David Tyas Global HEOR - Lundbeck Example of Health Technology Assessment (HTA) of a therapy for the reduction of alcohol consumption David Tyas Global HEOR - Lundbeck

Contents Introduction into a HTA process Summary of our submission Use SMC as an example but equally could be from many other countries Summary of our submission Main argument Types of analysis Clarification question stage Summary of questions (what sort) Final recommendation

Economic Evaluations in Europe Norway: Pharmacoeconomic data required for reimbursement; official guidelines in operation. Finland: Pharmacoeconomic evidence mandatory for evaluating new therapies for reimbursement and may also be requested for existing therapies. UK: NICE, SMC, and AWMSG evaluates the cost effectiveness of medicines. Sweden: Cost-effectiveness data required for reimbursement. Ireland: Guidelines for pharmacoeconomic studies prepared; cost-effectiveness data may be requested. Denmark: Cost-effectiveness data may be requested for reimbursement decisions. Netherlands: Pharmacoeconomic evidence explicitly required for reimbursement of new products. France: Not a formal requirement but increasingly used in reimbursement decisions. Guidelines prepared. Poland: C/E and BIA may be requested. HTA agency. Belgium: Formal requirement for economic evaluation. Spain: Health technology assessment at a regional level. Germany: Guidelines prepared. Institute for Quality and Efficiency in the Health Service established in 2004. Italy: Cost-effectiveness considered in pricing and reimbursement decisions. Greece: Guidelines for pharmacoeconomic studies prepared; cost-effectiveness data may be requested. Portugal: Cost-effectiveness data incorporated into reimbursement decisions.

SMC process Manufacturers submission Clarification questions Draft advice Final recommendation

Example of a HTA submission dossier - SMC requirements Chapter 1 Registration Details Chapter 2 Overview and Positioning Chapter 3 Comparative Efficacy Chapter 4 Comparative Safety Chapter 5 Clinical Effectiveness Chapter 6 Pharmaco-Economic Evaluation Chapter 7 Resource Implications Total ~ 100 pages

Nalmefene Main arguments and data

Total Alcohol Consumption (g/day) Indication Nalmefene is indicated for the reduction of alcohol consumption in adult patients with alcohol dependence who have a high drinking risk level (DRL), without physical withdrawal symptoms and who do not require immediate detoxification. WHO category Total Alcohol Consumption (g/day) Women Men Very high-risk consumption > 60 > 100 High-risk consumption 40–60 60–100 Medium-risk consumption 20–40 Low-risk consumption 1–20 1–40

Relative risk for all-cause mortality by average daily intake of alcohol

Stages of alcohol abuse/ dependence Place in therapy Abstinence Reduction Treatment intensity Brief intervention Early Middle Late Stages of alcohol abuse/ dependence

3 RCTs in patients with alcohol dependence Clinical efficacy 3 RCTs in patients with alcohol dependence Study name Study duration Patients enrolled High drinking risk ESENSE 1 (Mann 2013; Wim van den Brink 2013) 24-week 604 (306+298) 350 180+170 ESENSE 2 (Gual 2013; Wim van den Brink 2013) 718 (358+360) 317 (155+162) SENSE (Wim van den Brink 2014) 52-week 675 (509+166) 187 Lundbeck’s sponsored phase III programme for nalmefene comprises three clinical trials, all if them multi-centre, randomised, double-blind, placebo-controlled, parallel group studies of 20 mg nalmefene, as-needed use, in patients with alcohol dependence according to the DSM-IV criteria. The aim of the program was to demonstrate the efficacy, safety, and tolerability of nalmefene, as-needed use, for the reduction of alcohol consumption in patients with alcohol dependence. Two of the studies were of 6-month duration (ESENSE 1 and ESENSE 2) with a randomisation 1:1 and the third one was a 12-month study (SENSE) with a randomisation 3:1 as it was primarily designed as a safety study, therefore the larger intended exposure to nalmefene. Please note that the selected dose, 20 mg of nalmefene hydrochloride salt, corresponds with 18 mg NMF base, and that will be the strenght specified in the label following approval. The three studies were conducted in Europe and enrolled about 2,000 individuals with alcohol dependence. Medical advice and support to enhance motivation and adherence were included in all treatment arms in the studies. No abstinence treatment goal was imposed and abstinence was not required when entering the study. Mann et al. 2013. Biol Psychiatry 73(8) 706-713 Gual et al. 2013. Eur Neuropsychopharmacol 23(11) 1432-42 Wim van den Brink et al. 2014. J Psychopharmacol Wim van den Brink et al. 2013. Alcohol and Alcoholism. 1–9

Pharmaco Economic analysis Objective: To show nalmefene is cost-effective Treatment alternatives: Nalmefene + psychosocial support Psychosocial support alone Perspective: Healthcare system Time horizon: 1 year: period covered by RCTs 5 years Population: nalmefene indication as informed by phase III clinical programme

General concept of the model Decrease costs Reduction of alcohol intake Reduction of alcohol-attributable harms and mortality Increase QALYs Severe morbidities and injuries considered: Transport injuries Injuries other than transport Ischaemic heart disease Ischaemic stroke Liver cirrhosis Pancreatitis lower respiratory infections Quality-Adjusted Life Year (QALY) QALY=patient quality of life * patient survival

Clarification questions

Patient discontinuation Calculation of number of days taking therapy Application of utility in the model Proportion who receive care at a specialist level Real world discussion of relapse rate

Final recommendation

Questions….