bioequivalence of orally inhaled drug products...
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Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Bioequivalence of Orally Inhaled Drug Products (OIDP)
Gustavo Mendes Lima Santos Coordinator of Therapeutic Equivalence
General Office of Medicines
IV Simposium SINDUSFARMA – IPS/FIP – ANVISA June 22, 2015
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Why discuss OIDPs?
• Asthma: over 300 million affected in the world;
• In Brazil it is estimated that 10% of the population has asthma;
• OIDPs were included in the programme Farmácia Popular;
• Farmácia Popular budget in 2012 was approximately USD 3 billion;
• Number of diseases treated by OIDPs has increased.
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Orally Inhaled Drug Products
• Intended for drug delivery to the sites of action in the lung;
• Lower Doses → Greater Effect;
• Limiting factors: Pulmonary Deposition and Drug Delivery From Device;
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Pulmonary Deposition
• Influence the amount of drug available in the site of action;
Taburet A.M., Schmit B. Pharmacokinetic optimisation of asthma treatment. Clin Pharmacokinet. 1994 May; 26(5): 396-418.
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Pulmonary Deposition
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Pulmonary Deposition
Lippmann, M. Respiratory System. ILO Encyclopaedia: http://www.ilocis.org/documents/chpt10e.htm#JD_Ch10_19
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Drug Delivery From Device
• Influence the amount of drug delivered;
• Most Common Delivery Systems:
– Pressurized Metered Dose Inhalers (pMDI);
– Nebulizers;
– Dry Powder Inhalers (DPI)
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Pressurized Metered Dose Inhalers (pMDI)
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Pressurized Metered Dose Inhalers (pMDI)
Source: http://www.globalasthmareport.org/management/inhalers.php
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Pressurized Metered Dose Inhalers (pMDI)
• Advantages:
– Cost;
– Transportation;
– Conservation.
• Disadvantages:
– Coordination of the inhalation movement;
– Only 10% to 20% of the dose is delivered in the site of action (due to the particle size and speed);
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Nebulizers
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Nebulizers
Source: https://en.wikipedia.org/wiki/Nebulizer#
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Nebulizers
• Jet and Ultrasonic Nebulizers;
• Advantages:
– Formulations without conservants (single dose flasks);
– Breath sync not required;
– Patients with handling problems (children, arthritis).
• Disadvantages:
– Price;
– Transportation (power supply required);
– Variability of particle size: only 4,2% of labeled dose is available for inhalation (Hickey and Evan, 1996);
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Dry Powder Inhalers
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Dry Powder Inhalers
• Single Unity Dose Devices (Inhaled Capsules):
Source: https://www.imgbusddy.com
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Dry Powder Inhalers
• Multi-Dose Devices (Diskus):
Source: http://www.wikihow.com/Use-an-Inhaler#
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Dry Powder Inhalers
• Multi-Dose Devices (Diskus):
Source: www.admit-online.info Source: www.mims.com
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Dry Powder Inhalers
• Advantages:
– Transportation;
– Conservation;
– Drug Characteristics for Formulation.
• Disadvantages:
– Capacity to deliver the drug (particle size and device related);
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Therapeutic Equivalence for OIDPs
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Challenges for Demonstration of Therapeutic Equivalence for OIDPs
• Classical bioequivalence approach is considered inadequate;
• Unharmonized regulatory requirements among countries;
• Devices Similarity;
• Acceptance criteria for In vitro comparability tests;
• Adequate in vivo models to demonstrate efficacy and safety.
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Regulatory Requirements for Therapeutic Equivalence of OIDPs in US and EU
Lee et al. Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India. The AAPS Journal. 2015 May 23.
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Regulatory Requirements for Therapeutic Equivalence of OIDPs in Brazil
• Resolution RDC nº 37, August 3rd 2011: – Solutions in vitro tests only
– Suspensions and Powders in vitro and in vivo tests
• Specific guidance not issued: Technical Note n° 01/2013, 25 march 2013 (only for in vitro tests);
• Case-by-case analysis;
• Theme included in Anvisa’s Regulatory Agenda 2015-2016.
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Regulatory Requirements for Therapeutic Equivalence of OIDPs in Brazil
• Device Comparability:
– Does the operation mechanism of the device exacerbate differences in patients’ efforts and handling?
– Does the shape and dimension of the device exacerbate differences in patients’ efforts and handling?
– Evidence of similarities could be demonstrated in patient handling studies
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Regulatory Requirements for Therapeutic Equivalence of OIDPs in Brazil
• In vitro Comparability:
Lee et al. Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India. The AAPS Journal. 2015 May 23.
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Regulatory Requirements for Therapeutic Equivalence of OIDPs in Brazil
• Aerodynamic Particle Size Distribution:
Source: http://www.pharmacopeia.cn/v29240/usp29nf24s0_c601_viewall.html
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Aerodynamic Particle Size Distribution (APSD)
Source: http://fy.chalmers.se/OLDUSERS/molnar/lectures/Measurement%20Methods%20II.htm
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Aerodynamic Particle Size Distribution (APSD)
• Challenges:
– Statistical Approaches (modified chi-quare, population bioequivalence);
– Acceptance Criteria;
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Regulatory Requirements for Therapeutic Equivalence of OIDPs in Brazil
• In vivo comparability:
– Efficacy related to pulmonary deposition; • crossover PK studies, with inhibition of absorption from the gastrointestinal tract
through administration of activated charcoal (if necessary);
– Safety related to total quantity of drug available systemically; • crossover PK studies, without inhibition of absorption from the gastrointestinal
tract through administration of activated charcoal;
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Pharmacokinetic Studies
• Challenges :
– Are PK studies correlated to the amount of drug available in the lung?
– Are PK studies correlated to the region of deposition of the drug in lung (central/peripheral)?
– Are PK studies correlated to the amount of time that the drug stays in the lung?
– Goyal and Hochhaus, 2010: Simulations results correlating AUC to pulmonary deposition and Cmax to residence time in lung.
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Regulatory Requirements for Therapeutic Equivalence of OIDPs in Brazil
• If pharmacokinetic studies are not feasible, pharmacodynamic studies would be acceptable:
– Proposed Endpoints:
• Sputum eosinophilia
• Exhaled nitric oxide (eNO)
• Bronchoconstriction challenges
• Spirometry
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Pharmacodynamic Studies
• Challenges :
– Sensitivity to differentiate products;
• Dose-response relation;
• High variability of the biomarker.
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Final Considerations
• Important to discuss international harmonization of regulatory criteria;
– PQRI and IPAC-RS
• Stimulation of Research of more biorelavant techniques;
• Anvisa come to a guidance for industry for registration of OIDPs.
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References
• Brazil. Ministry of Health. Resolution SAS/MS nº 709 of 17 december 2010. Accessible via http://portal.saude.gov.br/portal/arquivos/pdf/pcdt_asma.pdf
• Brazil. Federal Government. Popular Pharmacy Program. Accessible via http://portal.saude.gov.br/portal/saude/area.cfm?id_area=1095
• Brazilian Health Surveillance Agency. 2011. Resolution RDC nº 37, 3 august 2011. Provides information about biowaiver and substitution of bioequivalence studies. Accessible via http://www.in.gov.br/imprensa/visualiza/index.jsp?jornal=1010&pagina=6&data=05/03/2007
• Brazilian Health Surveillance Agency. 2003. Resolution RDC nº 16, 2 march 2007. Provides information about generic drugs registration. Accessible via http://www.crfrj.org.br/crf/arquivos/file/ConcursoEstagiarios2010/RDC16_2007MODIFICADA.pdf
• Panamerican Heath Organization. 2005.Term of Cooperation 37 for Brazilian health surveillance system reorganization. Accessible via http://new.paho.org/bra/index.php?option=com_content&view=article&id=182&Itemid=610
• Brazilian Health Surveillance Agency. 2009. Normative instruction nº 12, 15 october 2009. Provides information about tests for evidence of pharmaceutical equivalence and bioavailability / bioequivalence for nasal sprays and aerosols controlled dose. Accessible via http://portal.anvisa.gov.br/wps/wcm/connect/ce6dfe8047458eff9843dc3fbc4c6735/U_IN-ANVISA-12_151009.pdf?MOD=AJPERES
• United States Food and Drug Administration. 2013. Draft Guidance on Albuterol Sulfate. Accessible via http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346985.pdf
• United States Food and Drug Administration. 2013. Draft Guidance on Budesonide. Accessible via http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346985.pdf
• European Medicines Agency. Committee for Medicinal Products for Human Use. 2009. 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. Accessible via http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003504.pdf
• Therapeutic Products Directorate, Health Canada: Guidance to establish equivalence or relative potency of safety and efficacy of a second entry short-acting beta2-agonist metered dose inhaler. 1999. Accessible via: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/mdi_bad-eng.pdf
• Therapeutic Products Directorate, Health Canada: Guidance for Industry Pharmaceutical Quality of Inhalation and Nasal Products. 2006. Accessible via:http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/chem/inhalationnas-eng.php
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References
• Newman SP and Chan HK: In vitro/In vivo comparisons in pulmonary drug delivery. J Aerosol Med Pulm Drug Deliv. 2008; 1(21): 77-84.
• Byron PR, Hindle M, Lange CF, Longest W, McRobbie D, Oldham MJ, Olsson B, Thiel CG, Wachtel H, Finlay WH: In vivo-in vitro correlations: predicting pulmonary drug deposition from pharmaceutical aerosols. J Aerosol Med Pulm Drug Deliv. 2010; 23 (sup. 2): S59-S69.
• Mitchel J and Dolovich MB: Clinically relevant test methods to establish in vitro equivalence for spacers and valved holding chambers used with pressurized metered dose inhalers (pMDIs). J Aerosol Med Pulm Drug Deliv. 2012. 4 (25). 217-242.
• Daley-Yates PT, Parkins DA: Establishing bioequivalence for inhaled drugs: weighting the evidence. Expert Opin Drug Deliv. 2011 Nov;8(11):1531-2.
• Meakin BJ, Cainey J, Woodcock PM: Effect of exposure to humidity on terbutaline delivery from turbuhaler dry power inhalation devices. Eur Respir J. 1993, 6(5):760-1.
• Adams WP, Ahrens RC, Chen ML, Christopher D, Chowdhury BA, Conner DP, Dalby R, Fitzgerald K, Hendeles L, Hickey AJ, Hochhaus G, Laube BL, Lucas P, Lee SL, Lyapustina S, Li B, O’Connor D, Parikh N, Parkins DA, Peri P, Pitcainr GR, Riebe M, Roy P, Shah T, Singh GJP, Sharp SS, Suman JD, Weda M, Woodcock J, Yu L: Demonstrating bioequivalence of local acting orally inhaled products (OIPs): workshop summary report. J Aerosol Med Pulm Drug Deliv. 2010: 1 (23). 1-29.
• Weber B, Lee SL, Lionberger R, Li BV, Tsong Y, Hochhaus G: A sensitivity analysis of the modified chi-square ratio statistic for equivalence testing of aerodynamic particle size distribution. AAPS Journal. 2013; 2 (15): 465-476.
• Hickey AJ: A USP perspective on dissolution testing for aerosol drugs. Resp Drug Deliv. 2012. 169-175.
• Schumacher J and Leiner S: A critical evaluation of the revised and new USP chapter for aerosols: <601> and <5>. 2012.
• Son YJ, McConville JT: Development of a standardized dissolution test method for inhaled pharmaceutical formulations. Int J Pharm. 2009 1;382 (1-2):15-22.
• Arora D, Shah KA, Halquist MS, Sakagami M. In vitro aqueous fluid-capacity-limited dissolution testing of respirable aerosol drug particles generated from inhaler products. Pharm Res. 2010, 27(5):786-95.
• Goyal N and Hochhaus G: Demonstrating bioequivalence using pharmacokinetics: theoretical considerations across drug classes. Resp Drug Deliv. 2010, 261-272.
• O’Connor D, Adams WP, Chen ML, Daley-Yates P, Davis J, Derendorf H, Ducharm MP, Fuglsang A, Herrle M, Hochhaus G, Holms SM, Lee SL, Li BV, Lyapustina S, Newman S, Oliver M, Patterson B, Peart J, Poochikian G, Hoy P, Shah T, Singh GJP, Sharp SS: Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report. J Aerosol Med Pulm Drug Deliv. 2011: 3 (24). 1-17.
Agência Nacional
de Vigilância Sanitária www.anvisa.gov.br
Thank you!
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