1 Produit physique Information et Engagement de résultat

2 1/Un « produit physique»-A-Substance active B-Formulation galénique -C-Emballage

3 2/ Une « documentation » établie au cours des différentes phases d’essais cliniques elle permet d’obtenir l’autorisation de mise sur le marché elle sert de base à l’information du prescripteur elle sert à démontrer aux organismes payeurs le service médical rendu et son amélioration.

4 Un médicament est un « produit »-1-Substance active 2-Formulation galénique -3-Emballage

5 Drug substance (Active pharmaceutical ingredient) APIDrug product (Dosage form; Finished product)

6 La Substance active Substance ayant un effet pharmacologique susceptible de se traduire par une application thérapeutique Substance pouvant être produite sous forme pure à grande échelle, de manière reproductible et économiquement et écologiquement viable Substance susceptible d’être dosée ainsi que ses impuretés, ses produits de dégradation et ses métabolites Toxique potentiel

7 Une substance ayant un effet pharmacologique susceptible de se traduire par une application thérapeutique

9 Une substance ayant un effet pharmacologique susceptible de se traduire par une application thérapeutique a. Dans le prolongement des essais pharmacologiques de discovery, il faudra montrer l’efficacité du principe actif dans des modèles animaux de la pathologie ciblée

10 Modèle animal d’obésitéModèle animal de migraine

11 Une substance ayant un effet pharmacologique susceptible de se traduire par une application thérapeutique a. Dans le prolongement des essais pharmacologiques de discovery, il faudra montrer l’efficacité du principe actif dans des modèles animaux de la pathologie ciblée b. Pour la mise en place des essais cliniques il faudra générer une relation dose-réponse entre la quantité administrée et l’effet pharmacologique et déterminer une durée d’action.

12 relation dose-réponse entre la quantité administrée et l’effet pharmacologique

13 2. Une substance pouvant être produitepure, de qualité constante et de stabilité suffisante. de manière reproductible (y compris les impuretés). La voie de synthèse sera souvent très différente de celle suivie lors de la découverte. à grande échelle, de manière reproductible et économiquement et écologiquement viable

14 En 1995, apparait sur le marché le Saquinavir, le premier inhibiteur de la protéase du virus du sidaIl est suivi en 1996, par un second médicament de la même classe thérapeutique: le Ritonavir (Norvir) qui est commercialisé sous la forme d’une solution buvable dosée à 80 mg/mL Les résultats sont spectaculaires 

15 En 1998, une nouvelle forme cristalline très peu soluble commença à précipiter dans les flacons de Ritonavir (Norvir), menaçant d’entrainer un arrêt de la production. 170 mg/mL 20 mg/mL

16 3. Une substance susceptible d’être dosée au moyen de méthodes analytiques qui:Devront permettre de doser le principe actif - dans les fluides physiologiques - dans les formulations Devront faire l’objet d’une validation. Devront aussi permettre le dosage - des impuretés produites lors de la fabrication et du vieillissement - des métabolites détectés lors des études de pharmacocinétique.

17 Métabolisme Hépatique du Ritonavir Structure des Onze Principaux Métabolites

18 Métabolisme Hépatique du Ritonavir identification des Onze Principaux Métabolites par Chromatographie

19 4. Un principe actif est un toxique potentiel qu’il faudra évaluer:Tests cellulaires de mutagénicité et de génotoxicité. Toxicité aigue après une dose unique ou sur une période de 24 heures Toxicité sub-aigue selon un régime qui reflète l’application clinique envisagée. Réalisée sur deux espèces dont un non-rongeur. Toxicité chronique, sur une période dépassant 6 mois permet d’évaluer les risques associés à l’usage prolongé de la substance. Carcinogénicité : généralement sur des rongeurs pendant 2 ans. Incidence sur la fertilité, tératogénicité, développement post-natal

20 Marge Thérapeutique relation dose-réponse entre la quantité administrée et l’effet pharmacologique

21

22 La Forme Galénique 1. C’est la forme sous laquelle sera administré la substance active (comprimé, gélule, solution injectable, aérosol ….) 2. Des formes simplifiées seront utilisées au cours des premiers essais cliniques (ex. des gélules remplies manuellement). Elles doivent être stable pendant la durée des essais. 3. La forme définitive sera développée durant les essais de phase I et II et adoptée lors des essais de phase III.

23 2/ Une « documentation » Etablie au cours des différentes phases d’essais cliniques elle permet d’obtenir l’autorisation de mise sur le marché elle sert de base à l’information du prescripteur et du patient elle sert à démontrer aux organismes payeurs le service médical rendu et son amélioration.

24 La documentation comprend les informations suivantes- Pharmacologie clinique Indication(s) thérapeutiques - Contre-indications - Précautions - Effets secondaires - Dosage et administration - Interactions Médicamenteuses ….

25 Fabrication du Produit physique Information et Engagement de résultat

26 Cost of Good Sold / SalesGenerics Brand Name Biologics J Pharm Innov (2008) 3:30–40

27 Brand Name ~ 27% Biologics ~ 13% Fabrication du Produit physique Brand Name ~ 73% Biologics ~ 87% Information et Engagement de résultat

28

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

30 Link disease and target.Hit generation: HTS rational design In silico screen Hits confirmation Potency Cytotoxicity Preliminary animal efficacy Initial SAR Potency Selectivity PK/ ADME Tox properties Full SAR Pharmacological profile Administration route Preclinical tox D/D Interactions people Safety people Efficacy Dose ranging Safety people Efficiency Safety r&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su Les “informations” sont acquises aux cours des phases précliniques et cliniques

31 Costs to discover and develop a new molecular entityp(TS): probability of technical success r&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su WIP: work in process NATURE Drug Discovery vol 9 | March 2010 | 203

32 Costs to discover and develop a new molecular entityr&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su NATURE Drug Discovery vol 9 | March 2010 | 203

33 Costs to discover and develop a new molecular entityr&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su NATURE Drug Discovery vol 9 | March 2010 | 203

34 Treatment Cost per patient = + Cost of Production + MG&A R&D cost Treatment Cost per patient = + Cost of Production + MG&A For one Treatment Number of patients 1000 millions patients = 100 $ Blockbuster Model 400 millions $ patients = $ Orphan Drug Model 10.000

35 The Shift to High-Priced Innovator Drugs in the USA

36 The Shift to High-Priced Innovator Drugs in the USA

37 Clinical Development of a new molecular entityNATURE Drug Discovery vol 9 | March 2010 | 203 r&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su

38 the drug development process is divided into six distinct phases:Regulatory preclinical studies Phase-Ia Phase-Ib Phase-IIa Phase-IIb Phase-III

39 The preclinical phase :The preclinical phase is defined as the phase from the first good laboratory practice (GLP) toxicology dose (at least two mammalian species), prior to human trials authorization through to an investigational new drug (IND, US) application or first clinical trial application (CTA, EU) before first-in-human (FIH) testing.

41

42 Phase I trials are subdivided into: Phase Ia:In single ascending dose studies (SAD), small groups of subjects (3-5) are given a single dose of the drug. If they do not exhibit any adverse side effects, and the pharmacokinetic data are in line with predicted safe values, the dose is escalated (X2), and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (the drug is said to have reached the maximum tolerated dose (MTD).

43 Phase I trials are subdivided into:Phase Ia: In single ascending dose studies (SAD), small groups of subjects (3-5) are given a single dose of the drug. If they do not exhibit any adverse side effects, and the pharmacokinetic data are in line with predicted safe values, the dose is escalated (X2), and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (the drug is said to have reached the maximum tolerated dose (MTD).

44 Phase I trials are subdivided into:Phase Ia: In single ascending dose studies (SAD), small groups of subjects (3-5) are given a single dose of the drug. If they do not exhibit any adverse side effects, and the pharmacokinetic data are in line with predicted safe values, the dose is escalated (X2), and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (the drug is said to have reached the maximum tolerated dose (MTD).

45 TeGenero and TGN1412 phase-1TGN1412 is a monoclonal antibody is a TCR-independent agonist binding to CD28 present at the surface of CD4+ T-cells. TGN1412

46 TGN1412, a monoclonal antibody is a TCR-independent agonist binding to CD28 present at the surface of CD4+ T-cells. The phase-I trial conducted by Parexel was a double-blind, randomized, placebo-controlled study, with two of the eight subjects receiving a placebo, and six receiving 0.1 mg per kg (1/500th of the highest dose found safe in preclinical experiments with macaques). Within half an hour all six subjects experienced a catastrophic systemic organ failure corresponding to a cytokine release syndrome resulting in angioedema, swelling of skin and mucous membranes.

47 TGN1412, a monoclonal antibody is a TCR-independent agonist binding to CD28 present at the surface of CD4+ T-cells. The phase-I trial conducted by Parexel was a double-blind, randomized, placebo-controlled study, with two of the eight subjects receiving a placebo, and six receiving 0.1 mg per kg (1/500th of the highest dose found safe in preclinical experiments with macaques). Within half an hour all six subjects experienced a catastrophic systemic organ failure corresponding to a cytokine release syndrome resulting in angioedema, swelling of skin and mucous membranes.

48 The therapeutic Index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. A phase-I trial is not designed to evaluate the therapeutic effect

49 Phase I trials are subdivided into: Phase Ib:In multiple ascending doses studies (MAD), a group of subjects receives multiple low doses of the drug, while samples (of blood, urine …) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated. Dose levels and dosing frequency are chosen in order to achieve steady state therapeutic drug levels.

50

51 Phase-II Phase II trials are aimed at evaluating the candidate drug’s efficacy in a patient population, leading up to clinical proof of concept (PoC). Phase II trials are also subdivided into Phase IIa and Phase IIb: Phase IIa studies are generally smaller (typically <200 patients) and designed to mainly address early evidence of drug activity and to assess dosing requirements. Phase IIb studies include larger numbers of patients (typically <400 patients) and are designed to demonstrate clinical proof of concept and an understanding of dose response. Genetic testing for polymorphic metabolism enzymes (Cyp2D6 or 2C9…), are performed particularly when there is evidence of variation in metabolic rate between individuals.

52 Phase II clinical trials of ADX10059 (mGluR5 allosteric inhibitor) in Gastro-Esophageal Reflux Disease (GERD) Phase IIa trial: Two days single-blind study in 24 patients. Objectives: evaluate the effect of a single dose using continuous 24-hour pH recording in the lower esophagus, and on the occurrence of patient-recorded clinical symptoms of GERD. Phase IIb trial: Two weeks of administration twice daily in 103 GERD patients. Objectives: evaluate the effects on esophageal function and reflux events using impedance pH monitoring and esophageal manometry.

53 Phase-III Phase III trials are designed to assess the effectiveness of the new drug and its value in clinical practice. Phase III studies are randomized trials involving large patient groups (300–3,000 or more depending upon the disease and the end points). Due to the difficulty in recruiting patients, they are in general multicenter trials. Phase-III represent the definitive assessment of how effective the drug is, in comparison with the current reference treatment (or a placebo if no approved reference treatment is available). This assessment is based on the achievement of predetermined end-points: “Results, condition or events associated with individual study patients that are used to assess study treatments”. (FDA) Primary end point: single endpoint parameter that will define the success or the failure of the drug. Secondary end point(s): other endpoints pre-specified, may be powered for hypothesis testing

54 Direct Endpoints (FDA)All drugs have safety risks. Therefore, the only reason that a patient would want to take a drug would be if the drug: – improved survival – resulted in a benefit that was detectable by the patient (improvement in symptoms, in functional capacity), or – decreased the chances of developing a condition or disease complication that is itself apparent to the patient and is undesirable (e.g. stroke). Therefore, a primary endpoint should be a direct measure of one of these. A primary endpoint should generally not be a measure of something that is not important to the patient. (exception: validated surrogate endpoint).

55 Surrogate endpoint – used instead of direct endpoint –Ideally, the surrogate parameter should exist within the therapeutic pathway between the drug and meaningful benefit – i.e. the drug results in the therapeutic benefit by virtue of its effect on the surrogate parameter. Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint ex hepatitis C: SVR-24 Sustained Viral Response (Detection of HCV RNA negative 24 weeks after the end of treatment).

56 Hepatitis C Natural HistoryThe full evolution of the disease takes 20 to 40 years it is impossible to evaluate the success of a therapy on direct clinical end-points.

57 Goal of hepatitis C treatment : Primary end-pointSVR 24: Detection of HCV RNA negative 24 weeks after 48 weeks of treatment.

58 Surrogate endpoint – used instead of direct endpoint –Ideally, the surrogate should exist within the therapeutic pathway between the drug and meaningful benefit – i.e. the drug results in the therapeutic benefit by virtue of its effect on the surrogate Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint ex Cholesterol LDL Reduction as primary endpoint as opposed to a reduction in CV morbidity or mortality

59 Phase-II: “A single-blind, placebo-controlled study to examine the effects of torcetrapib, a potent inhibitor of CETP, on plasma lipoprotein levels in 19 subjects with low levels of HDL cholesterol”

60 Phase-III: “A randomized, double-blind study involving 15,067 patients at high cardiovascular risk.The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event.” The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib. Kaplan–Meier Curves for the Primary Composite Outcome

61 Phase-III: “A randomized, double-blind study involving 15,067 patients at high cardiovascular risk.The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event.” Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. A $800 million failure Kaplan–Meier Curves for the Primary Composite Outcome

62 New Drug Submission (NDA) - Regulatory EMA / FDAr&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su NATURE Drug Discovery vol 9 | March 2010 | 203

63 The New Drug Application (NDA).Since 2003, the CTD (Common Technical Document) is the mandatory format for NDAs in the EU and Japan, and strongly recommended for NDAs submitted to the FDA. The CTD is organized into five modules. Module 1 is region specific and Modules 2, 3, 4 and 5 are intended to be common for all regions. In July 2003

64 critical assessment of the pharmacologic, pharmacokinetic, and toxicologic evaluationcritical assessment of the clinical data chemical and pharmaceutical data data summarisation and integration

65 CABOMETYX International non-proprietary name (INN): cabozantinib. Pharmaco-therapeutic group (ATC Code): other antineoplastic agents, protein kinase inhibitors (L01XE26). Background Information on the procedure Scientific Discussion Problem statement Disease or condition … Management Quality aspects Active substance Finished Medicinal Product Recommendations for future quality development Non-Clinical aspects Pharmacology Pharmacokinetics Toxicology Ecotoxicology Discussion on the non-clinical aspects Conclusion on the non-clinical aspects.

66 Scientific Discussion (continued)Clinical aspects Pharmacokinetics Pharmacodynamics Discussion Clinical efficacy Dose response study Main study Clinical safety Discussion on clinical safety Conclusion on clinical safety Risk management plan Pharmacovigilance Product information

67 Benefit-Risk Balance Therapeutic context Disease or condition Available therapies and unmet medical need Main clinical studies Favourable effects Uncertainties and limitations about favourable effects Unfavourable effects Uncertainties and limitations about unfavourable effects Benefit-risk assessment and discussion Importance of favourable and unfavourable effects Balance benefit-risk Conclusions Recommendations: The Committee for Medicinal Products for Human Use concluded that the benefit/risk balance of Cabometyx is positive.

68 The Committee for Medicinal Products for Human Use concluded that the benefit/risk balance of DrugXXX is positive

69 The prescriber concludes that the benefit/risk balance of giving DrugXXX to patientYYY is positive

70 Commercial success

71

72 Discovery and development of a new molecular entity is a highly inefficient process.r&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su NATURE Drug Discovery vol 9 | March 2010 | 203

73 r&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su Discovery and development of a new molecular entity is a highly inefficient process. NATURE Drug Discovery vol 9 | March 2010 | 203

74 Virtual screening compounds Animal Pharmacology 100 compounds (g) High throughput Screening compounds (mg) Clinical trials 10 compounds (kg) attrition 9/10

75 Failures during discovery and development of a new molecular entityr&D model yielding costs to successfully discover and develop a single new molecular entity. The model defines the distinct phases of drug discovery and development from the initial stage of target-to-hit to the final stage, launch. The model is based on a set of industry-appropriate R&D assumptions (industry benchmarks and data from Eli lilly and Company) defining the performance of the R&D process at each stage of development (see supplementary information s2 (box) for details). R&D parameters include: the probability of successful transition from one stage to the next (p(Ts)), the phase cost for each project, the cycle time required to progress through each stage of development and the cost of capital, reflecting the returns required by shareholders to use their money during the lengthy R&D process. With these inputs (darker shaded boxes), the model calculates the number of assets (work in process, WIP) needed in each stage of development to achieve one new molecular entity (nME) launch. Based on the assumptions for success rate, cycle time and cost, the model further calculates the ‘out of pocket’ cost per phase as well as the total cost to achieve one nME launch per year (Us$873 million). lighter shaded boxes show calculated values based on assumed inputs. Capitalizing the cost, to account for the cost of capital during this period of over 13 years, yields a ‘capitalized’ cost of $1,778 million per nME launch. It is important to note that this model does not include investments for exploratory discovery research, post-launch expenses or overheads (that is, salaries for employees not engaged in R&D activities but necessary to support the organization). AnAlysis 206 | MARch 2010 | vOlUME 9 © 20 Macmillan Publishers Limited. All rights reserved 10 Nature Reviews | Drug Discovery p(TS): Phase II p(TS): Phase III Cost: lead optimization Cycle time: Phase III p(TS): Phase I p(TS): su irreversibility of the “prototype” NATURE Drug Discovery vol 9 | March 2010 | 203

76 NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419

77 Results of a comprehensive longitudinal review of AstraZeneca’s small-molecule drug projects from 2005 to 2010. 142 drug discovery and development projects at AstraZeneca. The review covered projects from all therapeutic areas that had been active, from the phases following the completion of preclinical research through to the end of clinical testing in Phase II. The key aims of the review were to understand the major reasons for project closure and to identify the features of projects that correlated with successful outcomes.

78 In addition, it was significant lower for Astra zenecca.Transition through proof of concept (Phase II) is the area with the highest rate of attrition. In addition, it was significant lower for Astra zenecca. Success was defined as the percentage of projects that moved from the indicated phase to the next phase. NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419

79 Efficacy was the major reason for project closure in phase IIb (88%).Safety was the major reason for project closure in Preclinical phase (82%). Efficacy was the major reason for project closure in phase IIb (88%). NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419

80 Safety

81 Safety: target organs Major organ systems involved in preclinical and clinical safety closures.

82 Safety: on-target versus off-targetDuring preclinical testing, 75% of safety closures were compound-related (due to ‘off-target’ actions other than at the primary pharmacological Target) By contrast, the proportion of target-related safety closures rose substantially in the clinical phase and was responsible for almost half of the safety-related project closures. Late failures were often due to a collapse in the predicted margins between efficacious doses and safety outcomes

83 Incidence of the level of confidence in preclinical safety profileLevel of confidence that teams had in their preclinical safety profile.

84 Incidence of the level of confidence in preclinical safety profileLevel of confidence that teams had in their preclinical safety profile. Projects with preclinical safety signals often closed owing to safety issues in the clinic. Projects with minimal preclinical safety signals rarely failed as a result of clinical safety issues.

85 Lack of efficacy

86 Efficacy was the major reason for project closure in phase IIb (88%), where costs are the highest.NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | JUNE 2014 | 419

87 Reasons for lack of clinical efficacy

88 1/ Target linkage to disease not established40% of failed projects lacked data demonstrating: a clear linkage of the target to the disease or access to a well-validated animal model of the disease. Projects that showed genetic target linkage to the disease or a strong understanding of the role of the target in the disease etiology were less likely to fail owing to a lack of efficacy.

89 1/ Target linkage to disease not establishedHuman linkage data (even if functional) may not be fully predictive of the validity of a target. For example, a naturally occurring human variant of the CCR5 gene (CCR5‑Δ32), producing a non-functional receptor, was negatively associated with rheumatoid arthritis. Preclinical models also supported the therapeutic potential of this approach. Nevertheless, several CCR5 antagonists failed to show clinical benefit in patients despite achieving exposure at the target.

90 1/ Target linkage to disease not establishedAvailability of efficacy biomarkers at the start of Phase II is a strong predictor of success (82% versus 29%).

91 2/ Dose limited by compound characteristicsAZD3778, a dual CCR3 and H1-antagonist was developed for the treatment of asthma. AZD3778 inhibits the binding of a CCR3 radioligand, to the CCR3-receptor expressed on CHO-cells with an IC50 of 8 nM. From in vitro experiments on whole blood, of AZD3778, the A2 (the concentration required to produce a two-fold shift of the agonist response) for CCR3 was 200 nM due to Plasma Protein Binding. In a proof-of-principle clinical trial, AZD 3778 had undesirable pharmacokinetic properties with high protein binding and a much shorter half-life than expected in humans. In addition, safety concerns limits human dosing.

92 3/ Indication selected does not fit strongest preclinical evidenceConfidence in patient selection in Phase II-b: High confidence in patient selection positively correlated (90%) with active projects in Phase IIb, whereas low confidence in patient selection correlated with project closures in the same phase owing to a lack of clinical efficacy

93

94 Key factors underlying project failuresfive key technical factors (the five Rs) were identified as substantial contributors to project failures. the right target: the strength and quality of target validation the right tissue: demonstration of target engagement the right safety: reasonable safety margins the right patient: patient stratification plans the right commercial potential: the medical value proposition.

95

96 Right target: the importance of solid biological and disease understanding:Direct evidence of target linkage to human disease, Genetic evidence from animal models, Understanding the biology underpinning the target and/or disease aetiology, Confidence in preclinical and clinical data generated using animal models, Data generated with tool compounds in the preclinical or clinical setting, Validated efficacy biomarkers.

97 Right target: the importance of solid biological and disease understanding:Preclinical data on anticoagulants intended to treat thrombosis or acute coronary syndrome have a high level of confidence: previous clinical experience known validity and translation of the models, confidence in the data generated from preclinical models By contrast, target confidence in oncology, is low because based on screens with or poor translation to clinical outcomes Such as subcutaneous tumour xenograft models that do not accurately replicate the human disease: they often use immunocompromised animals; the human tumour material is not introduced at the site of its primary source; and, for many patients with cancer, morbidity is due to metastatic disease rather than the primary tumour.

98 Right tissue: appropriate pharmacokinetics/pharmacodynamics (PK/PD) modellingDemonstration in both preclinical and clinical models, that the candidate drug achieved exposure in the target organ and achieved sufficient pharmacological activity. Appropriate understanding of PK/PD pharmacokinetic properties, together with the target engagement and pharmacological activity relative to the target organ.

99 Right tissue: appropriate pharmacokinetics/pharmacodynamics (PK/PD) The greatest challenge occurs when the pharmacological target and blood are separated by a barrier, such as the blood– brain barrier. The use of imaging techniques, particularly position emission tomography (PET), to understand the relationship between blood exposure, brain receptor occupancy and efficacy has been effective in the development of CNS-active drugs.

100

101

102 The use of biomarkers as inclusion or exclusion criteria, for enrolling patients into clinical studies has increased dramatically since the sequencing of the human genome.

103

104 A REMS proposal may be required for New Drug Applications (NDAs), Biologic License Applications (BLAs), Abbreviated New Drug Applications (ANDAs), When “a risk evaluation and mitigation strategy is necessary to ensure that the benefits of the drug involved outweigh the risks of the drug.” The drug, which has been shown to be effective, but is associated with a serious adverse drug experience, can be approved only if, or would be withdrawn unless, such elements are required as part of the REMS

105 “Elements to ensure safe use” may require that -Health care providers who prescribe the drug have particular training or experience or are specially certified. Pharmacies, practitioners, or health care settings that dispense the drug are specially certified The drug be dispensed to patients only in certain health care settings, such as hospitals. The drug be dispensed to patients with evidence or other documentation of safe use conditions, such as lab results (ie pregnancy test). Each patient using the drug be subject to certain monitoring Each patient using the drug be enrolled in a registry

106 Alvimopan is a peripherally acting μ-opioid antagonist.With limited ability to cross the blood–brain barrier, many of the undesirable side-effects of the opioid agonists such as constipation are minimized without affecting analgesia. Alvimopan accelerates the gastrointestinal recovery period and is approved for the treatment of postoperative ileus.

107

108 ENTEREG is available only to hospitals that perform surgeries that include a bowel resection and dispensed by pharmacies that are enrolled in the E.A.S.E. ENTEREG REMS Program. This program is designed to ensure that ENTEREG is used in accordance with the FDA-approved label and requires that: The E.A.S.E. ENTEREG REMS Program Kit has been received by the hospital and education on the benefits and risks of ENTEREG has been provided to the healthcare practitioners who are responsible for ordering, dispensing, or administration of ENTEREG. The certified hospital pharmacy has pharmacy systems, order sets, protocols, and/or other measures in place to limit the use of ENTEREG to no more than 15 doses per patient for administration in the hospital inpatient setting only. The certified hospital pharmacy will not dispense ENTEREG for outpatient use and will not transfer ENTEREG to any hospital pharmacy not enrolled with the E.A.S.E. ENTEREG REMS Program Healthcare professionals should report all suspected adverse events associated with the use of ENTEREG.

109 Prescriber and Pharmacist Information Brochure

110 Sales for Praluent were about $12 million between July 2015 and February 2106 (9,500 prescriptions)Repatha, sales totaled roughly $16 million and nearly between August 2015 and February 2016 (11,800 prescriptions)

111 Drug program phase transitions from 2006 to 2015 (7455 programs from 1103 companies)

112 Nature review DD 818 | DECEMBER 2016 | VOLUME 15