Rome, 31 January 2023. The following text summarises the intervention of Valeria Violaowner of Pharma Value, during the presentation of the 6th OSSFOR Annual Report 2022, a tool for analysis and in-depth study on orphan drugs, realised through the collaboration between Osservatorio Malattie Rare (O.Ma.R.) and the Centro per la Ricerca Economica Applicata alla Sanità (C.R.E.A. Sanità).

The OSSFOR report included the article 'Proposal for regulatory reform of 648/96 for 'timely access' of innovative medicines' by Valeria Viola, Ginevra Mastroianni (Pharma Value) and Cinzia Timpano (University of Eastern Piedmont).

The topic discussed in the Sala Zuccari of Palazzo Giustiniani concerned a proposal for regulatory reform linked to the hypothesis of a revision of the innovative drugs fund that would allow 'early access' of drugs on the 648/96 list at their first authorised indication.

The study started from a study of the 648 list applications received in 2020-2021.

Law 646/96

Law 648 is a law that allows drugs not yet authorised in Italy, but authorised in other states, or drugs that are still undergoing clinical trials, to be reimbursed by the SSN.

This law has been amended over the years, in particular the 2014 amendment allowed that even where there was a therapeutic alternative but the drug was cheaper (principle of cost-effectiveness), supported by scientific evidence, there could be the possibility of inclusion in the list of drugs fully reimbursed by the National Health Service.

Another modality of 648 is applied where there is a drug that has a marketing authorisation, but the indication for which there is a request for inclusion has not yet been authorised, i.e. for medicines used in a different therapeutic indication.

Data considered in the analysis

The analysis work covered all applications for inclusion received in 2020-2021, Pharma Value, however, continued to follow up these drugs in 2022 and 2023 as well, to check whether they had received innovation, reimbursement, and to monitor timing.

For a comparison on the topic between the 2020-2021 and the 2018-2019 biennium read our article Analysis of applications for the inclusion of drugs on the 648/96 list .

The analysis focused only on certain types of requests, i.e. those for drugs that have received marketing authorisation but are not yet reimbursed in Italy.

What emerged from the study is that in 2020-2021 all applications in 648and thus also those for an extension of therapeutic indications other than those authorised on the grounds of cost-effectiveness, were 133, of these 10 were new medicines and already had a positive opinion of EMA. One of these was excluded from the analysis because it was a drug with a therapeutic indication for the treatment of COVID that was authorised 648 but then allocated a special fund for COVID drugs.

Of these new active ingredients, of which 133 drugs, 9 were new active ingredients for innovative medicines authorised in other countries but not in Italy and for medicines not yet authorised but undergoing clinical trials. The study followed these 9 (among them for 2 the CTS gave a favourable opinion for inclusion in 648 and for 7 an unfavourable opinion), making a sketch of them.

Among these 9 drugs, 8 are orphan drugs and 1 is non-orphan, i.e. it does not have a rare disease status, but it is for patients in a fourth line of therapy and therefore for a small and specific population: all 9 share a narrow patient indication.

Of these 9 drugs, 4 have subsequently received recognition as innovative, 5 are non-innovative, but of these some are still under evaluation so may have received innovation.

Looking at those reimbursed by the National Health Service, it emerges that of these 1 had a class C, 5 were reimbursed and 3 are still in the Price & Reimbursement procedure, of these 9, again, 5 are paediatric, 2 are advanced therapies.

Cost estimation

A cost estimate of the annual expenditure for these new active ingredients was made, starting from the prices of drugs that had a completed Price & Reimbursement procedure (ex-factory price), or from the tender price of drugs sold in Cnn.

An estimate of the aggregate expenditure cost for these drugs was then derived: the total value amounted to 91,000,000.

The average cost of therapy per patient treated was 120,000 euro.

Main findings

The points worth reflecting on are therefore:

• there were few applications in 648 for new active substances,
• most of the applications are extensions of indications of already authorised drugs,
• of these 9 were given few positive opinions.

It is assumed that the low number of positive opinions can be attributed to a difficult cost calculation, where for a new active ingredient to enter the list 648 there is a lack of tracking of that drug, it is difficult to understand which expenditure item the regions are contributing to and how much the Regional Health Service spends.

Moreover, also through a discussion with institutional stakeholders, it is stressed that the payer sees the approval of a 648 associated with surreptitious use and the possibility of a dominant position of pharmaceutical companies during negotiation: where a drug is already reimbursed in 648, it is feared that the company will no longer be proactive in negotiating with AIFA,. It is also true that the 2019 Negotiation Criteria Decree gave the opportunity for a corrective to this risk, giving the possibility to negotiate with a simplified dossier for drugs in 648.

Another critical issue that emerged from the analysis is the risk of an 'open claim' in 648, which occurs when the clinician, not yet knowing what indication the EMA will recommend, or in order to give a larger patient population a chance, makes a claim with a very open indication. It may happen that the CTS's place in therapy assessment only elects a subpopulation for reimbursement. This difference between the therapeutic indications envisaged for entry on the 648/96 list and those subsequently approved for reimbursement could create difficulties if the population benefiting from the drug free of charge is reduced.

A problem would arise - for example - with regard to the need to ensure continuity of treatment for those patients subsequently excluded.

Innovative drugs and drugs on the 648/96 list

"What is the reason why the approval of a new active ingredient in 648/96 should be included in the fund for innovations? This was the question put to the audience present.

Both meet an important therapeutic need, both have added therapeutic value. The evidence of their efficacy is managed for innovative drugs through the GRADE methodology and evaluated by the AIFA offices and the CTS, while in the 648 a report is sent by the applicant (clinician, association, scientific society) with a bibliography of publications and ongoing studies. where it describes the ongoing studies and evaluated by the AIFA Pre-Authorisation Area and the CTS.

Proposed regulatory reform linked to the review of the Innovative Medicines Fund

'The new active ingredients entering the 648 respond to the characteristics of innovative drugs, both meet an important therapeutic need and both have added therapeutic value, what should be harmonised is the validation of scientific evidence'. This is the solution proposed by Viola. He continues: "the fund for innovative drugs could be large enough to contain the 648 requests for new active ingredients.  Incidentally, the estimate made did not include the negotiation contemplated by the 2019 Negotiating Criteria Decree, which means that once approved on the 648 list, they could also be negotiated.

What, then, should the regulatory revision provide for?

"Together with the application for 648, an assessment of innovativeness should be made; the CTS could only admit drugs not yet authorised in Italy or with ongoing trials if it recognised the innovativeness requirement. This would allow patients in need to have access to these drugs quickly, but most importantly, it would allow economic coverage already provided by the system.

On the website of the Orphan Drug Observatory you can download the VI OSSFOR Report.