1 Un médicament est: 1/ un Produit 2/ une Documentation et un Engagement

2 1/Un médicament est un « produit » -A-Principe actif -B-Formulation galénique -C-Emballage

Drug product (Dosage form; Finished product) API: Active Pharmaceutical Ingredient

4 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.

5 1/Un médicament est un « produit » -A-Principe actif

6 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

Global pharmaceutical market: US$ 956 billion Global overall API market: US$108 billion in 2010 Part of High Potency API:US$ 9 billion in

Global pharmaceutical market: US$ 956 billion Global excipients market: USD 5 billion in

Global pharmaceutical market: US$ 956 billion Global overall API market: US$108 billion in 2010 Global excipients market: USD 5 billion in 2011 Total excipient + API:US$ 113 billion ~10 % 10

Principe actif Classe pharmaceutique Boîtes vendues en 2010 (France) Producteurs en Europe* Producteurs hors d'Europe* ParacétamolAnalgésiques265 millions0 %100 % AmoxicillineAntiobiotiques38 millions39 %61 % Metformine Médicaments du diabète 21 millions18 %82 % IbuprofèneAnti-inflammatoires18 millions0 %100 % Oméprazole troubles de l'acidité gastrique 13 millions30 %70 % Doxycycline Antibiotiques2 millions0 %100 % Menaces sur la sécurité de nos médicaments - Stéphanie Benz - Publié dans l’expansion le 08/11/2012

(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 12

15 1/Un médicament est un « produit » -A-Principe actif -B-Formulation galénique -C-Emballage

16 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.”

Cost of goods sold (COGS) also referred to as materials and production cost. Cost of goods sold is an aggregate figure that includes all costs incurred in producing the goods including write-offs from plant, property and equipment, raw materials, inventory, etc.

J Pharm Innov (2008) 3:30–40

"Everything we want to know about the cost of Active Pharmaceutical Ingredient (API) and the corresponding tablet but are afraid to ask."

Modafinil cost for the production of 1 pound of API

Modafinil cost for the production of Xxx tablets corresponding to 1 pound of API

Finished tablet cost: $ 0.05 Average wholesale selling price of the 200 milligram tablet Modafinil is $10.58 Pharmaceutical companies sell the tablets to other companies for further sale to consumers. In 2010, 200 milligram Provigil/Modafinil tablets sold for about $15.00-$16.00 per tablet at a national drug chain. AWP: Prix ​​ de gros moyen

"Average Wholesale Price" (AWP) Prix de gros moyen La ThalidomideLèpre et Myélome multiple

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 = $ / 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 = $ / 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 27

the rate of return on stock is equal to the increase in the share price, plus the dividend yield R&D and return on stocks for big Pharmas and profitable Biotechs 28

Celgene Corporation (CELG)

Synthèse semi industrielle de la thalidomide 30

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. 31

US$ 550 / kgUS$ 250 / kg US$ 2000 / kg US$ 1000 / kg 32

US$ 550 / kg MW = 219 US$ 250 / kg MW = 146 US$ 2000 / kg MW = 162 US$ 1000 / kg MW = Thalidomide MW = 258

US$ 50 / mole US$ 55 / mole US$ 224 / mole US$ 122 / mole Cout total / mole: = US$ 451 Thalidomide MW = 258 Reagents Cost / kg ~ 1800 US$ 34

Synthèse industrielle de la thalidomide 35

US$ 750 / tonne US$ 900 / tonne US $240 / tonne US $1000 / tonne MW: 148 MW: 147 MW: 102 MW: 60 Thalidomide MW =

148 x 750 $ x = 0,11 $ 147 x 900 $ x = 0,13 $ 102 x 1000$ x = 0.1 $ 60 x 240 $ x = 0.01 $ Total réactifs = 0.35 $ / mole Thalidomide MW = 258  ~ 1.4 US$ par kg Synthèse industrielle de la thalidomide Cout des produits de départ Cout de la fabrication? 37

Please call Celgene ( ) to register for the S.T.E.P.S.™ program. 38

S.T.E.P.S. TM Process of obtaining thalidomide… Physician visit Consent signed Mandatory contraceptive counseling Pregnancy testing Educational video Prescription provided to a pharmacist registered with S.T.E.P.S. TM Physician phone survey Patient phone survey Pharmacist phones Celgene gives authorization #, receives dispensing authorization Receive an authorization # for prescription Celgene Interactive Voice Response System Patient receives Thalidomid ® 39

TERATOLOGY THE JOURNAL OF ABNORMAL DEVELOPMENT 54: (1996) Thalidomide, a Current Teratogen in South America 41

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. 42

43 La Simvastatine L’impact de génériques

The industrial process to produce Simvastatin from Lovastatin is a Merck Sharp and Dhome modified method consisting in eight steps 44

Simvastatin10 mg50 Comprimés €76 Simvastatin20 mg50 Comprimés €84 Simvastatin10 mg70 Comprimés €93 Simvastatin20 mg70 Comprimés €101 Simvastatin10 mg100 Comprimés €118 Simvastatin20 mg100 Comprimés €127 Prix par gramme selon le packaging: 50 cps à 10 mg76 € / 500 mg = 152 € 100 cps à 20 mg127 € / 2000 mg  63,5 €/g

46 Prix par gramme: 76 € / 500 mg = 152 € 127 € / 2000 mg = 63,5 € Prix par kg de PA dans le médicament: 76 € / 500 mg = € 127 € / 2000 mg = € Standard:EP5 Productivity: 5 MT/month Unit Price/Payment: USD 430 /kg - China USD 4780/ kg - India Prix par kilo de principe actif:

336 x 20 = 6,720 g  8$/g

Generic, brand and reimbursement (drug tariff) price decay

49 Les antiretroviraux

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

DosagePrix de l’API / Kg stavudine (d4T)30mg370 $ lamivudine (3TC) 150mg160 $ nevirapine (NVP) 200mg150 $ stavudine (d4T) + lamivudine (3TC) + nevirapine deux fois par jour Quel est le cout annuel en API?

Cout de l’API / 38 Kg stavudine (d4T)3Kg370 x 3 = 1110 $ lamivudine (3TC)15Kg160 x 15 = 2400 $ nevirapine (NVP)20Kg150 x 20 = 3000 $ total38Kg6510 $ Prix au Kg1Kg6510 / 38 = 171,3 $ API dans le traitement annuel ( ) x 2 x 365 = 0,277 Kg 47,4 $

Since 2005, the originator price has decreased by 32% whereas the generic price has dropped by 61%. Evolution of the lowest price quoted for developing countries since 2005:

55 Les « biologics »

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, 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 $7500 an ounce ($ a kilo). » PRIX au kilo: Etanercept API:Euro € Or:Euro € ENBREL is available as 25 mg/0.5 mL or 50 mg/mL prefilled syringes (2%)

J Pharm Innov (2008) 3:30–40 Biotechs

61 Les médicaments Orphelins

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 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.

65 Un médicament est: 1/ un Produit 2/ une Documentation et un Engagement

66 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.

Le cout de la R&D

70 Treatment Cost per patient = R&D cost Number of patients + Cost of Production + MG&A For one Treatment patients 400 millions $ patients millions = $ = 250 $ Blockbuster Model Orphan Drug Model Blockbuster versus Orphan Drug Models

71

72 Hépatite C

The US launch prices for 12 weeks of treatment with simeprevir and sofosbuvir, are $ and $84 000, respectively.

Sofosbuvir solvadi

76 Proportion of patients with HCV genotype 1 and undetectable hepatitis C virus RNA after treatment with Sofosbuvir

Hepatitis C Prevalence

WHO Treatment guidelines for virus highlight challenge of paying for expensive drugs in low-income countries. Campaigners in India

Genotype prevalence in the world

Egypt

Rien n’a de valeur, tout a seulement un prix.