The Italian Payers’ approach to new anti-hepatitis C drugs
Un lunga intervista al direttore dell’Agenzia del Farmaco Italiana, prof. Luca Pani che spiega l’approccio italiano ai nuovi farmaci innovativi per l’epatite C.
Hepatitis C Virus (HCV) infection is a heterogeneous disease which is estimated to affect up to at least 1,2 million people in Italy. Indeed, of all European countries, Italy is thought to be the one with the highest number of infected individuals. Moreover most of them are undiagnosed.
As HCV may be considered a silent epidemic posing a national and global public health problem with serious consequences, we chose to approach it from multiple perspectives, considering also the ethical implications of an effective but too highly priced cure with all the consequent impact on sustainability for one of the few fully publically funded national health systems like the Italian one.
Undoubtedly, some of these new drugs such as sofosbuvir represent innovative therapies, but other molecules and fixed drugs combinations have already been approved in Europe and in the USA or have received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).
As far as HCV infection is concerned research and clinical trials are showing significant effective benefit/risk profile for interferon-free short-term (down to 8 weeks) treatments that will, most likely, result in greater adherence due to better tolerability and overall cost reduction for non-pharmacological support for these patients.
In Italy, sofosbuvir was approved with AIFA directorial resolution on 12th November, 2014 (“Determina 12 November 2014”), and six categories of the most severe patients were granted totally free of charge reimbursement status on 6th, December2014. The Italian national health system is facing a cost for the pharmacological treatment of HCV infections with new compounds (telaprevir and boceprevir included) of over 850 million euro in the period 2013-2016.
Our commitment to ensure progressively full coverage for all patients in need of this type of therapy will require rigorous choices in the evaluation of innovation and added therapeutic benefit, in order to accurately identify the criteria for progressive access to medications and a strong post-marketing registry based on on-line monitoring of the efficacy and safety profiles in clinical practice to be included in the pricing negotiation.
Reconciling the evaluation of innovation with widespread access to new drugs while trying to maintain overall sustainability of the entire system is a difficult task, especially in a situation where the Italian national health system covers the costs of all essential drugs and more than 70% of the total national budget for drugs (19,9 billion euro /annually ) is paid by the State which continues to provide universal health care to all.
A strategy of expenditure restraint which all Regulatory Agencies have been trying to implement to date, has been based on fierce negotiation of starting prices (not very successful) and a cost/volume agreement (more successful in some European countries) considering that eradication of HCV infection should finally result in a contraction of the cost for global health assistance for this disease.
With this in mind, during the negotiations for sofosbuvir, AIFA has taken – into consideration right from the beginning all the other new drugs under registration , thinking that their costs would be largely influenced by sofosbuvir’s reference price and most importantly by price volumes discounts. The AIFA strategy, under the direct auspices of the Health Ministry, was designed to lay the foundations for an ambitious pharmaceutical plan with the goal of eradication of HCV infection in 6-8 years in Italy.
In order to achieve such an ambitious task AIFA inaugurated a new negotiating strategy choosing to undertake a public and transparent dialogue involving all the main players: patients, physicians, scientific societies and manufacturers. Furthermore, AIFA has involved other European National Agencies with the aim to identify and learn shared strategies, evaluating the opportunity to try new models capable of facing the changes in the global pharmaceutical scenario, following a scientific-regulatory-economic and a social ethical approach.
Given the exceptional nature of the case and the improvement seen in the efficacy/safety profile of these new drugs (not only sofosbuvir) leading to possible eradication of the disease, even before starting the negotiation process with the MAH, AIFA adopted a number of extraordinary procedures, bringing together for the first time in joint session its two Committees [The Technical Scientific Commission (CTS) and The Prices Reimbursement Committee (CTS)] and calling for an additional extraordinary meeting session outside the scheduled agenda.
In parallel and independently from the price negotiation procedure, thanks to an agreement with the MAHs for most of these new compounds, AIFA started a procedure for the free supply of several anti-HCV drugs in “compassionate-use” in accordance with Italian Law DM 08/05/2003 which made treatments available in most urgent cases (i.e. patients with recurrent severe hepatitis after liver transplantation, fibrosing cholestatic hepatitis or chronic hepatitis with fibrosis > METAVIR F2 or patients with decompensated cirrhosis who were on the organ transplant waiting list for liver transplantation and MELD <25). In addition to these first patients, AIFA then gradually included HCV-infected individuals enrolled on the list for liver transplantation with hepatocellular carcinoma in compensated cirrhosis (MELD <15) with the following clinical features:
- Hepatocellular carcinoma within the Milan criteria (presence of single nodule diameter <5 cm or multifocal neoplasia limited to a maximum of three nodules, each of a diameter not exceeding 3 cm, absence of extra hepatic tumor localization and absence of tumor vascular invasion of the intrahepatic or extra hepatic venous branches);
- Hepatocellular carcinoma not treatable with other radical methods (surgical resection or radiofrequency);
- The risk of neoplastic progression during the stay on waiting list is sufficiently low to ensure a permanence time on waiting list congruous with the chance to get the most benefit from antiviral therapy (at least 3 months).
This identical strategy has been followed successfully for the combination Paritaprevir / r-ombitasvir and dasabuvir for patients infected with HCV genotype 1 ineligible or intolerant to interferon therapy and included in the following categories:
- Recurrence of hepatitis after liver transplantation (fibrosing cholestatic hepatitis or chronic hepatitis with fibrosis METAVIR F0-2);
- Compensated cirrhosis (Child-Turcotte-Pugh score A) in the absence of significant comorbidities;
- Chronic liver disease with fibrosis grade METAVIR F3 in patients unresponsive to dual therapy (pegIFN + RIBA);
- Chronic hepatitis with extra-hepatic manifestations HCV-related clinically relevant (e.g. symptomatic cryoglobulinemic syndrome moderate to severe or lymphoproliferative syndromes), regardless of the degree of fibrosis.
Meanwhile, starting from a significant (albeit not publically disclosable) cut in price for sofosbuvir the negotiation process of other medications related to HCV infections such as simeprevir and daclatasvir has been completed.
Indeed the agreement reached on the cost of treatment and on reimbursment admission procedures for simeprevir was also particularly innovative for the Italian national health system and again represented a first time for AIFA. In order to ensure economical sustainability the negotiated agreement was based on a procedure of de-listing from the same company of drugs which shared the same therapeutic indications such as Telaprevir, for which the agreed cap limit for the last 24 months had not been already reached.
So after guaranteeing the continuity of care for patients already under treatment with telaprevir, the drug was excluded from reimbursement while its remaining resources were redirected to cover the treatments starting with simeprevir at no additional cost for the Italian national health system until the original budget for telaprevir would be reached and when a mandatory renegotiation for simeprevir would start again. This situation will not only allow to treat patients with a drug that has shown increased efficacy and better tolerability compared to telaprevir, but it will also ensure that the Italian national heath system will reimburse the therapy with the best cost-benefit ratio, simultaneously facilitating the economic coverage of the new treatment and a more efficient allocation of resources. Most importantly this agreement set a legislative precedent in negotiating managed entry agreement for the Italian system and it was repeated once again for the combination sofosbuvir-ledipasvir at an even a better volume price discount than that for sofosbuvir alone and, again, with no impact on the Italian national health system’s budget.
It must be said that the approach that has allowed AIFA to close a swift and successful negotiation for the reimbursement of sofosbuvir, simeprevir, daclatasvir and sofosbuvir+ledispavir, within the deadline requested by the Ministry of Health to assure the treatment of the largest possible number of patients, has been made also possible – unfortunately – by the high prevalence of HCV infection in Italy, that allowed an “aggressive” correlation between the two parameters (price and volume), starting from an average price of €37.000 Euro per patient, which is generally lower than the rest of Europe, with further rebates directly linked to the sold drug quantities at a non-public price. The progressive criteria of appropriateness have been specified by the CTS, after carefully considering the point of views of patients and specialists.
Despite favourable average and final prices for all these drugs, global spending remained significantly high which is why, through an amendment to the Italian “ Stability and Growth Pact law”, the Ministry of Health obtained the allocation of a specific innovative (not only for HCV drugs) fund of one billion Euro for the next two years with an aim to start the desired process of eradication of the disease from the Ministry of Finance and Economics.
Moreover considering that, with the mandatory genotyping for these patients, we are entering the precision medicine era and the task of Regulatory Agencies is to offer real innovation with more effective and targeted therapies, AIFA intends to evaluate all of them with an on-line regulatory registry to gauge both therapeutic efficacy, risk- benefit and benefit-cost ratio in real-life context use.
Given all the above reasons the authorization of sofosbuvir, simeprevir, daclatasvir and sofosbuvir ledipasvir contemplates a continuous, real-time, monitoring system through a common register that has been designed in collaboration once again with internal and external experts.
Nevertheless, if on the one hand we have to limit expenditure to those in real need we cannot close the doors to innovation let alone to the hopes of the sick. In Italy, the Ministry of Health has established criteria for distribution and has determined the conditions of eligible patients; at present, the local authorities (Regioni) are identifying the facilities through which the drugs will be made available.
From our personal experience it seems preferable to start “joint negotiations” between European Countries’ Payer Authorities and MAH in order not only to standardize the evaluation and the recognition of innovation but also to obtain better price agreements on a much larger population of patients.
Italy has proactively been promoting this type of initiative despite the limited time available for anti HCV infection drugs, a European joint-procurement procedure has not been finalized yet.
Prof Luca Pani
Director General Italian Medicines Agency
www.agenziafarmaco.gov.it
Fonte: hepbecppa.org
