Quantifying the Dual Value and Governance Risks of Early Access Programs in Oncology: A Single-Centre Analysis and National Policy Framework

Quantifying the Dual Value and Governance Risks of Early Access Programs in Oncology: A Single-Centre Analysis and National Policy Framework | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Quantifying the Dual Value and Governance Risks of Early Access Programs in Oncology: A Single-Centre Analysis and National Policy Framework Mauro Iannopollo, Miriam Ricasoli, Virginia Maragna, Daniele Checcacci, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9212433/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Early Access Programs (EAPs) and Named Patient Programs (NPPs) in Italy, governed by the Decreto Lorenzin (2017), are the primary route through which oncology patients access innovative therapies pending reimbursement by the Agenzia Italiana del Farmaco (AIFA). Their institutional value has not been systematically quantified, and key governance gaps remain formally undescribed. Methods Retrospective analysis of all EAPs and NPPs managed at AUSL Toscana Centro (Pistoia and Pescia) during 2025. Drug-cost savings were calculated from official AIFA ex-factory prices. We introduce a Dual-Value EAP Accounting Framework integrating drug-cost savings with quality-adjusted life year (QALY)-based clinical value, and compare Italian, French, and German early access governance. Results Eleven programmes covering 23 patients were active. Gross drug-cost saving from nine priced programmes was €761,728 (net ~€533,000 after 30% discount). The ribociclib adjuvant programme (EAP NATALEE; €268,721; 10 patients) was the largest contributor; QALY-based valuation adds an estimated €150,000 at €30,000/QALY. Total administrative burden was 181.7 hours (0.114 full-time equivalent [FTE]), yielding a 168:1 return on investment. Conclusions A proactively managed EAP portfolio at a single medium-sized centre generated substantial dual value. Three critical governance gaps are identified: absence of real-time AIFA portal transparency, prohibition on company-initiated programme information, and unregulated institutional incentives in intraclass settings. Five reforms — modelled on French and German governance frameworks — could address all gaps within existing AIFA regulatory mandate, without primary legislative change. The Dual-Value Framework relies on routinely available data and is directly replicable across publicly funded oncology centres. JEL codes: I11 · I13 · I18 · H51 early access programs named patient programs oncology dual-value framework pharmacoeconomics QALY governance AIFA Italian NHS Introduction In Italy, access to innovative oncological therapies before formal price and reimbursement negotiation by the Agenzia Italiana del Farmaco (AIFA) occurs primarily through two mechanisms: Early Access Programs (EAPs), which provide pre-marketing authorisation access under the compassionate use framework, and Named Patient Programs (NPPs), which allow individual patient access to authorised-but-not-yet-reimbursed products. Both are regulated under Ministerial Decree 7 September 2017 (the Decreto Lorenzin) [1]. The interval between European Medicines Agency (EMA) marketing authorisation and AIFA reimbursement in Italy averages 14–18 months, one of the longest in the European Union [2, 5]. This delay represents a clinically significant access gap, particularly in diseases where the approved therapy addresses an unmet therapeutic need or offers substantial efficacy gains over available alternatives. During this period, EAPs and NPPs represent the primary mechanism through which Italian patients can access the most innovative therapies. Despite their clinical and economic significance, systematic quantification of EAP value at the institutional level is rare in the Italian literature [3, 6]. The few published analyses focus predominantly on the economic burden of delayed access from the payer perspective [5, 7], rather than on the institutional value generated by proactive EAP management. Furthermore, the Italian EAP governance architecture presents three structural weaknesses that have received little formal analytical attention: the absence of AIFA portal transparency on active programmes, the prohibition on company-initiated programme promotion, and the inadequate framework for clinical justification when reimbursed alternatives exist. This paper addresses both dimensions. We report a single-centre analysis of EAP/NPP activity in 2025 at AUSL Toscana Centro (Pistoia and Pescia), introduce a Dual-Value EAP Accounting Framework integrating drug-cost savings with quality-adjusted life year (QALY)-based clinical value, and provide a structured comparative analysis of critical governance gaps with concrete reform proposals. Regulatory framework: the Italian EAP ecosystem The Decreto Lorenzin of 2017 distinguishes between two principal access mechanisms [1]. Compassionate use ( uso compassionevole ) applies to unauthorised medicinal products or authorised products used outside the approved indication, where no therapeutic alternative exists and there is a reasonable expectation of clinical benefit. NPPs operate where the product has received EMA marketing authorisation but AIFA reimbursement has not yet been granted; the product is provided free of charge by the pharmaceutical company under individual patient request. Both mechanisms are grounded in Article 83 of Regulation (EC) No 726/2004. Under the Decreto Lorenzin, EAPs — corresponding to group compassionate use — are available for patients with serious, rare, or life-threatening conditions for whom no adequate reimbursed therapeutic alternative exists, provided the drug has completed at least a Phase II clinical trial. The procedural pathway for either mechanism is administratively intensive. The prescribing physician must submit a formal clinical justification documenting the absence of reimbursed alternatives, which triggers a gratuity letter from the pharmaceutical company, submission to the institutional Ethics Committee (CE), and Hospital Pharmacy order. Where the drug is not commercially available in Italy but is authorised elsewhere in Europe, an additional Nulla Osta Sanitario (NOS) from the Ministry of Health is required, adding 4–12 weeks to the process [14]. Methods Study design and setting We conducted a retrospective descriptive analysis of all EAPs and NPPs managed by the Hospital Pharmacy Unit in collaboration with the Medical Oncology Units of Ospedale San Jacopo (Pistoia) and SS. Cosma e Damiano (Pescia), AUSL Toscana Centro, during calendar year 2025. Data collected included: number of active programmes, drugs involved, oncological indications, number of patients enrolled and treated, quantities of drug supplied free of charge, and estimated dates of AIFA reimbursement. No individual patient data are reported; Ethics Committee approval was not required under applicable Italian regulations for this type of institutional review. This study was conducted at a single medium-sized oncology centre; however, all processes analysed reflect nationally standardised regulatory procedures established by the Decreto Lorenzin, supporting applicability of the findings and the proposed Dual-Value Framework to other publicly funded oncology centres operating within the Italian NHS regulatory environment. AI-assisted writing tools (Claude, Anthropic) were used for drafting and language editing support. All analytical content, data collection, calculations, and conclusions were developed and approved by the authors. Economic valuation: drug-cost component The economic value of free drug supply was calculated exclusively using official AIFA ex-factory prices sourced from the Italian Official Gazette and AIFA pricing determinations publicly available at the time of data collection. Two programmes involving drugs without an official Italian or European reimbursement price (sevabertinib, repotrectinib) were excluded from the economic analysis. We report both the gross ex-factory value and a conservative net estimate assuming a 30% average negotiated discount, consistent with published estimates of AIFA managed entry discounts for oncology drugs [3]. Economic valuation: QALY-based component (Dual-Value EAP Accounting Framework) Beyond drug-cost saving, EAPs generate a second dimension of value: the clinical benefit produced in patients who access effective therapy during the reimbursement latency period. For programmes where published QALY gain data are available, we apply the following framework: (a) incremental QALY gain per patient derived from published cost-effectiveness analyses using conservative lower-bound values from sensitivity analyses; (b) pro-rated QALY value limited to the reimbursement latency period, not the full lifetime horizon; (c) monetised QALY value calculated at the AIFA threshold of €30,000/QALY [11]. This approach intentionally undervalues total clinical benefit, as any continued benefit beyond the latency period accrues regardless of the access pathway. The pro-rated estimate assumes a linear accrual of QALY gain over time — that is, that each month of treatment access during the latency period contributes an equal fraction of the annual incremental QALY benefit reported in the source cost-effectiveness model. Utility weights are derived from the published cost-effectiveness analysis cited for each programme (Canadian EQ-5D-derived weights for ribociclib [10]), applied conservatively as a lower-bound proxy in the absence of Italian-context utility data. We designate this integrated approach the Dual-Value EAP Accounting Framework, combining drug-cost savings with pro-rated QALY-based clinical value to allow institutions to report the full economic and clinical return of EAP activity in a single auditable figure. This framework is not a cost-effectiveness analysis of EAPs per se, but a tool for communicating complete institutional value to decision-makers who typically receive only drug-cost data. Administrative burden analysis Administrative burden was quantified using a bottom-up workflow analysis, cataloguing each discrete administrative step, the responsible professional, time required per occurrence, and frequency. Detailed workflow data are provided in Online Resources 1 and 2. Results EAP/NPP portfolio 2025 In 2025, 11 EAP/NPP programmes were active across 11 different oncological indications, involving 23 treated patients. Table 1 provides a descriptive overview of all 11 programmes. Table 1 EAP/NPP programmes 2025, AUSL Toscana Centro. Savings calculated at AIFA ex-factory prices. Two programmes without Italian ex-factory pricing excluded from economic analysis. Programme Drug (brand) Indication Pts Free supply Est. saving (ex-factory) NPP (Daiichi-Sankyo) Trastuzumab deruxtecan (Enhertu®) NSCLC HER2-mut 2 24 vials €55,981 EAP ADRIATIC (AstraZeneca) Durvalumab (Imfinzi®) LS-SCLC 1 12 vials €33,241 EAP MATTERHORN (AstraZeneca) Durvalumab (Imfinzi®) GC/GEJC periop. 1 9 vials €24,931 NPP (Astellas/MSD) Pembrolizumab + enfortumab vedotin Urothelial carcinoma 1 4 + 20 vials €40,678 EAP NATALEE (Novartis) Ribociclib (Kisqali®) BC HR+/HER2 − adj. 10 60 + 16 packs €268,721 EAP PAPILLON (Janssen) Amivantamab (Rybrevant®) NSCLC EGFR ex20ins 2 84 vials €117,348 EAP AEGEAN (AstraZeneca) Durvalumab (Imfinzi®) NSCLC periop. 2 48 vials €132,964 EAP RUBY (GSK) Dostarlimab (Jemperli®) Endometrial carcinoma 1 12 packs €75,288 EAP Zolbetuximab (Astellas) Zolbetuximab (Vyloy®) GC/GEJC adv. CLDN18.2+ 1 24 vials €12,576 NPP (Bayer) — excl. Sevabertinib NSCLC HER2m 1 — Excluded (no price) NPP (BMS) — excl. Repotrectinib NSCLC ROS1/NTRK 1 — Excluded (no price) TOTAL (9 priced) 21 €761,728 adj. adjuvant; periop. perioperative; LS-SCLC limited-stage small-cell lung cancer; GC gastric cancer; GEJC gastroesophageal junction cancer; HER2-mut HER2-mutated; ex20ins exon 20 insertion; BC breast cancer. Drug-cost saving: gross and net estimates The gross ex-factory saving across nine programmes was €761,728. Applying a conservative 30% discount assumption to reflect typical AIFA-negotiated price reductions, the estimated net saving to the NHS is approximately €533,000. The ribociclib adjuvant programme (EAP NATALEE) accounts for the largest single contribution (€268,721 gross; ~€188,000 net), driven by high patient volume (10 patients) and duration of adjuvant treatment (up to 3 years under NATALEE protocol). QALY-based valuation: application to the ribociclib programme The ribociclib adjuvant programme provides the most robust basis for QALY-based valuation. The NATALEE trial demonstrated an absolute invasive disease-free survival (iDFS) benefit at 4 years of approximately 3.2% over endocrine therapy alone in the high-risk population. A published cost-effectiveness analysis from a Canadian payer perspective estimated an incremental QALY gain of approximately 0.84 QALY per patient over a lifetime horizon [ 10 ]. For the present analysis, a conservative pro-rated estimate of 0.5 QALY per patient is applied, limited to the reimbursement latency period (estimated at 15 months; EMA approval: 27 November 2024; AIFA reimbursement: 7 March 2026). This estimate is derived from a Canadian payer perspective and may not fully reflect Italian-specific utility weights; it should be interpreted as a conservative proxy pending Italian-context cost-effectiveness data. The QALY-based clinical value estimate for the ribociclib programme is exploratory and derived from published utility weights and treatment duration assumptions reported in the literature. This estimate is intended to illustrate the potential magnitude of clinical benefit associated with early access rather than to provide a formal cost-effectiveness evaluation. No sensitivity analysis was performed given the descriptive nature of the study. Applying the AIFA threshold of €30,000/QALY: 10 patients × 0.5 QALY × €30,000 = €150,000 (AIFA threshold) 10 patients × 0.5 QALY × €20,000 = €100,000 (individual WTP estimate [ 11 ]) Adding this QALY-based component to the drug-cost saving (€268,721) produces a total estimated programme value of €368,721–€418,721 for ribociclib alone — approximately 56% higher than the drug-cost estimate alone. Administrative burden and return on investment Total documented administrative burden for 2025 was 181.7 hours (0.114 FTE based on 1,600 productive hours/year). Detailed workflow data by activity type and by programme are provided in Online Resources 1 and 2, respectively. At a gross employment cost of €40,000/year for a hospital pharmacy technician — the appropriate staffing level for administrative EAP work — the annual administrative cost is approximately €4,540. The return on investment (ROI) is therefore 168:1 against gross ex-factory drug-cost savings (€761,728 ÷ €4,540), rising to approximately 237:1 when QALY-based clinical value is included. The ROI figure reveals that the current system implicitly transfers a real and documentable workload onto existing clinical and pharmacy staff without formal recognition, dedicated staffing, or compensation, while generating an institutional economic benefit two orders of magnitude larger. The cost is not absent; it is invisible and unfunded. Structural governance gaps Critical gap 1: AIFA portal silence and network-dependent access Italian regulations require AIFA to maintain a public registry of authorised compassionate use programmes. In practice, this static webpage is not integrated into the operational monitoring portal that hospital pharmacists and oncologists use daily. Discovery of available programmes relies primarily on direct communication from pharmaceutical company Medical Affairs personnel (formally prohibited under current AIFA regulations) and physician-to-physician informal networks. This creates a structural access inequity: patients treated at centres with highly networked oncologists are substantially more likely to benefit from available EAPs than equivalent patients at less-connected centres. If the €761,728 saving realised at AUSL Toscana Centro (serving ~ 250,000 population) were scaled to Italy's ~ 200 accredited oncology centres, the estimated national annual value of proactively managed EAPs would be in the order of €130–150 million. Critical gap 2: administrative burden without proportional resource allocation The procedural chain for each EAP activation requires an estimated 10–18 hours of professional time per programme initiation, and 2–4 hours per patient cycle renewal (see Online Resources 1 and 2). No Italian NHS institution currently allocates dedicated administrative personnel to EAP management. The 181.7-hour annual burden documented here represents approximately 11.4% of one FTE — a volume that clearly justifies formal part-time allocation at a cost less than 2% of the economic value generated. Critical gap 3: governance risk from misaligned institutional incentives Any system combining (a) a formal requirement to exclude reimbursed alternatives as a condition of EAP access, (b) large and measurable institutional savings from EAP programmes, and (c) no independent audit mechanism will predictably generate a risk of misalignment between clinical justification and economic interest. Two paradigmatic cases illustrate this vulnerability: Case 1 — Durvalumab (EAP) versus pembrolizumab and nivolumab (reimbursed) : In multiple indications relevant to Italian clinical practice — including perioperative NSCLC and limited-stage SCLC — durvalumab was accessible via EAP during 2025 while pembrolizumab and nivolumab were AIFA-reimbursed in the same or comparable indications. No head-to-head randomised data demonstrate the clinical superiority of durvalumab in these settings. The institutional economic incentive — three durvalumab programmes totalling €191,136 — constitutes an unregulated factor that may influence clinical justification. Case 2 — Adagrasib (EAP) versus sotorasib (reimbursed) in KRAS G12C-mutated NSCLC : Sotorasib received AIFA reimbursement for previously treated NSCLC in 2023. Adagrasib, a second-generation KRAS G12C inhibitor sharing the same molecular target and indication, was accessible via NPP during 2025. No predictable patient-level contraindication to sotorasib that adagrasib systematically avoids has been established. A formal clinical justification claiming sotorasib contraindication in a patient without specific hepatic disease or relevant comorbidity is therefore clinically unsustainable as a systematic criterion. The cases presented are illustrative of structural vulnerabilities within the current regulatory framework and should not be interpreted as evidence of inappropriate clinical conduct by individual practitioners. They demonstrate how, in the absence of formalised value-based selection criteria and explicit institutional incentive alignment, intraclass early access settings may generate allocation patterns that are suboptimal from a system-efficiency perspective. Comparative European frameworks: France and Germany The French model: Accès Précoce France operates the most structurally advanced early access system in Europe. The 2021 reform replaced the Autorisation Temporaire d'Utilisation (ATU) with the Autorisation d'Accès Précoce (AAP), consolidating six pre-existing schemes into two coherent pathways and transferring decision-making authority from the regulatory agency (ANSM) to the health technology assessment body (HAS) [ 15 ]. Between July 2021 and mid-2024, HAS issued 288 AAP decisions (approval rate 80%), approximately half in oncology. Three features are particularly relevant: (1) public transparency through a continuously updated HAS registry of all AAP decisions; (2) centralised reimbursement at 100% by the Caisse Nationale d'Assurance Maladie at a freely set manufacturer price with a retrospective payback clause; (3) mandatory real-world data collection via a structured patient monitoring protocol (PUT-RD) whose outputs feed directly into the HTA dossier. The Italian system shares the clinical rationale but lacks all three structural features. The German model: AMNOG Germany's AMNOG (in force since 2011) resolves the access gap through automatic reimbursement at launch: every EMA-approved product is immediately reimbursed at the manufacturer's freely set launch price for twelve months, during which the G-BA and IQWiG conduct a mandatory benefit assessment against an appropriate comparative therapy (ACT) [ 16 ]. Compassionate use under German law applies only in the genuinely pre-authorisation setting. From 2011 through November 2023, 944 AMNOG assessments were completed; 53% of non-orphan drugs received a decision of 'no added medical benefit' relative to the ACT — underscoring the importance of rigorous comparator evaluation. Comparative synthesis Table 2 summarises the three systems across seven governance dimensions. Italy's absence of a real-time public registry is unique among major European economies. Italy's absence of mandatory real-world data collection means the clinical value generated by EAPs is lost to the evidence base. Italy's absence of a structured comparator evaluation framework leaves the key clinical justification question — is there an adequate reimbursed alternative? — to individual physician assessment without independent verification. Table 2 Comparative analysis of early access frameworks: Italy, France, and Germany. Dimension Italy (Decreto Lorenzin) France (AAP 2021) Germany (AMNOG + § 21 AMG) Access trigger No reimbursed alternative; physician-initiated Severe disease, no alternative, presumed innovation; company application to HAS Automatic reimbursement at launch (12 months); compassionate use only pre-EMA Regulatory body AIFA (post-hoc) HAS + ANSM (prospective HTA decision) G-BA/IQWiG (AMNOG benefit assessment) Public registry Absent / not searchable in real time Transparent HAS registry, updated continuously G-BA public database of all assessments Reimbursement model Free drug from company; NHS pays nothing 100% NHS reimbursement; company sets free price with payback clause Automatic NHS reimbursement at launch price (12 months) Real-world data Not mandated; no systematic collection Mandatory PUT-RD protocol; feeds into HTA dossier Post-AMNOG registry for drugs with non-quantifiable benefit Comparator evaluation Implicit exclusion; no independent audit HAS explicitly evaluates availability of alternatives as eligibility criterion AMNOG uses ACT (appropriate comparative therapy) as mandatory reference Company role Prohibited from promoting; passive supply Active applicant to HAS; required to submit HTA dossier Active dossier submission at launch; mandatory pricing negotiation AAP Autorisation d'Accès Précoce; AMNOG Arzneimittelmarktneuordnungsgesetz; HAS Haute Autorité de Santé; ANSM Agence Nationale de Sécurité du Médicament; G-BA Gemeinsamer Bundesausschuss; IQWiG Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen; PUT-RD Protocol d'Utilisation Thérapeutique et de Recueil de Données; ACT appropriate comparative therapy. Policy reform proposals AIFA portal transparency AIFA should implement a real-time, searchable public registry of all active EAP and NPP authorisations, including the drug name, indication, eligibility criteria summary, sponsoring company contact, and Ethics Committee reference. This registry should be updated within 30 days of any new programme authorisation and generate automated email notifications to registered oncologists and pharmacists in relevant therapeutic areas. Implementation would require administrative decision rather than legislative change. Standardised dual-value institutional reporting Institutions managing EAPs should be required to report annually to their Direzione Sanitaria and institutional Ethics Committees using a standardised template including both drug-cost savings and QALY-based clinical value. This would provide governance bodies with complete value information, create a national dataset for aggregate impact assessment, and enable comparison of EAP activity across institutions. Mandatory structured clinical justification for intraclass EAPs For all EAP or NPP requests involving a drug in a class for which at least one reimbursed alternative exists, AIFA should require a structured clinical justification document that explicitly addresses: (a) the evidence base distinguishing the EAP drug from the reimbursed alternative; (b) the specific patient characteristics making the alternative inadequate; and (c) a declaration that clinical justification is independent of institutional economic benefit. This document should include, as a standard field, the estimated gross economic value of the programme to the institution — already calculable from AIFA ex-factory prices. Dedicated administrative infrastructure Oncology centres managing five or more active EAP/NPP programmes should be entitled to fund one dedicated pharmacy technician position from the documented drug-cost savings generated by the portfolio, without requiring separate budget allocation. This self-financing model is both operationally sustainable and administratively straightforward within existing NHS accounting frameworks. Mandatory real-world data collection A mandatory real-world data collection requirement — structured as a lightweight patient registry integrated into the existing AIFA monitoring portal, with data entry at each resupply cycle — would generate a national EAP outcomes dataset within 24 months of implementation. Following the French PUT-RD model, the dataset should be minimal (approximately 8–12 variables per patient per cycle: performance status, treatment continuation, reason for discontinuation if applicable, primary adverse events), completable within the resupply documentation workflow in an estimated 10–15 minutes per patient per cycle. Discussion This analysis makes four original contributions to the existing literature. First, the Dual-Value EAP Accounting Framework is introduced as the first standardised instrument for complete EAP value quantification from routinely available data. Second, precise administrative burden quantification for an Italian EAP portfolio is provided using a bottom-up workflow analysis (181.7 hours; 168:1 ROI) rather than estimates. Third, institutional incentive misalignment in intraclass EAP settings is formally characterised as a structural architecture problem. Fourth, a structured European comparison with France and Germany identifies directly implementable reforms for the Italian regulatory context [ 2 , 4 , 7 ]. The governance risk identified in Section 5 requires careful contextualisation. The prescribing physicians who activate EAPs are, in the great majority of instances, acting in good faith on the basis of genuine clinical judgement. The problem is a system design that has not anticipated the interaction between the clinical justification requirement, the prohibition on company-initiated promotion, and the scale of economic incentives that EAPs now generate. As oncology drug prices escalate and the reimbursement gap widens, the institutional economic value of EAP portfolios will continue to grow. Ethics Committees play a central role in the governance of Early Access Programs, ensuring procedural compliance, patient protection, and ethical oversight of non-standard treatment access. However, their current mandate is primarily focused on individual patient-level appropriateness and regulatory adherence. It does not extend to the evaluation of system-level efficiency, opportunity cost, or incentive alignment. As a result, key governance gaps persist at the interface between clinical decision-making and resource allocation. Several limitations should be acknowledged. Although this analysis is based on a single-centre experience, all administrative processes described reflect nationally standardised regulatory requirements and are therefore likely to be reproducible across similar oncology settings, although centre-specific factors such as pharmacy staffing and patient volume may influence the absolute administrative burden. The proposed Dual-Value framework relies exclusively on routinely available institutional data, supporting its scalability and applicability to other publicly funded healthcare systems. Larger reference centres likely manage substantially greater volumes. The QALY-based valuation for ribociclib depends on a Canadian payer perspective cost-effectiveness model [ 10 ] — currently the most relevant published analysis available — and may not perfectly reflect Italian clinical practice patterns or utilities; Italian-context cost-effectiveness data are not yet available in the published literature. The administrative cost estimate uses a pharmacy technician salary (€40,000/year) as the staffing reference, whereas in practice EAP management is predominantly performed by qualified hospital pharmacists whose employment cost is substantially higher; ROI figures should therefore be interpreted as upper-bound estimates. The governance risk analysis is structurally inferential — it identifies a systemic vulnerability rather than documenting actual instances of inappropriate justification. Future work should include multi-centre surveys, systematic analysis of Ethics Committee justification documentation in intraclass EAP settings, and prospective clinical outcome tracking. Conclusions EAPs in Italian oncology generate dual value that current reporting frameworks systematically underestimate. A proactively managed portfolio of 11 programmes at a single medium-sized centre generated €761,728 in drug-cost savings and an estimated additional €150,000 in QALY-based clinical value for the ribociclib programme alone, with a documented 168:1 ROI for administrative costs. AUSL Toscana Centro is neither a comprehensive cancer centre nor a highly specialised reference institution; the documented portfolio is therefore likely a conservative estimate of what occurs at larger referral centres. The absence of systematic national EAP reporting means that single-centre data currently provide the only granular quantification available to inform policy — which is itself an argument for the transparency reforms proposed. The Dual-Value EAP Accounting Framework provides a replicable, institution-level reporting tool that any oncology centre can implement from routinely available data — AIFA ex-factory prices and published cost-effectiveness estimates — without additional data collection. Five structural reforms are necessary to realise the full potential of this system equitably and without governance risk. All could be implemented within the current regulatory mandate of AIFA, without primary legislative change. Statements and Declarations Acknowledgments: The authors did not receive support from any organisation for the submitted work. No funding sources contributed to study design, data collection, analysis, or the decision to submit for publication. Competing interests: The authors have no relevant financial or non-financial interests to disclose. No honoraria, consulting fees, or other payments were received from any pharmaceutical company referenced in this work. Ethics approval: Retrospective analysis of anonymised institutional pharmacy data. No individual patient data are reported. Ethics Committee approval was not required under applicable Italian regulations for this type of institutional review. Data availability: The datasets generated during the current study (aggregate pharmacy administrative records) are available from the corresponding author on reasonable request. Author contributions: MI conceived the study, performed the literature synthesis, and wrote the first draft. MR, VM, DC, MD, GC, VM2, MD2, and VP contributed to data collection and workflow analysis. GB contributed to the pharmacoeconomic framework and critically revised the manuscript. All authors read and approved the final manuscript. References Decreto Ministeriale 7 settembre: Disciplina dell'uso terapeutico di medicinale sottoposto a sperimentazione clinica. Gazz. Uff. Repub. Ital. n. 228, 29 settembre 2017. (2017) Tarantola, A., Otto, M.H., Armeni, P., et al.: Early access programs for medicines: comparative analysis among France, Italy, Spain, and UK and focus on the Italian case. J. Pharm. Policy Pract. 16 , 67 (2023). https://doi.org/10.1186/s40545-023-00570-z Pinto, C., Polistena, B., Spandonaro, F.: Advancing early access policies for innovative cancer drugs: a scoping review and explorative analysis in the Italian setting. J. Med. Econ. (2024). https://doi.org/10.1080/13696998.2024.2377697 Popoli, P., Giuliani, G., Cavaliere, A., Jommi, C.: Early access programs for medicines: a reform proposal for the Italian National Health Service. Glob Reg. Health Technol. Assess. 11 , 148–153 (2024). https://doi.org/10.33393/grhta.2024.3098 Vancoppenolle, J.M., Franzen, N., Koole, S.N., et al.: Differences in time to patient access to innovative cancer medicines in six European countries. Int. J. Cancer. 154 , 886–894 (2024). https://doi.org/10.1002/ijc.34753 Jommi, C., Pantellini, F., Stagi, L., Verykiou, M., Cavazza, M.: The economic impact of compassionate use of medicines. BMC Health Serv. Res. (2021). https://doi.org/10.1186/s12913-021-07255-w Cowling, T., Nayakarathna, R., Wills, A.L., et al.: Early access for innovative oncology medicines: a different story in each nation. J. Med. Econ. 26 , 944–953 (2023). https://doi.org/10.1080/13696998.2023.2237336 NICE/NHS England: Cancer Drugs Fund: Proposed arrangements from April 2022. NHS England, London (2022) Sra, M.S., Sasi, A., Batra, A., Bakhshi, S., Ganguly, S.: Cost-effectiveness of adjuvant abemaciclib and ribociclib in high-risk hormone receptor-positive early breast cancer: an Indian perspective. JCO Glob Oncol. 10 , e2300433 (2024). https://doi.org/10.1200/GO.23.00433 Brezden-Masley, C., Soliman, D., Sehdev, S., El Ouagari, K., Danyliv, A., Stellato, D.: Cost-effectiveness analysis of ribociclib plus endocrine therapy versus endocrine therapy alone in the adjuvant treatment of HR+/HER2 – early breast cancer: a Canadian payer perspective. ESMO Open. 10(Suppl. 4104766 (2025). https://doi.org/10.1016/j.esmoop.2025.104765 [Congress abstract; full peer-reviewed publication pending] Mason, H., Jones-Lee, M., Donaldson, C.: Modelling the monetary value of a QALY: a new approach based on UK data. Health Econ. 18 , 933–950 (2009). https://doi.org/10.1002/hec.1416 Apolone, G., Ardizzoni, A., Buzzetti, G., et al.: Early access in oncology: why is it needed? Glob. Reg. Health Technol. Assess. (2019). https://doi.org/10.1177/2284240319857072 Gori, S., di Maio, M., Pinto, C., et al.: Disparity in the 'time to patient access' to new anti-cancer drugs in Italian regions. Tumori. 97 , 442–448 (2011) AIFA: Procedure per la rimborsabilità dei farmaci ad uso compassionevole ai sensi del DM 7 settembre 2017. AIFA, Roma (2018) HAS: Bilan des accès précoces aux médicaments: 288 décisions en trois ans. (2025). has-sante.fr/jcms/p_3470178 . Accessed Pharmaceutical Technology: Germany Amends and Approves the New Medical Research Act. pharmtech.com. July 2024 Additional Declarations No competing interests reported. Supplementary Files EAPEJHEOnlineResources.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9212433","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":611744487,"identity":"f556a008-b110-4503-9093-b68f8de5c9c2","order_by":0,"name":"Mauro Iannopollo","email":"data:image/png;base64,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","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":true,"prefix":"","firstName":"Mauro","middleName":"","lastName":"Iannopollo","suffix":""},{"id":611744488,"identity":"d6359754-80bd-4419-9bf6-3748f9de505f","order_by":1,"name":"Miriam Ricasoli","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"","lastName":"Ricasoli","suffix":""},{"id":611744492,"identity":"f510ca5e-7a40-422c-86cd-f364db5a31df","order_by":2,"name":"Virginia Maragna","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Virginia","middleName":"","lastName":"Maragna","suffix":""},{"id":611744493,"identity":"6e66a31b-7442-411c-9e09-96513360a765","order_by":3,"name":"Daniele Checcacci","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Daniele","middleName":"","lastName":"Checcacci","suffix":""},{"id":611744495,"identity":"d3a90459-5781-4746-bcf0-ae24676265e6","order_by":4,"name":"Michelina D'Alessandro","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Michelina","middleName":"","lastName":"D'Alessandro","suffix":""},{"id":611744498,"identity":"95a4ed0a-7a55-4d91-9a5a-f8f2dbc70687","order_by":5,"name":"Greta Cipriani","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Greta","middleName":"","lastName":"Cipriani","suffix":""},{"id":611744499,"identity":"23eb7f59-da32-4b5f-b036-3c17954c0d37","order_by":6,"name":"Valentina Massa","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Massa","suffix":""},{"id":611744501,"identity":"f6da7b05-faac-457a-b7bf-c9c1d1cf2225","order_by":7,"name":"Matilde Destefanis","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Matilde","middleName":"","lastName":"Destefanis","suffix":""},{"id":611744502,"identity":"208adab9-1289-45af-b7f8-4681d10b328c","order_by":8,"name":"Valeria Palmieri","email":"","orcid":"","institution":"AUSL Toscana Centro — Pistoia and Pescia Hospitals","correspondingAuthor":false,"prefix":"","firstName":"Valeria","middleName":"","lastName":"Palmieri","suffix":""},{"id":611744510,"identity":"8c5925f3-f285-4f83-9f17-628c41080f83","order_by":9,"name":"Greta Berti","email":"","orcid":"","institution":"University of Florence","correspondingAuthor":false,"prefix":"","firstName":"Greta","middleName":"","lastName":"Berti","suffix":""}],"badges":[],"createdAt":"2026-03-24 13:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9212433/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9212433/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105727479,"identity":"b49f0ba1-a870-4b49-bd95-da08ad28d01b","added_by":"auto","created_at":"2026-03-30 10:43:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1167478,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9212433/v1/c7541215-3487-4a90-879c-6c1aedb9ca0c.pdf"},{"id":105701619,"identity":"78605762-8d63-4895-b514-a48283ca84dd","added_by":"auto","created_at":"2026-03-30 06:10:30","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":11436,"visible":true,"origin":"","legend":"","description":"","filename":"EAPEJHEOnlineResources.docx","url":"https://assets-eu.researchsquare.com/files/rs-9212433/v1/1e1b6576fa1337e4cc9d52a3.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Quantifying the Dual Value and Governance Risks of Early Access Programs in Oncology: A Single-Centre Analysis and National Policy Framework","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn Italy, access to innovative oncological therapies before formal price and reimbursement negotiation by the Agenzia Italiana del Farmaco (AIFA) occurs primarily through two mechanisms: Early Access Programs (EAPs), which provide pre-marketing authorisation access under the compassionate use framework, and Named Patient Programs (NPPs), which allow individual patient access to authorised-but-not-yet-reimbursed products. Both are regulated under Ministerial Decree 7 September 2017 (the Decreto Lorenzin) [1].\u003c/p\u003e\n\u003cp\u003eThe interval between European Medicines Agency (EMA) marketing authorisation and AIFA reimbursement in Italy averages 14\u0026ndash;18 months, one of the longest in the European Union [2, 5]. This delay represents a clinically significant access gap, particularly in diseases where the approved therapy addresses an unmet therapeutic need or offers substantial efficacy gains over available alternatives. During this period, EAPs and NPPs represent the primary mechanism through which Italian patients can access the most innovative therapies.\u003c/p\u003e\n\u003cp\u003eDespite their clinical and economic significance, systematic quantification of EAP value at the institutional level is rare in the Italian literature [3, 6]. The few published analyses focus predominantly on the economic burden of delayed access from the payer perspective [5, 7], rather than on the institutional value generated by proactive EAP management. Furthermore, the Italian EAP governance architecture presents three structural weaknesses that have received little formal analytical attention: the absence of AIFA portal transparency on active programmes, the prohibition on company-initiated programme promotion, and the inadequate framework for clinical justification when reimbursed alternatives exist.\u003c/p\u003e\n\u003cp\u003eThis paper addresses both dimensions. We report a single-centre analysis of EAP/NPP activity in 2025 at AUSL Toscana Centro (Pistoia and Pescia), introduce a Dual-Value EAP Accounting Framework integrating drug-cost savings with quality-adjusted life year (QALY)-based clinical value, and provide a structured comparative analysis of critical governance gaps with concrete reform proposals.\u003c/p\u003e\n\u003cp\u003eRegulatory framework: the Italian EAP ecosystem\u003c/p\u003e\n\u003cp\u003eThe Decreto Lorenzin of 2017 distinguishes between two principal access mechanisms [1]. Compassionate use (\u003cem\u003euso compassionevole\u003c/em\u003e) applies to unauthorised medicinal products or authorised products used outside the approved indication, where no therapeutic alternative exists and there is a reasonable expectation of clinical benefit. NPPs operate where the product has received EMA marketing authorisation but AIFA reimbursement has not yet been granted; the product is provided free of charge by the pharmaceutical company under individual patient request.\u003c/p\u003e\n\u003cp\u003eBoth mechanisms are grounded in Article 83 of Regulation (EC) No 726/2004. Under the Decreto Lorenzin, EAPs \u0026mdash; corresponding to group compassionate use \u0026mdash; are available for patients with serious, rare, or life-threatening conditions for whom no adequate reimbursed therapeutic alternative exists, provided the drug has completed at least a Phase II clinical trial.\u003c/p\u003e\n\u003cp\u003eThe procedural pathway for either mechanism is administratively intensive. The prescribing physician must submit a formal clinical justification documenting the absence of reimbursed alternatives, which triggers a gratuity letter from the pharmaceutical company, submission to the institutional Ethics Committee (CE), and Hospital Pharmacy order. Where the drug is not commercially available in Italy but is authorised elsewhere in Europe, an additional Nulla Osta Sanitario (NOS) from the Ministry of Health is required, adding 4\u0026ndash;12 weeks to the process [14].\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eStudy design and setting\u003c/h2\u003e\n\u003cp\u003eWe conducted a retrospective descriptive analysis of all EAPs and NPPs managed by the Hospital Pharmacy Unit in collaboration with the Medical Oncology Units of Ospedale San Jacopo (Pistoia) and SS. Cosma e Damiano (Pescia), AUSL Toscana Centro, during calendar year 2025.\u0026nbsp;Data collected included: number of active programmes, drugs involved, oncological indications, number of patients enrolled and treated, quantities of drug supplied free of charge, and estimated dates of AIFA reimbursement. No individual patient data are reported; Ethics Committee approval was not required under applicable Italian regulations for this type of institutional review. This study was conducted at a single medium-sized oncology centre; however, all processes analysed reflect nationally standardised regulatory procedures established by the Decreto Lorenzin, supporting applicability of the findings and the proposed Dual-Value Framework to other publicly funded oncology centres operating within the Italian NHS regulatory environment.\u003c/p\u003e\n\u003cp\u003eAI-assisted writing tools (Claude, Anthropic) were used for drafting and language editing support. All analytical content, data collection, calculations, and conclusions were developed and approved by the authors.\u003c/p\u003e\n\u003ch2\u003eEconomic valuation: drug-cost component\u003c/h2\u003e\n\u003cp\u003eThe economic value of free drug supply was calculated exclusively using official AIFA ex-factory prices sourced from the Italian Official Gazette and AIFA pricing determinations publicly available at the time of data collection. Two programmes involving drugs without an official Italian or European reimbursement price (sevabertinib, repotrectinib) were excluded from the economic analysis. We report both the gross ex-factory value and a conservative net estimate assuming a 30% average negotiated discount, consistent with published estimates of AIFA managed entry discounts for oncology drugs [3].\u003c/p\u003e\n\u003ch2\u003eEconomic valuation: QALY-based component (Dual-Value EAP Accounting Framework)\u003c/h2\u003e\n\u003cp\u003eBeyond drug-cost saving, EAPs generate a second dimension of value: the clinical benefit produced in patients who access effective therapy during the reimbursement latency period. For programmes where published QALY gain data are available, we apply the following framework: (a) incremental QALY gain per patient derived from published cost-effectiveness analyses using conservative lower-bound values from sensitivity analyses; (b) pro-rated QALY value limited to the reimbursement latency period, not the full lifetime horizon; (c) monetised QALY value calculated at the AIFA threshold of \u0026euro;30,000/QALY [11]. This approach intentionally undervalues total clinical benefit, as any continued benefit beyond the latency period accrues regardless of the access pathway. The pro-rated estimate assumes a linear accrual of QALY gain over time \u0026mdash; that is, that each month of treatment access during the latency period contributes an equal fraction of the annual incremental QALY benefit reported in the source cost-effectiveness model. Utility weights are derived from the published cost-effectiveness analysis cited for each programme (Canadian EQ-5D-derived weights for ribociclib [10]), applied conservatively as a lower-bound proxy in the absence of Italian-context utility data.\u003c/p\u003e\n\u003cp\u003eWe designate this integrated approach the Dual-Value EAP Accounting Framework, combining drug-cost savings with pro-rated QALY-based clinical value to allow institutions to report the full economic and clinical return of EAP activity in a single auditable figure. This framework is not a cost-effectiveness analysis of EAPs per se, but a tool for communicating complete institutional value to decision-makers who typically receive only drug-cost data.\u003c/p\u003e\n\u003ch2\u003eAdministrative burden analysis\u003c/h2\u003e\n\u003cp\u003eAdministrative burden was quantified using a bottom-up workflow analysis, cataloguing each discrete administrative step, the responsible professional, time required per occurrence, and frequency. Detailed workflow data are provided in Online Resources 1 and 2.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEAP/NPP portfolio 2025\u003c/h2\u003e \u003cp\u003eIn 2025, 11 EAP/NPP programmes were active across 11 different oncological indications, involving 23 treated patients. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e provides a descriptive overview of all 11 programmes.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEAP/NPP programmes 2025, AUSL Toscana Centro. Savings calculated at AIFA ex-factory prices. Two programmes without Italian ex-factory pricing excluded from economic analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgramme\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug (brand)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePts\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFree supply\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEst. saving (ex-factory)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPP \u003cem\u003e(Daiichi-Sankyo)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTrastuzumab deruxtecan (Enhertu\u0026reg;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNSCLC HER2-mut\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 vials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;55,981\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAP ADRIATIC \u003cem\u003e(AstraZeneca)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDurvalumab (Imfinzi\u0026reg;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLS-SCLC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 vials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;33,241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAP MATTERHORN \u003cem\u003e(AstraZeneca)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDurvalumab (Imfinzi\u0026reg;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGC/GEJC periop.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 vials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;24,931\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPP \u003cem\u003e(Astellas/MSD)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePembrolizumab\u0026thinsp;+\u0026thinsp;enfortumab vedotin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUrothelial carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4\u0026thinsp;+\u0026thinsp;20 vials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;40,678\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEAP NATALEE\u003c/b\u003e \u003cem\u003e(Novartis)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRibociclib (Kisqali\u0026reg;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBC HR+/HER2\u0026thinsp;\u0026minus;\u0026thinsp;adj.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e10\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e60\u0026thinsp;+\u0026thinsp;16 packs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026euro;268,721\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAP PAPILLON \u003cem\u003e(Janssen)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmivantamab (Rybrevant\u0026reg;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNSCLC EGFR ex20ins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84 vials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;117,348\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAP AEGEAN \u003cem\u003e(AstraZeneca)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDurvalumab (Imfinzi\u0026reg;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNSCLC periop.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48 vials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;132,964\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAP RUBY \u003cem\u003e(GSK)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDostarlimab (Jemperli\u0026reg;)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEndometrial carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12 packs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;75,288\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEAP Zolbetuximab \u003cem\u003e(Astellas)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eZolbetuximab (Vyloy\u0026reg;)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGC/GEJC adv. CLDN18.2+\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 vials\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026euro;12,576\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPP \u003cem\u003e(Bayer) \u0026mdash; excl.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevabertinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNSCLC HER2m\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eExcluded (no price)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPP \u003cem\u003e(BMS) \u0026mdash; excl.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRepotrectinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNSCLC ROS1/NTRK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eExcluded (no price)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTOTAL (9 priced)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e21\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026euro;761,728\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eadj. adjuvant; periop. perioperative; LS-SCLC limited-stage small-cell lung cancer; GC gastric cancer; GEJC gastroesophageal junction cancer; HER2-mut HER2-mutated; ex20ins exon 20 insertion; BC breast cancer.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDrug-cost saving: gross and net estimates\u003c/h3\u003e\n\u003cp\u003eThe gross ex-factory saving across nine programmes was \u0026euro;761,728. Applying a conservative 30% discount assumption to reflect typical AIFA-negotiated price reductions, the estimated net saving to the NHS is approximately \u0026euro;533,000. The ribociclib adjuvant programme (EAP NATALEE) accounts for the largest single contribution (\u0026euro;268,721 gross; ~\u0026euro;188,000 net), driven by high patient volume (10 patients) and duration of adjuvant treatment (up to 3 years under NATALEE protocol).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eQALY-based valuation: application to the ribociclib programme\u003c/h2\u003e \u003cp\u003eThe ribociclib adjuvant programme provides the most robust basis for QALY-based valuation. The NATALEE trial demonstrated an absolute invasive disease-free survival (iDFS) benefit at 4 years of approximately 3.2% over endocrine therapy alone in the high-risk population. A published cost-effectiveness analysis from a Canadian payer perspective estimated an incremental QALY gain of approximately 0.84 QALY per patient over a lifetime horizon [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. For the present analysis, a conservative pro-rated estimate of 0.5 QALY per patient is applied, limited to the reimbursement latency period (estimated at 15 months; EMA approval: 27 November 2024; AIFA reimbursement: 7 March 2026). This estimate is derived from a Canadian payer perspective and may not fully reflect Italian-specific utility weights; it should be interpreted as a conservative proxy pending Italian-context cost-effectiveness data. The QALY-based clinical value estimate for the ribociclib programme is exploratory and derived from published utility weights and treatment duration assumptions reported in the literature. This estimate is intended to illustrate the potential magnitude of clinical benefit associated with early access rather than to provide a formal cost-effectiveness evaluation. No sensitivity analysis was performed given the descriptive nature of the study.\u003c/p\u003e \u003cp\u003eApplying the AIFA threshold of \u0026euro;30,000/QALY:\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e10 patients \u0026times; 0.5 QALY \u0026times; \u0026euro;30,000 = \u0026euro;150,000 (AIFA threshold)\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003e10 patients \u0026times; 0.5 QALY \u0026times; \u0026euro;20,000 = \u0026euro;100,000 (individual WTP estimate [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e])\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdding this QALY-based component to the drug-cost saving (\u0026euro;268,721) produces a total estimated programme value of \u0026euro;368,721\u0026ndash;\u0026euro;418,721 for ribociclib alone \u0026mdash; approximately 56% higher than the drug-cost estimate alone.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eAdministrative burden and return on investment\u003c/h2\u003e \u003cp\u003eTotal documented administrative burden for 2025 was 181.7 hours (0.114 FTE based on 1,600 productive hours/year). Detailed workflow data by activity type and by programme are provided in Online Resources 1 and 2, respectively. At a gross employment cost of \u0026euro;40,000/year for a hospital pharmacy technician \u0026mdash; the appropriate staffing level for administrative EAP work \u0026mdash; the annual administrative cost is approximately \u0026euro;4,540. The return on investment (ROI) is therefore 168:1 against gross ex-factory drug-cost savings (\u0026euro;761,728 \u0026divide; \u0026euro;4,540), rising to approximately 237:1 when QALY-based clinical value is included.\u003c/p\u003e \u003cp\u003eThe ROI figure reveals that the current system implicitly transfers a real and documentable workload onto existing clinical and pharmacy staff without formal recognition, dedicated staffing, or compensation, while generating an institutional economic benefit two orders of magnitude larger. The cost is not absent; it is invisible and unfunded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStructural governance gaps\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eCritical gap 1: AIFA portal silence and network-dependent access\u003c/h2\u003e \u003cp\u003eItalian regulations require AIFA to maintain a public registry of authorised compassionate use programmes. In practice, this static webpage is not integrated into the operational monitoring portal that hospital pharmacists and oncologists use daily. Discovery of available programmes relies primarily on direct communication from pharmaceutical company Medical Affairs personnel (formally prohibited under current AIFA regulations) and physician-to-physician informal networks.\u003c/p\u003e \u003cp\u003eThis creates a structural access inequity: patients treated at centres with highly networked oncologists are substantially more likely to benefit from available EAPs than equivalent patients at less-connected centres. If the \u0026euro;761,728 saving realised at AUSL Toscana Centro (serving\u0026thinsp;~\u0026thinsp;250,000 population) were scaled to Italy's\u0026thinsp;~\u0026thinsp;200 accredited oncology centres, the estimated national annual value of proactively managed EAPs would be in the order of \u0026euro;130\u0026ndash;150\u0026nbsp;million.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eCritical gap 2: administrative burden without proportional resource allocation\u003c/h2\u003e \u003cp\u003eThe procedural chain for each EAP activation requires an estimated 10\u0026ndash;18 hours of professional time per programme initiation, and 2\u0026ndash;4 hours per patient cycle renewal (see Online Resources 1 and 2). No Italian NHS institution currently allocates dedicated administrative personnel to EAP management. The 181.7-hour annual burden documented here represents approximately 11.4% of one FTE \u0026mdash; a volume that clearly justifies formal part-time allocation at a cost less than 2% of the economic value generated.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCritical gap 3: governance risk from misaligned institutional incentives\u003c/h2\u003e \u003cp\u003eAny system combining (a) a formal requirement to exclude reimbursed alternatives as a condition of EAP access, (b) large and measurable institutional savings from EAP programmes, and (c) no independent audit mechanism will predictably generate a risk of misalignment between clinical justification and economic interest. Two paradigmatic cases illustrate this vulnerability:\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e \u003cp\u003e \u003cb\u003e\u0026mdash; Durvalumab (EAP) versus pembrolizumab and nivolumab (reimbursed)\u003c/b\u003e: In multiple indications relevant to Italian clinical practice \u0026mdash; including perioperative NSCLC and limited-stage SCLC \u0026mdash; durvalumab was accessible via EAP during 2025 while pembrolizumab and nivolumab were AIFA-reimbursed in the same or comparable indications. No head-to-head randomised data demonstrate the clinical superiority of durvalumab in these settings. The institutional economic incentive \u0026mdash; three durvalumab programmes totalling \u0026euro;191,136 \u0026mdash; constitutes an unregulated factor that may influence clinical justification.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 2\u003c/strong\u003e \u003cp\u003e \u003cb\u003e\u0026mdash; Adagrasib (EAP) versus sotorasib (reimbursed) in KRAS G12C-mutated NSCLC\u003c/b\u003e: Sotorasib received AIFA reimbursement for previously treated NSCLC in 2023. Adagrasib, a second-generation KRAS G12C inhibitor sharing the same molecular target and indication, was accessible via NPP during 2025. No predictable patient-level contraindication to sotorasib that adagrasib systematically avoids has been established. A formal clinical justification claiming sotorasib contraindication in a patient without specific hepatic disease or relevant comorbidity is therefore clinically unsustainable as a systematic criterion.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eThe cases presented are illustrative of structural vulnerabilities within the current regulatory framework and should not be interpreted as evidence of inappropriate clinical conduct by individual practitioners. They demonstrate how, in the absence of formalised value-based selection criteria and explicit institutional incentive alignment, intraclass early access settings may generate allocation patterns that are suboptimal from a system-efficiency perspective.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eComparative European frameworks: France and Germany\u003c/h2\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003eThe French model: Acc\u0026egrave;s Pr\u0026eacute;coce\u003c/h2\u003e \u003cp\u003eFrance operates the most structurally advanced early access system in Europe. The 2021 reform replaced the Autorisation Temporaire d'Utilisation (ATU) with the Autorisation d'Acc\u0026egrave;s Pr\u0026eacute;coce (AAP), consolidating six pre-existing schemes into two coherent pathways and transferring decision-making authority from the regulatory agency (ANSM) to the health technology assessment body (HAS) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Between July 2021 and mid-2024, HAS issued 288 AAP decisions (approval rate 80%), approximately half in oncology.\u003c/p\u003e \u003cp\u003eThree features are particularly relevant: (1) public transparency through a continuously updated HAS registry of all AAP decisions; (2) centralised reimbursement at 100% by the Caisse Nationale d'Assurance Maladie at a freely set manufacturer price with a retrospective payback clause; (3) mandatory real-world data collection via a structured patient monitoring protocol (PUT-RD) whose outputs feed directly into the HTA dossier. The Italian system shares the clinical rationale but lacks all three structural features.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eThe German model: AMNOG\u003c/h2\u003e \u003cp\u003eGermany's AMNOG (in force since 2011) resolves the access gap through automatic reimbursement at launch: every EMA-approved product is immediately reimbursed at the manufacturer's freely set launch price for twelve months, during which the G-BA and IQWiG conduct a mandatory benefit assessment against an appropriate comparative therapy (ACT) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Compassionate use under German law applies only in the genuinely pre-authorisation setting. From 2011 through November 2023, 944 AMNOG assessments were completed; 53% of non-orphan drugs received a decision of 'no added medical benefit' relative to the ACT \u0026mdash; underscoring the importance of rigorous comparator evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eComparative synthesis\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarises the three systems across seven governance dimensions. Italy's absence of a real-time public registry is unique among major European economies. Italy's absence of mandatory real-world data collection means the clinical value generated by EAPs is lost to the evidence base. Italy's absence of a structured comparator evaluation framework leaves the key clinical justification question \u0026mdash; is there an adequate reimbursed alternative? \u0026mdash; to individual physician assessment without independent verification.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparative analysis of early access frameworks: Italy, France, and Germany.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDimension\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eItaly (Decreto Lorenzin)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFrance (AAP 2021)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eGermany (AMNOG + \u0026sect;\u0026nbsp;21 AMG)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAccess trigger\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo reimbursed alternative; physician-initiated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere disease, no alternative, presumed innovation; company application to HAS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAutomatic reimbursement at launch (12 months); compassionate use only pre-EMA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRegulatory body\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAIFA (post-hoc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHAS\u0026thinsp;+\u0026thinsp;ANSM (prospective HTA decision)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eG-BA/IQWiG (AMNOG benefit assessment)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePublic registry\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsent / not searchable in real time\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTransparent HAS registry, updated continuously\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eG-BA public database of all assessments\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReimbursement model\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFree drug from company; NHS pays nothing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100% NHS reimbursement; company sets free price with payback clause\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAutomatic NHS reimbursement at launch price (12 months)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReal-world data\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNot mandated; no systematic collection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMandatory PUT-RD protocol; feeds into HTA dossier\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePost-AMNOG registry for drugs with non-quantifiable benefit\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eComparator evaluation\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eImplicit exclusion; no independent audit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHAS explicitly evaluates availability of alternatives as eligibility criterion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAMNOG uses ACT (appropriate comparative therapy) as mandatory reference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCompany role\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProhibited from promoting; passive supply\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eActive applicant to HAS; required to submit HTA dossier\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eActive dossier submission at launch; mandatory pricing negotiation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eAAP Autorisation d'Acc\u0026egrave;s Pr\u0026eacute;coce; AMNOG Arzneimittelmarktneuordnungsgesetz; HAS Haute Autorit\u0026eacute; de Sant\u0026eacute;; ANSM Agence Nationale de S\u0026eacute;curit\u0026eacute; du M\u0026eacute;dicament; G-BA Gemeinsamer Bundesausschuss; IQWiG Institut f\u0026uuml;r Qualit\u0026auml;t und Wirtschaftlichkeit im Gesundheitswesen; PUT-RD Protocol d'Utilisation Th\u0026eacute;rapeutique et de Recueil de Donn\u0026eacute;es; ACT appropriate comparative therapy.\u003c/em\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003ePolicy reform proposals\u003c/h2\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eAIFA portal transparency\u003c/h2\u003e \u003cp\u003eAIFA should implement a real-time, searchable public registry of all active EAP and NPP authorisations, including the drug name, indication, eligibility criteria summary, sponsoring company contact, and Ethics Committee reference. This registry should be updated within 30 days of any new programme authorisation and generate automated email notifications to registered oncologists and pharmacists in relevant therapeutic areas. Implementation would require administrative decision rather than legislative change.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eStandardised dual-value institutional reporting\u003c/h2\u003e \u003cp\u003eInstitutions managing EAPs should be required to report annually to their Direzione Sanitaria and institutional Ethics Committees using a standardised template including both drug-cost savings and QALY-based clinical value. This would provide governance bodies with complete value information, create a national dataset for aggregate impact assessment, and enable comparison of EAP activity across institutions.\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eMandatory structured clinical justification for intraclass EAPs\u003c/h2\u003e \u003cp\u003eFor all EAP or NPP requests involving a drug in a class for which at least one reimbursed alternative exists, AIFA should require a structured clinical justification document that explicitly addresses: (a) the evidence base distinguishing the EAP drug from the reimbursed alternative; (b) the specific patient characteristics making the alternative inadequate; and (c) a declaration that clinical justification is independent of institutional economic benefit. This document should include, as a standard field, the estimated gross economic value of the programme to the institution \u0026mdash; already calculable from AIFA ex-factory prices.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003ch2\u003eDedicated administrative infrastructure\u003c/h2\u003e \u003cp\u003eOncology centres managing five or more active EAP/NPP programmes should be entitled to fund one dedicated pharmacy technician position from the documented drug-cost savings generated by the portfolio, without requiring separate budget allocation. This self-financing model is both operationally sustainable and administratively straightforward within existing NHS accounting frameworks.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec27\" class=\"Section3\"\u003e \u003ch2\u003eMandatory real-world data collection\u003c/h2\u003e \u003cp\u003eA mandatory real-world data collection requirement \u0026mdash; structured as a lightweight patient registry integrated into the existing AIFA monitoring portal, with data entry at each resupply cycle \u0026mdash; would generate a national EAP outcomes dataset within 24 months of implementation. Following the French PUT-RD model, the dataset should be minimal (approximately 8\u0026ndash;12 variables per patient per cycle: performance status, treatment continuation, reason for discontinuation if applicable, primary adverse events), completable within the resupply documentation workflow in an estimated 10\u0026ndash;15 minutes per patient per cycle.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis analysis makes four original contributions to the existing literature. First, the Dual-Value EAP Accounting Framework is introduced as the first standardised instrument for complete EAP value quantification from routinely available data. Second, precise administrative burden quantification for an Italian EAP portfolio is provided using a bottom-up workflow analysis (181.7 hours; 168:1 ROI) rather than estimates. Third, institutional incentive misalignment in intraclass EAP settings is formally characterised as a structural architecture problem. Fourth, a structured European comparison with France and Germany identifies directly implementable reforms for the Italian regulatory context [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe governance risk identified in Section 5 requires careful contextualisation. The prescribing physicians who activate EAPs are, in the great majority of instances, acting in good faith on the basis of genuine clinical judgement. The problem is a system design that has not anticipated the interaction between the clinical justification requirement, the prohibition on company-initiated promotion, and the scale of economic incentives that EAPs now generate. As oncology drug prices escalate and the reimbursement gap widens, the institutional economic value of EAP portfolios will continue to grow.\u003c/p\u003e \u003cp\u003eEthics Committees play a central role in the governance of Early Access Programs, ensuring procedural compliance, patient protection, and ethical oversight of non-standard treatment access. However, their current mandate is primarily focused on individual patient-level appropriateness and regulatory adherence. It does not extend to the evaluation of system-level efficiency, opportunity cost, or incentive alignment. As a result, key governance gaps persist at the interface between clinical decision-making and resource allocation.\u003c/p\u003e \u003cp\u003eSeveral limitations should be acknowledged. Although this analysis is based on a single-centre experience, all administrative processes described reflect nationally standardised regulatory requirements and are therefore likely to be reproducible across similar oncology settings, although centre-specific factors such as pharmacy staffing and patient volume may influence the absolute administrative burden. The proposed Dual-Value framework relies exclusively on routinely available institutional data, supporting its scalability and applicability to other publicly funded healthcare systems. Larger reference centres likely manage substantially greater volumes. The QALY-based valuation for ribociclib depends on a Canadian payer perspective cost-effectiveness model [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] \u0026mdash; currently the most relevant published analysis available \u0026mdash; and may not perfectly reflect Italian clinical practice patterns or utilities; Italian-context cost-effectiveness data are not yet available in the published literature. The administrative cost estimate uses a pharmacy technician salary (\u0026euro;40,000/year) as the staffing reference, whereas in practice EAP management is predominantly performed by qualified hospital pharmacists whose employment cost is substantially higher; ROI figures should therefore be interpreted as upper-bound estimates. The governance risk analysis is structurally inferential \u0026mdash; it identifies a systemic vulnerability rather than documenting actual instances of inappropriate justification. Future work should include multi-centre surveys, systematic analysis of Ethics Committee justification documentation in intraclass EAP settings, and prospective clinical outcome tracking.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eEAPs in Italian oncology generate dual value that current reporting frameworks systematically underestimate. A proactively managed portfolio of 11 programmes at a single medium-sized centre generated \u0026euro;761,728 in drug-cost savings and an estimated additional \u0026euro;150,000 in QALY-based clinical value for the ribociclib programme alone, with a documented 168:1 ROI for administrative costs. AUSL Toscana Centro is neither a comprehensive cancer centre nor a highly specialised reference institution; the documented portfolio is therefore likely a conservative estimate of what occurs at larger referral centres. The absence of systematic national EAP reporting means that single-centre data currently provide the only granular quantification available to inform policy \u0026mdash; which is itself an argument for the transparency reforms proposed.\u003c/p\u003e \u003cp\u003eThe Dual-Value EAP Accounting Framework provides a replicable, institution-level reporting tool that any oncology centre can implement from routinely available data \u0026mdash; AIFA ex-factory prices and published cost-effectiveness estimates \u0026mdash; without additional data collection. Five structural reforms are necessary to realise the full potential of this system equitably and without governance risk. All could be implemented within the current regulatory mandate of AIFA, without primary legislative change.\u003c/p\u003e"},{"header":"Statements and Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe authors did not receive support from any organisation for the submitted work. No funding sources contributed to study design, data collection, analysis, or the decision to submit for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose. No honoraria, consulting fees, or other payments were received from any pharmaceutical company referenced in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eRetrospective analysis of anonymised institutional pharmacy data. No individual patient data are reported. Ethics Committee approval was not required under applicable Italian regulations for this type of institutional review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe datasets generated during the current study (aggregate pharmacy administrative records) are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eMI conceived the study, performed the literature synthesis, and wrote the first draft. MR, VM, DC, MD, GC, VM2, MD2, and VP contributed to data collection and workflow analysis. GB contributed to the pharmacoeconomic framework and critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDecreto Ministeriale 7 settembre: Disciplina dell'uso terapeutico di medicinale sottoposto a sperimentazione clinica. Gazz. Uff. Repub. Ital. n. 228, 29 settembre 2017. (2017)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTarantola, A., Otto, M.H., Armeni, P., et al.: Early access programs for medicines: comparative analysis among France, Italy, Spain, and UK and focus on the Italian case. J. Pharm. Policy Pract. \u003cb\u003e16\u003c/b\u003e, 67 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s40545-023-00570-z\u003c/span\u003e\u003cspan address=\"10.1186/s40545-023-00570-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePinto, C., Polistena, B., Spandonaro, F.: Advancing early access policies for innovative cancer drugs: a scoping review and explorative analysis in the Italian setting. J. Med. Econ. (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/13696998.2024.2377697\u003c/span\u003e\u003cspan address=\"10.1080/13696998.2024.2377697\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePopoli, P., Giuliani, G., Cavaliere, A., Jommi, C.: Early access programs for medicines: a reform proposal for the Italian National Health Service. Glob Reg. Health Technol. Assess. \u003cb\u003e11\u003c/b\u003e, 148\u0026ndash;153 (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.33393/grhta.2024.3098\u003c/span\u003e\u003cspan address=\"10.33393/grhta.2024.3098\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVancoppenolle, J.M., Franzen, N., Koole, S.N., et al.: Differences in time to patient access to innovative cancer medicines in six European countries. Int. J. Cancer. \u003cb\u003e154\u003c/b\u003e, 886\u0026ndash;894 (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ijc.34753\u003c/span\u003e\u003cspan address=\"10.1002/ijc.34753\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJommi, C., Pantellini, F., Stagi, L., Verykiou, M., Cavazza, M.: The economic impact of compassionate use of medicines. BMC Health Serv. Res. (2021). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12913-021-07255-w\u003c/span\u003e\u003cspan address=\"10.1186/s12913-021-07255-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCowling, T., Nayakarathna, R., Wills, A.L., et al.: Early access for innovative oncology medicines: a different story in each nation. J. Med. Econ. \u003cb\u003e26\u003c/b\u003e, 944\u0026ndash;953 (2023). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/13696998.2023.2237336\u003c/span\u003e\u003cspan address=\"10.1080/13696998.2023.2237336\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNICE/NHS England: Cancer Drugs Fund: Proposed arrangements from April 2022. NHS England, London (2022)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSra, M.S., Sasi, A., Batra, A., Bakhshi, S., Ganguly, S.: Cost-effectiveness of adjuvant abemaciclib and ribociclib in high-risk hormone receptor-positive early breast cancer: an Indian perspective. JCO Glob Oncol. \u003cb\u003e10\u003c/b\u003e, e2300433 (2024). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/GO.23.00433\u003c/span\u003e\u003cspan address=\"10.1200/GO.23.00433\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrezden-Masley, C., Soliman, D., Sehdev, S., El Ouagari, K., Danyliv, A., Stellato, D.: Cost-effectiveness analysis of ribociclib plus endocrine therapy versus endocrine therapy alone in the adjuvant treatment of HR+/HER2\u0026thinsp;\u0026ndash;\u0026thinsp;early breast cancer: a Canadian payer perspective. ESMO Open. 10(Suppl. 4104766 (2025). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.esmoop.2025.104765\u003c/span\u003e\u003cspan address=\"10.1016/j.esmoop.2025.104765\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Congress abstract; full peer-reviewed publication pending]\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMason, H., Jones-Lee, M., Donaldson, C.: Modelling the monetary value of a QALY: a new approach based on UK data. Health Econ. \u003cb\u003e18\u003c/b\u003e, 933\u0026ndash;950 (2009). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/hec.1416\u003c/span\u003e\u003cspan address=\"10.1002/hec.1416\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eApolone, G., Ardizzoni, A., Buzzetti, G., et al.: Early access in oncology: why is it needed? Glob. Reg. Health Technol. Assess. (2019). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1177/2284240319857072\u003c/span\u003e\u003cspan address=\"10.1177/2284240319857072\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGori, S., di Maio, M., Pinto, C., et al.: Disparity in the 'time to patient access' to new anti-cancer drugs in Italian regions. Tumori. \u003cb\u003e97\u003c/b\u003e, 442\u0026ndash;448 (2011)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAIFA: Procedure per la rimborsabilit\u0026agrave; dei farmaci ad uso compassionevole ai sensi del DM 7 settembre 2017. AIFA, Roma (2018)\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHAS: Bilan des acc\u0026egrave;s pr\u0026eacute;coces aux m\u0026eacute;dicaments: 288 d\u0026eacute;cisions en trois ans. (2025). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehas-sante.fr/jcms/p_3470178\u003c/span\u003e\u003cspan address=\"http://has-sante.fr/jcms/p_3470178\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePharmaceutical Technology: Germany Amends and Approves the New Medical Research Act. pharmtech.com. July 2024\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"early access programs, named patient programs, oncology, dual-value framework, pharmacoeconomics, QALY, governance, AIFA, Italian NHS","lastPublishedDoi":"10.21203/rs.3.rs-9212433/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9212433/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEarly Access Programs (EAPs) and Named Patient Programs (NPPs) in Italy, governed by the Decreto Lorenzin (2017), are the primary route through which oncology patients access innovative therapies pending reimbursement by the Agenzia Italiana del Farmaco (AIFA). Their institutional value has not been systematically quantified, and key governance gaps remain formally undescribed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRetrospective analysis of all EAPs and NPPs managed at AUSL Toscana Centro (Pistoia and Pescia) during 2025. Drug-cost savings were calculated from official AIFA ex-factory prices. We introduce a Dual-Value EAP Accounting Framework integrating drug-cost savings with quality-adjusted life year (QALY)-based clinical value, and compare Italian, French, and German early access governance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEleven programmes covering 23 patients were active. Gross drug-cost saving from nine priced programmes was €761,728 (net ~€533,000 after 30% discount). The ribociclib adjuvant programme (EAP NATALEE; €268,721; 10 patients) was the largest contributor; QALY-based valuation adds an estimated €150,000 at €30,000/QALY. Total administrative burden was 181.7 hours (0.114 full-time equivalent [FTE]), yielding a 168:1 return on investment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA proactively managed EAP portfolio at a single medium-sized centre generated substantial dual value. Three critical governance gaps are identified: absence of real-time AIFA portal transparency, prohibition on company-initiated programme information, and unregulated institutional incentives in intraclass settings. Five reforms — modelled on French and German governance frameworks — could address all gaps within existing AIFA regulatory mandate, without primary legislative change. The Dual-Value Framework relies on routinely available data and is directly replicable across publicly funded oncology centres.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJEL codes: \u003c/strong\u003eI11 · I13 · I18 · H51\u003c/p\u003e","manuscriptTitle":"Quantifying the Dual Value and Governance Risks of Early Access Programs in Oncology: A Single-Centre Analysis and National Policy Framework","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-30 06:08:14","doi":"10.21203/rs.3.rs-9212433/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5991aa32-89c4-4f69-a524-de66e498e60f","owner":[],"postedDate":"March 30th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T17:23:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-30 06:08:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9212433","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9212433","identity":"rs-9212433","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}