Analysis by Pharma Value
A unified approach to innovativeness designation: removing the conditional/full distinction
The 2025 Budget Law extends access to the Innovative Medicines Fund to include therapies previously granted conditional innovativeness, provided they meet the newly established AIFA criteria. Notably, the updated framework removes the former distinction between full and conditional status: under the new rules, a medicine is either considered innovative or not, with no intermediate category.
To be eligible for Fund allocation, a treatment must meet three key requirements:
- the presence of a defined therapeutic need;
- a demonstrable added therapeutic value; and
- a quality of evidence rated as at least “moderate.
For orphan drugs and therapies targeting rare or ultra-rare conditions, a lower evidence threshold is accepted, with “low” quality evidence deemed sufficient for consideration.
Introducing a prevalence-based eligibility threshold: balancing innovation and budget impact
A key change in AIFA’s updated framework is the introduction of a prevalence-based eligibility criterion: only therapies targeting conditions with low to moderate prevalence may qualify for innovativeness designation. The rationale behind this restriction is to prevent the Innovative Medicines Fund from being disproportionately consumed by high-prevalence indications, which could pose a substantial burden on the national healthcare budget.
No official cut-off has been provided to distinguish moderate from high prevalence, reflecting the absence of a harmonized regulatory reference. Instead, the assessment is implicitly linked to the size of the effectively eligible population, considering the following elements:
- Limitations of use defined in the authorized indication
- Access restrictions under the National Health Service (SSN), as outlined in the AIFA monitoring registry
Prioritizing economic sustainability over the intrinsic value of therapeutic innovation
This paradigm shift raises concerns about the long-term implications for truly transformative therapies. As Pharma Value, we emphasize that under the new rules, medicines that originally justified the creation of the Innovative Medicines Fund, such as sofosbuvir for the treatment of hepatitis C, would no longer be eligible.
Sovaldi (sofosbuvir) was granted reimbursement in Italy on December 5, 2014. Due to the high budget impact of this groundbreaking therapy, capable of achieving viral eradication in a chronic, high-prevalence condition, the 2015 Budget Law (Law No. 190 of December 23, 2014) established a dedicated fund of €500 million for each of the years 2015 and 2016 to ensure sustainable patient access.
The introduction of a prevalence-based eligibility criterion shifts the focus of the innovativeness designation away from the intrinsic value of medical innovation and toward economic sustainability. As a result, therapies with the potential to eradicate high-prevalence diseases may be excluded from dedicated funding, not because they lack therapeutic value, but because their widespread use would generate unsustainable costs for the National Health Service (SSN).
This mechanism ends up penalizing precisely those treatments that would benefit most from financial support. Innovative therapies for high-prevalence conditions inherently carry a significant budget impact and should be matched by appropriate financing mechanisms to ensure timely and equitable patient access.
Ultimately, this policy marks a substantial shift: from recognizing therapeutic value to prioritizing the control of economic impact.
Assessing therapeutic need
AIFA provides a more granular definition of the types of therapies to be considered when assessing therapeutic need, including:
- medicinal products with overlapping indications,
- treatments used as comparators in pivotal clinical trials, and
- the Best Standard of Care.
This last category is particularly relevant, as it explicitly includes off-label therapies, thereby acknowledging their established role in real-world clinical practice.
Relevance of endpoints and comparison with reimbursed therapies in the assessment of added therapeutic benefit
Under the new innovativeness criteria, AIFA evaluates not only the magnitude of the clinical benefit but also the credibility and appropriateness of the endpoints. These must be clinically meaningful, validated according to internationally recognized standards, and aligned with the therapeutic area under consideration.
Importantly, AIFA now stipulates that the assessment of added therapeutic benefit must be conducted exclusively against therapies listed in the National Pharmaceutical Formulary. This means that treatments not yet reimbursed, or those available through Law 648/96, are excluded from the comparative analysis, even if they are commonly used in clinical practice. This approach contrasts with the negotiation criteria established by the Ministerial Decree of August 2, 2019.
As Pharma Value, we believe that this methodology, excluding 648/96-listed therapies as valid comparators, should be applied not only to products seeking innovativeness designation but more importantly to all orphan drugs undergoing price and reimbursement procedures. Comparisons involving treatments authorized under Law 648/96 present inherent limitations, as such therapies may not have been supported by indication-specific clinical trials with the same methodological rigor as the newly authorized medicine. Consequently, their efficacy and safety profiles may not be directly comparable to those of the product under evaluation.
Alignment with the methodological framework of the EU HTA Regulation
The new AIFA criteria show a clear methodological alignment with the principles established under the European HTA Regulation, particularly in the assessment of relative efficacy. This alignment strengthens the consistency between national evaluations and the Joint Clinical Assessment (JCA) and opens the door to the use of indirect comparisons at the national level, provided that they are conducted with appropriate methodological rigor.
The assessment of added therapeutic benefit is no longer based solely on the magnitude of clinical outcomes but also incorporates the quality of the data and the validity of the endpoints employed.
AIFA introduces a hierarchy of evidence reliability: anchored indirect comparisons, or those based on robust and validated methodologies, may be considered nearly as reliable as randomized controlled trials, though without being formally equated. In contrast, unanchored network meta-analyses and unstructured indirect comparisons are treated as observational studies and are therefore considered to have a lower level of reliability.
Class-level innovativeness
The updated criteria introduce the concept of class-level innovativeness, which allows access to the Innovative Medicines Fund, limited to the remaining portion of the 36-month period, to those medicinal products authorized for an indication already granted innovativeness status in another drug belonging to the same pharmacological class (that shares the same mechanism of action).
While the terminology is new, the underlying concept echoes the “follower” category defined in the 2017 criteria, though now presented in a revised and more structured formulation.
A reward criterion for drug development conducted in Italy
Finally, the President’s official determination introduces a clear political mandate by incorporating a reward criterion in the innovativeness designation process for drugs developed in Italy. Specifically, the Scientific and Economic Commission may take into account whether a significant portion of the drug’s development, either preclinical or clinical, was conducted within the national territory, thereby acknowledging and enhancing the value of Italian biomedical research.
Focus on antibiotics
Antibiotics classified as “reserve” according to the WHO AWaRe list are granted direct access to the Innovative Medicines Fund, up to a ceiling of €100 million, until the expiration of patent protection or data exclusivity. As such, they are not subject to AIFA’s innovativeness assessment.
The inclusion of these antibiotics in a publicly funded mechanism may appear seemingly contradictory: while it ensures access to essential therapies needed to fight antimicrobial resistance, it could also be interpreted as encouraging their use—potentially conflicting with national and international antimicrobial stewardship strategies.
However, this risk does not materialize in practice: access to the Fund for “reserve” antibiotics is strictly regulated and contingent upon prescription through the AIFA Web Registry, which is restricted to infectious disease specialists or, in their absence, to delegates from Hospital Infection Committees (CIO). This ensures a targeted and appropriate use of these therapies.
Therefore, the existence of a dedicated fund should not be interpreted as an incentive for indiscriminate use, but rather as a mechanism to ensure that no patient is denied access to a life-saving therapy for economic reasons, while also providing a return on investment for pharmaceutical companies committed to research and development in this high-need area.
In addition, antibiotics included in the list benefit from specific operational and financial advantages, such as:
- Direct access to the Fund, now reinforced by formal regulatory provisions
- Exemption from direct expenditure monitoring, with a significant impact on payback management and the financial liability of marketing authorization holders.
