EASL view on HCV compassionate use programmes Daniele Prati, MD EASL Governing Board Member Dept. Of Transfusion Medicine and Hematology, Ospedale Alessandro Manzoni, Lecco, Italy

EASL view The essential mission of the European Association for the Study of the Liver (EASL) is to promote liver research and to improve the treatment of liver disease throughout the world EASL, although has not taken a specific position with regards to access of patients with severe liver disease to unlicensed therapies, welcomes compassionate use programs for those who might otherwise progress beyond treatment boundaries, when the risk/benefit ratio of treatment is presumed to be positive.

What we are talking about Compassionate use programs Expanded access programs Named patient programs Named patient supply Temporary authorization for use A treatment option for patients suffering from a disease for which no satisfactory authorized alternative therapy exists or who cannot enter a clinical trial, using an unauthorized medicinal product

Comparison of the named patient compassionate use programme (NP- CUP) and the cohort compassionate use programme (Coh-CUP)

Issues and barriers to compassionate use Main: Lack of uniform legal framework in EU member states Safety issues Other: Concerns of potential damage/delays to clinical trials (competition) Marketing priorities and concerns by pharmaceutical companies (if serious adverse events are expected) Economical/reimbursement issues (who pays? How the NHSs can afford expensive treatments?)

Lack of uniform legal framework in EU member states Although EMA guidelines on CUP do exist and EMA’s opinion on a CUP can be applicable for all Member States throughout the EU, the Member States are not bound to follow the EMA’s recommendations because approval remains a national responsibility. The regulatory framework and management of CUPs are very different from one EU country to another, i.e. the eligibility conditions, regulatory procedure and review times vary greatly between the Member States

Sou H, Pharm Med 2010 Overview of compassionate use programs (CUPs) in selected EU countries

Compassion “Sympathetic consciousness of others' distress together with a desire to alleviate it”

Hojat M. Empathy in patient care. Springer, 2007 Empathy, sympathy and compassion are related to cognition and emotion

Safety of Telaprevir or Boceprevir in Combination with Peginterferon alfa/Ribavirin in Cirrhotic non-Responders: First Results of the French Early Access Program (ANRS C020-CUPIC) (Hezode C et al, ILC 2012)

Safety concerns In patients with advanced liver disease, both efficacy and safety profiles can less favorable than in clinical trials. In CUPs, lacking these data, the potential risks and benefit for patients of treatment cannot reliably be predicted. However, who decides what is a positive benefit/risk ratio in single patients who are at risk of severe outcomes? (patients and physicians perspectives can be different!)

Devereaux PJ et al. BMJ 2001;323: Accetablre number of bleeding to avoide a stroke physicianspatients Disagreement between patients and physician The maximum number of bleeding considered acceptable in 100 patients (with atrial fibrillation) over two years for use of warfarin was: (10.3 (±7.1) for physicians and 17.4 (±7.1) for patients p < 0.001

Mutiple Sclerosis BMJ 1997; 314: 1580–83.

Conclusions The definition of uniform policies for CUPs across different countries would be desirable. Defining the risk benefit ratio for patients with severe liver disease potentially candidate to CUPs is complex, and require prudent, open, and transparent discussion between patients and hepatologists. Frequently, patients are prepared to volunteer to expose themselves to increased risk because of their severe prognosis. The entire decision process for CUPs require specific regulations to protect the implementation of clinical trials and to limit the impact of liability concerns and financial/marketing issues on decisions on CUP implementation. CUPs are not specifically intended to provide data on safety and efficacy. However, when appropriately designed, they can be useful to design better clinical trials on particular patient populations. CUPs are not the solution to solve local delays in deciding on criteria for healthcare system reimbursement in some EU countries.