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Reimbursement of Rare Disease Drugs in Italy: Challenges and Hopes for the Future

When it comes to rare diseases, Italy has done a good job in bringing EMA-approved drugs, including orphan drugs, to the Italian market. But multiple challenges exist, many of which are hot topics in Italian healthcare today. These include the extended process of receiving approvals and reimbursement, initially at the national level and then at the regional level, resulting in long delays for sponsors trying to get drugs to the market and for patients awaiting treatment. The high cost of developing rare disease drugs leads to reimbursement challenges, and limited funding for Early Access Programs (EAPs) is problematic. In this context, Real-World Evidence (RWE) and Patient Reported Outcomes (PROMs) are key in informing the value of these drugs and supporting the process of reimbursement negotiations, but currently the system lacks standards and guidelines for collecting and using such tools and information on indirect costs.

Published on:
April 17, 2023
Written by:
Ilda Theka, Veronica Ottobrino
There are many initiatives underway and lots of ongoing discussion in the Italian healthcare system, much of which will directly have a positive impact on the development and market access of rare disease drugs."

Ilda Theka, Senior Consultant and ‌Veronica Ottobrino, Associate Consultant in Market Access, Alira Health are experts on the access and reimbursement of rare disease drugs in Italy. They reviewed the status and challenges facing all stakeholders in Italian healthcare, including sponsors, payers, and especially patients with rare diseases, and pointed to some optimistic signs for the future, including the major changes that lie ahead.

Reimbursing Rare Disease Drugs in Italy Today

For advanced therapies to treat rare diseases, Italy is well positioned in terms of both availability and reimbursement. A recent report on orphan drugs stated that, in 2021, EMA authorized 130 orphan drugs, most of them applicable to rare diseases, almost all of which are available in Italy and 80% of which are reimbursed by the National Health Service. The country has demonstrated the willingness to accept, adopt, and reimburse these drugs, and at the national level, there’s a focus on developing better guidelines and funding for drugs to treat and cure rare diseases.


Delayed approvals

Delayed approvals are a problem, however. AIFA (Agenzia Italiana del Farmaco) must first approve drugs , and sponsors should then pursue access at the regional level, which extends the time it takes for drugs to reach patients, especially given that Italy has 20 regions. Read more on the state of market access in Italy.

Regional discrepancies

Another challenge the regional discrepancies that might impact access and reimbursement of drugs for rare diseases. The Italian government approved a new national plan for rare diseases in February 2023 with the goal of harmonizing the regions to reduce the timeframe for approvals and the gaps in availability.  Meanwhile, sponsors should make an effort to engage with the regions, not only to discuss access to drugs and funding limitations but also in terms of how the disease is managed in the region. Rare diseases are often studied and treated in specific medical centers; for example, patients may have to travel to Rome from another region to participate in clinical trials and see specialists, which may be too difficult for some people. Understanding the struggles facing patients and providers within a region can help a sponsor develop a strategy tailored to the regional market dynamics and facilitate access to patients.

High costs

The high cost of innovative therapies for payers is another challenge. Of course, this is a problem in many countries, not just Italy, but the lower the available healthcare budget, however, the higher the burden. To encourage innovation in rare disease treatments, Law 648/96 and Law 326/2003 (5% fund) provides funding for innovative drugs through an EAP; however, as discussed at the 2023 Conferenza Nazionale Sulla Farmaceutica, the budget allocated to the latest EAP has gradually decreased during recent years in Italy. To improve this, the government recently added an additional 2%  to the existing 5% fund and updated the access criteria for this program. Management Entry Agreements (MEAs) are often used with expensive drugs, especially when there’s not enough clinical evidence to back up the value. As in other European countries, AIFA sets an initial price and the sponsor agrees to provide evidence at the end of the agreement, at which point, they will renegotiate the price. Of course, AIFA wants to be sure that what they reimburse is acceptable from both the clinical and safety points of view. Sometimes, though, an MEA ends but the sponsor and AIFA disagree about whether the agreed-upon outcomes were met. AIFA and the pharma companies need to agree on standard methods for determining the final outcomes of MEAs.

Tools like MEAs and EAPs are meant to accelerate access to these drugs for rare disease patients. But most of the time, the RWE gathered during these programs is not sufficient to meet AIFA requirements. Methodologies on how to collect and analyze data and more flexibility from AIFA are both needed.

Potential Solutions

In Italy, both manufacturers and other key stakeholders are suggesting a move towards value-based healthcare. With this approach, the price of a drug would not just take into account the cost to develop it, but what value-added services can be delivered. What data can be generated from the use of a drug to help with disease understanding and management? Can a digital solution gather evidence in terms of quality of life, PROMs, indirect costs, and more? Instead of looking only at the drug itself as it enters the market, this would be a more comprehensive approach that better defines the overall value of the drug and its impact. AIFA and the other stakeholders need to collaborate and define how this should be done in Italy.

Another source of conversation focuses on how AIFA could consider additional information during the price and reimbursement process, which could be particularly important for rare diseases. For example, as of now, indirect costs are not evaluated during the price and reimbursement negotiations. But in rare diseases, Italian patients are almost always looked after by caregivers (usually family), which generates high indirect costs and has a huge impact from an economic and social point of view. The problem is, how to quantify and standardize data on indirect costs?

Patient reported outcomes (PROMs) could also be evaluated as part of the process, but they are not today. PROMs are important data in rare diseases because they define the patient burden. Conversations are underway about how sponsors should collect real-world evidence (RWE) s, what kind of methodology they should leverage, and how these data can support the reimbursement discussions between pharmaceutical companies and AIFA. Data collection, storage, and analysis is made more difficult by Italy’s weak digital infrastructure.

In the past, the focus of negotiations was just on clinical trials, so the mindset is changing. Italy needs to develop standardized methods and parameters to analyze indirect costs and PROMs and define them in terms of valuation.

The Future of Rare Disease Drug Reimbursement in Italy

There are many initiatives underway and lots of ongoing discussion in the Italian healthcare system, much of which will directly have a positive impact on the development and market access of rare disease drugs.

Italy’s National Recovery and Resilience

Italy’s National Recovery and Resilience Plan (Piano Nazionale di Ripresa e Resilienza, PNRR) is set to help the country leave behind the impact of the pandemic, using NextGenerationEU (NGEU) funds. Public health and healthcare is a main component of the plan, which includes three main goals: digitization of the Italian healthcare system, addressing regional inequities, and the creation of life science hubs in order to promote the advancement of innovative therapies, all of which will benefit rare disease patients.

RWE, PROMs, digital health

RWE, PROMs, and digital health are hot topics for rare disease because all stakeholders agree that incorporating these data and tools is vital. There’s a lot of discussion with AIFA and other key partners, such as the National Center for Health Technology Assessment (HTA) and The Professional Society for Health Economics and Outcomes Research (ISPOR), on topics like health economic outcomes. The Italian Medical Society is focused on PROMs tools for specific diseases and starting to recommend them to be used in regulatory evaluations. AIFA wants to collaborate more with all stakeholders on how to leverage RWE in terms of evaluation, pricing, and investment discussions, and how to develop clear guidelines and standards.

Merge of CST and CPR

Another major development coming soon is that in July 2023, AIFA is expected to change its structure by merging its two committees, the Scientific Technical Committee (CTS) and the Price and Reimbursement Committee (CPR), into one. This will also impact timing and potential negotiation/discussion processes. More details are expected soon.


Perhaps the most significant future development is the European Union HTA (EUnetHTA), which for orphan drugs will go into effect in 2028. EUnetHTA was established to create an effective network for HTA across Europe and will have a major impact on not just approvals but also pricing and reimbursement, as all EU countries shift to one set of guidelines. Learn more from Alira Health’s whitepaper, “New European Health Technology Assessment Regulation.” The impact on Italy’s healthcare system and processes remains to be seen.

A multidisciplinary and multi-stakeholder approach is key to overcoming the challenges associated with reimbursement for rare disease drugs. The good news for Italian patients with rare diseases is that all stakeholders are working to improve the current situation and find ways to more rapidly and equitably bring treatments to the market.

In Alira Health we advise clients on the best approach to reimbursement at the national and regional levels. We have significant experience in rare disease and can work with you on navigating the challenging landscape and leverage the benefits that are available in Italy. We’re also monitoring the many changes that are coming and will help you stay up to date and understand how these new developments impact your product.

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