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COULON Marie MASCRET Alexandra POMARET Anne-Laure RASOLON Norontsoa Master 2 « Réglementation du médicament dans l’Union Européenne » What solutions for weightmanagement drugs? Facts, futur of regulatory and price for these drugs January 31st, 2012 1 FACTS 2 PLAN • Obesity in general • Overview of actual and further weightmanagement drugs • Evolution of EMA & FDA guidelines • How can we evaluate the price of the new weight-management drugs? 3 Obesity : key facts IN 2008 OBESITY HAS DOUBLED SINCE 1980 5TH LEADING RISK FOR GLOBAL DEATHS 2.8 million people die each year from overweight/obesity • 1.5 billion adult people in overweight • 43 million children under 5 in overweight • 500 million people obese DEVELOPMENT OF OBESITY IN LOW- / MIDDLE-INCOME COUNTRIES 4 Obesity • State of excess body fat Impairment of health • Defined by the Body Mass Index BMI = 18.5 Thiness Normal range Weight (kg) Height² (m) 25 30 Over weight 40 Obesity Morbid obesity • BMI : age and gender specific for children 5 What is “morbid obesity”? • BMI > 40 • US NIH definition : – Being 50-100 % above one's ideal body weight – Being 100 pounds above one's ideal body weight Thiness BMI = 17 Morbid obesity BMI = 50 SONG A.Y., RUBIN J.P. an al. Body Image and Quality of Life in Post Massive Weight Loss Body Contouring Patients. Obesity, 2006, vol.14, n°9, p.1226-6 1236. Available at < http://www.nature.com/oby/journal/v14/n9/pdf/oby2006187a.pdf > Obesity : a « chronical condition » A result of interaction between several factors • • • • Genetic Metabolic Environmental Behavourial A long-term therapy • Induce weight loss • Maintain weight loss 7 What are the causes of obesity? INCREASE IN INTAKE ENERGY-DENSE FOODS High in fat, salt and sugar DECREASE IN PHYSICAL ACTIVITY Sedentarization, modes of transportation... 8 Obesity : risks for health • Risks increase with severity of obesity • Major risk factors for chronic diseases Insulin resistance Cardiovascular diseases Type 2 diabetes mellitus Angina pectoris Veinous thromboses Pulmonary embolism Hyper lipidaemia Hypertension Impaired quality of life for obese patients 9 Hazard ratio for death and BMI in women CI = 95% Thiness Normal range Over weight Obesity Morbid obesity BERRINGTON DE GONZALES A., PHIL D., HARTGE P. and al. BMI and mortality among 1.46 million white adults. New England Journal of 10 Medicine. 2010; 363 : 2211-9 Hazard ratio for death and BMI in men CI = 95% Thiness Normal range Over weight Obesity Morbid obesity BERRINGTON DE GONZALES A., PHIL D., HARTGE P. and al. BMI and mortality among 1.46 million white adults. New England Journal of 11 Medicine. 2010; 363 : 2211-9 How can obesity be reduced? NON PHARMACOLOGICAL OPTIONS • Limit energy intake from total fat and sugar • Increase consumption of fruits and vegetables • Make regular physical activity Changes in behaviour PHARMACOLOGICAL OPTIONS • Only if non pharmacological options are not sufficient • Central acting anorectic agents • Drugs that inhibit the absorption of nutrients from the gastro-intestinal tract BARIATRIC SURGERY • Adjustable gastric band • Roux-en-Y gastric bypass • Vertical sleeve gastrectomy • Biliopancreatic diversion with a duodenal switch 12 PLAN • Obesity in general • Overview of actual and further weightmanagement drugs • Evolution of EMA & FDA guidelines • How can we evaluate the price of the new weight-management drugs? 13 ACOMPLIA® 14 ACOMPLIA® Selective cannabinoid-1 receptor (CB1) antagonist First-in-class Rimonabant 20mg Act in brain and peripheral tissues (including adipocytes) Affects energy balance, glucose and lipid metabolism and body weight 15 Discovery of the endocannabinoid system Cannabis sativa has been used for medical purpose, and as a drug of abuse, for 4000 years • The effects of low doses : feelings of “high”, relaxation, reduced anxiety… • A well-known effect of cannabis is an increase in appetite Only in the middle of the 20th century its constituents were identified : CB1 receptors on GABA neurons in pre synaptic, involving in the reward system • Chemical characterization of Δ9-THC, • Receptor CB1 responsible for the brain effects of cannabis, • Endogenous cannabinoidlike substances, • Enzymes for synthesis and hydrolysis • GABA : inhibition of reward system • Dopamine : activation of reward system Activation of receptors CB1 decrease of GABA release activation of reward system 16 Location of CB1 receptors in CNS Ioannides-Demos LL, Piccenna L, McNeil JJ., ”Pharmacotherapies for obesity: past, current, and future therapies”, Journal of Obesity 2011 ; 2011:179674. Epub 2010 Dec 12. 17 Rimonabant • Also found to be effective in smoking cessation • STRATUS : Studies with “Rimonabant and Tobacco Use Program” – To use rimonabant directly to aid in smoking cessation – To help preventing weight gain in former smokers – Safety issues : increase anxiety or depressive symptoms Effective for both uses • FDA – Without additional studies rimonabant could not be approved for smoking cessation therapy 18 In obesity and overweight 19 2002 : Clinical trials Four phase 3 clinical studies • RIO Europe, RIO Lipids, RIO Diabetes, and RIO North America Primary endpoints • Weight loss • Weight maintenance over a period of 1 year RIO Rimonabant In Obesity Secondary endpoints Pertinent exclusion criteria • Hypertension • TG levels, HDL-C • Quality of life • Glucose tolerance • Presence of any clinically significant neurological or psychiatric disease • History of severe depression 20 Good results in clinical trials… Després JP, Golay A, Sjöström L, ” Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia”, New England 21 Journal of Medicine, 2005 Nov 17;353(20):2121-34 … With adverses effects Gastrointestinal • Vomiting • Diarrhoea • Nausea 9% of rimonabant 20mg treated subjects vs. 5% of placebo treated subjects Psychiatric • Depressive disorders • Mood alterations with depressive symptoms • Anxiety Neurological events • Headache • Dizziness 22 ACOMPLIA® history in the EU June 2006 • Marketing Authorization in EU by centralised procedure • Market access in France • Under medical prescription • Refundable by primary health care insurance for March 2007 obese patients 23 Pharmacovigilance system Risk management plan • Databases, disease registry in UK • Customer Care program : used in patients at risk for health reason while avoiding use for cosmetic reasons • Monitoring rimonabant prescriptions • Further clinical trials • Special reporting in PSURs 24 • Contraindication added in SmPC: Ongoing major depressive illness and/or ongoing antidepressive treatment July 2007 June 2008 • CHMP meeting : uncertainties with the benefit/risk of Acomplia® • CHMP requested the MAH to submit further analyses on the above-mentioned safety concerns, the duration of treatment and potential subgroups that may be more likely to respond to the treatment October 2008 • The European Commission initiated a procedure under Article 20 of Regulation (EC) No 726/2004 • Requested the CHMP to assess the above concerns and its impact on the risk/benefit balance for Acomplia, and to give its opinion on measures necessary to ensure the safe and effective use of Acomplia 25 Assessment by CHMP 3rd PSUR, March 2008 • Reporting rate for depressive disorders had increased markedly during the last 6-month period compared to the first 1-year period of marketing (24 cases per 10,000 treated patients versus 13) • Aggressive behaviour, sleep disorders • The suicide cases reported in the ongoing clinical trials are of serious concern Results of the STRADIVARIUS trial (JAMA, April 2008) • Absolute reporting rate of psychiatric adverse events was higher compared to previous studies (43.4% vs 28.4%, p<0.001 for rimonabant and placebo, respectively) • Benefit of the weight reduction would be more limited with this short-term use of the product (compared to initials clinical trials) • Benefit/risk balance for rimonabant is considered as negative 26 November 2008 December 2008 • Marketing of Acomplia was suspended in all the Member States • Sanofi notified the European Commission of its decision to voluntarily withdraw its MA • No additional clinical data will be available to lift the suspension of the MA for Acomplia following its decision to discontinue the ongoing rimonabant clinical development program in all indications • European Commission issued a decision to withdraw the MA for Acomplia Janvier 2009 27 ZIMULTI® history in the US April 2005 February 2006 • A New Drug Application (NDA) was submitted to FDA • FDA sent Sanofi-Aventis an approvable letter with request Request • Additional data and analyses to more precisely characterize the potential drug-related adverse events • Estimate the effect size of rimonabant versus placebo on the above mentioned safety outcomes across multiple studies in the overall population, and especially in the referral population consisting of the obese and obese diabetic populations in phase 2 and phase 3 clinical trials 28 October 2006 • Sanofi-Aventis submitted a complete response to the NDA Conclusions •The incidence of suicidality – specifically suicidal ideation – was higher for 20 mg rimonabant compared to placebo •Similarly, the incidence of psychiatric adverse events, neurological adverse events and seizures were consistently higher for 20 mg rimonabant compared to placebo • The FDA Endocrinologic and Metabolic Drugs Advisory Committee unanimously voted not to recommend June 2007 approval of Rimonabant 29 SIBUTRAMINE 30 Sibutramine • Oral anorexiant • Similar mechanism like fenfluramine and dexfenfluramine • No adverse effects observed like primary pulmonary hypertension and valvular regurgitation • First study in diabetes type 2 31 Pharmacology Pre-synaptic neuron Neurotransmitters : Norepinephrine serotonin Post-synaptic neuron Sibutramine inhibit the reuptake of Serotonin and Norepinephrine SATIETY 32 Effects of Sibutramine SIBUTRAMINE Body weight Waist circumference Sympathomimetic activity LDL, TG HDL Blood Glucose, HbA1c Heart rate Blood pressure QT interval Cardiovascular outcomes?? 33 Clinical studies Primary endpoint : Weight loss 34 35 Meridia® (sibutramine hydrochloride monohydrate), Sponsor Briefing Document – EMDAC Meeting ,August 13th 2010 Clinical studies Secondary endpoints : Primary endpoint : Weight loss - Biochemical parameters of lipids: TG, LDL and HDL - Maintenance of weight loss with Sibutramine - Blood pressure 36 Meridia® (sibutramine hydrochloride monohydrate), Sponsor Briefing Document – EMDAC Meeting ,13 August 2010 37 Clinical studies Secondary endpoints : Primary endpoint : Weight loss Adverse events : - dry mouth, - anorexia, - insomnia, - constipation, - headache, - rhinitis - Biochemical parameters of lipids: TG, LDL and HDL - Maintenance of weight loss with Sibutramine - Blood pressure Cardiovascular diseases : - palpitations, - tachycardia, - vasodilatation, - blood pressure increase 38 SCOUT study • Target of the study : – Impact of long-term treatment with Sibutramine on death and the risk of developing cardiovascular events in a large group of overweight and obese patients with known or high risk of cardiovascular disease 39 SCOUT study 40 Meridia® (sibutramine hydrochloride monohydrate), Sponsor Briefing Document – EMDAC Meeting , August 13th 2010 SCOUT study : Results 41 Meridia® (sibutramine hydrochloride monohydrate), Sponsor Briefing Document – EMDAC Meeting , August 13th 2010 SCOUT study : Conclusions • Confirmation that sibutramine treatment promotes clinically relevant weight loss and maintenance of weight loss. • An increased risk of serious cardiovascular events (such as heart attack or stroke) in patients with known cardiovascular disease. • SCOUT validates the labeled contraindication for patients with a history of cardiovascular disease. • CHMP has concluded that the benefits of sibutramine do not outweigh its risks. 42 History in Europa 1999 • European Marketing Authorisation since 1999 June • Marketed in France : Sibutral® 10 or 15mg 2001 Feb • Suspension in Italy 2002 • European review June • January 2003 – March 2009 : SCOUT study (in Europe, Latin America, and Australia) 2002 July • France withdrawal 2007 Nov 2009 • The German medicines regulatory agency (BfArM) triggered a review under Article 107 of Directive 2001/83/EC. Aug • EMA : MA suspension 2010 43 History in USA 1997 Nov 2009 March 2010 • Marketed autorisation • Reductil®, Meridia® and Sibutrex® • Communication about an Ongoing Safety Review of Sibutramine, preliminary results of SCOUT study • FDA expected the full study report for SCOUT • Risk management plan for Meridia® : On the basis of the findings from August the SCOUT trial and the overall review of benefit/risk 2010 October 8th 2010 • MA suspended in US and Canada 44 ORLISTAT 45 Xenical® Belongs to a new class of pharmacological agents Potent, specific, irreversible inhibitor of pancreatic and gastric lipases Orlistat 120mg Covalently binding to a serine residue in the active site Indicated in conjunction with a mildly hypocaloric diet for the treatment of obese / overweight patients 46 Mechanism of action C. S. Elangbam, «Current Strategies in the Development of Anti-obesity Drugs and Their Safety Concerns», Vet Pathol 46:10–24 (2009) 47 Clinical trials Design • 1 or 2-year clinical trials • One 4-year clinical trial Secondary endpoints • Effects on obesity risk factors • LDL, HDL, Triglycerids, Diastolic, Insulin • Vitamin levels • Faecal fat excretion Primary endpoint • Weight loss Safety issues • Gastrointestinal • Abdominal pain/discomfort • Oily spotting from the rectum • Flatulence, Faecal urgency Faecal urgency 22.1% with orlistat 120 mg vs 6.7% with placebo 48 Good results for the primary endpoint J. S. Torgerson, J. Hauptman, M. N. Boldrin, L. Sjostrom, «XENical in the Prevention of Diabetes in Obese Subjects (XENDOS) Study », Diabetes Care 27:155–161, 2004 49 Scientific discussion Xenical®, EMA 50 Xenical® history in EU July 1998 September 1998 2003 July 2007 2008 • Marketing autorisation by centralized procedure by EMA • Market access in France • Medicine under prescription • Renewal of MA • Orlistat for sale without prescription • MA of Alli® (license to GSK) : Orlistat 60mg • Renewal of MA 51 Pharmacovigilance system Risk management plan for Alli® (Orlistat 60mg) • Close observation through routine pharmacovigilance system • No additional risk minimisation activities are required • Safety issues concerned : • Gastrointestinal disorders • Hypersensitivity events • Hypoglycaemia • Hepatobiliary disorders… 52 Safety problems in EU : hepatic toxicity • Between 1997 until January 2011 : 21 cases of suspected serious liver toxicity • 4 were cases of severe liver toxicity • 1 fatal case of hepatic failure, • 1 case of hepatic failure leading to liver transplantation, • 1 case of exacerbation of hepatitis • and 1 case of hepatitis. • Context of cumulative usage of these medicines in 38 million patients Xenical® • Between May 2007 and January 2011 : 9 reports of suspected severe liver injury • Some cases other possible explanations for liver injury were present and some cases provided insufficient information to allow assessment • Context of cumulative usage in 11 million patients Alli® 53 • Article 20 of Regulation (EC) 726/2004 • European review of the centrally authorised orlistat-containing medicines (Xenical® and Alli®) August 2011 • Initiated at the request of the European Commission September 2011 • Warning by Afssaps for Alli® and Xenical® • Risk of severes and rares liver injury under Orlistat • Most of liver injury are not severe Currently, re assessment of risk benefit of the 2 medicines by EMA 54 Xenical® history in US April 1999 February 2007 • Marketing Autorisation • MA of Alli® • Marketing status : OTC 55 Safety problems in US 1999 October 2008 • 32 reports of serious liver injury, including 6 cases of liver failure, in patients using orlistat were submitted to FDA’s March 2010 • FDA has approved a revised label to include new safety informations about cases of severe liver injury Currently • “The FDA’s analysis of these data is ongoing, and no definite association between liver injury and orlistat has been established at this time (…)” 56 Causal relationship ? Pharmacokinetic • Metabolism of orlistat occurs mainly within the gastrointestinal wall • Biliary concentrations of orlistat up to 43 ng/ml i.e. show that this drug is partially excreted in the bile and may be subject to enterohepatic cycling 57 Litterature • 1 clinical case (1999): The responsibility of orlistat in the acute liver injury as highly likely : • Other causes of acute hepatitis have been eliminated • The absence of stones in the gallbladder • The early recurrence of symptoms during the reintroduction of orlistat argues for the responsibility of the molecule Christos Christidis, Frédéric Mal, Brice Gayet, Catherine Guettier, Le Xenical® est-il hépatotoxique ?, Gastroentérologie Clinique et Biologique, 58 Vol 24, N° 3 - mai 2000, pp. 374-375 QNEXA® 59 Qnexa®: a combination of 2 previously approved products Phentermine Amphetamine: appetite suppresant (1/8 to 1/2 of marketed dose) Topiramate Anticonvulsivant (antiepileptic) :increase satiety due to decreased gastrointestinal motility (1/16 to 1/4 of marketed dose) Qnexa simultaneously addresses excessive apetite and high threshold for satiety. 60 Mechanism of action of amphetamine In the Brain: Outside the brain: • Release Adrenalin HUNGER FAT CardioV outcomes ? SAFETY Phentermine: An amphetamine Utilisation • short-term (usually interpreted as 'up to 12 weeks') to treat obesity, while following nonpharmacological approaches to weight loss such as healthy dieting and exercise History • 1959: Phentermine first received approval from the FDA as an appetite suppressing drug • 1997 : after 24 cases of heart valve disease in Fen-Phen users, fenfluramine and dexfenfluramine were voluntarily taken off the market at the request of the FDA. • Studies later proved that nearly 30% of people taking fenfluramine or dexfenfluramine had abnormal valve findings. The FDA did not ask manufacturers to remove phentermine from the market. • 2009: is the most prescribed weight-loss drug with approximately 6.1 million prescriptions written in 2009 62 Topiramate: an anticonvulsivant Clinical: topiramate GI motility energy expenditure Mechanism of action Caloric intake •Weight loss •Meaningful improvements in lipids, glycemic control, and blood pressure Birth defects ? SAFETY taste aversion Topiramate: an anticonvulsivant Utilisation • Used as an anticonvulsant to treat epilepsy in children and adults • Prevention of migraines • Used to counteract the weight gain associated with numerous antidepressants Authorization • Generic versions are available in Canada and these were approved by the Food and Drug Administration (FDA) in September 2006. • FDA approved for, and most frequently prescribed for, the prevention of migraines 64 Clinical studies: Phase III • Randomized, Double-blind, • Placebo-controlled, 3-arm, • Prospective trial • EQUIP study:1267 obeses with 1 or less comorbidites • CONQUER study:2,487 overweight and obese patients with more than 2 comorbidities as high blood pressure, high cholesterol or type 2 diabetes •Waist circumference •EQUIP study: •Systolic and diastolic blood pressure (BP), •Fasting glucose, • Lipid measures. •CONQUER study: •Weight loss •Proportion of patients achieving at least 10% weight loss • Once-a-day treatment with low-dose Qnexa, full-dose Qnexa or placebo • Patients were asked to follow a hypocaloric diet representing a 500calorie/day deficit and advised to implement a simple lifestyle modification program Design Treatment 2nd endpoints 1st endpoints • % changes in bodyweight ² • Proportion of patients achieving at least 5% weight loss 65 EQUIP study CONQUER study Adverses effects Dry mouth Tingling Constipation Not serious adverses effects Phase 3 extension: randomized, doublebind, placebo-controlled,SEQUEL-study • 866 patients of CONQUER study, 52wk study FDA approval history • Submit Qnexa NDA: 28/12/2009: 5 security questions: 28/10/2010: • Complete Response Letter FDA: • the FDA requested a comprehensive assessment of topiramate's and phentermine/topiramate's teratogenic potential • the FDA asked VIVUS to provide evidence that the elevation in heart rate associated with phentermine/topiramate does not increase the risk for major adverse cardiovascular events Suicidal ideation & depression Memory troubles Acid accumulation in organic liquids Increase of heart rate & relation to CV events Teratogenic potentiel • Resubmit Qnexa NDA to the FDA: for the treatment of obesity, including weight loss and maintenance of weight loss for obese patients (BMI > 30 kg/m2), or overweight patients (BMI > 27 kg/m2) with weight-related co-morbidities such as hypertension, type 2 17/10/2011: diabetes, dyslipidemia, or central adiposity (abdominal obesity). 3/11/2011: • Agree of FDA to review Qnexa NDA • The proposed labeling includes a contraindication for women of childbearing potential. • The resubmission also includes a proposed Risk Evaluation and Mitigation Strategy (REMS). • Review of Qnexa NDA to treat obesity on 02/02/2012 23/12/2011: • The company has been asked to remove the Qnexa contraindication for women of childbearing potential contained in the proposed label. 09/01/2012: • Qnexa would remain contraindicated for women who are pregnant To sum up... • Efficacy on the weight loss outcome • Safety problems discovered MOLECULE SAFETY PROBLEM ACOMPLIA® Psychiatric adverse events SIBUTRAL® Cardiovascular adverse events XENICAL® / ALLI® Hepatotoxicity QNEXA® CONTRAVE® Cardiovascular adverse events 73 PLAN • Obesity in general • Overview of actual and further weightmanagement drugs • Evolution of EMA & FDA guidelines • How can we evaluate the price of the new weight-management drugs? 74 EXAMPLE OF DIABETES MELLITUS 75 Diabetes mellitus • It is a serious disease that is rapidly assuming epidemic proportions. • Guideline requires sponsors to demonstrate that a new agent does not have an unacceptable cardiovascular risk. • To establish context, these are briefly reviewed before focusing on the new requierements themselves. 76 Context and evolution of regulation 2002 : Note for guidance 2007 : Press releases concerning Rosiglitazone 2008 : Concept paper 2011 : Guideline 77 2002 : Note for guidance • Cardiovascular disease is the main cause of morbidity and mortality in Type 2 diabetes. Any new medicinal product in this area must have well documented data regarding effects on blood pressure, hyperlipidaemia and clinical indicators of cardiac function. 78 2007 : Press releases concerning Rosiglitazone • Rosiglitazone : – first approved in 1999 in the United States as Avandia® – in 2000 in the European Union as Avandia® – also authorised in the EU since 2003 as Avandamet® (fixed dose combination with metformin) – since 2006 as Avaglim® (fixed dose combination with glimepiride) • Rosiglitazone is a member of the thiazolidinedione class of antidiabetic agents 79 2007 : Press releases concerning Rosiglitazone • In 2000 : rosiglitazone was containdicated in patients with a history of cardiac failure CHMP has kept rosiglitazone under close surveillance for cardiovascular effects • In 2007 : benefits > risks • On June 28th, after the 2010 renewal opinion, new data emerged, suggesting that rosiglitazone may be linked to an increased risk of heart problems • September 2010 : suspension of rosiglitazone by EMA 80 2008 : Concept paper • Relative to the design of efficacy studies and to safety evaluation in the following situations : – Studies in children – Cardiovascular outcomes studies – Combination studies with insulin – Prevention of diabetes indication • Consistent approach in development and assessment of these products 81 2011 : Guideline • Guideline in clinical investigation of medicinal products in the treatment of diabetes mellitus. • September 16th, 2011 : Adoption by CHMP for release for consultation. • November 18th, 2011 : End of consultation. 82 Efficacy (1) • Primary efficacy endpoint : – A favourable effect on blood glucose control with glycohaemoglobin (HbA1c) measure (normal value <6%) – All drugs respond to this criteria 83 Efficacy (2) • Secondary efficacy endpoint : – Long term complications include macrovascular (coronary, cerebrovascular, and peripheral vascular diseases) and microvascular complications (retinopathy, nephropathy, and partly neuropathy). – A new glucose-lowering agent should preferably show a neutral or beneficial effect on parameters associated with cardiovascular risk (e.g. body weight, blood pressure, lipid levels). 84 Evolutions of efficacy • PK pop => quantify inter/intra individual variability of cinetic and identify sources of variability • More studies in long term complications • To show a neutral or beneficial effect on parameters associated with cardiovascular risk 85 Evolutions of safety • Assessment of cardiovascular safety • Sufficient information supporting the lack of a drug-induced excess cardiovascular risk 86 WEIGHT MANAGEMENT DRUGS 87 1996 1997 • FDA : Guidance for the clinical evaluation of weight-control drugs • Rimonabant was developed in accordance with the FDA’s 1996 draft Guidance for the Clinical Evaluation of Weight-Control Drugs • EMEA : Note for guidance 1998 • EU Market autorisation for Orlistat • 2003 & 2008 renewals • 2011 warning of AFSSAPS 1999 • MA Sibutramine by FDA • EU Market authorization for Sibutramine • 2010 suspended 2006 • EU Market autorisation for Rimonabant • 2008 suspended 88 1997 •EMEA : Note for guidance • Note for guidance on clinical investigation of drugs used in weight control (EU). • The goal of treatment of obesity is to prevent associated morbidity and mortality. 89 1996 2007 SECONDARY ENDPOINT : PRIMARY ENDPOINT : Weight loss Biochemical parameters of lipid and glucose metabolism as well as blood pressure, cardiac function, sleep apnoea episodes and quality of life SAFETY ASPECTS : - Characterization of adverse drug reactions in relation to duration of treatment, dose regimen and initial body weight or pattern of obesity. - No deleterious effects of cardiovascular risks factors. - To assess potential adverse effects reactions that are characteristic of the class of drug being investigated 90 2008 • New regulation in EU • Guideline on clinical evaluation of medicinal products used in weight control. • July 2005 – April 2006 : draft agreed by the efficacy working party. • November 15th, 2007 : adoption by CHMP. • May 31th, 2008 : date for coming into effect. 91 Innovations of 2007 (EU) … PRIMARY ENDPOINT : Demonstration of a clinically significant degree of weight loss of at least 10% of baseline weight SECONDARY ENDPOINTS : – Waist hip ratio, ultrasensitive Creactive protein, – The maintenance of weight loss or the prevention of weight regain SAFETY ASPECTS : - Interaction if patients receive multiple therapies, it increases probability of interaction 92 Comparison of the FDA and EMA regulatory guidelines 93 Primary efficacy endpoint FDA EMA Weight loss : Weight loss : After 1 year of treatment the difference in mean weight loss between the activeproduct and placebo-treated groups is: • at least 5% • the difference is clinically significant; or the proportion of subjects who lose ≥5% of baseline body weight in the active-product group is: • at least 35% • approximately double the proportion in the placebotreated group • the difference is statistically significant Demonstration of a clinically significant degree of weight loss of at least 10% of baseline weight, which is also at least 5% greater than placebo after a 12-month period 94 Sample population FDA BMI ≥ 30 kg/m2 or BMI ≥ 27 kg/m2 if accompanied by comorbidities, such as type 2 diabetes mellitus, hypertension, dyslipidemia, sleep apnoea and cardiovascular disease EMA BMI ≥ 30 kg/m2 or BMI ≥ 25 kg/m2 plus associated or secondary effects of obesity, such as hypertension, hyperlipidaemia, diabetes mellitus or impaired glucose tolerance/impaired fasting glucose or cardiovascular disease 95 Efficacy variables FDA EMA Centrally acting drugs: must evaluate neuropsychiatric function No deleterious effects on the cardiovascular system 96 Secondary efficacy endpoints FDA EMA Blood pressure Pulse rate Lipids Fasting glucose Insulin Ultrasensitive C-reactive protein Sleep apnoea episodes Mechanical joint distress Infertility Psychosocial aspects 97 Future • For these drugs, the primary endpoint is the weight loss. • Why couldn’t we chose another endpoint like a decrease of cardiovascular disease in special population? • Or a primary endpoint like treatment of diabetes mellitus, but in taken notice of past stories, the secondary criteria would be obesity. 98 Future • Obesity: an important need, few pharmacological options • Drug using for new pharmacological targets in development 99 100 Future • Obesity: an important need, few pharmacological options • Drug using for new pharmacological targets in development • Companies waiting for the new guidelines 101 PLAN • Obesity in general • Overview of actual and further weightmanagement drugs • Evolution of EMA & FDA guidelines • How can we evaluate the price of the new weight-management drugs? 102 FACTS • Medical burden of obesity in the US ≈ $147 billion per year (CDC) • Direct & indirect costs of obesity • Correlation between BMI and co-morbidity factors 103 Weight loss can be successful without weight-management drugs Patients with at least one cardiovascular risk factor Weight loss followed by - Patient himself - In person support - Remote support (telephone, e-mail...) APPEL L.J., CLARJ M.J. and al. Comparative effectiveness of weight-loss onterventions in clinical pratice. The New England Journal of Medicine. 2011, vol.365, n°21, p.1959-1968 Obese patients cost more for healthcare system, but for a shorter period than the healthy people Values from 2003 Impact ++ on medication spendings between 30-40 years old Affects the distribution of costs over various healthcare segments RAPPANGE D.R., BROUWER W.B.F., HOOGENVEEN R.T., VAN BAAL P.H.M. Healthcare cost and obesity prevention. Drug costs and other sector-specific consequences. Pharmacoeconomics. 2009; 27 (12): 1031-1044 105 Difference in lifetime costs between the “healthyliving” and obese cohorts, categorized by healthcare sectors (values from 2003) Until 50 years-old Obesity prevention : -Saving costs in all sectors -Lower disease incidence when healthy so less costs -Saving in medication : less drugs against diabetes, oesteo arthritis... After 50 years-old Increase +++ in long-term care expenditure -Alzheimer disease ... -Just a little difference for medicines Savings on drugs for obesity-related diseases outweight the additional costs for other diseases in life-years gained 106 RAPPANGE D.R., BROUWER W.B.F., HOOGENVEEN R.T., VAN BAAL P.H.M. Healthcare cost and obesity prevention. Drug costs and other sector-specific consequences. Pharmacoeconomics. 2009; 27 (12): 1031-1044 How can we find a solution? • 1 Time • Intake of vitamins all life-long • Diversion of the system • Can be stopped • No efficacy • SAEs • Return on Investment for the company Bariatric surgery Weightmanagement drugs Find a price cheaper than surgery 107 And avoid medical turism to lose weight ... 108 Thank you for your attention. 109