European Equivalence Considerations for Orally Inhaled Products (OIPs) for Local Action Frankfurt, Germany, October 2010.

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1 European Equivalence Considerations for Orally Inhaled Products (OIPs) for Local Action Frankfurt, Germany, October 2010 Experience with Canadian Guidance: Similarity and Distinction Relative to European Approach Myrna B Dolovich, PEng Assoc Clin Prof Medicine Faculty of Health Sciences Michael DeGrooteSchool of Medicine, McMaster University, Canada mdolovic@mcmaster.ca 1 Acknowledgements W Racz, PhD, Professor Emeritus, Dept of Pharmacology and Toxicology Queen's University, Kingston ON Member SAC-RAT to HC Irvin Mayers, MD, FRCPC Dept Medicine, University of Alberta, Edmonton, Alberta Chair, SAC-RAT to HC 2 1

2 Disclaimer The views expressed in this presentation are those of the authors and do not necessarily represent the official position of Health Canada or the Scientific Advisory Committee- Respiratory and Allergy Therapeutics (SAC- RAT) 3 To Be Discussed Discuss rationale for HC Guidances for OIP SMEPs HC approval paradigm In Vitro(HC/EMeA): SMEPs vs Innovator (RP) Physicochemical properties of AI, excipients Limits on test results: ED and ACI data Characterization with and without spacers In Vivo Guidances(HC/EMeA) HC Clinical guidances for COPD, asthma Study design key points Response limits Testing with spacers Sputum as primary end-point in ICS Guidance HC -PK PD Use of radio-labelled deposition measurements 4 2

3 Guidances In vitro HC and EMEA Guidance for Industry Pharmaceutical Quality of Inhalation and Nasal Products pdf In vivo HC Draft Guidance 2007: Submission Requirements for Subsequent Market Entry Inhaled Corticosteroid Products for Use in the Treatment of Asthma Record of Proceedings Nov 13, 2009: Initial discussions concerning data requirements for Subsequent Market Entry (SME) long-acting beta-agonists (LABA) used to treat COPD. In vivo EMEA CPMP/EWP/4151/00 Rev. 1 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) 5 HC Process for Developing Guidelines SAC-RAT Stakeholders Input Draft Document V i=1 Comments Reviewed by SAC Sent for Public Review Draft Document v n Public Comments on Draft Document Final Health Canada Guidance Published in English and French 6 3

4 Process for developing Guidelines Health Canada has a number of Scientific Advisory Committees (SAC) to assist in the development of guidelines. At an initial meeting of SAC, stakeholders are invited to make presentations on the scientific merits of the methodologies to be used in the guideline for a particular type of drug product. SAC reviews all the presentations and recommends guidelines for bioequivalence. A draft document is prepared and posted for comment by all stakeholders, and the comments incorporated into a final document. Guideline is finalized then published in English and French. 7 Principles of Guidelines The scientific criteria for guidelines for solid oral dosage forms (35 plus years of HC experience) - are the foundation for guidelines for other dosage forms. Pharmacokinetic studies are preferred to pharmacodynamic studies. Pharmacodynamicstudies are acceptable if pharmacokinetic studies are not feasible. Data must be sufficient to demonstrate efficacy, ie. Bioequivalent. In vitro data required but does not form the basis of bioequivalence. 8 4

5 Development of Bioequivalence Guidelines for Orally Inhaled Products Pharmacokinetic measurements cannot be made reliably (need to differentiate between lung and swallowed fraction -?charcoal block). Pharmacodynamic endpoint: Should be consistent with the action of the drug. Should be reproducible. Dose -Steep part of the dose response curve, not guaranteed with a pmdi, but dose must produce a clinically relevant response vs placebo. Should be able to measure onset of response. Guidelines allow for a uniform methodology for industry and regulators. Guidelines are very important large improvement in quality of the data in the submissions. 9 In Vitro Characterization/Quality Effective Date : Health Canada /10/01 EMEA 2006/10/01 GUIDANCE FOR INDUSTRY Pharmaceutical Quality of Inhalation and Nasal Products 10 5

6 HC vsemea In vitro Issues 1. Spacers/HC in vitro/in vivo(many spacers; different patient groups); S/HC for DPIs(eg., Exubera device) 2. Stage Poolingfor full PSD data: criteria selected before analysis; useful to do or not? 3. Delivery device: pmdisall same;?? DPI design can be different as long as Dosage Form, ED, FPM same?? 4. FPM and IFR: need to obtain ED, PSD at low, med, high IFR (also optimal IFR) as patient usage 5. Package labeling clear instructions for use, cleaning of spacers/holding Chambers 11 Comparative T/RP Studies for SMEPs EMEA and HC In VitroGuidance Health Canada Appendix I Potential impact of S&E of drug product Formulation Physicochemical properties of AI Physicochemical properties of drug product Delivery device Delivered Dose uniformity Content uniformity/ uniformity of dosage units Particle/droplet size distribution Drug Delivery Rate and Total Drug Delivered EMEA Appendix I Safety, #batches tested Extractables/Leachables Delivered Dose uniformity and FPM over patient flow range Particle/droplet size distribution Drug Delivery Rate and Total Drug Delivered Pharmacopoeial Excipients 12 6

7 Importance of PSD Data µg Formulations BDP (µg) Actuator Coarse Particle Dose Emitted Dose Metered Dose 10 0 Fine Particle Dose Beclazone 50 QVAR Beclovent HFA BDP HFA BDP CFC BDP QVAR approved for a 1:2.5 substitution vs CFC BDP BZ50 approved for a 1:1 substitution vscfc BDP M Dolovich In: Inhaled Steroids in Asthma eds Schleimer, O Byrne, Szefler, Brattsand 2002 vol163 Chap Spacer/Holding Chamber Issues (1) EMEA -Sec and HC In VitroGuidance Sec 3.1(f) pmdi Fine Particle Mass with and without spacer/hc before and after cleaning changes with inhalation instructions (e.g.,time delay, multiple breaths/tidal breathing) No data required for HCsused with DPIs 14 7

8 1. Spacer(S)/Holding Chamber (HC) Issues (2) EMEA In Vitro Guidance Appendix III Validation required for S/HC when used in a particular patient population (e.g. paediatrics, administration of high dose steroids relevant information on the S/HC chamber must be given in the Summary of Product Characteristics e.g., use of a specific S/HC; cleaning instructions in addition to in vitro studies, the suitability of the spacer should be supported by appropriately designed clinical studies. Any claims exceeding instructions for use and handling, e.g. reduction in the amount of large particles, must be supported by in vitro data Stage Pooling Several approaches to combining data from full PSD measurements HC and EMEA In VitroGuidance: criteria for pooling of data must be in place before analysis started AIM approach for QC AIM approach to model lung deposition in adult subjects Are we missing information by pooling stages? 16 8

9 Two HFA134a-BDP solution pmdis QVAR BZ50 p Emitted Dose (EM), µg 43.7 ± ± CI MMAD - µm CI+Inlet(EM) FPM<4.7 µm, µg FPF %EM<4.7 µm FPM and FPF Ratio, F f 1.47 QVAR approved for a 1:2.5 substitution vs CFC BDP BZ50 approved for a 1:1 substitution vscfc BDP M Dolovich ISAM BZ-50 QVAR ED 40.6 ±3.2µg MMAD 0.99 µm FPM 25.9 µg FPF 62.7% ED 43.7 ±3.7µg MMAD 1.01 µm FPM 17.6 µg FPF 42.8% % Emitted Dose Stage Groupings -% Emitted Dose BZ QVAR * * * * * 0 ACI Stage Filter Jet Throat ECD<µm >9.0 * p < M Dolovich ISAM

10 3. What about generic delivery devices By definition, there are no generic DPIs 19 Formulation HC and EMEA API same Excipients T:RP ±10% Device HC and EMEA differences justified 20 10

11 HC -Physicochemical Properties of Drug Substance: Crystalline Structure Q1: Does Health Canada ask that the crystalline structure of the SEP be submitted and that it also be very similar to the innovator? A: Different polymorphs or crystalline structures between SEP and CRP are allowed as per the HC policy Interpretation of "Identical Medicinal Ingredient" (IMI 2003) insofar as the pharmaceutical equivalence (PE) is concerned. However, due to challenges of establishing BE for locally acting orally inhaled drug products, generic sponsors are certainly encouraged to use the crystalline structure or polymorphic form that is very similar to the innovator. 21 Formulation HC and EMEA API same Excipients T:RP ±10% Device HC and EMEA differences justified 22 11

12 Generic DPIs Benosid N Inhaler Farmasan Jethaler Ratiopharm Rotahaler, Cipla India Budesonide Cyclocaps-Bud Cambridge Consultants Ring tablets for the Jethaler DPI 23 HC - SMEP Delivery Device Q2:For dry powder inhalers: does the delivery device have to be similar or near identical to the innovator if the drug delivered is otherwise the same? A: You are referred to Appendix I, Section I.1.(d) Delivery device attributes of the HC- EMEA joint guidance "Pharmaceutical Quality of Inhalation and Nasal Products" which states the following: cont d 24 12

13 HC - SMEP Delivery Device "Results of a qualitative and quantitative analysis of the physical attributes and operating characteristics of the delivery devices (as related to the functionality of the systems) for the CRP and the SEP (e.g..dimensions, materials used) should be submitted. Differences should be scientifically justified and the potential impact on the safety and efficacy of the drug product (e.g. deposition and absorption characteristics, effect on patient compliance) should be discussed.this will be taken into consideration when determining whether the products are considered to be comparable dosage forms." In other words, generic sponsors are certainly encouraged to use the delivery device that is similar or near identical to the innovator; if not, the claim for comparable dosage forms or PE may be questioned. 25 Canadian Inhaled Corticosteroid Guidance* * in Draft Form 26 13

14 Clinical Perspective Subsquent entry product less expensive Costs important from individual and societal perspective But does it work like the innovator? Inhaled drugs are difficult to assure equivalence Physical characteristics are similar Non-medicinal ingredients are similar Are clinical effects equivalent? 27 Assessing Therapeutic Equivalency in vitro: assessment of particle size, reproducibility of emitted dose, + other tests in vivo: will the new drug treat patients as well clinical bioequivalence - effective as Canadian Reference Product - establish safety and side effects lung deposition similar distribution = clinical bioequivalence 28 14

15 Canadian ICS Guidance- Key Points Study Design Double-blind randomized, three arm trial, test, reference and placebo. Study Population: Steroid naïve patients (6 weeks free of ICS). Mild to moderate severity uncontrolled but stable asthma, FEV1 >60% and 3% or > eosinophilsin sputum. Primary Efficacy Sputum eosinophils(inflammatory marker). Secondary Efficacy FEV1 29 Canadian ICS Guidance- Key Points Choice of Dose: Lowest dose marketed by the reference product (one actuation for a pmdi). Clinical Efficacy Criteria: Each active drug product (test and reference) must have at least a 50% reduction in total eosinophilcount vsplacebo or 12% change in FEV1. Change from baseline in % eosinophils. Orchange in FEV1 from baseline

16 Canadian ICS Guidance- Key Points Therapeutic equivalence criteria: The 90% CI of the T/R ratio of mean change from baseline of the efficacy endpoint should be within % on log transformed data or untransformed data. 31 Airway Eosinophils: CumulativeDose (by time) response to ICS Patients with eosinophilic bronchitis with uncontrolled asthma Treated with escalating doses of fluticasone pmdi 50, 100, 200,and 400 µg/d each for 7 days; doses via Aerochamber AM and PM Largest percent decrease noted with smallest dose of fluticasone(50 µg/day) Kelly et al., J Allergy Clin Immunol 117:989-94, 2006 Days of treatment 32 16

17 Change in Eosinophils With increasing dose of ICS Decreasing numbers of airway eosinophils (upper figure) With increasing dose of ICS Decreasing symptom score (lower figure) Eosinophilsbetter measure of response to ICS Kelly et al., J Allergy Clin Immunol 117:989-94, Assessment of systemic exposure Systemic exposure of a second market entry ICS should be assessed in a pharmacokinetic study. Cross-over, Single dose at the upper limit of dosing range (3 puffs) in healthy adults with plasma drug concentrations determined over the elimination phase. The PK parameters that are compared are: AUCt -90% CI of the test to reference should be between % Cmax- The relative mean measured Cmaxof the test to reference should be between %. If plasma values cannot be measured than a pharmacodynamicstudy assessing the effect on the hypothalamic pituitary-adrenal axis should be conducted

18 1. Spacer/Holding Chamber Issues (3) EMEA 2009 Clinical Guidance asthma, COPD adults, pediatrics Sections and 6.2 Spacers may significantly increase lung deposition particularlywhen pmdi technique poor efficacy and safety may notbe equivalent between spacers or same spacer with different pmdis may be dependent on patient population adults vs children AM FEV 1 vsfine Particle Dose % Baseline BDP MDI BUD DPI FLU MDI *pmdis: + Optichamber/TS FP DPI FP MDI TAA MDI Fine Particle Dose (µg < 4.7 µm) Data from M Dolovich, McMaster University for Nair et al Can RespirJ 2003 DICE/MICE NHLBI ACRN Clinical Trials 36 18

19 1. Spacer/Holding Chamber Issues (4) EMEA 2009 Clinical Guidance asthma, COPD adults, pediatrics Sections and 6.2 required to be available for use with all pmdis, and always with children drug available (ED) from spacer affected by materials of manufacture, time delay between actuation and inhalation of pmdi, washing/ preparation; patient interface if data collected with one or more specific spacers, approval of OIP only with those spacers test product characterized under same conditions as reference -no spacer, specific spacer 37 Comparison: Health Canada and EMEA ICS Clinical Trials Health Canada EMEA Particle Distribution Yes Pulmonary deposition Pharmacokinetic Study Pharmacodynamic Study Yes? Yes (BE) Safety Efficacy -Eosinophil Count Yes No Safety Efficacy -Bronchodilation FEV 1 (2 nd ) FEV 1 -Dose 1 puff (lowest 2 doses (steep part of marketed) dose response curve 38 19

20 Pulmonary Deposition for Demonstrating Therapeutic Equivalence EMEA In Vivo Guidances EMEA allows a T/RP therapeutic equivalence comparison based on pulmonary deposition (adults only) if in vitro data fails to demonstrate equivalence Pulmonary deposition can be assessed by PK or imaging studies 2D Imaging studies regarded as supportive data for therapeutic equivalence; if equivalence demonstrated, PK or clinical studies need to be done Total and regional deposition data to be reported as well as oropharynx, mouthpiece, actuator and exhalation filter as % drug administered Equivalent lung deposition of T/RP if the 90%CI of radioactivity within range of for total lung and each region of the lung Need to assure that radio-labellingof product has a negligible influence on deposition characteristics M Dolovich PATS Additional Health Canada Clinical Guidances for SMEPs 1999 Short-Acting Beta 2 Agonists Study Design Bronchodilation Study Design Bronchoprotection 2010 Long-Acting Beta Agonists Currently DRAFTGuidance Patient population: COPD 40 20

21 SMEPs-Short Acting Beta 2 Agonists Study Design Bronchodilation (preferred to Bronchoprotection design) Double blind randomized four Period, four treatment cross-over (2 doses for each of test and reference one and two puffs administered as a single dose) Study Population: Subjects with airflow obstruction FEV 1 /VC of 80% after drug withheld. Should represent a range of severity and acute reversibility as shown by 15% increase in FEV 1 after 2 puffs of the reference product. Stable disease. Primary Efficacy Change in FEV 1 from baseline, measured over 6 hours to define the AUEC 0-6, the time of onset and duration of response. 41 Safety: SABA Bronchodilation Study cont d Heart Rate, ECG, BP, and hand tremor. Choice of dose: One and two puffs Represents 2 points on the doseresponse curve. In some cases a 3 rd dose, 4puffs may be needed. Therapeutic Equivalence Criteria: The 90% CI for relative potency for maximum FEV 1 and AUFC must be within % Vital signs and adverse effects of test cannot be worse than the reference 42 21

22 SABA Bronchoprotection HC/SME - SABA Study cont d Study Design Bronchoprotection Double blind randomized four Period, four treatment cross-over (2 doses for each of test and reference one and two puffs administered as a single dose) One or two pre-study days (Baseline challenge) and 4 study days (bronchoprotection) Study Population Subjects with asthma and hyperresponsivenessto methacholine, with PC 20 4mg/ml when baseline FEV 1 is 70% of predicted. (Disease should be stable over the test period and if steroids used subjects must be on a stable dose) PC 20 Should increase 4 fold after 2 puffs of the reference 43 SABA Bronchoprotection Study cont d Methodology: Determine PC 20 Standardized Methacholinechallenge tests conducted with each dose on 4 separate days. Determine pc 20 Primary Efficacy Change in PC 20 Safety Heart rate, blood pressure, and hand tremor. Safety study at usual dose and a dose higher than usually prescribed. The cardiovascular effects and adverse effects of the test cannot be worse than the reference assessed at the usual dose and at a high dose

23 SABA Bronchoprotection Study cont d Therapeutic Equivalence Criteria The 90% CI for the relative potency for test to reference PC 20 must be within 80 to 125% 45 Comparison: Health Canada and EMEA SABA Health Canada EMEA Physical Properties Yes Efficacy Cross-over Bronchodilation (preferred) Broncho-protection (2 nd ) Yes Cross-over Bronchodilation Accepted Subjects Asthmatic Asthmatic Dose Safety One and 2 puffs, 3 if required Short term -usual dose and high dose long term safety not needed. Safety also assessed in the efficacy trial At least 2 doses on steep part of curve PK and/or PD (max recommended dose) 46 23

24 SMEPs Long-acting Beta agonists. Guidance under development Design likely to be similar to SABA, but study population would be COPD; 3 period cross-over Efficacy: FEV 1 Measured over at least 12 hours. Dose: Lowest dose marketed by reference. Safety: PK study at the highest dose in volunteers. Also assess QTcinterval, heart rate, serum K + and glucose. Long term safety studies are not required for a SME LABA. 47 Submission Requirements for Subsequent Market Entry Inhaled LABA Products for Use in COPD PD studies key criteria DRAFT COPD GUIDANCE fairly uniform population (stable, requiring no intervention in the preceding 6 weeks, stage 2-3 severity (GOLD) criteria; male/female, age (40+ yrs), smoking history (current or past, for 10+ pk-yrs randomized 3-arm (Test, Reference, Placebo) cross-over, single-dose design one dose, the lowest dose marketed by the sponsor of the Canadian RP, should be used to determine efficacy. The following is recommended: 12µg for Formoterol, and 50µg for Salmeterol. 72 hours between doses (a minimum of 6 half-lives) Standard sample size calculations primary efficacy endpoint: AUC of the FEV1 response recommended PK data is the primary safety signal. Secondarily, the subjects would be studied for QTcinterval, heart rate, serum potassium and glucose levels

25 Why separate guidance for Inhaled Corticosteroids and Bronchodilators Mechanism of action different, thus study is different in design, duration and endpoint Value in a specific document for each type of drug. May be combined in the future with a common approach but each class of drug would need a specific section. Less confusion??? Guidances are published as they are finalized 49 Conclusions With respect to SMEPs, Many similarities between Health Canada and EMEA Guidances Important differences exist Companies seeking regulatory approval are encouraged to meet with the appropriate agencies for confirmation of directions to be taken for approvals Data is key Safety is of prime importance 50 25

26 micrograms ICS: Label Claim vs Emitted Mass and Fine Particle Mass FLU pmdi* TAA + TS* BDP pmdi* FP pmdi* BUD TH FP DH 0 Label Claim Emitted Mass Fine Particle Mass * EM, FPM for pmdis are with Optichamber Spacer, TAA with Tube Spacer, Data from M Dolovich, McMaster University for DICE/MICE NHLBI ACRN Clinical Trials Dolovich & Dhand The Lancet, accepted for publication Corticosteroid pmdi, DPI Aerosols: Emitted Mass 250 p<0.001 Emitted Dose (µg) p<0.001 p< Label Claim Vanceril Aerobid Flovent Azmacort Flovent Pulmicort MDI" Opti MDI" Opti MDI" Opti + Spacer Diskhaler Turbuhaler 84 µg 250 µg 44 µg 200 µg 50 µg 100 µg Inhaler Data from M Dolovich, McMaster University for DICE/MICE NHLBI ACRN Clinical Trials MDI: Ex-Actuator & Ex-OptiChamber Azmacort: Ex-Tube Spacer DPI: Ex-Device 52 mean " sd, n = 3-6 devices 26

27 Corticosteroid pmdi, DPI Aerosols: Fine Particle Mass Fine Particle Dose (µg < 4.7 µm) Label Claim p=0.058 p=0.244 p=0.200 Vanceril Aerobid Flovent Azmacort Flovent Pulmicort MDI" Opti MDI" Opti MDI" Opti + Spacer Diskhaler Turbuhaler 84 µg 250 µg 44 µg 200 µg 50 µg 100 µg Inhaler Data from M Dolovich, McMaster University for DICE/MICE NHLBI ACRN Clinical Trials MDI: Ex-Actuator & Ex-OptiChamber Azmacort: Ex-Tube Spacer DPI: Ex-Device 53 mean " sd, n = 3-6 devices Literature 10/July/01/JBB pdf 10/July/01/JBB pdf 54 27