the previous 7529). Such 0.28% difference can be considered an acceptable margin of error.
Starting from the region with the higher number of dispensing center, we found that in Lombardy 13 and 23 centers out of 54 account for 75.59% and 90.17% of the CDUs, respectively. In Lazio, 7 and 12 centers out of 32 account for 76.11% and 90.42% of the CDUs, respectively. In Piedmont, 7 and 15 centers out of 32 account for 76.35% and 90.40% of the CDUs, respectively. In Tuscany, 8 and 14 centers out of 31 account for 76.02% and 90.88% of the CDUs, respectively. In Veneto, 7 and 12 centers out of 28 account for 73.65% and 90.14% of the CDUs, respectively. In Sicily, 8 and 13 centers out of 26 account for 73.82% and 90.34% of the CDUs, respectively. In Emilia-Romagna, 7 and 10 centers out of 23 account for 77.84% and 91.82% of the CDUs, respectively. In Puglia, 6 and 11 centers out of 20 account for 76.98% and 91.09% of the CDUs, respectively. In Campania, 4 and 7 centers out of 16 account for 71.95% and 91.10% of the CDUs, respectively. In Marche, 4 and 8 centers out of 13 account for 71.42% and 91.73% of the CDUs, respectively. In Liguria, 1 and 4 centers out of 11 account for 75.26% and 90.94% of the CDUs, respectively. In Abruzzo, 3 and 4 centers out of 11 account for 76.30% and 92.59% of the CDUs, respectively. In Sardinia, 4 and 5 centers out of 9 account for 78.30% and 88.16% of the CDUs, respectively. In Calabria, 4 and 5 centers out of 9 account for 80.00% and 90.59% of the CDUs, respectively. In Friuli Venezia Giulia, 2 and 3 centers out of 8 account for 70.59% and 89.84% of the CDUs, respectively. In Umbria, 1 and 2 centers out of 6 account for 69.86% and 96.17% of the CDUs, respectively. In the autonomous province of Bolzano, 2 centers out of 5 account for 90.90% of the CDUs. In the autonomous province of Trento, 1 center out of 2 account for 96.87% of the CDUs. In Basilicata, 2 and 3 centers out of 3 account for 71.86% and 100.00% of the CDUs, respectively. In Molise, 1 center out of 3 account for 87.50% of the CDUs. In Valle d’Aosta, there is a single center dispensing CDUs.
Detailed data of dispensing center in each region are reported as Supplementary Material available online. In these supplementary tables, the centers accounting for about 75% of the CDUs are highlighted in green; additional centers, accounting for up to 90% of the CDUs are highlighted in pale blue.
Table 1 summarizes the data for the whole country. Overall, 93 centers out of 343 (i.e., 27.11% of the total) account for about 75% (74.82%±2.9%) of CDUs dispensed in Italy, whereas 156 centers out of 343 (i.e., 45.48% of the total) account for about 90% (91.14%±2.2%) of CDUs dispensed in Italy.
DISCUSSION
In this study we have demonstrated that, despite a good diffusion of CDUs in all Italian regions (with a number of centers involved and patients treated in each region broadly proportional to the inhabitants of the region) [5], the handling of CDUs is restricted to a relatively low number of dispensing centers in each region. In fact, about 75% of all CDUs were managed by less than 30% of the centers, and about 90% of all CDUs were managed by less than 50% of the centers throughout the country. In 6 regions out of 20 (i.e., 30% of total), namely Valle d’Aosta, Liguria, Umbria, Lazio, Molise and Campania, the centers accounting for 75% of dispensed CDUs were concentrated in a single town; this fact has a special relevance for those regions with large populations, i.e., Lazio and Campania, whose major centers are all located in Rome and Naples, respectively.
These findings are somewhat expected, reflecting the hub-and-spoke organizational model of the National Health System (NHS). Consistent with this concept is the fact that 40 out of the 93 centers dispensing 75% of all CDUs are academic hospitals and 20 out of 93 centers are research hospitals (IRCCS), with 8 centers being both academic hospitals and IRCCS.
Which are the drawbacks of this situation? One obvious consideration is that, since CDUs have been defined as an important manner to provide critical patients with innovative treatments, some inequity exists on this regard between the patients living near the major CDUs dispensing centers and those living in less served areas. Again, this condition can be conveyed within the general hub-and-spoke organization model of NHS.
Figures and tables
| Region | N. of Centers | N. of Centers accounting for ≈75% of CDUs | N. of Centers accounting for ≈90% of CDUs |
|---|---|---|---|
| Lombardy | 54 | 13 | 23 |
| Lazio | 32 | 7 | 13 |
| Piedmont | 32 | 7 | 15 |
| Tuscany | 31 | 8 | 14 |
| Veneto | 28 | 7 | 12 |
| Sicily | 26 | 8 | 13 |
| Emilia-Romagna | 23 | 7 | 10 |
| Puglia | 20 | 6 | 11 |
| Campania | 16 | 4 | 7 |
| Marche | 13 | 4 | 8 |
| Liguria | 11 | 1 | 4 |
| Abruzzo | 11 | 3 | 4 |
| Sardegna | 9 | 4 | 5 |
| Calabria | 9 | 4 | 5 |
| Friuli Venezia Giulia | 8 | 2 | 3 |
| Umbria | 6 | 1 | 2 |
| Autonomous province of Bolzano | 5 | 2 | 2 |
| Basilicata | 3 | 2 | 1 |
| Molise | 3 | 1 | 3 |
| Autonomous province of Trento | 2 | 1 | 1 |
| Valle d’Aosta | 1 | 1 | 1 |
| Total | 343 | 93 (27.11%) | 156 (45.48%) |
| CDU: compassionate drug use. | |||
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