Considerations for Evaluation of Bioequivalence and Interchangeability of Orally Inhaled Products

Transcription

1 Considerations for Evaluation of Bioequivalence and Interchangeability of Orally Inhaled Products Sven Stegemann Sept 16, 2015 Institute for Process and Particle Engineering, Pharmaceutical Engineering Graz University of Technology

2 Table of content General Regulation Bioequivalence for DPI products Next generation APIs and formulation Regulatory Bioequivalence considerations Case studies Conclusions 2

3 General regulation 3

4 European Guidelines for OIP 4

5 EMA Guidelines on quality of OIP Requirements for DPI Extractables and Leachables Delivered Dose Uniformity and FPM over lifetime of container Delivered Dose Uniformity and FPM over patient flow rate FPM with Spacer Particle Size Distribution Actuator and Mouthpiece deposition Shaking requirements Initial and Repriming Requirements Cleaning Requirements Low Temperature and Temperature cycling performance Effect of moisture 5 Cornelia Hippchen, 2 nd Open Forum Istanbul

6 Clinical Investigation of Medicinal Products for Asthma (COPD) 4.1. Selection of patients 4.2. Methods to assess efficacy 4.3. Study design Pharmacodynamic studies Pharmacokinetic studies Therapeutic exploratory guidelines Main efficacy studies Design Comparators and concomitant treatments Blinding/masking Selection of the primary endpoints Selection of secondary endpoints 6

7 FDA Guideline on quality for OIP FDA general guidelines for OIP PQRI Safety Thresholds & Best Practices For Extractables & Leachables in OINDP (Extractables/Leachables) FDA - MDI/DPI Draft Guidance (Inhalation Product Performance & Characterization) FDA Guidance on Inhalation solution, suspension, spray and nasal spray products Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action CDRH - Reviewer Guidance for Nebulizers, Metered Dose Inhalers, Spacers and Actuators, (Product Characterization including Leachables) FDA - Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (Packaging Characterization) CHMP, CVMP - Guideline for Plastic Immediate Packaging Materials (Packaging Characterization) USP <381>, <661> (Physicochemical), USP<87>, USP<88> (Biocompatibility) 7

8 FDA Guideline on quality for OIP Analytical methods Particle/droplet Size Distribution Dose Content Uniformity Compendial Method Parametric Tolerance Interval Testing (PTIT) Aerodynamic Particle Size Distribution Extractables/Leachables Testing Spray Pattern/Plume Geometry 8

9 FDA Guideline on quality for OIP Cascade Impactor to measure aerodynamic particle size distribution Andersen cascade impactor (ACI), next generation impactor (NGI), multistage liquid impinger (MSLI), abbreviated impactor measurement (AIM) Flow rate, volume, pressure drop, temperature, humidity, plate coatings Effective Data Analysis (EDA) of Aerodynamic Particle Size Distribution Laser Diffraction to measure particle geometry Sample uniformity, solution vs. suspension, in line vs. on line 9

10 FDA Guideline on quality for OIP Published Nov 13,

11 Bioequivalence for DPI products 11

12 In vivo bioequivalence testing Bioequivalence testing for inhalation products is a challenge, because regional and topical effect low dose / differentiating dose Variable administration capabilities / patient interface Measurable parameter PK profile FEV value (Forced expiratory volume) exhaled nitric oxide (eno) test Bioequivalence versus therapeutic interchangeability 12

13 Basic clinical pharmacology Effect (%) 100 µg drug in the lung 500 Effect (%) Differentiating dose Effect µg drug in the lung & 0.50 mg Effect (%) 100 µg drug in the lung Dose (mg) & 2.0 mg Non-differentiating dose Measuring beyond plateau dose does not demonstrate interchangeability µg drug in the lung Source: Lars Bergstrom, Istanbul

14 Turbuhaler vs. pmdi 140 FEV (% of baseline) 1 TBH 0.50 TBH 0.25 pmdi 0.50 Bioequivalent? pmdi Hours since dose administration Borgström et al. Am J Resp Crit Care Med,

15 Turbuhaler vs. pmdi FEV (% of baseline) 1 TBH 0.50 TBH 0.25 pmdi 0.50 pmdi 0.25 Not Bioequivalent Hours since dose administration Borgström et al. Am J Resp Crit Care Med,

16 Charcoal block In case bioequivalence is tested via plasma level, the orally absorbed fraction needs to be eliminated Co-administration of a slurry of charcoal is swirled around in the oral cavity and swallowed 5 g Inhalation 5 g 10 g 10 g 10 g 10 g - 2 min + 2 min 1 h 2 h 3 h 4 h Water ad lib Borgström and Nilsson Pharm Res, 7: (1990) 16

17 E max Model 17

18 Response scale vs dose scale test Response rate and dose rate is typically determined by escalating the ED 50 doses and measuring a relevant biomarker (exhaled nitric oxide (eno) endpoint for ICS and bronchodilatation or broncho-provocation endpoint for LABA) Singh GJPS

19 Response scale vs dose scale test While the Response Scale Test/Ref remains the same, the Dose scale is sensitive to PD differences [mcg] 19

20 Next generation of APIs and formulations 22

21 Next generation of APIs (eg glucocorticoids) The new generation of glucocorticoids have: Higher glucocorticoid receptor binding affinity lower systemic exposure Improved therapeutic index greater lipophilicity, slower dissolution and pulmonary absorption higher plasma protein binding, lower unbound fractions in the plasma larger volumes of distribution have high systemic clearance, high first-pass metabolism and low oral bioavailability Daley-Yates BJCP

22 Next generation of APIs (eg glucocorticoids) Next generation of Devices have: improved device efficacy for inhaled corticosteroid molecules Improved efficacy by replacing CFC MDIs with HFA MDIs that emit smaller particles increase in device efficiency for both in DPI and HFA MDIs appears to result in a small improvement in the therapeutic index Therapeutic index is defined as the daily dose that produces 20% cortisol suppression divided by either the low mid ( ) or mid high ( ) therapeutic daily dose Daley-Yates BJCP

23 Next generation of formulation A new approach in DPI formulation is the use of porous particles (with a very low density) Porous particles with a particle size of up to 100 µm Can be formulated with amino acids (e.g. Leucine), sugars, lipids, phospholipids, polymers to enhance dissolution or stability Sponge like particles 25

24 Next generation of formulation Inhalation product using porous particles Example: Tobramycin (TOBI, Novartis) Distearoylphosphatidylcholine (endogenous pulmonary surfactant) used as an excipient Manufactured by spray drying Geller et al

25 Next generation of APIs & formulation Next generation APIs, devices and formulation will impact BE studies for generic versions Higher receptor binding Longer PD/higher therapeutic index Increasing lipophilicity Lower oral BA/high systemic metabolism Improved device/propellant performance Functional excipients (eg amino acids) 27

26 Regulatory Bioequivalence considerations 28

27 Committee for medicinal products for human use (CHMP) GUIDELINE ON THE REQUIREMENTS FOR CLINICAL DOCUMENTATION FOR ORALLY INHALED PRODUCTS (OIP) INCLUDING THE REQUIREMENTS FOR DEMONSTRATION OF THERAPEUTIC EQUIVALENCE BETWEEN TWO INHALED PRODUCTS FOR USE IN THE TREATMENT OF ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN ADULTS AND FOR USE IN THE TREATMENT OF ASTHMA IN CHILDREN AND ADOLESCENTS London, 22 January 2009 Doc. Ref. CPMP/EWP/4151/00 Rev. 1 29

28 EMA Guidelines CPMP/EWP/4151/00 Rev. 1 Determination of equivalence complete individual stage particle size distribution profile in case of flow rate dependency, the comparative in vitro data should be obtained with a range of flow rates taking into account the intended patient population efficacy and safety will depend on the amount of active substance that reaches the lung and on the deposition site distribution safety will also be influenced by the rate and extent of systemic absorption from the gastrointestinal tract (i.e. the swallowed fraction) the in vitro comparison should be performed for the stages which are relevant to the efficacy and safety of the medicinal product in vivo 30

29 EMA Guidelines CPMP/EWP/4151/00 Rev. 1 Determination of equivalence in-vitro (Impactor) The comparison should be performed per impactor stage or justified group of stages. At least 4 groups of stages are expected. Justification should be based on the expected deposition sites in the lungs. The maximum allowable in vitro difference should be indicated and justified, e.g. +/- 15% may be justifiable. Per impactor stage or justified group of stages the 90% confidence intervals for the observed in vitro differences must be calculated. Based on the pre-established maximum allowable differences, a decision regarding equivalence can be made 31

30 EMA Guideline CPMP/EWP/4151/00 Rev. 1 In vitro similar? Lung deposition similar? PD similar? No No Yes Yes Yes EMA OIP guideline to demonstrate bioequivalence Similar safety? Yes Equivalent No Yes No Phase 3 similar? No Not equivalent 32

31 Directive 2001/83, art Hybrids EWP comment March 2009: Orally inhaled products are definitely not generics but hybrids. But there are many more guidelines. 33

32 FDA approach for demonstrating equivalence Formulation and Device Design FDA requirements to demonstrate bioequivalence Comparative Systemic Exposure Studies Bioequivalence of Dry Powder inhalers Comparative In Vitro Tests Pharmacodynamic or clinical Endpoint studies 34

33 FDA approach for demonstrating equivalence FDA draft Guideline July 15, 2014 A submitter of a premarket notification submission (often referred to as a 510(k)) must demonstrate to the Food and Drug Administration (FDA) in its 510(k) submission that the new device is substantially equivalent (SE) to a legally marketed (predicate) device. Formulation related aspects Device related aspects Q1 :Qualitative sameness Q2: Quantitative difference permissible 3 Larry Lee 2011 GPhA/FDA Fall Technical Conference 35

34 FDA approach for demonstrating equivalence FDA initiates and funded research in 2013 dedicated to generic OIP 36

35 FDA approach for demonstrating equivalence FDA is issuing product specific guidelines, detailing the nonclinical and clinical requirements for a generic version Fluticasone Salmeterol FDA Generic guidance.pdf 37

36 FDA approach for demonstrating equivalence Bioequivalence for Fluticasone-Salmeterol generic Lionberger GPhA Oct

37 Fluticasone-Salmeterol generic guidance FDA FDA also targets the equivalence of the device Device A sponsor is encouraged to submit a working model and engineering drawings of the product to the Office of Generic Drugs (OGD) prior to the abbreviated new drug application (ANDA) submission, in order to ensure eligibility of the T device under a 505(j) pathway. The T product should have the following characteristics: Passive (breath-actuated) device Pre-metered multi-dose format 60 doses External operating procedures consisting of (1) Open, (2) Click, (3) Inhale, and (4) Close Similar size and shape to the R product Comparable device resistance to the R product Dose counter In addition, the robustness of the T product should be demonstrated. 39

38 Case study 40

39 Ipratropium generic Ipratropium bromide as MDI by Cipla Submitted in UK as a Reference Member State through the Decentralised Procedure One single dose bioequivalence study 41

40 Budesonid-formoterol generic Bufomix Easyhaler as DPI by Orion Pharma Applied to the Swedish authority by Orion Pharma through the Decentralised Procedure One pilot study and three pivotal studies have been performed with the final Bufomix Easyhaler formulation. The studies were conducted both with and without charcoal blockade and hence both lung deposition and total systemic exposure have been evaluated. Since bioequivalence could not be demonstrated for all parameters in the first two parallel studies (PAX-PILOT and REPECO), two additional studies were conducted in parallel (REFLI and TRIPECO). In these studies bioequivalence was demonstrated for budesonide, but not for all parameters for formoterol. 42

41 Budesonid-formoterol generic Differences were observed in bioequivalence but justified as follows: A plausible explanation of the difficulties in demonstrating bioequivalence may be the variability in FPD between different batches of the reference product. Batch to batch variability in FPD for orally inhaled products is a well recognised problem. To be able to obtain reliable results in the pharmacokinetic studies it is therefore important to test several batches in vitro in order to find a batch representative of the reference product on the market, i.e. with a FPD as close to the median of several tested batches as possible. The same test batch was used in all studies while four different references batches were used. All reference batches are considered representative regarding FPD, using a limit of median ± 15%.The FPD of the different reference batches did however vary from the lower to the higher end within this range. 43

42 Salmoterol-fluticasone generic PAR Salmeterol/Fluticasone STADA Generic The applicant has submitted 5 clinical studies to demonstrate equivalent efficacy and safety of the test product versus the reference product. Two studies were pharmacokinetic (PK) studies investigating lung deposition study NEO 045 and systemic bioactivity of Fluticasone and Salmeterol in study NEO 053. The applicant considers these two studies the pivotal studies for this hybrid essential similarity application with SERETIDE Evohaler as a reference product. An additional supportive safety study PRC/CRD/25/08 is included in the dossier. 44

43 Fluticasone formoterol new FDC PAR Flutiform Napp Pharmaceuticals New FDC In total 20 clinical trials (9 phase 1 & 2, 11 phase 3) Efficacy and safety with individual drugs separately Efficacy and safety with similar combination therapies and Seretide Efficacy and safety administered with and without spacers Efficacy and safety consistency across different patient subgroups Trials were performed in healthy volunteers, mild and severe asthma/copd patients 45

44 Conclusions 46

45 Conclusions DPI products must be seen as a targeted drug delivery and the plasma concentration is not representative for performance Establishing equivalence between two different DPI products through in vitro testing (cascade impactor) is most unlikely In vivo bioequivalence testing much more complex than oral BE and quite specific for each product, might include an efficacy study in disease patients Regulatory Guidance on developing generic DPIs exist in Europe and USA, where they are considered to be hybrids or 505(b)(2) application Patient interface is much more important than in oral products Product specific guidelines are being developed in USA (and Europe) which also include the device component 47

46 Thank you for listening! Sven Stegemann, PhD Graz University of Technology Professor for Patient Centric Drug Development & Manufacturing Inffeldgasse Graz Austria phone: