Study designs and PD/Clinical endpoints to demonstrate therapeutic equivalence: European Views

IPAC-RS/University of Florida Study designs and PD/Clinical endpoints to demonstrate therapeutic equivalence: European Views 20 th March 2014 Dr. Alfredo García - Arieta Head of the Service of Generic Medicines Division of Pharmacology and Clinical Evaluation Department of Human Use Medicines Spanish Agency for Medicines and Health Care Products

Disclaimer This presentation represents the author s personal views and does not necessarily represents the policy or recommendations of the Spanish Agency for Medicines and Health Care Products 2

Structure The concept of relative potency Possible study designs Spanish criterion and experience Different European Views 3

The concept of relative potency It is an old methodology Parametric analysis based on Finney bioassay Finney DJ, 1952. Statistical Methods in Biological Assay Third edition 1978 In the field of bioequivalence Only used for OIPs In North America In Canada only for SABAs 4

The concept of relative potency Not used in other locally acting products Cutaneous corticosteroids http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070234.pdf Nasal corticosteroids http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070111.pdf Gastrointestinal drugs Sulfasalazine http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm199673.pdf Mesalamine http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm320002.pdf Orlistat http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm201268.pdf Acarbose http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm170242.pdf 5

Relative Potency Dose - Response Curve Response 1,2 1 0,8 0,6 0,4 0,2 0 A small difference in the y-axis represents a 2-fold difference in the X-axis (dose reaching the lungs) Relative potency = equal effect dose ratio It takes half as much of test formulation to produce the same effect as the reference 0 100 200 300 400 500 Dose (micrograms) Y-axis Acceptance range 6

Structure The concept of relative potency Possible study designs Spanish criterion and experience Different European Views 7

Possible study designs: Spanish criterion: SABA and LABA Bronchoprovocation or bronchodilation model SABA Canadian Guideline: Guidance to Establish Equivalent or Relative Potency of Safety and Efficacy of a Second Entry Short-Acting Beta2-Agonist Metered Dose Inhaler, 1999 LABA Same design with minor modifications SAMA and LAMA Same principles 8

Possible study designs: Spanish experience: SABA and LABA Chiesi Formoterol component of Foster pmdi Formoterol component of Foster Nexthaler Meda Formatris Novolizer 9

Possible study designs: Spanish criterion: ICS The parallel design recommended in the CHMP guideline is not reasonable A cross-over design is essential Any variable showing a sufficiently step dose response curve would be welcome Better if reflecting inflammation» Methacholine PD 20» NOe» Sputum Eosinophils 10

Inhaled corticosteroids No guidance by FDA Discussion Paper and Draft by TPD in Canada Old EU PtC (2004) Barnes PJ, Pedersen S, Busse WW. Efficacy and safety of inhaled corticosteroids. New developments. Am J Respir Crit Care Med 1998; 157(3 Pt 2):S1-53 A comparison at one dose level is the worst approach New OIP Guideline (2009) Far from optimal, but usable and better than nothing 11

First possible design Ahrens model (Cross-over design, FEV 1 ) Ahrens RC, Teresi ME, Han SH et al. Asthma stability after oral prednisone: a clinical model for comparing inhaled steroid potency. Am J Respir Crit Care Med 2001; 164(7):1138-1145 Ahrens RC, Hendeles L, Teresi ME et al. Stability of asthma following maximization of lung function with a highdose inhaled corticosteroid (ICS) burst: a more precise method for comparing clinical potency of ICS. J.Aerosol Med. 16[2], 197. 2003 Ahrens RC, Hendeles L, Teresi M et al. Relative potency of beclomethasone propionate (BDP), delivered by HFA- MDI, and fluticasone propionate (FP) delivered by Diskus. Eur.Respir.J. 22[Suppl 45], 236S. 2003 12

PD endpoints requiring less sample size 13

Sample sizes for parallel and 4- period crossover designs 14

Second possible design Lipworth model (Cross-over, PD 20 ) Lipworth BJ, Sims EJ, Das SK et al. Dose-response comparison of budesonide dry powder inhalers using adenosine monophosphate bronchial challenge. Ann Allergy Asthma Immunol 2005; 94(6):675-681 Fardon TC, Burns P, Barnes ML et al. A comparison of 2 extrafine hydrofluoroalkane-134a-beclomethasone formulations on methacholine hyperresponsiveness. Ann Allergy Asthma Immunol 2006; 96(3):422-430 15

Second possible design Lipworth model (Cross-over, PD 20 ) Clearie KL et al. Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide. Br J Clin Pharmacol. 2011 Apr;71(4):504-13. 16

Pulmicort HFA vs. CFC Cmax: 0.89; 90% CI 0.77 1.04 AUC: 1.03; 90% CI 0.9 1.18 Clearie KL, et al. Br J Clin Pharmacol. 2011 (4):504-13 17

Third alternative FDA proposal for eno (Cross-over) It was already used as secondary variable by Lipworth BJ, Sims EJ, Das SK et al. Doseresponse comparison of budesonide dry powder inhalers using adenosine monophosphate bronchial challenge. Ann Allergy Asthma Immunol 2005; 94(6):675-681 It would be possible to compare eno and PD 20 While 100 g of QVAR significantly suppressed FE NO, 400 g of QVAR is required to significantly attenuate methacholine airway hyper-responsiveness 18

4 th alternative: Sputum Eosinophilia What if the placebo is ignored?

NOe vs. eosinophils and FEV 1 Nolte et al. Dose-dependent anti-inflammatory effect of inhaled mometasone furoate/formoterol in subjects with asthma. Respir Med. 2013 May;107(5):656-64.

NOe vs. eosinophils and FEV1

NOe vs. eosinophils and FEV 1 22

Combination products (ICS + LABA) A study for each component At least 2 doses with the lowest strength Single dose study for LABA ICS effect is negligible ICS study with a specific endpoint for ICS: inflammation eno Sputum eosinophils If no specificity: give the same amount of LABA with an additional device to compensate 23

Problems without solution Higher strengths PD study only possible with the lowest strength Proportional lung deposition Combination products (β 2 A + AntiCh) In vitro PK lung deposition and PK safety studies 24

Possible study designs: Spanish experience: ICS AstraZeneca Pulmicort CFC changed to Pulmicort HFA Clearie et al. 2011. Pharmacokinetic and pharmacodynamic comparison of hydrofluoroalkane and chlorofluorocarbon formulations of budesonide. Br J Clin Pharmacol. 2011 Apr;71(4):504-13 25

Structure The concept of relative potency Possible study designs Spanish criterion and experience Different European views 26

Different European Views A country considers the estimation of the 90% CI of relative potency essential. Some countries are satisfied with showing: Statistically significant slope/differences between the high and the low doses Equivalence between high doses of T and R and low doses of T and R This does not ensure equivalence! 27

Different European Views: FDC of ICS+LABA Some countries are satisfied with: Three-arm study: parallel 6-8 weeks Equivalent response FDC T vs. FDC R FEV 1 superiority of ICS+LABA vs. ICS Accepted as proof of assay sensitivity Only demonstrates LABA > Placebo Nothing to do with ICS or equivalence 28

FACET STUDY shows that such design is inadequate 29

100 or 400 μg Budesonide w & w/o 12 μg Formoterol

Delta FEV 1 0.23 L (Santanello et al. 1999) or 7.0 % 0.20 L (Usually employed) or 6.0%

Delta PEFRm 18.79 L/min (Santanello et al. 1999) 15 L/min (usually employed)

Notable difference in exacerbations

If only one therapeutic dose is marketed Some assessors believe in ICH E10 Assay sensitivity can be obtained with three arm studies (test, reference and placebo), showing that both active treatments are superior to placebo As placebo is unethical: Two non-zero doses levels of test vs. at least one dose of the reference High dose > Low dose in test product Equivalence between T and R at low dose 34

Proposals for salmeterol Supra-therapeutic doses in controlled setting No D-R and it will fail as far as I know Develop a lower strength of the test to show assay sensitivity RP can be estimated but they will assess equivalence in response at one dose level, which is methodologically wrong Take the lower strength in a different dosage form: Test DPI 50 mcg vs. Serevent Accuhaler 50 mcg, placebo and Evohaler 25 mcg 35

Pediatric development Some MS would like a comparison in adults and another in children Charcoal is not ethical in children Adult indication based on PK Pediatric indication needs PD (Paradox) Some MS prefer a comparison in adults and a pediatric PK study for bridging PK w/o charcoal (safety) in children as bridge Others do not need pediatric development 36

Development of new FDC BDP + FF and FP + FF Complete developments, include several trials, including Comparison with R monocomponents Insensitive comparisons: 1 dose level Evidence of some degree of efficacy, since placebo is not ethical Not as proof of therapeutic equivalence with both monocomponents 37

Small improvement FDC: ICS+LABA FEV 1 is primary variable The contribution of the ICS component is measured 12 h after last administration But some effect of the LABA component remains after 12 h ICS effect should be measured 24 h after last administration 38

Thank you very much for your attention! Any questions? 39