Global & regional health technology assessment, Jun 17, 2024
tenutasi il 21 e il 22 settembre 2023. Il GdL ha visto la partecipazione, come nelle precedenti e... more tenutasi il 21 e il 22 settembre 2023. Il GdL ha visto la partecipazione, come nelle precedenti edizioni dei Seminari di Mogliano, di soggetti istituzionali (Agenzia Italiana del Farmaco, AIFA, e Regioni) e stakeholder (clinici, referenti per i pazienti e imprese) (cfr. Ringraziamenti). Nello specifico, il coordinatore del GdL ha individuato i temi chiave oggetto della proposta di riforma, inquadrandola nell'attuale contesto degli EAP in Italia e condividendola in una prima sessione plenaria del Seminario. Il GdL ha discusso le possibili opzioni di riforma in due sessioni distinte, la prima finalizzata a ricevere in modo aperto le proposte dei partecipanti al GdL, la seconda di condivisione di un percorso comune, che si sono concretizzate in una presentazione validata dal GdL e presentata in plenaria con commenti da parte dei partecipanti di altri GdL. Il paper è diviso in due parti. Nella prima viene descritto in sintesi lo stato attuale degli EAP in Italia. Nella seconda vengono illustrati i risultati del GdL. I programmi di accesso precoce disponibili in Italia Garantire ai pazienti un rapido accesso a farmaci potenzialmente efficaci è un obiettivo importante per ciascun sistema sanitario, e ciò è tanto più vero nel caso di malattie gravi e prive di opzioni terapeutiche di provata efficacia. Per farmaci a designazione orfana che abbiano già ottenuto l'Autorizzazione all'Immissione in Commercio (AIC) in
Background Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for... more Background Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for healthcare payers because of the uncertainty on impact at market launch, high cost and important organisational impact. The literature has focused on their assessment, appraisal and market access solutions. No evidence on the costs sustained to implement CART is available and a few studies reported the cost of the CART clinical pathway, including the activities that are remunerated through inpatient or outpatient fee-for-service/episode. This paper aims at filling the information gap, assessing the cost of implementing CART activity and the full cost of managing the CART clinical pathway. Methods Cost analysis relied on the Activity Based Costing approach, which was applied to two Italian healthcare organisations, both CART Centres authorized by the regional governments with a minimum of 20 patients treated with the first two CART therapies launched on the market. Results The cost of implementing CART was estimated at €1.31 million (calculated for one of the organizations with complete data). Most of these costs (77%) were generated by quality assurance activity. The mean cost per patient entering the CART pathway (59 and 27) and surviving at follow-up (21 and 5) ranges from €48K to €57K and from €96K to €106K, respectively. Fees for hospitalization and infusion of gene therapy accounts for more than 70% of these costs. The actual hospitalisation cost varies greatly across patients and is in general lower than the fee-for-episode paid by the region to the hospital. Conclusions Despite its limitations (exploratory nature; the time spent by staff on activities which are not remunerated through fees was estimated through interviews with the CART coordinators; cost items are not fully comparable), this research highlighted the relevant organisational and economic impact of CART and provided important insights for policy makers and healthcare managers: the necessity to invest resources in CART
Background New indications for existing medicines are increasing over time. In most countries, dr... more Background New indications for existing medicines are increasing over time. In most countries, drug pricing and reimbursement conditions are renegotiated every time a new indication is approved. There is a growing interest in the price negotiation model for new indications, specifically comparing an indication-based versus blended approach. However, little evidence currently exists regarding the complexity of these negotiations and their impact on actual prices. Italy has recently transitioned from an indication-based approach to a blended price model. This study aims to measure the impact of price and reimbursement negotiation of new indications on discounts (i.e. actual prices) and on the negotiation duration, used as a proxy of its complexity. Methods We considered new indications approved through a European centralized procedure from January 2013 to March 2022 for which the price and reimbursement status was approved in Italy between January 2015 and March 2022, amounting to 52 new indications. Data on the timeframe of the Italian price and reimbursement process and its phases were obtained from publicly available sources. Discounts for the first indication and their subsequent increases for new indications were estimated by comparing ex-factory prices and tendered prices. To calculate p-values, we employed the Mann-Whitney test, and multiple regression models were utilized to examine correlations between negotiation time and the characteristics of the medicines. Results The mean time to reimbursement was 603 days, in contrast to 583 days for the first launch. Price negotiation took longer for rare diseases, cancer drugs, and in case of therapies with minor added therapeutic value. On average, the additional discount (on top of discounts for prior indications) was 13%, significantly lower than the mean discount for the first indications approved (24.9%). The discounts increment was lower, but negotiation took longer if a Managed Entry Agreement accompanied the final agreement. Additionally, discounts have increased over the years. Conclusion The negotiation for new indications takes longer than the first one, and provides, on average, an additional discount of 13%. While our findings bear the potential for significant policy implications, they necessitate prudent interpretation due to a limited number of observations. The increasing trend in additional discounts over time applied to all indications in recent negotiations, may suggest a descending trend of value for new indications and a shift from an indication-based pricing approach to a blended model. Otherwise, budget impact considerations might have outweighed a value-based approach in the recent negotiations. If so, two potential options for restoring a value-based approach are returning to an indication-based pricing or giving explicit and higher weight to value within a blended model.
The use of health technology assessment (HTA) to inform policy-making is established in most deve... more The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company's perspective, as market prospects are strongly influenced by third-party payers' coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed.
European Journal of Health Economics, Oct 27, 2015
Objectives This paper aims at covering a literature gap on the effects of copayments, prescriptio... more Objectives This paper aims at covering a literature gap on the effects of copayments, prescription quotas and therapeutic reference pricing on public and private expenditures and volumes (1) When these policies are implemented in different areas at different times, (2) estimating their impact in the short and long run, (3) assessing the extent to which these impacts are interdependent, (4) scrutinising the extent to which the effects are mediated by prescribers' and patients' behaviours. Methods Monthly regional data on pharmaceutical expenditures, volumes and policies in Italy from 2000 to 2014 are analysed using a difference-indifferences model enriched to capture short-versus long-term effects and simultaneous and interactive effects. Sobel-Goodman test and bootstrap analyses were used to test for mediation. Results The three policies have different short-and longrun effects. Interactions support the hypothesis of reinforcing effects. Behavioural reactions to policies such as reducing the demand or total per capita expenditures mediate the impact of policies, thus explaining the different effects between the short and long term. Conclusions Evidence on the impact over time of regional policies diversely introduced in different times have important policy implications. First, pharmaceutical policies interact with each other, and the combined effect may be different from what we would expect from the sum of each single policy. Hence, policymakers should be very careful in designing mixed policies for their unexpected combined effects. Second, the impact of policies tends to reduce over time. If longer-term impact is desired, it would be appropriate to introduce some adjustments over time. Third, policies have multiple effects, and this should be considered when they are designed. Finally, pharmaceutical policies may have an unintended impact on health and health care.
Early access programs (EAPs) generally refer to patient access to medicines/indications before ma... more Early access programs (EAPs) generally refer to patient access to medicines/indications before marketing authorization, possibly extended to price and reimbursement approval. These programs include compassionate use, which is usually covered by pharmaceutical companies, and EAPs reimbursed by third-party payers. This paper aims at comparing EAPs in four European countries (France, Italy, Spain, UK) and providing empirical evidence on EAPs in Italy. The comparative analysis was conducted through a literature review (including scientific and grey literature), complemented by 30-min semi-structured interviews with local experts. The Italian empirical analysis employed data available on the National Medicines Agency website. Although EAPs are very different across countries, they exhibit some common features: (i) eligibility criteria refer to the absence of valid therapeutic alternatives and a presumed favourable risk–benefit profile; (ii) payers do not allocate a pre-determined budget ...
Background Italy is Europe’s third largest pharmaceutical market, yet it ranks only ninth in the ... more Background Italy is Europe’s third largest pharmaceutical market, yet it ranks only ninth in the number of NIH-registered clinical trials per capita. The aim of our study was to explore stakeholders’ perception of Italy as place to undertake clinical trials, and to estimate the potential economic impact of selected reforms in terms of incremental trial activity. Methods The Survey of Attitudes towards Trials in Europe (SAT-EU Study) was an anonymous, web-based survey which systematically assessed factors impacting clinical trial site selection in Europe. Estimates of Italian economic impact were developed in collaboration with AICRO (Association of Italian Contract Research Organisations). Results Responses were obtained from 485 professionals in 34 countries (15% residing in Italy) representing over 100 institutions, spanning BioPharma Clinical Research Organizations (CROs), and Academic Clinical Trial Units (CTUs). Italy ranked tenth of twelve in terms of accessibility and transpa...
Background Innovative medicines are provided with dedicated funds and immediate market access in ... more Background Innovative medicines are provided with dedicated funds and immediate market access in Italy. Innovativeness evaluation considers unmet need, added therapeutic value, and quality of the evidence. Objective We aimed to evaluate the internal consistency and drivers of the innovativeness appraisal process. Methods Appraisal reports on innovativeness refer to 1997-2021. We used both a descriptive approach and probabilistic multivariate analysis, using logistic regression models to compute odds ratios and 95% confidence intervals. The dependent variable is innovativeness status (innovative vs. non-innovative; full innovativeness vs. conditional innovativeness). Explanatory variables, besides the three above-mentioned domains, are the year of evaluation, drug type, target disease and population, and the number and type of available studies. Results Among the 141 medicines scrutinized, 31.9%, 29.8%, and 38.3% were evaluated as fully innovative, conditionally innovative, and non-innovative, respectively. Added therapeutic value and the quality of the evidence were associated with the odds of receiving innovative status, and full compared with conditional innovativeness; unmet need was not a predictive variable. Other factors played a minor role: medicines for both solid tumours and rare diseases are more likely to be judged innovative; conditional innovativeness is more probable for medicines for rare diseases. Conclusions Innovativeness status is driven by the added therapeutic value and quality of evidence. The appraisal process is internally consistent and predictable. This provides industry with a clear indication of what is needed to ensure that access to their medicines is prioritized.
Global & Regional Health Technology Assessment, 2021
This article illustrates a consensus opinion of an expert panel on the need and usefulness of a f... more This article illustrates a consensus opinion of an expert panel on the need and usefulness of a framework for price and reimbursement (P&R) process and managed entry agreements (MEAs) for orphan medicines in Italy. This opinion was gathered in three rounds: an introductory document was sent to the panel and discussed during a recorded online meeting. A second document was sent to the panel for their review. In the third step the final document was validated. Members of the expert panel are the authors of the article. The panel agreed that Italy does not need a specific value framework for orphan medicines, driving the P&R process. Rather, a more structured value framework for all medicines tailored to the specific drugs can be useful. For orphan drugs, the panel advocated for a multidisciplinary approach and the contribution of different stakeholders to value assessment, and acknowledged the importance of addressing, more than for other drugs, unmet needs, equity issues and societal...
Background and aimEvidence on determinants of prices for orphan medicines is scarce and not avail... more Background and aimEvidence on determinants of prices for orphan medicines is scarce and not available for Italy. The aim of this paper is to provide an evidence on variables affecting the annual treatment cost of orphan drugs in Italy, testing the hypothesis of a negative correlation with the dimension of the target population and a positive correlation with the added therapeutic value of the drug and the quality of the evidence of pivotal studies.MethodsDrugs with a European orphan designation reimbursed in Italy in the last 6 years (2014–2019) were considered. Univariate, cluster analysis and multiple regression models were used to investigate the correlation between the annual treatment cost and, as explanatory variables, the dimension of the target population, the existence of Randomized Clinical Trials as a proxy of the quality of the pivotal studies, the added therapeutic value.ResultsIn the univariate analysis prevalence and added therapeutic value, as expected, have a negati...
Journal of Pharmaceutical Policy and Practice, 2021
Background Advanced therapy medicinal products (ATMPs) represent an important cornerstone for inn... more Background Advanced therapy medicinal products (ATMPs) represent an important cornerstone for innovation in healthcare. However, uncertainty on the value, the high average cost per patient and their one-shot nature has raised a debate on their assessment and appraisal process for pricing and reimbursement (P&R) purposes. This debate led experts providing for recommendations on this topic. Our primary objective is to investigate the ATMPs P&R process in the main five European countries and to understand if this process is consistent with published P&R expert recommendations. We also investigated the current ATMP pipelines to understand if future ATMPs will create challenges for their P&R process. Methods P&R framework for ATMPs in the European Major five (EU5) countries was investigated through a literature search on PubMed, institutional websites of National Health Authorities and grey literature. The ATMPs pipeline database was populated from a clinical trial database (clinicaltria...
This paper illustrates a conceptual model for a new Patient Reported Outcome measure (PROM) aimed... more This paper illustrates a conceptual model for a new Patient Reported Outcome measure (PROM) aimed at measuring financial toxicity (FT) in oncological setting in Italy, where citizens are provided universal health care coverage. Methods Focus groups with overall 34 patients/caregivers in three different Italian centres (from Northern, Centre and Southern Italy) and an open-ended survey with 97 medical oncologists were undertaken. Transcripts from focus groups and the open-ended survey were analyzed to identify themes and links between themes. Themes from the qualitative research were supplemented with those reported in the literature; concepts identified formed the basis for item development, that were then tested through the importance analysis (with 45 patients) and the cognitive debriefing (with other 45 patients) to test relevance and comprehension of the first draft PRO instrument. Results Ten domains were extracted by analyzing 156 concepts generated from focus groups and the openended survey. After controlling for redundancy, 55 items were generated and tested through the importance analysis. After controlling comprehension and feasibility through cognitive debriefing interviews, a first version of the questionnaire consisting of 30 items was devised. Conclusions This qualitative study represents the first part of a study conducted to develop a new PROM to assess FT in Italy, by using a bottom up approach that makes the most of patients' experiences and the health system analysis. clinicaltrials.gov NCT03473379 first posted on March 22, 2018
e18840 Background: The economic impact of clinical trials in the perspective of trial sites has b... more e18840 Background: The economic impact of clinical trials in the perspective of trial sites has been already investigated. Instead, there is no evidence on the economic net benefit of compassionate use programs for medicines (CUP). This research aims to fill the information gap, investigating the economic consequences of 8 CUP in Italy carried out from May 2015 to December 2020 in the hospitals’ perspective. These programs concern five cancer medicines (alectinib, atezolizumab, cobimetinib, polatuzumab vedotin, trastuzumab emtansine TDM-1), for a total of 8 programs. Methods: Economic net benefit includes avoided costs for standard of care (SoC) the patient would have received if he/she has not joined the CUP and costs not covered by the pharmaceutical industry and sustained by the hospital hosting CUP. The latter include costs of adverse event (only severe sides effects generating hospitalisation and ascribed to medicines used in CUP), combination therapies and diagnostic procedure...
Global & Regional Health Technology Assessment: Italian; Northern Europe and Spanish, 2015
Innovation and drugs price and reimbursement: a comparison between Italy and the other major EU c... more Innovation and drugs price and reimbursement: a comparison between Italy and the other major EU countries This paper aims at investigating (i) differences and commonalities of drugs Price and Reimbursement (P&R) criteria between Italy and the other major EU countries and (ii) comparative advantages, pitfalls and possible reforms of the Italian model. In the main EU countries P&R is converging towards a contractual model where therapeutic added value and economic impact are playing a crucial role. However there are still important differences across countries in the way added value is measured, the comparators are chosen and the economic impact is integrated with clinical evidence. Compared to the other systems the main advantages of the Italian model are (i) the explicit adoption of a multiple criteria approach, which has allowed a higher flexibility in P&R negotiation, and (ii) that managed market entry contracts have been often used to manage uncertainty at market launch. However, the assessment process is not transparent, innovativeness and premium price have never been explicitly integrated and price negotiation is strongly influenced by a budget silos approach. The former two pitfalls can be faced in the short-term, whereas giving up spending caps on drugs would require a longer-term political consensus.
Global & Regional Health Technology Assessment: Italian; Northern Europe and Spanish, 2018
Introduction: This article aims at investigating the 5-year budget impact of rituximab biosimilar... more Introduction: This article aims at investigating the 5-year budget impact of rituximab biosimilars in Italy. Methods: A budget impact analysis model was developed in accordance with the International Society For Pharmacoeconomics and Outcomes Research recommendations. Drug acquisition and drug administration costs were considered since the risk/benefit profile of biosimilars and the originator was assumed to be overlapping. The perspectives of hospitals and payers were used. Input data were retrieved from the literature and validated/integrated by an expert panel of seven clinicians from various Italian regions. A dynamic incidence-based approach was used. Results: From the hospital perspective, adopting a rituximab biosimilar would produce savings of €79.2 and €153.6 million over 3 and 5 years, respectively. The results are very similar if the payer perspective is considered, with a cumulated savings of about €153.4 million in 5 years. Lymphoma and chronic lymphocytic leukaemia would account for the most significant savings. Discussion: Despite its limitations, this study provides the first Italian evaluation of the financial impact of rituximab biosimilars and also incorporates the effects of biosimilars on the pricing strategies of the originator (dynamic impact). This dynamic effect is more relevant than the impact of the treatment shift from the originator to biosimilars. Our hope is that these savings will be used to cover new cost-effective drugs and not just for cost-cutting policies.
Global & Regional Health Technology Assessment: Italian; Northern Europe and Spanish, 2018
Il Regolamento CE n° 726/2004 (1), nell'ambito della revisione della normativa farmaceutica europ... more Il Regolamento CE n° 726/2004 (1), nell'ambito della revisione della normativa farmaceutica europea, relativamente all'accesso precoce da parte dei pazienti per esigenze di tutela della salute, afferma che "al fine di soddisfare … le legittime aspettative dei pazienti e per tener conto del progresso sempre più rapido della scienza
Background Within (European) healthcare systems, the predominant goal for pharmaceutical expendit... more Background Within (European) healthcare systems, the predominant goal for pharmaceutical expenditure is cost containment. This is due to a general belief among healthcare policy makers that pharmaceutical expenditure-driven by high prices-will be unsustainable unless further reforms are enacted. Objective The aim of this paper is to provide more realistic expectations of pharmaceutical expenditure for all key stakeholder groups by estimating pharmaceutical expenditure at 'net' prices. We also aim to estimate any gaps developing between list and net pharmaceutical expenditure for the EU5 countries (i.e. France, Germany, Italy, Spain, and the UK). Methods We adjusted an established forecast of pharmaceutical expenditure for the EU5 countries, from 2017 to 2021, by reflecting discounts and rebates not previously considered, i.e. we moved from 'list' to 'net' prices, as far as data were available. Results We found an increasing divergence between expenditure measured at list and net prices. When the forecasts for the five countries were aggregated, the EU5 (unweighted) average historical growth (2010-2016) rate fell from 3.4% compound annual growth rate at list to 2.5% at net. For the forecast, the net growth rate was estimated at 1.5 versus 2.9% at list. Conclusions Our results suggest that future growth in pharmaceutical expenditure in Europe is likely to be (1) lower than previously understood from forecasts based on list prices and (2) below predicted healthcare expenditure growth in Europe and in line with long-term economic growth rates. For policy makers concerned about the sustainability of pharmaceutical expenditure, this study may provide some comfort, in that the perceived problem is not as large as expected.
Chronic kidney disease (CKD) is an important public health problem. Most of the evidence on its c... more Chronic kidney disease (CKD) is an important public health problem. Most of the evidence on its costs relates to patients receiving dialysis or kidney transplants, which shows that, in these phases, CKD poses a high burden to payers. Less evidence is available on the costs of the predialytic phase. The aim of this study was to estimate the annual cost of patients with CKD not receiving dialysis treatment, using the Italian healthcare system perspective and a prospective approach. A 3-year observational study (December 2010-September 2014) was carried out to collect data on resource consumption for 864 patients with CKD. Costs were estimated for both patients who completed the follow-up and dropouts. The mean annual total (healthcare) cost per patient equalled €2723 (95% confidence interval 2463.0-2983.3). Disease severity (higher CKD stage), multiple comorbidities, dropout status and belonging to the southern region are predictive of higher costs. Pharmaceuticals, hospitalisation, a...
Journal of Market Access & Health Policy, 2017
Background: Many established products (EPsmarketed for eight years or more) are widely used off-l... more Background: Many established products (EPsmarketed for eight years or more) are widely used off-label despite little evidence on benefit-risk ratio. This exposes patients to risks related to safety and lack of efficacy, and healthcare providers to liability. Introducing new indications for EPs may represent a high societal value; however, manufacturers rarely invest in R&D for EPs. The objective of this research was to describe incentives and disincentives for developing new indications for EPs in Europe and to investigate consequences of current policies. Methods: Targeted literature search and expert panel meetings. Results: Within the current European-level and national-level regulatory framework there are limited incentives for development of new indications with EPs. Extension of indication normally does not allow the price to be increased or maintained, the market protection period to be extended, or exclusion from a reference price system. New indication frequently triggers reevaluation, resulting in price erosion, regardless of the level of added value with the new indication. In consequence, manufacturers are more prone to undertake R&D efforts at early to mid-stage of product life cycle rather than with EPs, or to invest in new chemical entities, even in therapeutic areas with broad off-label use. This represents a potentially missed opportunity as developing new indications for EPs offers an alternative to off-label use or lengthy and expensive R&D for new therapies, opens new opportunities for potentially cost-effective treatment alternatives, as well as greater equity in patients' access to treatment options. Conclusion: There are potential benefits from the development of new indications for EPs that are currently not being realized due to a lack of regulatory and pricing incentives in Europe. Incentives for orphan or paediatric drugs have proven to be effective in promoting R&D. Similarly, incentives to promote R&D in EPs should be developed, for the benefit of patients and healthcare systems.
Technological innovation in healthcare yields better health outcomes but also drives healthcare e... more Technological innovation in healthcare yields better health outcomes but also drives healthcare expenditure, and governments are struggling to maintain an appropriate balance between patient access to modern care and the economic sustainability of healthcare systems. Health Technology Assessment (HTA) and centralized procurement are increasingly used to govern the introduction and diffusion of new technologies in an effort to make access to innovation financially sustainable. However, little empirical evidence is available to determine how they affect the selection of new technologies and unit prices. This paper focuses on medical devices (MDs) and investigates the combined effect of various HTA governance models and procurement practices on the two steps of the MD purchasing process (i.e., selecting the product and setting the unit price). Our analyses are based on primary data collected through a national survey of Italian public hospitals. The Italian National Health Service is an ideal case study because it is highly decentralized and because regions have adopted different HTA governance models (i.e., regional, hospital-based, double-level or no HTA), often in combination with centralized regional procurement programs. Hence, the Italian case allows us to test the impact of different combinations of HTA models and procurement programs in the various regions. The results show that regional HTA increases the probability of purchasing the costliest devices, whereas hospital-based HTA functions more like a costcontainment unit. Centralized regional procurement does not significantly affect MD selection and is associated with a reduction in the MD unit price: on average, hospitals located in regions with centralized procurement pay 10.1% less for the same product. Hospitals located in regions with active regional HTA programs pay higher prices for the same device (þ23.2% for inexpensive products), whereas hospitals that have developed internal HTA programs pay 8.3% on average more for the same product.
Global & regional health technology assessment, Jun 17, 2024
tenutasi il 21 e il 22 settembre 2023. Il GdL ha visto la partecipazione, come nelle precedenti e... more tenutasi il 21 e il 22 settembre 2023. Il GdL ha visto la partecipazione, come nelle precedenti edizioni dei Seminari di Mogliano, di soggetti istituzionali (Agenzia Italiana del Farmaco, AIFA, e Regioni) e stakeholder (clinici, referenti per i pazienti e imprese) (cfr. Ringraziamenti). Nello specifico, il coordinatore del GdL ha individuato i temi chiave oggetto della proposta di riforma, inquadrandola nell'attuale contesto degli EAP in Italia e condividendola in una prima sessione plenaria del Seminario. Il GdL ha discusso le possibili opzioni di riforma in due sessioni distinte, la prima finalizzata a ricevere in modo aperto le proposte dei partecipanti al GdL, la seconda di condivisione di un percorso comune, che si sono concretizzate in una presentazione validata dal GdL e presentata in plenaria con commenti da parte dei partecipanti di altri GdL. Il paper è diviso in due parti. Nella prima viene descritto in sintesi lo stato attuale degli EAP in Italia. Nella seconda vengono illustrati i risultati del GdL. I programmi di accesso precoce disponibili in Italia Garantire ai pazienti un rapido accesso a farmaci potenzialmente efficaci è un obiettivo importante per ciascun sistema sanitario, e ciò è tanto più vero nel caso di malattie gravi e prive di opzioni terapeutiche di provata efficacia. Per farmaci a designazione orfana che abbiano già ottenuto l'Autorizzazione all'Immissione in Commercio (AIC) in
Background Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for... more Background Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for healthcare payers because of the uncertainty on impact at market launch, high cost and important organisational impact. The literature has focused on their assessment, appraisal and market access solutions. No evidence on the costs sustained to implement CART is available and a few studies reported the cost of the CART clinical pathway, including the activities that are remunerated through inpatient or outpatient fee-for-service/episode. This paper aims at filling the information gap, assessing the cost of implementing CART activity and the full cost of managing the CART clinical pathway. Methods Cost analysis relied on the Activity Based Costing approach, which was applied to two Italian healthcare organisations, both CART Centres authorized by the regional governments with a minimum of 20 patients treated with the first two CART therapies launched on the market. Results The cost of implementing CART was estimated at €1.31 million (calculated for one of the organizations with complete data). Most of these costs (77%) were generated by quality assurance activity. The mean cost per patient entering the CART pathway (59 and 27) and surviving at follow-up (21 and 5) ranges from €48K to €57K and from €96K to €106K, respectively. Fees for hospitalization and infusion of gene therapy accounts for more than 70% of these costs. The actual hospitalisation cost varies greatly across patients and is in general lower than the fee-for-episode paid by the region to the hospital. Conclusions Despite its limitations (exploratory nature; the time spent by staff on activities which are not remunerated through fees was estimated through interviews with the CART coordinators; cost items are not fully comparable), this research highlighted the relevant organisational and economic impact of CART and provided important insights for policy makers and healthcare managers: the necessity to invest resources in CART
Background New indications for existing medicines are increasing over time. In most countries, dr... more Background New indications for existing medicines are increasing over time. In most countries, drug pricing and reimbursement conditions are renegotiated every time a new indication is approved. There is a growing interest in the price negotiation model for new indications, specifically comparing an indication-based versus blended approach. However, little evidence currently exists regarding the complexity of these negotiations and their impact on actual prices. Italy has recently transitioned from an indication-based approach to a blended price model. This study aims to measure the impact of price and reimbursement negotiation of new indications on discounts (i.e. actual prices) and on the negotiation duration, used as a proxy of its complexity. Methods We considered new indications approved through a European centralized procedure from January 2013 to March 2022 for which the price and reimbursement status was approved in Italy between January 2015 and March 2022, amounting to 52 new indications. Data on the timeframe of the Italian price and reimbursement process and its phases were obtained from publicly available sources. Discounts for the first indication and their subsequent increases for new indications were estimated by comparing ex-factory prices and tendered prices. To calculate p-values, we employed the Mann-Whitney test, and multiple regression models were utilized to examine correlations between negotiation time and the characteristics of the medicines. Results The mean time to reimbursement was 603 days, in contrast to 583 days for the first launch. Price negotiation took longer for rare diseases, cancer drugs, and in case of therapies with minor added therapeutic value. On average, the additional discount (on top of discounts for prior indications) was 13%, significantly lower than the mean discount for the first indications approved (24.9%). The discounts increment was lower, but negotiation took longer if a Managed Entry Agreement accompanied the final agreement. Additionally, discounts have increased over the years. Conclusion The negotiation for new indications takes longer than the first one, and provides, on average, an additional discount of 13%. While our findings bear the potential for significant policy implications, they necessitate prudent interpretation due to a limited number of observations. The increasing trend in additional discounts over time applied to all indications in recent negotiations, may suggest a descending trend of value for new indications and a shift from an indication-based pricing approach to a blended model. Otherwise, budget impact considerations might have outweighed a value-based approach in the recent negotiations. If so, two potential options for restoring a value-based approach are returning to an indication-based pricing or giving explicit and higher weight to value within a blended model.
The use of health technology assessment (HTA) to inform policy-making is established in most deve... more The use of health technology assessment (HTA) to inform policy-making is established in most developed countries. Compared to licensing agencies, HTA agencies have different interests and, therefore, different evidence requirements. Criteria for coverage or reimbursement decisions on pharmaceutical compounds vary; however, it is common to include, as part of the HTA, a comparative effectiveness evaluation. This type of clinical data might go beyond that required for market authorization, thus creating an additional evidence gap between the regulatory and the reimbursement submission. The relevance of submissions to HTA agencies is consistently increasing in a pharmaceutical company's perspective, as market prospects are strongly influenced by third-party payers' coverage. In this study, we aim to describe current HTA activities with a potential impact throughout the drug development process of pharmaceuticals, with a comparative emphasis on the systems in place in Italy and in the UK. Based on an extensive literature and website review, we identified three major classes of HTA activities, beyond mainstream HTA, with the potential to influence the drug development program: 1) horizon scanning and early HTA; 2) bipartite and tripartite early dialogue between manufacturers, regulators, and HTA assessors; and 3) managed market entry agreements. From early stages of clinical research up to postauthorization studies, there is a trend toward increased collaboration between parties, anticipation of market access evidence collection, and postmarketing risk-sharing. Heterogeneity of HTA practices increases the complexity of the market access environment. Overall, there are signals that market access departments are gaining importance in the pharmaceutical companies, but there is still a lack of evidence and reporting on how the increasing relevance of HTA has reshaped the way clinical development is designed and managed.
European Journal of Health Economics, Oct 27, 2015
Objectives This paper aims at covering a literature gap on the effects of copayments, prescriptio... more Objectives This paper aims at covering a literature gap on the effects of copayments, prescription quotas and therapeutic reference pricing on public and private expenditures and volumes (1) When these policies are implemented in different areas at different times, (2) estimating their impact in the short and long run, (3) assessing the extent to which these impacts are interdependent, (4) scrutinising the extent to which the effects are mediated by prescribers' and patients' behaviours. Methods Monthly regional data on pharmaceutical expenditures, volumes and policies in Italy from 2000 to 2014 are analysed using a difference-indifferences model enriched to capture short-versus long-term effects and simultaneous and interactive effects. Sobel-Goodman test and bootstrap analyses were used to test for mediation. Results The three policies have different short-and longrun effects. Interactions support the hypothesis of reinforcing effects. Behavioural reactions to policies such as reducing the demand or total per capita expenditures mediate the impact of policies, thus explaining the different effects between the short and long term. Conclusions Evidence on the impact over time of regional policies diversely introduced in different times have important policy implications. First, pharmaceutical policies interact with each other, and the combined effect may be different from what we would expect from the sum of each single policy. Hence, policymakers should be very careful in designing mixed policies for their unexpected combined effects. Second, the impact of policies tends to reduce over time. If longer-term impact is desired, it would be appropriate to introduce some adjustments over time. Third, policies have multiple effects, and this should be considered when they are designed. Finally, pharmaceutical policies may have an unintended impact on health and health care.
Early access programs (EAPs) generally refer to patient access to medicines/indications before ma... more Early access programs (EAPs) generally refer to patient access to medicines/indications before marketing authorization, possibly extended to price and reimbursement approval. These programs include compassionate use, which is usually covered by pharmaceutical companies, and EAPs reimbursed by third-party payers. This paper aims at comparing EAPs in four European countries (France, Italy, Spain, UK) and providing empirical evidence on EAPs in Italy. The comparative analysis was conducted through a literature review (including scientific and grey literature), complemented by 30-min semi-structured interviews with local experts. The Italian empirical analysis employed data available on the National Medicines Agency website. Although EAPs are very different across countries, they exhibit some common features: (i) eligibility criteria refer to the absence of valid therapeutic alternatives and a presumed favourable risk–benefit profile; (ii) payers do not allocate a pre-determined budget ...
Background Italy is Europe’s third largest pharmaceutical market, yet it ranks only ninth in the ... more Background Italy is Europe’s third largest pharmaceutical market, yet it ranks only ninth in the number of NIH-registered clinical trials per capita. The aim of our study was to explore stakeholders’ perception of Italy as place to undertake clinical trials, and to estimate the potential economic impact of selected reforms in terms of incremental trial activity. Methods The Survey of Attitudes towards Trials in Europe (SAT-EU Study) was an anonymous, web-based survey which systematically assessed factors impacting clinical trial site selection in Europe. Estimates of Italian economic impact were developed in collaboration with AICRO (Association of Italian Contract Research Organisations). Results Responses were obtained from 485 professionals in 34 countries (15% residing in Italy) representing over 100 institutions, spanning BioPharma Clinical Research Organizations (CROs), and Academic Clinical Trial Units (CTUs). Italy ranked tenth of twelve in terms of accessibility and transpa...
Background Innovative medicines are provided with dedicated funds and immediate market access in ... more Background Innovative medicines are provided with dedicated funds and immediate market access in Italy. Innovativeness evaluation considers unmet need, added therapeutic value, and quality of the evidence. Objective We aimed to evaluate the internal consistency and drivers of the innovativeness appraisal process. Methods Appraisal reports on innovativeness refer to 1997-2021. We used both a descriptive approach and probabilistic multivariate analysis, using logistic regression models to compute odds ratios and 95% confidence intervals. The dependent variable is innovativeness status (innovative vs. non-innovative; full innovativeness vs. conditional innovativeness). Explanatory variables, besides the three above-mentioned domains, are the year of evaluation, drug type, target disease and population, and the number and type of available studies. Results Among the 141 medicines scrutinized, 31.9%, 29.8%, and 38.3% were evaluated as fully innovative, conditionally innovative, and non-innovative, respectively. Added therapeutic value and the quality of the evidence were associated with the odds of receiving innovative status, and full compared with conditional innovativeness; unmet need was not a predictive variable. Other factors played a minor role: medicines for both solid tumours and rare diseases are more likely to be judged innovative; conditional innovativeness is more probable for medicines for rare diseases. Conclusions Innovativeness status is driven by the added therapeutic value and quality of evidence. The appraisal process is internally consistent and predictable. This provides industry with a clear indication of what is needed to ensure that access to their medicines is prioritized.
Global & Regional Health Technology Assessment, 2021
This article illustrates a consensus opinion of an expert panel on the need and usefulness of a f... more This article illustrates a consensus opinion of an expert panel on the need and usefulness of a framework for price and reimbursement (P&R) process and managed entry agreements (MEAs) for orphan medicines in Italy. This opinion was gathered in three rounds: an introductory document was sent to the panel and discussed during a recorded online meeting. A second document was sent to the panel for their review. In the third step the final document was validated. Members of the expert panel are the authors of the article. The panel agreed that Italy does not need a specific value framework for orphan medicines, driving the P&R process. Rather, a more structured value framework for all medicines tailored to the specific drugs can be useful. For orphan drugs, the panel advocated for a multidisciplinary approach and the contribution of different stakeholders to value assessment, and acknowledged the importance of addressing, more than for other drugs, unmet needs, equity issues and societal...
Background and aimEvidence on determinants of prices for orphan medicines is scarce and not avail... more Background and aimEvidence on determinants of prices for orphan medicines is scarce and not available for Italy. The aim of this paper is to provide an evidence on variables affecting the annual treatment cost of orphan drugs in Italy, testing the hypothesis of a negative correlation with the dimension of the target population and a positive correlation with the added therapeutic value of the drug and the quality of the evidence of pivotal studies.MethodsDrugs with a European orphan designation reimbursed in Italy in the last 6 years (2014–2019) were considered. Univariate, cluster analysis and multiple regression models were used to investigate the correlation between the annual treatment cost and, as explanatory variables, the dimension of the target population, the existence of Randomized Clinical Trials as a proxy of the quality of the pivotal studies, the added therapeutic value.ResultsIn the univariate analysis prevalence and added therapeutic value, as expected, have a negati...
Journal of Pharmaceutical Policy and Practice, 2021
Background Advanced therapy medicinal products (ATMPs) represent an important cornerstone for inn... more Background Advanced therapy medicinal products (ATMPs) represent an important cornerstone for innovation in healthcare. However, uncertainty on the value, the high average cost per patient and their one-shot nature has raised a debate on their assessment and appraisal process for pricing and reimbursement (P&R) purposes. This debate led experts providing for recommendations on this topic. Our primary objective is to investigate the ATMPs P&R process in the main five European countries and to understand if this process is consistent with published P&R expert recommendations. We also investigated the current ATMP pipelines to understand if future ATMPs will create challenges for their P&R process. Methods P&R framework for ATMPs in the European Major five (EU5) countries was investigated through a literature search on PubMed, institutional websites of National Health Authorities and grey literature. The ATMPs pipeline database was populated from a clinical trial database (clinicaltria...
This paper illustrates a conceptual model for a new Patient Reported Outcome measure (PROM) aimed... more This paper illustrates a conceptual model for a new Patient Reported Outcome measure (PROM) aimed at measuring financial toxicity (FT) in oncological setting in Italy, where citizens are provided universal health care coverage. Methods Focus groups with overall 34 patients/caregivers in three different Italian centres (from Northern, Centre and Southern Italy) and an open-ended survey with 97 medical oncologists were undertaken. Transcripts from focus groups and the open-ended survey were analyzed to identify themes and links between themes. Themes from the qualitative research were supplemented with those reported in the literature; concepts identified formed the basis for item development, that were then tested through the importance analysis (with 45 patients) and the cognitive debriefing (with other 45 patients) to test relevance and comprehension of the first draft PRO instrument. Results Ten domains were extracted by analyzing 156 concepts generated from focus groups and the openended survey. After controlling for redundancy, 55 items were generated and tested through the importance analysis. After controlling comprehension and feasibility through cognitive debriefing interviews, a first version of the questionnaire consisting of 30 items was devised. Conclusions This qualitative study represents the first part of a study conducted to develop a new PROM to assess FT in Italy, by using a bottom up approach that makes the most of patients' experiences and the health system analysis. clinicaltrials.gov NCT03473379 first posted on March 22, 2018
e18840 Background: The economic impact of clinical trials in the perspective of trial sites has b... more e18840 Background: The economic impact of clinical trials in the perspective of trial sites has been already investigated. Instead, there is no evidence on the economic net benefit of compassionate use programs for medicines (CUP). This research aims to fill the information gap, investigating the economic consequences of 8 CUP in Italy carried out from May 2015 to December 2020 in the hospitals’ perspective. These programs concern five cancer medicines (alectinib, atezolizumab, cobimetinib, polatuzumab vedotin, trastuzumab emtansine TDM-1), for a total of 8 programs. Methods: Economic net benefit includes avoided costs for standard of care (SoC) the patient would have received if he/she has not joined the CUP and costs not covered by the pharmaceutical industry and sustained by the hospital hosting CUP. The latter include costs of adverse event (only severe sides effects generating hospitalisation and ascribed to medicines used in CUP), combination therapies and diagnostic procedure...
Global & Regional Health Technology Assessment: Italian; Northern Europe and Spanish, 2015
Innovation and drugs price and reimbursement: a comparison between Italy and the other major EU c... more Innovation and drugs price and reimbursement: a comparison between Italy and the other major EU countries This paper aims at investigating (i) differences and commonalities of drugs Price and Reimbursement (P&R) criteria between Italy and the other major EU countries and (ii) comparative advantages, pitfalls and possible reforms of the Italian model. In the main EU countries P&R is converging towards a contractual model where therapeutic added value and economic impact are playing a crucial role. However there are still important differences across countries in the way added value is measured, the comparators are chosen and the economic impact is integrated with clinical evidence. Compared to the other systems the main advantages of the Italian model are (i) the explicit adoption of a multiple criteria approach, which has allowed a higher flexibility in P&R negotiation, and (ii) that managed market entry contracts have been often used to manage uncertainty at market launch. However, the assessment process is not transparent, innovativeness and premium price have never been explicitly integrated and price negotiation is strongly influenced by a budget silos approach. The former two pitfalls can be faced in the short-term, whereas giving up spending caps on drugs would require a longer-term political consensus.
Global & Regional Health Technology Assessment: Italian; Northern Europe and Spanish, 2018
Introduction: This article aims at investigating the 5-year budget impact of rituximab biosimilar... more Introduction: This article aims at investigating the 5-year budget impact of rituximab biosimilars in Italy. Methods: A budget impact analysis model was developed in accordance with the International Society For Pharmacoeconomics and Outcomes Research recommendations. Drug acquisition and drug administration costs were considered since the risk/benefit profile of biosimilars and the originator was assumed to be overlapping. The perspectives of hospitals and payers were used. Input data were retrieved from the literature and validated/integrated by an expert panel of seven clinicians from various Italian regions. A dynamic incidence-based approach was used. Results: From the hospital perspective, adopting a rituximab biosimilar would produce savings of €79.2 and €153.6 million over 3 and 5 years, respectively. The results are very similar if the payer perspective is considered, with a cumulated savings of about €153.4 million in 5 years. Lymphoma and chronic lymphocytic leukaemia would account for the most significant savings. Discussion: Despite its limitations, this study provides the first Italian evaluation of the financial impact of rituximab biosimilars and also incorporates the effects of biosimilars on the pricing strategies of the originator (dynamic impact). This dynamic effect is more relevant than the impact of the treatment shift from the originator to biosimilars. Our hope is that these savings will be used to cover new cost-effective drugs and not just for cost-cutting policies.
Global & Regional Health Technology Assessment: Italian; Northern Europe and Spanish, 2018
Il Regolamento CE n° 726/2004 (1), nell'ambito della revisione della normativa farmaceutica europ... more Il Regolamento CE n° 726/2004 (1), nell'ambito della revisione della normativa farmaceutica europea, relativamente all'accesso precoce da parte dei pazienti per esigenze di tutela della salute, afferma che "al fine di soddisfare … le legittime aspettative dei pazienti e per tener conto del progresso sempre più rapido della scienza
Background Within (European) healthcare systems, the predominant goal for pharmaceutical expendit... more Background Within (European) healthcare systems, the predominant goal for pharmaceutical expenditure is cost containment. This is due to a general belief among healthcare policy makers that pharmaceutical expenditure-driven by high prices-will be unsustainable unless further reforms are enacted. Objective The aim of this paper is to provide more realistic expectations of pharmaceutical expenditure for all key stakeholder groups by estimating pharmaceutical expenditure at 'net' prices. We also aim to estimate any gaps developing between list and net pharmaceutical expenditure for the EU5 countries (i.e. France, Germany, Italy, Spain, and the UK). Methods We adjusted an established forecast of pharmaceutical expenditure for the EU5 countries, from 2017 to 2021, by reflecting discounts and rebates not previously considered, i.e. we moved from 'list' to 'net' prices, as far as data were available. Results We found an increasing divergence between expenditure measured at list and net prices. When the forecasts for the five countries were aggregated, the EU5 (unweighted) average historical growth (2010-2016) rate fell from 3.4% compound annual growth rate at list to 2.5% at net. For the forecast, the net growth rate was estimated at 1.5 versus 2.9% at list. Conclusions Our results suggest that future growth in pharmaceutical expenditure in Europe is likely to be (1) lower than previously understood from forecasts based on list prices and (2) below predicted healthcare expenditure growth in Europe and in line with long-term economic growth rates. For policy makers concerned about the sustainability of pharmaceutical expenditure, this study may provide some comfort, in that the perceived problem is not as large as expected.
Chronic kidney disease (CKD) is an important public health problem. Most of the evidence on its c... more Chronic kidney disease (CKD) is an important public health problem. Most of the evidence on its costs relates to patients receiving dialysis or kidney transplants, which shows that, in these phases, CKD poses a high burden to payers. Less evidence is available on the costs of the predialytic phase. The aim of this study was to estimate the annual cost of patients with CKD not receiving dialysis treatment, using the Italian healthcare system perspective and a prospective approach. A 3-year observational study (December 2010-September 2014) was carried out to collect data on resource consumption for 864 patients with CKD. Costs were estimated for both patients who completed the follow-up and dropouts. The mean annual total (healthcare) cost per patient equalled €2723 (95% confidence interval 2463.0-2983.3). Disease severity (higher CKD stage), multiple comorbidities, dropout status and belonging to the southern region are predictive of higher costs. Pharmaceuticals, hospitalisation, a...
Journal of Market Access & Health Policy, 2017
Background: Many established products (EPsmarketed for eight years or more) are widely used off-l... more Background: Many established products (EPsmarketed for eight years or more) are widely used off-label despite little evidence on benefit-risk ratio. This exposes patients to risks related to safety and lack of efficacy, and healthcare providers to liability. Introducing new indications for EPs may represent a high societal value; however, manufacturers rarely invest in R&D for EPs. The objective of this research was to describe incentives and disincentives for developing new indications for EPs in Europe and to investigate consequences of current policies. Methods: Targeted literature search and expert panel meetings. Results: Within the current European-level and national-level regulatory framework there are limited incentives for development of new indications with EPs. Extension of indication normally does not allow the price to be increased or maintained, the market protection period to be extended, or exclusion from a reference price system. New indication frequently triggers reevaluation, resulting in price erosion, regardless of the level of added value with the new indication. In consequence, manufacturers are more prone to undertake R&D efforts at early to mid-stage of product life cycle rather than with EPs, or to invest in new chemical entities, even in therapeutic areas with broad off-label use. This represents a potentially missed opportunity as developing new indications for EPs offers an alternative to off-label use or lengthy and expensive R&D for new therapies, opens new opportunities for potentially cost-effective treatment alternatives, as well as greater equity in patients' access to treatment options. Conclusion: There are potential benefits from the development of new indications for EPs that are currently not being realized due to a lack of regulatory and pricing incentives in Europe. Incentives for orphan or paediatric drugs have proven to be effective in promoting R&D. Similarly, incentives to promote R&D in EPs should be developed, for the benefit of patients and healthcare systems.
Technological innovation in healthcare yields better health outcomes but also drives healthcare e... more Technological innovation in healthcare yields better health outcomes but also drives healthcare expenditure, and governments are struggling to maintain an appropriate balance between patient access to modern care and the economic sustainability of healthcare systems. Health Technology Assessment (HTA) and centralized procurement are increasingly used to govern the introduction and diffusion of new technologies in an effort to make access to innovation financially sustainable. However, little empirical evidence is available to determine how they affect the selection of new technologies and unit prices. This paper focuses on medical devices (MDs) and investigates the combined effect of various HTA governance models and procurement practices on the two steps of the MD purchasing process (i.e., selecting the product and setting the unit price). Our analyses are based on primary data collected through a national survey of Italian public hospitals. The Italian National Health Service is an ideal case study because it is highly decentralized and because regions have adopted different HTA governance models (i.e., regional, hospital-based, double-level or no HTA), often in combination with centralized regional procurement programs. Hence, the Italian case allows us to test the impact of different combinations of HTA models and procurement programs in the various regions. The results show that regional HTA increases the probability of purchasing the costliest devices, whereas hospital-based HTA functions more like a costcontainment unit. Centralized regional procurement does not significantly affect MD selection and is associated with a reduction in the MD unit price: on average, hospitals located in regions with centralized procurement pay 10.1% less for the same product. Hospitals located in regions with active regional HTA programs pay higher prices for the same device (þ23.2% for inexpensive products), whereas hospitals that have developed internal HTA programs pay 8.3% on average more for the same product.
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Papers by Claudio Jommi