Since the coming into force of the Regulation 2007/1394 (i.e. ATMP Regulation) until the data cut off of on 31 December 2023, the EC has granted marketing authorizations for 25 ATMPs (Fig. 1); roughly one third (7 out of 25) was subsequently withdrawn from the European market following the decision of the MAHs owing to various causes [23]. In particular, only Zalmoxis [24] was withdrawn because of the failure of a post-authorization phase 3 study to meet its primary endpoint, while the other six withdrawals were owing to commercial reasons [2], after the drugs were on the market for an average time of 3.5 years [25,26,27,28,29]. Withdrawn products were excluded from the analysis as well as one ATMP for which no dossier for pricing and reimbursement (P&R) has been submitted up to the data cut-off date. Hence, we included in our analysis 17 authorized ATMPs in Italy with a reimbursement decision or with an ongoing P&R evaluation whose characteristics are summarized in Table 1. On the basis of the definitions set out in the Regulation [30], the majority are gene therapies (13 out of 17; 75.5%), while 2 are tissue therapies and 2 are somatic cell therapies. Gene therapies can be further divided into ex-vivo gene therapies (8/13; 61.5%), such as CAR-T therapies, and in-vivo gene therapies (5/13; 38.5%). In terms of therapeutic area, 58.8% (10/17) are intended to treat non-oncologic conditions while 41.2% (7/17) have onco-haematologic indications. The vast majority of these ATMPs (15 out of 17; 88.2%) were granted an orphan designation, pursuant regulation 141/2000 on orphan medicines [31], thus accessing fast-track authorisation procedures, such as the conditional marketing authorization (CMA) or the authorisation under exceptional circumstances (UEC). Indeed, in our dataset, the majority of medicines were approved via special procedures, i.e. 41.2% (n = 7) received a CMA and 11.8% (n = 2) received an authorisation UEC, while 8 (47.0%) received a full approval (Table 1).

Flow chart of the ATMPs authorized by the European Commission included in the analysis up to 31 December 2023. AIFA Italian Medicines Agency; ATMPs advanced therapy medicinal products; INHS Italian National Health System; P&R pricing and reimbursement

As of 31 December 2023, 12 authorized ATMPs concluded the evaluation of the P&R dossier with a final decision published in the Italian OG, with a positive decision in the majority of cases: 9 out of 12 (75.0%) are reimbursed and 3 (25.0%) are not, while 5 are currently under evaluation (Table 1). The average ex-factory price of the nine reimbursed ATMPs is €1,175,458.9€, with price tags ranging from 95,000€ to 3,500,000€.

Between the publication of the reimbursement decision for the first ATMP and the expenditure data cut off of 31 December 2023, 6 of the 9 reimbursed ATMPs were directly purchased at least once by INHS facilities (Fig. 1). Two ATMPs (Strimvelis and Limbmeldy) indicated for ultra-rare diseases with an expected incidence in Italy of no more than two patients per year each were never directly purchased through the INHS.

To evaluate the time needed for an ATMP to reach the bed of a patient in Italy, we analysed the duration of the different phases of their life cycle. For all 17 ATMPs authorized by the EMA we measured the time from the first clinical trial to the publication of the EC decision (Fig. S1). For 12 ATMPS with a final decision in the Italian OG we extended the analysis to the end of the evaluation by regulatory agencies. Finally, for six ATMPs we could also calculate the time to first patient access, considered as the first purchase of the drug by an Italian health facility (Fig.S1).

As shown in Table 2 and Fig. S2, clinical development had an average duration of 9.8 years (3588 days) while the average duration of the European assessment was 1.5 years (547 days). In Italy, the average time for the P&R assessment for ATMPs was 1.2 years (446 days, n = 12 ATMPs), which is in line with the time necessary to appraise new orphan drugs (484 days in average) [32]. From the beginning of the EMA evaluation to the publication of the reimbursement decision in the Italian OG, the total regulatory time was 3.2 years.

We have subsequently analysed the time to first patient access, data was available for 6/12 ATMPs showing high variability, with a national average time ranging from 148 to 611 days after the OG publication (Table 2).

By disaggregating the access time data and focusing at the regional level we can observe that regions, such as Molise, Sardegna, Marche, Friuli Venezia Giulia and Abruzzo, have a longer average patient access time (450–1313 days on average); the shortest access times were registered in Lombardia, Emilia Romagna and Toscana (116–131 days on average). The highest variability was observed in Friuli Venezia Giulia (northern Italy) and Sardegna (southern Italy; Fig. 2). The longest times were relative to the first treatments with Yescarta and Kymriah (1342 and 1283 days both in Molise, respectively), the shortest (4 and 33 days in Umbria and Puglia, respectively) were registered for the first treatments with Tecartus and Zolgensma, respectively. When looking at access times by geographical areas (Table 3) we can see that, nationally, time to patient access averages at 340.6 days (median time 216.0 days). Northern and central Italy average at 281.5 and 290.9 days respectively, while southern Italy averages at 436.8 days.

Days to patient access for each region. Data are shown in days as mean (lozenge) and median (middle bar), boxes range from first to third quartile and whiskers span from minum to maximum. The number above each box represents the number of ATMPs acquired by the INHS. ATMPs advanced therapy medicinal products; INHS Italian National Health System

To measure the level of preparedness for ATMP administration in all Italian regions we have analysed the number of health facilities authorized to administer ATMPs, and those that have performed at least one treatment (Table 4). The distribution remains rather heterogeneous, and very strikingly, while the facilities authorized to ATMP administration cover all Italian regions, on average 56% of them are actually active. 107 health facilities are authorized for ATMP administration in Italy (without distinction on the type of ATMP), which corresponds to 1.8 facilities for one million inhabitants (pmp). This ratio differs slightly when zooming into the different geographical areas where northern Italy has 1.7 facilities pmp (46 authorized), central Italy has 1.4 facilities pmp (16 authorized) and southern Italy has 2.3 facilities pmp (45 authorized facilities). However, when looking at the active facilities, the national average drops to one facility pmp with the lowest ratio in Southern Italy (0.8 facilities), followed by Central Italy (0.9 facilities pmp) and Northern Italy (1.2 facilities pmp). Therefore, while 74% and 69% of authorized facilities in Central and Northern Italy are active, only 33% of all authorized facilities are active in Southern Italy, leaving regions, such as Molise, Basilicata and Sardegna with no coverage. This also entails that some regions, such as Marche, have two centres pmp, while others have four times less or none at all. Similarly, only 3.8 treatments pmp were administered in Southern Italy in 2023, compared with 8.1 treatments pmp in Northern Italy and 5.4 in Central Italy. However, when calculating the number of treatments performed per centre in each region or geographical area, the national average of six treatments per centre is rather close to the Northern, Central and Southern Italy averages, ranging from 5.1 to 6.5. Although a greater variability is uncovered at the regional level, where in regions, such as Emilia Romagna, 19,5 treatments per facility were performed in 2023, while in Marche 1 treatment per facility was performed (Table 4).

The expenditure data analysis was conducted on six ATMPs directly purchased by the INHS in the period from August 2016 to December 2023 (Table 1). The expenditure trend reflects the progressive market entry of new ATMPs starting in May 2017. From 2016 to 2018 no or negligible expenditure data were retrieved. After 2019, the expenditure trends increased with a CAGR of 205% from 2019 to 2023 (Table 5). Overall, despite the high costs per treatment of these medicines (Table 1), their impact on the total INHS expenditure in 2023 (26.3 Bln €) is 4.6‰ and accounts for 7.4‰ when compared with the expenditure for medications directly purchased by health facilities (16.4 Bln€, Table 5).

The expenditure for ATMPs is driven by CAR-T ex-vivo gene therapies (106.7 Mln € in 2023) with an increasing trend, while all other AMTPs generated a lower expenditure (14.7 Mln€ in 2023), in decline compared with 2021 and 2022 (Tab.5).

The regional expenditure trend from 2016 to 2023 confirms the progressive spread of ATMPs over time and across territories, starting with very few regions in 2017 and 2019 to 86% coverage of the national territory in 2023, with a particular surge registered from 2020 onwards (Table 6). In 2023, the highest expenditure share was observed in the Northern regions (57.7% of the national ATMP expenditure), with Lombardia (26.6Mln €) leading the list. However, regions from other areas of Italy were also very active, for instance, comparing data from 2022 and 2023, expenditure increased the most in Abruzzo (+ 181.4%), Piemonte (+ 117.9%) and Veneto (+ 106.8%).

When looking at the 360 ATMP treatments administered in 2023 we can observe that 18.3% of these were for Italian patients who were not resident in the region of treatment. This phenomenon, know as inter-regional mobility is owing to the fact that, in Italy, patients are free to chose any accredited health facility in the country for the treatment they need [33]. Some regions are more active than others in treating non-resident patients, in particular 55% and 30.8% of all treatments performed in Campania and Emilia Romagna in 2023, respectively, were for patients coming from other Italian regions (Table 6). The majority of inter-regional movements in 2023 were aimed at receiving CAR-T treatments; however, in the case of Campania, patients came from all over Italy to be treated with Luxturna.