Year in review. Vit Perlik Director of Regulatory Science and Clinical Development

Transcription

1 Year in review Vit Perlik Director of Regulatory Science and Clinical Development

2 Content Year in review Covering September 2013 to September 2014 Where the regulation goes selection of events for illustration purposes US FDA steer EU practical example Limitations of the IVIVC PharmInvent 2

3 EU EMA 9 December 2014 PharmInvent 3

4 EU Summary: no QndA still OIP OIP guidance stepwise approach In vitro characterization Pharmaceutical equivalence/evaluation API same form (i.e. salt, ester, hydrate etc.) and in the solid state (powder, suspension) Identical pharmaceutical dosage form Comparison of devices within +/- 15% for device resistance, inhaled volume through the device, delivered dose, particle size distribution profile, Similar flow rate dependency at 10th, 50th and 90th percentile Qualitative and/or qualitative differences in excipients PharmInvent 4

5 EU Summary: no QndA still OIP In vivo characterization PK equivalence/evaluation (Cmax, AUC, Tmax) Pulmonary deposition (absorption from lungs) Imaging studies possible (methodology under development) Systemic exposure (sum of absorption from lungs and gastrointestinal tract) Therapeutic equivalence (PD endpoints acceptable) Two non-zero levels needs to be studied One dose level needs to be shown to be superior to the other Generally independent program for children is required considering the approved / target indications PharmInvent 5

6 US FDA 9 December 2014 PharmInvent 6

7 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate Draft of product specific guideline to establish bioequivalence Intended for the generic development of ADVAIR DISKUS 100/50, 250/50, 500/50 from GSK Very detailed description of levels for comparison PharmInvent 7

8 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate Major message Presented as an guidance additional information Related to excipients in formulation qualitative and quantitative sameness (± 5% of the reference) PharmInvent 8

9 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate FDA guidance additional information cont. Related to device Eligibility of the device for 505(j) suggested to be checked first PharmInvent 9

10 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate FDA guidance additional information cont. Related to device Eligibility of the device for 505(j) suggested to be checked first Test product requirements Breath actuated, pre-metered, 60 doses, dose counter, operating procedure (open, click, inhale, close), similar size and shape, resistance PharmInvent 10

11 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate First level AND In vitro characterization Single actuation content Aerodynamic particle size distribution Additional comments Drug deposition on individual sites of device, each stage of cascade impactor and filter Mass balance accountability (sum of all deposition sites) Median aerodynamic diameter, fine particle dose PharmInvent 11

12 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate AND Second level AND PK characterization For all strength Minimum number of inhalations to describe PK Healthy subjects Study design: rinse the mouth with water after inhalation, spit the water out, do not swallow Analytes: fluticasone, salmeterol AUC, Cmax T/R % PharmInvent 12

13 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate AND Third level Clinical BE study Low strength administered twice daily Parallel group design, 2 weeks run-in, with 4 weeks treatment Placebo controlled comparison of Test and Reference product Asthma patients 12 years and older PharmInvent 13

14 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate AND Third level cont. BE endpoint AUC FEV1 0-12h on the first treatment day (efficacy of salmeterol component) FEV1 in the morning prior to the dosing on the last day (efficacy of fluticasone component) Baseline adjustment (change from baseline) FEV1 determined as pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose T/R % for AUC FEV1 0-12h and FEV1 PharmInvent 14

15 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate AND Third level cont. Inclusion criteria Diagnosed with asthma min 12 weeks prior to screening FEV1 of 40% and 85% of predicted value Non-smokers past yera Reversibility 15% of FEV1 within 30 min following 360 mcg of albuterol Standardized on-demand medication Standardized medication w/o oral, parenteral corticosteroids, oral SABA PharmInvent 15

16 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate AND Third level cont. Exclusion criteria Life-threatening asthma Evidence of cardiovascular comorbidities Hypersensitivity to any study medication Medication with interaction potential e.g. Beta-blockers Ongoing viral or bacterial infection PharmInvent 16

17 US FDA Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate AND Third level cont. Additional comments Run-in period of at least 2 weeks to establish FEV1 baseline values Definition of study compliant subjects of at least 75% and not more than 125% of study drug doses Test and Reference should be superior to placebo in order to establish study sensitivity Concomitant medication documented needs to be well documented AEs carefully reported and evaluated PharmInvent 17

18 US FDA conclusion Draft Guidance on Fluticasone Propionate; Salmeterol Xinafoate FDA combination of the of the evidence level (in vitro and in vivo PK and clinical) vs Stepwise approach of EMA level (in vitro or in vivo PK or clinical) In vitro strong emphases on device similarity In vivo PK FDA (rinsing and spiting of the water out) vs. PK EMA (pulmonary deposition and systemic exposure) Clinical BE study Study sensitivity FDA placebo and one strength vs. Study sensitivity EMA two non zero levels with statistically significant difference PharmInvent 18

19 EU EMA practice 9 December 2014 PharmInvent 19

20 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Budesonide/formoterol Asthma and COPD in adults 18 years and older Original proposal with adolescents Two strength mid (160/4.5µg) and high (320/9µg) originally all three strength submitted Hybrid application Article 10(3) of Directive 2001/83/EC to reference product Symbicort Turbuhaler PharmInvent 20

21 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Several scientific advices starting in 2009 Submission 29 January 2013 List of Questions July 2013 Response 18 October 2013 List of outstanding issues 19 December 2013 Response 20 January 2014 CHMP positive opinion 2014 PharmInvent 21

22 Development based on DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Pharmacokinetic equivalence (each strength) One PD and one safety study No Phase 3 study Lowest strength withdrawn Neither in vitro nor in vivo bioequivalence demonstrated Formulation development DD, APSD Pilot program micronized API and lactose of varying PSD verified in vitro and consequently in pilot in vivo study No new non-clinical data performed Pharmacological and toxicological effects well documented PharmInvent 22

23 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 PIF study has been performed Different target populations as per OIP Pediatric and adult asthma patients COPD patients Healthy volunteers All able to generate flows to use the device 10th, 50th and 90th percentile identified for in vitro evaluation 40, 60 and 90 L/min was used (COPD) PharmInvent 23

24 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Clinical development Pilot study (-101) high strength (two FPD formulations) 18 healthy subjects BUD AUC 90%CI OK, Cmax OK and out for B, yet PE in FOR AUC 90%CI out for A, OK for B, Cmax out for A and for B, yet PE in Pilot study (-102) low strength (two FPD formulations) BUD formulation A higher, B lower PK FOR formulation A higher, B AUC OK, Cmax PE in PharmInvent 24

25 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Clinical development Pivotal study (-103) low strength with and without charcoal 88 healthy subjects BUD systemic and lung deposition OK, FOR AUC OK for both and Cmax higher for both conditions Pivotal study (-104) middle strength with and without charcoal 90 subjects BUD systemic and lung deposition high, FOR even higher PharmInvent 25

26 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Clinical development Pivotal study (-105) high strength 1 with and without charcoal 88 healthy subjects Presented as supportive BUD and FOR systemic high, pulmonary OK Pivotal study (-107) high strength 2 without charcoal, replicate study 72 subjects Presented as supportive BUD systemic OK, FOR AUC OK, Cmax out Higher Cmax addressed in the PD study PharmInvent 26

27 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Clinical development Pilot study (-110) middle strength 20 subjects Addressing issues with the FOR Cmax and higher systemic exposures Blend strength and plus bigger particles of API and plus lactose particle size, high strength formulation and half sized cup Particle size of API suggested as a parameter affecting BE PharmInvent 27

28 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Clinical development Pivotal study (-109) high strength with and without charcoal, plus Ref replication 90 healthy subjects, replication of the Reference BUD and FOR systemic and lung deposition OK CONGRATULATIONS!!!! PharmInvent 28

29 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Clinical development Pivotal study (-108) middle strength with and without charcoal 90 healthy subjects, replication of the Reference Half sized cup compared to high strength, with coarser particles of FOR BUD systemic and pulmonary OK though below unity, FOR OK as well CONGRATULATIONS!!! PharmInvent 29

30 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Pharmacodynamic double-blind, double-dummy study 56 healthy subjects Cardiovascular safety parameters (QT, heart rate, blood pressure, glucose and potassium) Covering higher Cmax in BE studies Low and high strength evaluated Cumulative exposure: inhalations with 29, 28, and 26 minutes from start Small differences in Cmax does not translate to clinically significant changes PharmInvent 30

31 Clinical development - children DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Safety study low strength, double-blind, double-dummy, 2 week, cross-over, placebo controlled To support successful middle and high strength and extrapolated the data to low 78 children with asthma ICS safety using change of the growth rate evaluated by kneemometry (short term growth rate), Secondary 24h cortisol urinary excretion and AM and PM PEF Non-inferiority not demonstrated (95% CI below the NI margin of 0.2 mm/week Flaws: different formulation, cup size impacting PK thus low strength not granted Bridging to adolescents NO efficacy not demonstrated, further doses and regimens needed PharmInvent 31

32 DuoResp Spiromax, February 2014 Teva Centralized Procedure, EMA/CHMP/175692/2014 Conclusion Bioequivalence demonstrated based on BE on PK level (medium and high strength) Two strength granted Middle 160/4.5 μg per dose High 320/9 μg per dose Adult population only (asthma and COPD) Development per strength (IVIVC?) Children and adolescents specific development needed PharmInvent 32

33 Fuglsang Aug 2014 Approval of Generic Fluticasone: A Difficult Exercise in Regulatory Science US FDA vs EU requirements 36 in vitro tests 12 pharmacokinetic tests 2 pharmacodynamic tests The author documents overall burden to prove BE in all parameters in vitro in vivo correlations (IVIVCs) for inhalation drugs are still not characterized % of all pivotal pharmacokinetic or pharmacodynamic trials are currently failing PharmInvent 33

34 Fuglsang Aug 2014 Approval of Generic Fluticasone: A Difficult Exercise in Regulatory Science Conclusion Due to floating point estimate not the confidence interval author conclude lack of useful IVIVCs Good in vitro match does not assure match in vivo despite the existing good IVIVC Ethical concerns connected with pivotal studies on the bases of in vitro data only PharmInvent 34

35 Conclusion Further development of IVIVC methodology needed Anatomical throat models (Olsson et al., 2013) Patient simulated flow profiles for in vitro testing Substantial reflection/review of current regulatory practice needed Clinical study sensitivity (EMA) Burden of testes needed to prove equivalence of the Test and Reference product (FDA) Pediatric indications Do we need to verify the performance in pediatric clinical trials? (FDA vs EMA) PharmInvent 35

36 Thank you for your attention PharmInvent 36