Transcript Diapositive 1 - Moodle Lille 2

Un médicament est:
1/ un Produit
2/ une Documentation
et un Engagement
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1/Un médicament est un « produit »
-A-Principe actif
-B-Formulation galénique
-C-Emballage
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2/ Une « documentation »
Cette documentation :
 est établie au cours des différentes phases d’essais
cliniques
 permet d’obtenir l’autorisation de mise sur le marché
 sert de base à l’information du prescripteur
 sert à démontrer aux organismes payeurs le service
médical rendu et son amélioration.
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Drug substance (Active pharmaceutical ingredient) API
Drug product (Dosage form; Finished product)
Le Principe actif / API
1. Substance ayant un effet pharmacologique susceptible
de se traduire par une application thérapeutique
2. Substance pouvant être produite sous forme pure à
grande échelle, de manière reproductible et
économiquement viable
3. Substance susceptible d’être dosée ainsi que ses
impuretés, ses produits de dégradation et ses
métabolites
4. Toxique potentiel
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Global excipients market:
USD 5 billion in 2011
Global overall API market:
US$108 billion in 2010,
Total excipient + API:
US$ 113 billion
High Potency Active Pharmaceutical Ingredients: US$ 9 billion in 2011,
Global pharmaceutical market:
US$ 956 billion
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The U.S. is the largest market for API; followed by Japan and Germany in 2010.
Menaces sur la sécurité de nos médicaments
Par Stéphanie Benz - publié le 08/11/2012 à 11:01
Les principes actifs, ces molécules au coeur de nos pilules et de nos sirops, sont
massivement importés d'Asie. Les risques de pénurie, de fraude ou de mauvaise
qualité rendent alarmante cette dépendance stratégique.
SÉCURITÉ DES MÉDICAMENTS - Près de 80% (en volume) des molécules qui
sont au cœur de nos médicaments viennent d'Asie.
Principe actif
Classe
pharmaceutique
Boîtes
vendues en
2010 (France)
Producteurs
en Europe*
Producteurs
hors
d'Europe*
Paracétamol
Analgésiques
265 millions
0%
100 %
Amoxicilline
Antiobiotiques
38 millions
39 %
61 %
21 millions
18 %
82 %
0%
100 %
13 millions
30 %
70 %
2 millions
0%
100 %
Metformine
Ibuprofène
Oméprazole
Médicaments du
diabète
Anti-inflammatoires 18 millions
troubles de l'acidité
gastrique
Doxycycline
Antibiotiques
Menaces sur la sécurité de nos médicaments
Publié dans l’expansion le 08/11/2012 à 11:01
- Stéphanie Benz -
(1) includes cost of goods sold without cost for raw material;
(2) assessment of direct personnel cost reduction from approximately 60 to 6 € total salary dollars
(tsd)/FTE
(3) assessment of direct personnel cost reduction from approximately 6 to 3 € tsd/FTE
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Why Asia? Cost Comparison: West vs. Asia
Rock Bottom FTEs....
DMF Development Costs
250
1000
200
750
800
150
100
K US$
150
80
70
600
400
50
200
50
200
0
USA
EU
Eastern
Europe
India
0
China
EU
India
API Prices
5000
4000
Euro/ Kg
K US$/ply
200
4000
3000
2000
2000
800
1000
0
EU Producer
India
China
Source: Arthur D. Little
Drug Product
A finished dosage form, for example, tablet, capsule,
or solution that contains a drug substance, generally,
but not necessarily, in association with one or more
other ingredients.”
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API : Active Pharmaceutical Ingredient
(Principe Actif)
accounts for the expenses of raw materials, reagents and solvents among others
COGS : Cost of Goods
Accounts for API / Formulation / Packaging
Overall manufacturing price of the formulated drug
in-house value of the product at the stage of readiness for delivery to customers
the contribution of the API is 10–12% at its maximum value and 0.5% at its minimum.
API : Active Pharmaceutical Ingredient (Principe Actif):
accounts for the expenses of raw materials, reagents and solvents among others
COGS : Cost of Goods Sold (couts de Production)
Accounts for API / Formulation / Packaging
The share of the API in the COGS varies substantially for individual drugs:
from 5% to 40%
J Pharm Innov (2008) 3:30–40
La Thalidomide
Lèpre et Myélome multiple
"Average Wholesale Price" (AWP)
Prix de gros moyen 2008
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Entre 1998 et 2004, Celgene a augmenté le prix de la thalidomide de
$6.00 à $29.00 pour une gélule de 50 mg
Cout par kg = 580 000 $ / kg
En 2008, la thalidomide est vendue au prix de
$ 107 pour une gélule de 50 mg
$ 207 pour une gélule de 200 mg
Cout par kg = 2 140 000 $ / kg (gélule de 50 mg)
Le prix d’une gélule de 100 mg de thalidomide au Brésil est $0.07.
 Cout par kg = 700 $ / kg
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R&D and return on stocks for big Pharmas and profitable Biotechs
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the rate of return on stock is equal to the increase in the share price, plus the dividend yield
Synthèse semi industrielle de la thalidomide
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Synthèse semi-industrielle de la thalidomide
The procedure can easily be used to prepare thalidomide at the 100-g
scale in the laboratory, and it was successfully scaled up to the
multikilogram scale.
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US$ 550 / kg
US$ 250 / kg
US$ 2000 / kg
US$ 1000 / kg
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US$ 550 / kg
MW = 219
US$ 250 / kg
MW = 146
US$ 2000 / kg
MW = 162
US$ 1000 / kg
MW = 137
Thalidomide MW = 258
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US$ 55 / mole
US$ 50 / mole
Cout total / mole:
55 + 50 + 224 + 122 =
US$ 451
US$ 224 / mole
US$ 122 / mole
Thalidomide MW = 258
Reagents Cost / kg ~ 1800 US$
25
Synthèse industrielle de la thalidomide
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US$ 750 / tonne
MW: 148
US$ 900 / tonne
MW: 147
US $1000 / tonne
Thalidomide MW = 258
MW: 60
MW: 102
US $240 / tonne
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Synthèse industrielle de la thalidomide
Cout des produits de départ
148 x 750 $ x 10-6 = 0,11 $
147 x 900 $ x 10-6 = 0,13 $
102 x 1000$ x 10-6 = 0.1 $
60 x 240 $ x 10-6 = 0.01 $
Total réactifs
= 0.35 $ / mole
Thalidomide MW = 258  ~ 1.4 US$ par kg
Cout de la fabrication?
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Please call 1-888-4Celgene (1-888-423-5436)
to register for the S.T.E.P.S.™ program.
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Physician visit
S.T.E.P.S.TM
Process of obtaining
thalidomide…
Receive an authorization #
Physician phone survey
• Consent signed
• Mandatory contraceptive
counseling
• Pregnancy testing
• Educational video
Prescription provided to a
pharmacist registered with
S.T.E.P.S.TM
for prescription
Celgene Interactive Voice Response
System
Patient phone survey
Pharmacist phones Celgene gives
authorization #, receives dispensing
authorization
Patient receives
Thalidomid®30
TERATOLOGY THE JOURNAL OF ABNORMAL DEVELOPMENT 54:273-277
(1996)
Thalidomide, a Current
Teratogen in South America
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where leprosy is common, the thalidomide-children
are more frequent
Brazil consumes only
400 kg of the 1200 kg
thalidomide produced in
the country each year.
Two thirds of the drug is
either exported - legal or
smuggled - or sold on
the Brazilian Black
Market.
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La Simvastatine
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The industrial process to produce Simvastatin from Lovastatin is a Merck Sharp
and Dhome modified method consisting in eight steps
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36
overall yield from 1 to 2 :49%.
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Simvastatin
10 mg
50 Comprimés
€76
Simvastatin
20 mg
50 Comprimés
€84
Simvastatin
10 mg
70 Comprimés
€93
Simvastatin
20 mg
70 Comprimés
€101
Simvastatin
10 mg
100 Comprimés
€118
Simvastatin
20 mg
100 Comprimés
€127
Prix par gramme selon le packaging:
50 cps à 10 mg
76 € / 500 mg = 152 €
100 cps à 20 mg
127 € / 2000 mg = 63,5 €
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Prix par kilo de principe actif:
Standard:
EP5
Productivity:
5 MT/month
Unit Price/Payment:
USD 430 /kg - China
USD 4780/ kg - India
Company:
Prix par gramme:
Prix par kg de PA dans le médicament:
76 € / 500 mg = 152 €
76 € / 500 mg = 152 000 €
127 € / 2000 mg = 63,5 €
127 € / 2000 mg = 63 500 €
Shanghai Jiangbei
Pharmaceutical Co.,
Ltd.
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336 x 20 = 6,720 g  8$ / g 8000$/kg
Effect of generic competition between 2000 and 2001 of triple combination
therapy made up of stavudine (d4T)+lamivudine (3TC)+nevirapine (NVP) 30mg+ 150mg+ 200mg.
Price per patient per year
stavudine (d4T) + lamivudine (3TC) + nevirapine deux fois par jour
Dosage
Prix de l’API / Kg
stavudine (d4T)
30mg
370 $
lamivudine
(3TC)
150mg
160 $
nevirapine
(NVP)
200mg
150 $
Quel est le cout annuel en API?
Cout de l’API / 38 Kg
stavudine (d4T)
3Kg
370 x 3 = 1110 $
lamivudine (3TC)
15Kg
160 x 15 = 2400 $
nevirapine (NVP)
20Kg
150 x 20 = 3000 $
total
38Kg
6510 $
Prix au Kg
1Kg
6510 / 38 = 171,3 $
API dans le
traitement annuel
(30 + 150 +
47,4 $
200) x 2 x 365 =
0,277 Kg
Evolution of the lowest price quoted for developing countries since 2005:
Since 2005, the originator price has decreased by 32% whereas the generic
price has dropped by 61%.
Pharmaceutical Value Chain
26%
3%
100%
R&D
Overhead 2%
Mnfctr
17%
Tax 7%
4%
Formulation
production
(excipients,
mnfctr, packing)
Corporate
overhead,
sales &
marketing
Raw
materials
41%
Cost of active
pharmaceutical
ingredient (API)
Additional cost for
formulation manufacturer
Cost of Final
Product
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Targets for Savings
Large reductions at the API level:
• Sourcing to low-cost API suppliers,
• Driving efficiency through scale,
• Reducing gross margin
Overhead 2%
Mnfctr
17%
Tax 7%
26%
Cost of active
pharmaceutical
ingredient (API)
100%
R&D
4%
Formulation
production
(excipients,
mnfctr, packing)
Raw
materials
41%
3%
Corporate
overhead,
sales &
marketing
Reductions in formulation costs:
• Cross-subsidization of overhead
• Reductions in margin
• Scale-based savings (very small)
Additional cost for
formulation manufacturer
Cost of Final
Product
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Tales from the Pharm: The $15000 delivery error :: OnThePharm
Today before my shift I got a phonecall asking me to stop by one of
our other stores to pick a mis-delivery of Enbrel that had been
delivered the day before
Today before my shift I got a phonecall asking me to stop by one of our
other stores to pick a mis-delivery of Enbrel that had been delivered the
day before.
Lucky for us, the pharmacist over there opened the box and saw what it
was and was able to refrigerate it before it got warm.
What you see in the picture below has an AWP of…
$15,151.48
The average wholesale price (AWP) is a prescriptions drug term referring to the average price at which
wholesalers sell drugs to physicians, and pharmacies,.
« I wonder if armored car drivers often make delivery errors on this scale?
And if their deliveries have to be stored at a specific temperature?
To give you an idea of how valuable this is, the entire volume of liquid here
is 56mL.
Assuming that it has the density of water, that means there’s 56g of fluid,
which is a hair under 2 ounces.
Right now, Gold is sitting at $480 an ounce.
Enbrel has a value of $7500 an ounce ($242.000 a kilo). »
ENBREL is available as 25 mg/0.5 mL or 50 mg/mL prefilled syringes (2%)
PRIX au kilo:
Etanercept API:
Or:
Euro € 5.835.800
Euro €
30.600
Enbrel Production Problems
2002: “It's no secret that Immunex can't make enough of its Enbrel
etanercept rheumatoid arthritis drug to meet demand”
The main patent on Enbrel in the US was set to expire in October 2012, and in Europe in
February 2015. But a new patent could prevent biosimilar competition in the US until 22
November 2028. By that time, Enbrel will have been on the market for 30 years.
39 NMEs were approved by the FDA in 2012
the highest in more than a decade — 63% higher than the average
of 24 NMEs from 2003 through 2011.
20 were first in class,
22 received Fast Track designation, Priority Review and/or
accelerated approval.
The total cost for one course of treatment with the 32 NME approved in
2012 and having disclosed prices would be about $2.4 million.
Research and Development Process
ONE
FDAAPPROVED
DRUG
5
PHASE 1
PHASE 2
PHASE 3
Number of Volunteers
20-100
LARGE
SCALE
MFG
100-500
1000-5000
6-7 YEARS
SOURCE: PhRMA 2008, Stages of Drug Development Process and attrition rate of compounds
as they travel through the drug development process over time.
0.5-2
YEARS
PHASE 4: POST MARKETING SURVEILLANCE
250
3-6 YEARS
FDA
REVIEW
CLINICAL TRIALS
NDA SUBMITTED TO FDA
5,000-10,000
COMPOUNDS
PRE
CLINICAL
IND SUBMITTED TO FDA
PRE-DISCOVERY
DRUG
DISCOVERY
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R&D cost
Treatment Cost per patient =
Number of patients
10.000.000 patients
+ Cost of Production + MG&A
For one Treatment
1000 millions
= 100 $
Blockbuster Model
= 40.000 $
Orphan Drug Model
10.000.000
400 millions $
10.000 patients
10.000
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