Transcript Obesity - Moodle Lille 2

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
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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