Different clinical conditions may involve common pathways, mechanisms, or mediators, thus some drugs, especially those used in oncology and immunology, have multiple therapeutic indications [1,2,3,4,5,6,7,8,9]. Multiple indications of medicines have led to a significant challenge in current drug pricing and reimbursement systems in many countries. Several studies have investigated how prices are negotiated following an extension of indications (EoIs), but it is not possible to define a standardized method for evaluating each indication because of the heterogeneity of drug samples and the different negotiation methods used in pricing and reimbursement systems.

Traditionally, a single price has been applied to drugs regardless of the number of indications they treat. However, this approach often fails to capture the varying clinical value across indications, delays access for patients, and reduces incentives for pharmaceutical companies to expand research and development into new indications [10]. The need for a more nuanced system of drug pricing that accounts for the differential benefits across indications has given rise to concepts such as indication-based pricing (IBP) [11].

There are three primary models of IBP: distinct brands with separate pricing for each indication, an average price across all indications, and a single price with differential discounts for various indications [12]. Many countries have adopted mechanisms to align drug prices with outcomes, such as monitoring drug use by indication and linking reimbursement to clinical outcomes [13]. Systems such as managed entry agreements (MEAs), clinical restrictions, and risk-sharing arrangements are frequently used [14]. However, implementing IBP requires substantial changes in how medicines are priced, procured, and monitored, as the administrative burden of tracking drug use by indication remains a significant concern [15, 16].

Recent studies indicate that drug pricing is often not commensurate with the clinical benefits provided [17, 18]. This raises concerns about the quality of evidence used, particularly for initial approvals that often rely on single-arm studies or open-label randomized controlled trials. These trials receive regulatory advantages despite being based on weaker evidence [19, 20]. In oncology, a “narrow-first” strategy is common, where the first indication launched demonstrates the highest clinical benefit in a smaller, well-defined population. This approach allows for differentiated pricing and builds a favorable reference point for later indications. Conversely, a “broad-first” strategy, often seen in targeted autoimmune therapies (e.g., anti-TNF, IL-inhibitors, JAK inhibitors), seeks to maximize early revenue by targeting broader patient populations [21].

A consensus of 16 experts from 11 countries assessed current payment models, focusing on the challenges posed by drugs with multiple indications. They identified opportunities to optimize existing systems to improve patient access and support pharmaceutical innovation. Differentiating pricing based on value at the indication level emerged as a key solution, with approaches such as blended pricing, single prices with differential adjustments, and outcome-based payments discussed [22]. These discussions highlight the complexity of developing pricing and reimbursement models that balance access, value, and health system sustainability.

In Italy, the reimbursement and price-setting procedure for EoIs is subject to a structured decision-making process, often leading to a price reduction. After European approval by the European Medicines Agency (EMA), the Italian Medicines Agency (AIFA) decides on the reimbursement of an EoI by the Italian National Health Service (INHS). This process involves evaluating the therapeutic positioning of the drug, the risk–benefit ratio compared with alternatives, added therapeutic value, and cost-effectiveness. These steps enable value-based pricing for each indication, ensuring patient access and controlling pharmaceutical expenditure.

Italy used IBP in the past [16] on the basis of the presence of MEAs, but, as Rossini et al. showed [23], this approach prolonged negotiation times and reduced incremental discounts. Consequently, Italy transitioned to a blended pricing model (BPM), prioritizing budget impact over clinical value during negotiations for new indications. This shift has significant pharmacoeconomic implications, including longer negotiation durations, uniform discounts, and less differentiation based on specific indication value. A recent report [24] highlights that while IBP aligns better with value-based healthcare, its complexity and administrative burdens have driven a preference for the BPM. This simpler model, however, inadequately differentiates between indications.

Currently, the most common pricing model in Italy for new indications is the blended price approach. A single, weighted average price is negotiated for all indications, with the additional discount often weighted by the revenue impact of the new indication. Applying a single discount across the molecule simplifies administrative management at the regional level, as it is often unclear for which indication the drug will be prescribed and used (except when regulated by specific registries).

However, the continuous introduction of new therapeutic indications hinders determining the economic value of drugs, particularly as NHS expenditure rises; it is thus crucial to evaluate how the frequency of negotiated EoIs influences discount rates over time. Rossini et al. [23] focused on analyzing the impact of price and reimbursement negotiations for new drugs, particularly regarding the discounts achieved and the length of the negotiation process. Conversely, the aim of our study is to determine the average discount negotiated during extensions of indication and identify the specific factors (determinants) that affect the additional discount agreed upon. Although other studies [25, 26] have sought to explore how multi-indication medicines are handled in the Italian context, there is still limited evidence on the key determinants influencing negotiations. The negotiation timeline is not taken into account, as it is not a direct factor in the discount itself and depends on various elements, including subjective ones [27].