Phase I in clinical drug development

Transcription

1 Phase I in clinical drug development M2 Pharmacocinétique 31 janvier 2013 Philippe Grosjean Sanofi R&D Clinical Sciences and Operations 1

2 New drug investigations in human Objectives of the clinical investigations of drugs or devices in human Therapeutic (efficacy and adverse events) Pharmacodynamic (including the mechanism of action) Pharmacokinetics (ADME) 2

3 The Drug Development Process RESEARCH DEVELOPMENT BIRTH LIFE 2 years 1 to 2 years 1 to 2 years 6 to 8 years 1 year Contin. RESEARCH INTO CHEMICAL STARTING POINTS Conception Target selection Test Development Synthesis SCREENING (+ High Throughput Screening) OPTIMIZATION Intrinsic activity Selectivity Oral absorption Duration of action Efficacy in relevant animal models PRECLINICAL EVALUATION IN VITRO AND IN ANIMAL Chemical Development General Pharmacology Analytical Methods Stability Safety Toxicity Metabolism and Pharmacokinetics Formulation CLINICAL EVALUATION IN MAN PHASE I PHASE II PHASE III Tolerance and pharmacokinetics Biological activity and research of a therapeutic effect Determination of the optimal dose Confirmation of the therapeutic effect and tolerance PREPA- RATION and SUBMISSION of a NEW DRUG APPLICATION DOSSIER P R O D U C T I O N MARKETING LCM LIFE CYCLE MANAGEMENT Active Molecules (lead compounds) P H A R M A C O V I G I L A N C E 50,000 to 500,000 molecules

4 Economic aspects: development costs 4

5 Reason for development discontinuation 5

6 Different phases of clinical development Phases Objectives I IIa IIb III Safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug (except oncology and growth factor ) in healthy subjects Assess dosing requirements (how much drug should be given) in subgroups of patients. Assess efficacy (how well the drug works at the prescribed dose(s)). Dose-effect relationship Assess (confirm) the therapeutic efficacy, the tolerance compared to reference drug at a larger scale in the target population IIIb, IV Post-marketing studies (tolerability, extension of indication, other populations, regulatory requests ) 6

7 Phases of development Non-Clinical Phase I Phase IIa Phase IIb Phase IIIa Phase IIIb Phase IV Discovery Pre-clinical Clinical Dev. Phase I First in Man Clinical trials in healthy subjects first (6 to 100 subjects) Voluntary participation Compensation related to study participation No direct medical benefit Numerous objectives Tolerance and its relationship with the dose Pharmacokinetic studies Later phases support Interactions Special populations Pharmacodynamic Rapid studies (several months to complete) Approval Launch 7

8 Clinical development plan Summarizes the rationale, the objectives, the strategy of investigational product development Study needs Study links relationship - chronology Go/no go criteria Plan discussed with the Health Authorities at the beginning of development Regular meetings during the course of development At specific times (e.g. end of phase II ) Specific guidelines (ICH, FDA, EMA ) 8

9 Schematic presentation of a clinical plan Carcinogenicity Tox 1 Tox 3 Tox 6 FIM Food effect RD Interaction PK 1 Metabolism PDyn Dose finding endpoint x New formulation Interaction PK 2 Dose finding endpoint y Efficacy 1 Y1 Y2 Y3 Registration support Efficacy

10 Regulatory environment (1/2) Strict international regulatory environment Declaration of Helsinki and its revisions (1964) ICH recommendations Good Clinical Practices Country-dependent regulations (e. g. Ethics committees, IRB ) USA : Code of Federal Regulation of the FDA (Food and Drug Administration) Europe : European directive (2001, France 2004) France : Loi «Huriet» (modifiée à la suite de la Directive Européenne sur les Essais cliniques) : autorisation des lieux de recherches, consentement, Comités de Protection des Personnes, fichier national des volontaires sains... La loi distingue deux grandes catégories de recherches biomédicales Celles dont on attend un bénéfice individuel direct et immédiat, pour la personne (malade) qui s y prête ou une partie des personnes concernées. Celles dénommées sans bénéfice individuel direct où aucune des personnes ne peut tirer un bénéfice personnel et immédiat pour sa santé 10

11 Regulatory environment (2/2) The clinical development is conditioned by a scientific and technical dossier including animal experimental data within a precise regulatory and legal framework Before FIM: toxicology pre-requisites, characterization of the compound (part of the investigator s brochure ) Trials conduct: protection of the subjets, choice of clinical centers, methodology (statistics, reference, placebo, design ) Number of trials and number of subjects needed Information presented in a standard dossier (CTA clinical trial application / investigational medicinal product dossier EUR in force in France since August 2006) or IND investigational new drug (US) 11

12 Toxicology pre-requisites : phases I, II (Europe) Study Type Parameters assessed Pharmacology Vital functions (respiratory system, cardiovascular system, CNS ) Toxicokinetic and pharmacokinétic Acute and chronic toxicity Genotoxicity Reproduction Local tolerance Absorption,distribution, metabolism, excretion 2 species (rodent, non-rodent) Mutations, chromosomal aberrations Male fertility (not required for healthy male subjects inclusion), female fertility, embryogenesis, post and peri-natal abnormalities If needed (eg : topic, IV ) 12

13 Toxicology pre-requisites: phases I,II (US, EU) Planned duration of clinical trial Single dose Up to 2 weeks Up to 1 month Up to 3 months More than 3 months Minimum duration of toxicity studies Rodent Non-rodent 2-4 weeks 2 weeks 2-4 weeks 2 weeks 3 months 3 months 6 months 3 months 6 months chronic 13

14 Choice of dose in First-in-Man FDA approach Maximum recommended starting dose (MRSD) Example Allometric scaling Predicted human clearance Example MABEL Pharmacology rather than toxicology 14

15 Take into account animal toxicity findings Monitorability animal findings Laboratory ECG Exploratory parameters Histopathology Severity of findings Reversibility Type of findings Body systems Death Differences between species / gender Knowledge of the therapeutic class Definition of the No Observable Adverse Effect Level (NOAEL) 15

16 Animal PK Rat defined as the most sensitive species based on tolerability in 1-month toxicity studies in rat and dog Species Dose (mg/kg/day) C max (ng/ml) AUC (ng.h/ml) Male Female Male Female NOAEL First toxic dose Dog Rat Dog Rat NOAEL: No observable adverse effect level 16

17 First dose proposal for FIM Toxicology data: FDA approach Maximum Recommended Starting Dose (MRSD) Human Equivalent Dose: HED= NOAEL x BSA-CF NOAEL RAT and DOG : 3 mg/kg/day (or most sensitive species) BSA-CF: body surface area converting factor: for rat, for dog HED dog = 1.62 mg/kg HED rat = 0.49 mg/kg = lowest HED MRSD (mg) = HED rat x HBW x SF -1 Safety factor (SF) SF = 10 (default) HBW: human body weight = 60 kg (default) MRSD is (3 x x 60)/10 = 2.9 mg 17

18 Prediction of Human Clearance Allometric Scaling (Mahmood and Balian Method) Cl = a*(w) b Human Cl pred Rabbit Dog Rat Predicted CLhuman = 6.6 L/h Exponent of simple allometric equation (b=0.515) not included in 0.55 to 0.70 (no other correction needed e.g. brain weight ) Simple allometric approach could lead to underestimation 18

19 First dose proposal for FIM Toxicology data: allometric approach PK based approach FIM Dose (mg) = Cl human x AUC NOAEL rat / F x SF Cl human, lowest predicted clearance, 6.6 L/h AUC NOAEL, male rat, 1.43 mg.h/l AUC NOAEL, female rat, 8.57 mg.h/l Safety factor (SF) = 10 (default) Bioavailability F = 1 (default) Proposed First-in-man dose : (6.6 x 1.43) / (1 x 10) = 0.94 mg based on male rat (based on female rat = 5.7 mg) 19

20 First dose summary Toxicology approach species BSA / Dose-based (FDA) CL Pred /PK-based Rat 2.9 mg mg Recommendation to start with 1 mg 20

21 Considerations of the choice of the top dose Dose range should not significantly exceed the exposure at FTD in F rat (6.6 mg.h/ml) Dose/BSA approach Human Equivalent Dose (mg) = FTD (mg/kg) x BSA-CF In rat, FTD is 10 mg/kg, HED = 10 x = 1.62 mg/kg total dose = 97.2 mg (hbw 60 kg) In dog, FTD is 10 mg/kg, HED = 10 x = 5.41 mg/kg total dose = mg (hbw 60 kg) HED: lowest corresponding HED is 97.2 mg 21

22 Considerations of the choice of the top dose PK-based approach Human Equivalent Dose(mg) = Cl human (L/h) x AUC First toxic dose (mg.h/l) Cl human, lowest predicted clearance = 6.6 L/h AUC First toxic dose In male rat, FTD is 10 mg/kg, corresponding AUC is 6.6 mg.h/l 6.6 x 6.6L/h = 43.6 mg In female rat, FTD is 10 mg/kg, corresponding AUC is 39 mg.h/l 39 x 6.6 = mg In dog, FTD is 10 mg/kg, corresponding AUC is 72.4 mg.h/l 72.4 x 6.6L/h = mg HED: lowest corresponding HED is 43.6 mg Top dose capped by exposure < 6.6 mg.h/ml Consider Cmax when intravenous route 22

23 Dose proposal for FIM First and top doses proposal BSA / Dosebased CL Pred /PK-based Proposal Starting Dose 2.9 mg 0.94 mg 1 mg Top Dose 97.2 mg 80 mg 43.6 mg Human equivalent dose Top dose 80 mg if exposure < 6.6 mg.h/ml 23

24 Dose proposal for FIM: doses range proposal Dose Dose (mg) ratio HED Escalation rate 1 Starting dose 1 - NOAEL/10 Male (M) rat (3 mg/kg) ( Pred CL) Top dose * NOAEL M rat (3 mg/kg) ( Pred CL) < FTD/2 M rat (10 mg/kg) ( Pred CL) < FTD M rat (10 mg/kg) ( Pred CL) If AUC<FTD M rat (10mg/kg/day) and < NOAEL Female (F) rat (3mg/kg/day) * 80 mg or earlier with exposure <6.6 mg.h/ml 24

25 Pharmacological / biological effects (not only adverse effects) should guide the starting dose When the methods of calculation (e.g. NOAEL, MABEL) give different estimations of the first dose in man, the lowest value should be used. 25

26 The main challenge selection of a pertinent biological parameter for calculating the MABEL Preclinical efficacy or activity parameter in vivo Lowest dose showing a significant shift in efficacy or activity Then calculate the HED Receptor binding on human cells Concentration - percent occupancy For agonists, choose the concentration with low percent occupancy (10%) For antagonists, higher percent occupancy may be reasonable Use animal PK data to project concentrations in humans In vitro human cell responses Concentration response Use animal PK data to project concentrations in humans apply a safety factor (currently not specified) 26

27 Methodology of clinical trials Placebo Neutral substance that substitutes a drug in order to control or suscitate the psychologic effects linked to drug intake Essential for the use of blinding procedures Allows to answer the question, is the new treatment efficacious? Blinding Indicate that the nature of treatment is not known Allows to reduce the bias in clinical trials, in particular to evidence the placebo effect Single blind: only the subjects ignore the treatment received Double-blind: both the subjects and the investigator(s) ignore the treatment received and actually the sponsor as well 27

28 Parallel groups Screening W-3 Week1 W2 W3 W4 W5 W6 W7 Follow-up W8 R R R ED Dose 7 optional + PK Dose 5 R R ED Dose 6 + PK Dose 4 R R ED Dose 5 + PK Dose 3 R R ED Dose 4 + PK Dose 2 R R ED Dose 3 + PK Dose 1 R Dose 2 R n=4 R n=4 Dose 1 (8 subjects : 6V + 2 P) ED D1 D2 D7 dosing dosing R ED Randomization decision of dose escalation based on tolerability profile of dose n-1 and PK dose n-2 28

29 Parallel groups Pros Simple protocol Limits the study duration for a subject No carry-over effect, no period effect Cons Increases the number of subjects No assessments of the intra-individual variability 29

30 Cross-over Sequences A-B B-A Product A Product B Period 1 Period 2 Wash out Sequences A-E-D-C B-A-E-D C-B-A-E D-C-B-A E-D-C-B A Incomplete sequences B C D E Period 1 Period 2 Period 3 Period 4 Sequence BA 1-sequence 30

31 Cross-over Pros Decreases the number of subjects Assess the intra-individual variability Cons Increases the duration of study (per subject) Period effect Carry-over effect 31

32 First in Man Single dose Objectives Assess the tolerability and safety after single dose Define a maximum tolerated dose (MTD) or maximum adminsitered dose (MAD) Define the PK profile Design Double-blind, placebo controlled, parallel groups single dose 8 subjects per group (dose) with 2 placebo and 6 verum Usually, 5 to 7 ascending doses tested Assessments Adverse events, clinical laboratory, ECG, vital signs, other safety parameters, PD, biomarkers PK 32

33 First in Man Repeated dose Objectives Assess the tolerability and safety after repeated doses Define a MTD or MAD Define the PK profile Rac Design Double-blind, placebo controlled, parallel groups 7 to 14 days of administration (QD, or BID) 12 subjects per group (dose) with 3 placebo and 9 verum Usually, 2 to 4 ascending doses tested Assessments Adverse events, clinical laboratory, ECG, vital signs, other safety parameters, PD, biomarkers PK 33

34 Other phase I studies with safety/pd objective(s) DALA (Drug of abuse liability assessment) Part of the Registration Dossier for CNS acting drugs (primary or secondary effects) Based on behavioral effects in animals Dependence, overdose, and drug abuse liability potential TQT (Thorough QT study ) Assess effect of the investigational product on cardiac repolarization Pharmacodynamic Mechanism of action, biomarker Safety parameters Challenge tests Other Other, product-dependent 34

35 PK studies Numerous studies with a PK objective can be conducted during an investigational product (IP) development They occur at different stages of the drug development Type of studies include Drug-drug interactions Based on in vitro metabolic profile (CYP, transporters ), physico-chemical properties IP on other drugs PK profile Other drugs on the IP s PK profile Food (includes alcohol, fruit juices, high-fat meals, high-carbohydrate meals ) Metabolism Bioavailability Bioequivalence Absolute Relative Formulation comparisons Specific populations Hepatic impairment Renal impairment Elderly Children 35

36 PK to support development (1/5) Excretion balance and metabolism study Further development of drugs requires greater knowledge of the metabolism and excretion in human. To determine the excretion balance and systemic exposure of radioactivity after oral administration of [ 14 C]-drug; To determine the PK of the drug and its contribution to overall exposure of radioactivity; To determine the metabolic pathways of the drug and identify the chemical structures of the main metabolites Based upon the results, PK studies in patients with renal and/or hepatic impairments will be performed subsequently Identification of major metabolites N = 4 to 6 Collection of blood, urine, feces, expired 14 CO 2 Usually long collections periods >8 days (t 1/2z ) 36

37 PK to support development (2/5) Interaction with CYP3A4 substrate (midazolam) Effect of the IP on a drug s PK which is a substrate of CYP3A4 Depends on in vitro in human liver microsomes investigations Midazolam is exclusively metabolized by CYP3A4/3A5; after oral administration, its clearance reflects combined intestinal and hepatic CYP3A activity. The aim of this study is to assess the effect of a repeated administration of the IP on the pharmacokinetic profile of a single dose of midazolam, in healthy male and female subjects Classification of CYP3A inhibitors a single oral dose of midazolam allows discrimination between strong ( 5- fold increase in midazolam plasma AUC values), moderate (2 to 5-fold increase) and weak inhibitors (1.25 to 2-fold increase) Cross-over N = 12 37

38 PK to support development (3/5) Interaction with CYP3A inhibitor (ketoconazole) Effect of a potent CYP3A inhibitor on the PK of the IP Based on invitro studies that showed that the IP is metabolized by cytochrome P450 3A (CYP3A) isoenzyme Ketoconazole is a well-known potent CYP3A4 inhibitor Widely used as a reference inhibitor to test in vivo the potential effect of CYP3A inhibition on drugs being a substrate for this enzyme The aim of this study is to assess the effect of a repeated ketoconazole administration on the pharmacokinetic profile of a single oral dose of the IP, in healthy male subjects Cross-over N = 12 38

39 PK to support development (4/5) Cocktail interaction study When preclinical data suggest that an IP could have an impact on several subtypes of the cytochrome P450, potential drug-drug interactions, using a CYP probe cocktail (1A2, 2C9, 2C19, 2D6 and 3A4) can be investigated Probes showed identical PK when administered separately or when combined together (cocktail) Bioequivalence (cocktail versus each probe drug alone) was demonstrated for both Cmax and AUClast Combined administration of the five probes proved to be well tolerated Global approach enables the testing of several hypotheses in the same study, in a limited number of healthy subjects Assess the effect of the IP on the pharmacokinetics of each cocktail probe CYP2C9, 2C19 and 2D6 poor metabolizers (PM) will be excluded from this study 2C9 : warfarin: 10 mg single dose 1A2 : caffeine: 100 mg single dose 2C19 : omeprazole: 20 mg single-dose 2D6 : metoprolol: 100 mg single dose 3A4 : midazolam: 0.03 mg/kg single dose, leading to a 2 mg dose in this study population Cross-over N = 20 39

40 PK to support development (5/5) Interaction with food case study Safety Results: IP at 200 mg single dose was well tolerated in healthy subjects whatever the condition of administration (fasted or fed [standardized high-fat breakfast]) As compared to fasted administration, after a single oral dose of 200 mg administered following a high-fat food intake, Cmax and AUC strongly increase by 73.8-fold and 41.5-fold, respectively. 40

41 Transition to phase II Early phase I studies provided Safety and tolerability data Wide dose range (SD, RD) Pharmacokinetic data Drug-drug interactions (assess most co-prescribed drugs) Special populations Pharmacodynamic data Bridging studies Match safety/pd in target population Based on these data Phase II doses are selected Safety ratio Activity or efficacy / exposure ratio Treatment duration is defined according to the disease Phase I continues to support registration Early Phase I data 41

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