How a medicine reaches a patient in Italy before or outside its authorisation: the Legge 648 list, the 2017 compassionate use decree and the AIFA fund.
Italy has four main legal routes to a medicine before or outside its authorisation, and a doctor initiates every request. Under Legge 648/1996, AIFA lists medicines that the national health service (SSN) pays for in full where no valid alternative exists and, since 2014, off-label uses even where one exists, on parameters of economy and appropriateness. Under the decree of 7 September 2017, compassionate use, the company supplies the medicine free of charge after a favourable ethics committee opinion, which the committee sends to AIFA within three days. The AIFA 5 per cent fund reimburses named-patient treatment with orphan medicines and medicines awaiting marketing for serious conditions. Off-label prescription under Law 94/1998 is the doctor's responsibility and gives no right to SSN supply.
Picture an oncologist in Bologna whose patient has used every authorised option, with a medicine in mind that is still in trials or is authorised abroad but not in Italy. What can happen next is set by several Italian acts. This page is for that physician, for the hospital pharmacist, for patient associations and scientific societies that ask for a listing, and for company access teams. It explains who pays, who decides and which documents each route needs, and the FAQ answers what patients ask. For context, see managed access and early access explained.
The Italian Medicines Agency, Agenzia Italiana del Farmaco (AIFA), names four early access routes: Legge 648/1996, compassionate use, the AIFA national fund and the non-repetitive use of advanced therapies, and adds off-label prescription under Law 94/1998; all run under the prescribing doctor's responsibility (AIFA, n.d.-b). Italy's approach has been called varied, with different payers for the 648 list, the 5 per cent fund and compassionate use (Tarantola et al., 2023), and an Italian ethics committee found expanded access protocols misclassified, for example run as clinical trials (Iudicello et al., 2016). This page states the rules in force on 19 October 2026; it promises neither access nor reimbursement and suggests no route for any particular unlicensed medicine.
In Italy, Legge 648/1996 and the AIFA 5 per cent fund are paid with public money, while under compassionate use the company supplies the medicine free of charge.
Under Legge 648/1996 the SSN pays; under the national fund AIFA pays; under compassionate use the manufacturer supplies directly and free; for advanced therapies prepared on a non-repetitive basis the requesting centre bears the cost. Routes can be combined for a regimen of several medicines (AIFA, n.d.-b).
These routes sit inside EU law: Article 5(1) of Directive 2001/83/EC allows supply on a healthcare professional's unsolicited order for an individual patient, and Article 83 of Regulation (EC) No 726/2004 frames compassionate use for groups of patients (Directive 2001/83/EC; Regulation (EC) No 726/2004). AIFA states that the 2017 decree takes over the EMA guideline on compassionate use (AIFA, n.d.-d; European Medicines Agency, 2007). See also Article 5(1) and Article 83: two legal bases.
Legge 648/1996 converted Decree-Law 536 of 21 October 1996, whose Article 1(4) is the rule. Where no valid therapeutic alternative exists, the SSN pays in full for medicines on a list kept by the medicines commission: innovative medicines authorised in other states but not in Italy, medicines not yet authorised but under clinical trial, and medicines used outside the authorised indication. The cost was set at 30 billion lire a year, inside the SSN's ceiling for pharmaceutical spending (Legge 648/1996, art. 1). The text in force on Normattiva has read this way since 21 May 2014.
Today a medicine enters the list after an opinion of AIFA's Scientific and Economic Commission (CSE); once AIFA's decision is published in the Gazzetta Ufficiale, it may be prescribed at the SSN's full expense for everyone in Italy with the named condition (AIFA, n.d.-e). The decision is taken once, for a population, not case by case. AIFA publishes the Legge 648 lists, including one for rare diseases, dated 16 September 2026 when this page was checked (AIFA, n.d.-e). See the glossary entry Law 648/96.
The first inclusion rules required phase II results for all three groups (Commissione Unica del Farmaco, 2000); AIFA now asks for concluded studies, at least of phase II, showing adequate efficacy with an acceptable risk profile for the requested indication (AIFA, n.d.-e). That is AIFA's evidence test for a request, not a statement about any medicine. Since 2007 a separate section lists medicines with consolidated off-label use, supported by the literature, where an authorised alternative is missing (AIFA, n.d.-e).
The list serves off-label use widely: some 62 per cent of its indications were not in clinical development or had never been approved (Tarantola et al., 2023). In paediatrics, Law 648/96 and paediatric formularies support evidence-based prescribing beyond the label (Marchetti et al., 2026).
Decree-Law 36/2014, as converted by Law 79 of 16 May 2014, added paragraph 4-bis (Legge 79/2014, art. 3). Even where an authorised alternative exists, AIFA may, after its own assessment, list an off-label use at SSN expense if the indication is known and consistent with research in the national and international medical-scientific community, on parameters of economy and appropriateness, and must then monitor patient safety and take the necessary decisions promptly (Legge 648/1996, art. 1). The test is narrower than a general economic advantage. AIFA's form asks whether a request rests on economy under this article (AIFA, n.d.-a).
AIFA accepts a documented request from patient associations, scientific societies, health authorities and hospitals, universities and clinicians, or acts on the CSE's own indication (AIFA, n.d.-e), as the 2000 rules already allowed (Commissione Unica del Farmaco, 2000). The request is sent electronically on AIFA's mandatory form; other channels are not considered (AIFA, n.d.-a). AIFA's pre-authorisation secretariat gives a non-binding opinion, the CSE the final opinion, and the board of directors assesses the spending impact and decides; a favourable decision is published in the Gazzetta Ufficiale (AIFA, n.d.-e). One commentary argues that the list should serve unmet therapeutic needs and the fund individual, urgent requests (Addis, 2021).
Each provision states the indication, inclusion and exclusion criteria, therapeutic plan, any price or supply conditions and monitoring parameters (Commissione Unica del Farmaco, 2000). Three general conditions apply: written consent showing the patient knows the safety and efficacy data are incomplete; a plan and prescription by specialised hospital, university or research hospital (IRCCS) centres; and dispensing by the prescribing centre's pharmacy or the patient's local health authority (AIFA, n.d.-e). The consent form, in two copies on the centre's letterhead, states whether the medicine is authorised abroad, authorised for another indication or under trial, and that the data for the patient's condition are incomplete (Commissione Unica del Farmaco, 2000). No ethics committee opinion is required for each patient: the prescriber follows the provision and the centre sends the data.
For each patient, the centre sends AIFA and the regional health department age, sex, start date, clinical course, adverse events, any interruption and the end of the plan; regions forward spending data to AIFA every three months. Missing data lead AIFA to reconsider the listing (AIFA, n.d.-e). AIFA's monitoring includes registries for 648 indications (AIFA, n.d.-c), and a medicine stays listed while the need persists and until a new AIFA provision (Commissione Unica del Farmaco, 2000).
Once AIFA lists a medicine under Legge 648/1996 for a condition, any patient in Italy with that condition can receive it at the full expense of the national health service, under the listing's conditions.
Each of those steps carries a deadline and a counterparty, and they repeat in every country where a programme runs. Ideogen handles them for partners in Italy and across Europe, MENA, CIS and 94 markets worldwide: the notifications, the documentation file, the import route and the safety reporting. The decision to supply stays with the company. Talk to our experts about bridging access to unmet need in orphan and rare disease, where earlier access changes patient outcomes, at [email protected].
Here the company, not the state, provides the medicine, free of charge. The decree of 7 September 2017, published in the Gazzetta Ufficiale of 2 November 2017, defines compassionate use as free supply by the company and replaced the decree of 8 May 2003 (DM 7 settembre 2017, art. 1; DM 7 settembre 2017, art. 8). AIFA applies it and publishes a list of programmes, updated on 13 October 2026 (AIFA, n.d.-d). It distinguishes a programme, on one protocol for several patients, from nominal use for a single patient on the scientific evidence. See compassionate use, the compassionate use programme and what Article 83 actually says.
It covers medicines not yet authorised and under clinical trial, authorised medicines for other indications and authorised medicines not yet available in Italy (DM 7 settembre 2017, art. 1). 'Not yet authorised' includes medicines that have not completed Italian pricing and reimbursement, whatever their status abroad, and 'authorised but not yet available' means authorised with at least class C(nn) but not marketed in Italy (AIFA, 2025). Patients must have serious or rare diseases, rare tumours or life-threatening conditions, with no valid alternative or no access to a trial, or need continuity after a concluded trial (DM 7 settembre 2017, art. 2).
The legal evidence threshold, which is a condition of the request and not a claim about any medicine, is phase III trials in the same indication, or concluded phase II trials where life is in danger, plus GMP certification; for rare diseases and rare tumours, concluded phase I studies may suffice where the mechanism of action supports the request (DM 7 settembre 2017, art. 2).
Requests come from the doctor of a single patient, from doctors in several centres or multicentre groups, or from trial doctors for continuity; with only phase I data, from the head of a regional rare disease centre or a national rare tumours network centre, except for advanced therapies (DM 7 settembre 2017, art. 3). The doctor submits the request to the competent ethics committee, which may use an urgent procedure and sends its opinion to AIFA within three days; AIFA may restrict, suspend or prohibit use (DM 7 settembre 2017, art. 4). In urgent electronic consultations the three days run from their close, and each patient in a programme is assessed individually (AIFA, 2025).
The company's free supply is a precondition: the request includes its declaration (DM 7 settembre 2017, art. 4), obtained in advance, and after a favourable opinion no further AIFA approval is needed (AIFA, 2025). A company opening a programme informs AIFA of its dates and the presumed period of free supply, and gives notice of closure at least 30 days before (DM 7 settembre 2017, art. 5); AIFA asks for the activation notice at least 15 days before the start (AIFA, 2025). The decree does not oblige supply for as long as a patient benefits.
The doctor declares responsibility for treatment according to the protocol (DM 7 settembre 2017, art. 4) and reports suspected adverse reactions to the facility's pharmacovigilance manager or the national network, and to the ethics committee, within two days, or 36 hours for biological medicines; the company manages the reports and informs the committee (DM 7 settembre 2017, art. 7). The data do not replace marketing authorisation data but may support them (DM 7 settembre 2017, art. 6). See who does what in a managed access programme and a compassionate use request under Italy's 2017 decree.
Law 3 of 11 January 2018 set up a coordination centre at AIFA, which monitors committees and reports those that miss the deadlines of the EU Clinical Trials Regulation, and up to 40 territorial ethics committees, at least one per region, with up to three national committees, one for paediatric trials (Legge 3/2018, art. 2). The decree of 26 January 2023 named the 40, in force 120 days after publication on 7 February 2023, with exclusive competence for clinical trials and observational studies of medicines; regions may keep local committees for other functions (DM 26 gennaio 2023, art. 1; DM 26 gennaio 2023, art. 3).
Compassionate use is not a trial. For other ethical reviews, a centre may turn to a territorial committee or a local committee in its region (DM 30 gennaio 2023, art. 1), so it should confirm which committee handles its requests before an urgent case arises. For trials, governed by Regulation (EU) No 536/2014 (Regulation (EU) No 536/2014), the reform brought a single national ethics opinion, and sponsors proposed northern committees for 60.2 per cent of trials (Pierfelice et al., 2026).
Under Italy's decree of 7 September 2017, the ethics committee sends its compassionate use opinion to AIFA within three days of adopting it.
Under Law 326/2003, companies pay AIFA 5 per cent of their certified promotional spending, net of staff costs. Half forms a national fund for orphan medicines for rare diseases and medicines awaiting marketing for particular and serious diseases; half funds information, pharmacovigilance and research (Legge 326/2003, art. 48), including, since 2014, trials of off-label uses (Legge 79/2014, art. 3).
AIFA's authorisation of a 5 per cent fund request concerns the reimbursement of the cost, not the start of treatment.
Requests are nominal and come from the reference centre through the 'Gestionale Fondo 5%', in use since 1 July 2022; regional and facility approvers enable users. The authorisation lapses if treatment has not started within three months; the region advances the cost and AIFA reimburses paid invoices. Treatment may start without AIFA authorisation, which concerns reimbursement only (AIFA, 2023b). The fund's economic impact was 81.2 million euros in 2021, an average of 61,500 euros per patient (Tarantola et al., 2023).
AIFA's criteria of June 2023 require every inclusion criterion: a rare and particularly serious, life-threatening disease in clinical urgency, for single named cases; no valid reimbursed alternative; published data from at least phase II studies or, for rare diseases, of sufficient level; no access to earmarked regional funds; and documented refusal or impossibility of compassionate use or a trial. Any exclusion bars access, such as reimbursement in class A or H, a 648 listing or class C(nn) for the indication, a CHMP refusal or a refusal for the 648 list; medicines with a large impact on the fund may be unsuitable whatever the criteria, and if an indication later enters the 648 list, patients treated through the fund may continue through it (AIFA, 2023a).
Under Article 3 of Law 94/1998, in single cases and under direct responsibility, after informing the patient and obtaining consent, a doctor may use a medicine outside its authorised indication, route or method, if documentable data show the patient cannot usefully be treated with approved medicines and the use is published in accredited international journals. The prescription carries a code linking to the doctor's records, without the patient's name, so the health authority can trace the patient on request, and a breach is a disciplinary matter. This never gives a right to SSN supply outside the 648 list (Legge 94/1998, art. 3). AIFA, which calls it the former Di Bella law, states that the patient pays or, during a hospital stay, the health authority (AIFA, n.d.-b).
The Constitution protects health as a fundamental right and guarantees free care to the indigent (Costituzione, art. 32), and in 1998 the Constitutional Court held Article 3(4), read with Article 2, unconstitutional in so far as it denied SSN supply, to people of insufficient means, of the medicines used in the decree's oncology trial (Legge 94/1998). In a national survey, off-label prescribing was common in paediatric hospitals and a quarter of centres did not know its frequency (Arbo et al., 2025); in oncology, hospital pharmacists share in managing it (Bernardi & Pegoraro, 2008), always within national law (Lerose et al., 2012).
Each route has its own file; see also the Italian request files checklist. For compassionate use, the request to the ethics committee carries (DM 7 settembre 2017, art. 4):
AIFA also receives the patient notification, protocol, consent form, committee opinion and GMP evidence (AIFA, n.d.-d). A medicine from abroad enters through the Ministry of Health's border health office (USMAF-SASN) on a copy of the opinion (DM 7 settembre 2017, art. 4).
For the 5 per cent fund, the anonymised online file carries the rationale and why no alternative exists, an updated clinical report, the therapeutic plan, the cost estimate and a statement that no company or regional funds are available; a renewal adds a detailed clinical report with objective clinical parameters and any suspected adverse reactions (AIFA, 2023b), with the documented refusal or impossibility of compassionate use or a trial (AIFA, 2023a).
For a Law 648 inclusion, AIFA's mandatory form, on the requesting doctor's letterhead, dated and signed, is sent in PDF and Word and asks for (AIFA, n.d.-a):
AIFA manages prices and reimbursement, but regions enable access: in four regions, the mean time from AIFA's reimbursement decision to procurement awarding ranged from 135 days in Veneto to 361 in Puglia, and regions employed about 21 full-time staff on policies such as prescribing centre selection and regional formularies (Novaro et al., 2026). These figures concern reimbursed medicines, but the same regional layer carries early access. Under Legge 648/1996, specialised centres prescribe, the centre or local health authority pharmacy dispenses and spending data reach the region quarterly (AIFA, n.d.-e). Under the fund, the region advances the cost (AIFA, 2023b). See hospital pharmacy record-keeping for named patient supply.
Yes. Under the decree of 11 February 1997, the treating doctor sends the border health and customs offices the medicine's name and form, the foreign producer and authorisation holder, a declaration that it is authorised abroad, a quantity for no more than 90 days, the need in the absence of a valid alternative and a declaration of direct responsibility. The import must be justified by objectively exceptional features, and use must follow the conditions authorised in the country of origin. Except under the 648 list, public funds do not pay, unless a hospital buys the medicine for hospital use within its budget and any regional rules (DM 11 febbraio 1997). See named patient import and customs.
| Aspect | Legge 648/1996 | Compassionate use | 5 per cent fund | Off-label (Law 94/1998) |
|---|---|---|---|---|
| Who pays | SSN | The company, free | AIFA; region advances | Patient, or health authority in hospital |
| Scope | All eligible patients | One patient or a programme | One named patient | Single cases |
| Who starts it | Associations, societies, health authorities, universities, clinicians or the CSE | The treating doctor | The reference centre treating the patient | The treating doctor |
| Who decides | AIFA (CSE, board) | Ethics committee; AIFA informed | AIFA, on reimbursement | The doctor |
| Evidence | At least phase II | Phase III, II or I by case | At least phase II | Published use |
The table summarises the rules above (Legge 648/1996, art. 1; DM 7 settembre 2017, art. 2; AIFA, 2023a; Legge 94/1998, art. 3). The routes connect: AIFA's 648 form requires asking the company about free supply first (AIFA, n.d.-a), and the fund is closed to patients who can enter compassionate use or a trial (AIFA, 2023a). See who pays for early access.
Payers in France, Italy, Spain and the UK set no predetermined budget for early access, and total spending is unknown (Tarantola et al., 2023). In seven Italian oncology preparation units, 783 compassionate use authorisations from 2016 to 2021 gave access on average 514 days before reimbursement, with potential SSN savings of about 376 million euros, and Italy has no structured monitoring of compassionate use (Dell'Anno et al., 2024).
After authorisation, 60 of 283 AIFA registries supported payment-by-result agreements (Xoxi et al., 2021), and paybacks reached 327.5 million euros in 2019 to 2021, 0.9 per cent of public facility spending on medicines (Trotta et al., 2023). Among the countries compared, and excluding Germany, Italy had the shortest average time from authorisation to a reimbursement decision for orphan medicines, 18.6 months (Zamora et al., 2019), and among 22 countries it was one of those where most rare disease medicines were available (Detiček et al., 2018). Diverse programmes are a possible source of unequal access across Europe (Tarantola et al., 2023), and in seven other countries named-patient reimbursement was often unregulated (Rosenberg et al., 2025). See Italy's price and reimbursement negotiation.
Decree-Law 169 of 8 November 2022, converted by Law 196 of 16 December 2022, replaced AIFA's technical-scientific commission and pricing committee with a ten-member CSE (Decreto-legge 169/2022, art. 3), which took office on 26 March 2024 (AIFA, 2024) and now gives the opinion on 648 listings (AIFA, n.d.-e). In 2023 the ethics review of trials moved to the 40 territorial committees (DM 26 gennaio 2023). The Commission proposed in 2023 a regulation to replace Regulation (EC) No 726/2004 (European Commission, 2023). AIFA authorises advanced therapies prepared non-repetitively for one patient in public hospitals (AIFA, n.d.-f). Commentators call for monitoring protocols (Addis, 2021) and a national compassionate use observatory (Dell'Anno et al., 2024). See public registers of early access in Europe.
No. A listed medicine is prescribed at the full expense of the national health service, within the listing's indication and conditions, with the patient's written consent (AIFA, n.d.-e).
The treating doctor, several doctors or a multicentre group, through the competent ethics committee (DM 7 settembre 2017, art. 3).
The ethics committee sends its opinion and the documents to AIFA within three days of adopting it, and AIFA may restrict, suspend or prohibit the use (DM 7 settembre 2017, art. 4).
No. AIFA's authorisation concerns reimbursement, and it lapses if treatment has not started within three months (AIFA, 2023b).
No. AIFA states that the cost falls on the patient or, during a hospital stay, on the health authority (Legge 94/1998, art. 3; AIFA, n.d.-b).
The decree sets no fixed period. The company declares the presumed period of free supply and gives AIFA 30 days' notice before closing a programme (DM 7 settembre 2017, art. 5).
Agree free supply in advance, since the doctor’s request to the ethics committee includes the company’s declaration; notify AIFA of the programme’s dates and the presumed period of free supply, with the activation notice at least 15 days before the start; give AIFA at least 30 days’ notice before closing; supply the GMP evidence; and manage the adverse reaction reports and inform the committee. Ideogen runs this work for partners in Italy and across Europe, MENA, CIS and 94 markets worldwide. Ideogen does not decide access to any medicine. Talk to our experts about bridging access to unmet need in orphan and rare disease, where earlier access changes patient outcomes, at [email protected].
Ask who will pay and how many patients are concerned. One urgent patient, a medicine under trial and a willing company point to nominal compassionate use; several patients on one protocol, to a programme. One patient with a rare, serious condition and no other route points to the 5 per cent fund; a need shared by many patients, to a 648 request. Law 94/1998 allows off-label prescription without reimbursement (AIFA, n.d.-b).
A doctor initiates every request: the treating doctor for compassionate use, the fund and off-label use, and the requesting doctor who signs AIFA's form for a 648 inclusion. The ethics committee and AIFA decide within their powers, and the company decides whether to supply. Ideogen does not decide access to any medicine. See how named patient programmes work in Europe and how Ideogen supports partners with end-to-end commercialisation.
Addis, A. (2021). [Early but not too much]. Recenti Progressi in Medicina, 112(11), 707-708. https://doi.org/10.1701/3696.36847
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