Lessons Learned from Approval of Generic Nasal Products

Transcription

1 Lessons Learned from Approval of Generic Nasal Products Julie D. Suman, Ph.D President, Next Breath IPAC-RS/UF Orlando Inhalation Conference: Approaches in International Regulation March 20, 2014

2 Objectives In Vitro Bioequivalence Challenges Improving probablity of success Global regulatory requirements What parameters are relevant? In Vitro In Vivo 2

3 Approved US Generic Nasal Sprays 3Locally Acting Suspensions Locally Acting Solutions Systemic Solutions

4 Approaches for Bioequivalence Clinical endpoint Same as a clinical study Measure survival rate Pharmacodynamic (PD) endpoint More sensitive than a clinical study Measure lipid lowering Pharmacokinetic (PK) In Vitro Tests SENSITIVTY TO DETECT DIFFERENCES

5 In Vitro BE Statistical Analysis Per FDA Guidance In Vitro Test Statistical Process Single Actuation Content Uniformity Drug mass per actuation Droplet Size Dv50 Span Spray Pattern Ovality Ratio Area Plume Geometry Width Angle Particle Size by Microscopy Drug in Small Particles by Cascade Impaction (Sprays) Prime Reprime Population Bioequivalence (PBE) PBE PBE Point Estimate N/A Comparison of means by PBE Point Estimate Spray Pattern (SprayVIEW, Proveris Scientific)

6 Approaches for Increasing Success for In Vitro BE Evaluate RLD and Test during method development Perform pre-screening studies Avoid the temptation to compare averages and standard deviations to judge equivalence Sample variance is factored into the PBE equation 6

7 Droplet Size (Dv50) Method Comparison

8 Spray Pattern (Area) Method Comparison

9 Pre-BE Studies Investigate likely hood of a successful outcome KEY TEST METRICS Innovator and Generic Pumps tested with Innovator formulation Hand study determined actuation parameters All units acutated using Proveris Scientific platform Droplet size (DSD) measured at beginning and end of unit life using a Malvern Spraytec Spray pattern (SP) meaured using SprayVIEW Plume geometry (PG) measured using SprayVIEW Statistical analysis by population bioequivalence (PBE) and point estimates 9

10 IN VITRO BIOEQUIVALENCE: INNOVATOR VS GENERIC RESULTS All results show as average of 15 bottles Average Spray Pattern Results Dmax (mm) Dmin (mm) Ovality Ratio Area (mm 2 ) 3 cm 6 cm 3 cm 6 cm 3 cm 6 cm 3 cm 6 cm Innovator Generic Droplet Size Distribution - 3 cm Droplet Size Distribution - 6 cm Microns Innovator Generic Microns Innovator Generic Innovator Generic Spray Angle ( ) Plume Width (mm) Dv10 Dv50 Dv90 0 Dv10 Dv50 Dv90 IN VITRO BIOEQUIVALENCE SUMMARY Innovator Generic DSD - 3 cm DSD - 6 cm SP - 3 cm SP - 6 cm PG Dv50 (µm) Span Dv50 (µm) Span Ovality Ratio Area (mm 2 ) Ovality Ratio Area (mm 2 ) Plume Angle Plume Width Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Outcome of Population Bioequivalence (PBE) Statistics reported for Beginning of Life (BOL) and End of Life (EOL)

11 In Vitro BE Across Regulatory Bodies FDA Brazil (ANVISA) EMA Droplet Size Droplet Size Droplet Size officially Single Actuation Content Uniformity Spray Pattern Prime Reprime Particle Size Plume Geometry Particles < 10µm Single Actuation Content Uniformity Spray Pattern Prime Reprime Number of Metered Doses Pump Delivery Other in vitro tests appear to be used 11

12 FDA and Brazil Generic Pathways Agency FDA Bioequivalence (BE) In Vivo and/or In Vitro Pharmaceutical Equivalence (PE) Definition does not exist ANVISA In Vivo In Vitro 12 In Vitro Plume Geometry In Vivo Pharmacokinetics (PK) In Vivo Clinical Endpoint

13 13 Brazil PE Tests In Vitro Test Metric for Statistics Similarity to FDA BE Contents of an actuation on the total contents of the device (single actuation content uniformity) Dose mass (pump delivery) Droplet size distribution Spray pattern Number of doses Load and reload (prime and reprime) Mass (µg) of drug Spray weight (mg) No stats D50 Span Ovality Area Count No stats Mass of drug No stats Meet % LC Same Not required Same Same Not required Three orientations required not one Stats required

14 Which In Vitro Parameters are Relevant for BE? Spray 1 Drop 3 Drops Initial 30 mins Hardy, et. al. J. Pharm. Pharmacol., 1985

15 Desmopressin PK Profile Desmopressin (ug/ml Spray Pumps: 100uL 200 ul Nasal Drops: catheter pipet minutes *adapted from Harris, et al., J. Pharm. Sci. 1986

16 Desmopressin PD Profile 400 Spray Pumps: 100uL 200 ul Nasal Drops: catheter pipet Factor VIII minutes *adapted from Harris, et al., J. Pharm. Sci. 1986

17 Nasal Deposition and Biological Response Harris compared plasma levels, biological response and deposition pattern of 99m Tc- labelled desmopressin delivered by aqueous spray pump and nasal drops Biological response was found to be a function of deposition pattern and clearance within the nasal cavity Harris, et. al., Intranasal Administration of Peptides: Nasal Deposition, Biological Response & Absorption of Desmopressin. J. Pharm. Sci., 75(11) 1986

18 Plume Angle as a Function of Viscosity by Nasal Casts Deposition patterns of Afrin, Ayr and Zicam (Insertion depth = 5 mm; Spray angle = 45 ) Deposition area decreases with increase in viscosity Kundoor V, Dalby RN. Pharm Res Aug;28(8): Epub 2011 Apr 16. Effect of formulation- and administration-related variables on deposition pattern of nasal spray pumps evaluated using a nasal cast.

19 Droplet Deposition Images Spray Pump Nasal Nebulizer Nasal Spray Dv50 = 70µm

20 Pressurized Nasal Sprays Switch from CFC to HFA-134a Use in patients with runny nose Slower clearance Deposition primarily in anterior regions for HFA due to exit velocity % Retained in Nose Nasal pmdi Aqueous spray pump Time (minutes) Redrawn from Newman, S.P. et al., J. Laryngol. Otol., 1987

21 Particle Size Droplets dictates deposition pattern What happens to the suspended drug particles? Clearance - Mucociliary action - Physical removal Dissolution and uptake into cells Particle size dictates dissolution rate 21 - PRESENTATION TITLE - DATE

22 Dissolution Modified Transwell Method* 25 mm Transwell system was used. The polycarbonate membrane was replaced by glass microfiber filter eliminated the role of diffusion as the rate limiting step. Stirring was incorporated into the system to expedite the dissolution. A surfactant, like SDS, was included in the media for the in vitro dissolution of hydrophobic drugs and in order to get a dissolution rate that is comparable to the in vivo absorption. *Guenther Hochhaus, ISAM, mm Transwell system

23 Modified Transwell Method* Samples were collected from the receptor compartment at specific time intervals and analysed for drug content. A Weibull model was fitted to the data and the T63 for each set was compared. %Dissolved = 100 [1 exp (t/t63) ß T63 Time required to dissolve 63% of the drug ß Shape factor *Guenther Hochhaus, ISAM, 2013

24 Fluticasone Propionate Dissolution MDI spray DUSA 28.3 L/min Nasal spray 4-5 cm from filter DPI spray DUSA 30 L/min Dv10 (µm) Dv50 (µm) Dv90 (µm) FP DPI % FP NS % % Aggregate No. of replicates T63 (hours) Average amount (mcg) FP MDI FP DPI FP NS Presented by Next Breath and Malvern Instruments, RDD Europe 2013

25 Corticosteorid Dissolution Dissolution rate the same for all BDP particle sizes No statistical differences in cellular uptake Predict no sta s cal difference in local response Jin et al., RDD, 2010, vol 3, pp Benniger, Otolaryngol Head Neck Surg, 2003, vol 129, pp Q2 Average Beclomethasone Dipropionate (BDP) Particle Size (µm) Formula Dv10 Dv50 Dv90 M M M Corticosteroid Bioavailability (%) Intranasal administration Mometasone furoate <1 Beclomethasone dipropionate 44

26 What leads to clinical differences? Droplet Size Droplet Velocity Formulation Particle Size Plume Geometry? Plume geometry (Proveris Scientific) Nasal Spray Dv50 = 70µm Nasal Nebulizer Dv50 = 6µm

27 FDA Nasal Spray BE Requirements Locally Acting Solution In vitro only Systemically Acting Solution New guidances for Sprix and Imitrex In vivo: if not qualitatively (Q1) and quantitatively (Q2) the same OR In vitro: Q1 and Q2 Suspensions In vivo - Clinical endpoint to assess local delivery + - Clinical endpoint to assess systemic exposure OR - Clinical endpoint + - PK study for systemic exposure AND In vitro

28 Nasal Spray Generic Requirements Brazil All solution and suspension nasal sprays In Vitro (PE) AND In Vivo (BE) - PK ONLY EMA In Vitro In Vivo - PK - PD or Clinical Endpoint Is stepwise approach available to nasal sprays?

29 What In Vivo Studies are Relevant for Locally Acting Nasal Sprays? US Locally efficacy - Clinical endpoint or PD Safety - Systemic exposure (PK) Brazil PK only 29

30 What In Vivo Studies are Relevant for Locally Acting Nasal Sprays? Pharmacodynamic studies or clinical endpoint studies to document equivalence of action at the local site is difficult because ICS have relatively flat doseresponse curves on clinical endpoints Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, FDA, CDER, July 23, 2008 Issues with PD Less sensitive/high variability Top of dose response curve Is PK enough for locally acting nasal sprays? 30

31 31 Slide courtesy of Günther Hocchaus

32 32 Slide courtesy of Günther Hocchaus

33 Conclusions Do your homework on in vitro tests especially spray pattern What s needed Additional understanding is needed on dissolution including technique used Correlations between key in vitro parameters and in vivo performance Can PK with or without charcoal block be used in lieu of PD? 33

34 34 Thank you for your attention!