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How to Compare Two Different Metered-Dose Inhaler-Valved Holding Chambers in the Administration of Salbutamol FREE TO VIEW

Alfredo García-Arieta, PhD
Author and Funding Information

From the División de Farmacología y Evaluación Clínica, Subdirección de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios.

Correspondence to: Alfredo García-Arieta, PhD, División de Farmacología y Evaluación Clínica, Subdirección General de Medicamentos de Uso Humano, Agencia Española de Medicamentos y Productos Sanitarios, C/ Campezo, 1. Edificio 8, Planta 2 Oeste. Madrid 28022, Spain. e-mail: agarciaa@aemps.es


Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr García-Arieta is a regulatory assessor of products claiming equivalence. This manuscript represents the personal opinion of the author and does not necessarily represent the views or policy of the Spanish Agency for Medicines and Health Care Products.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;138(3):758-759. doi:10.1378/chest.10-0815
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To the Editor:

I read with interest the correspondence by Di Berardino et al (February 2010)1 to see how the difficult task of inhalation product comparison has been addressed.2 I agree that different valved holding chambers (VHCs) that are available for inhalation should not be used without evidence of equivalent efficacy/safety and compatibility between pressurized metered-dose inhalers (pMDIs) and VHCs, but I think that the authors’ proposal is not enough to ensure the correct delivery of aerosolized drugs. Conversely, it seems to be an excuse to use a new VHC without the required evidence.

The clinical response to a specific pMDI cannot be assumed to be equivalent if a different spacer is used or if a different pMDI is used with the same spacer. The development of a pMDI should always include the testing of at least one specific named spacer for use with the particular pMDI, which should be stated in the labeling. If the spacer is to be replaced subsequently by an alternative spacer, appropriate in vitro or in vitro and clinical data must be presented.3

The proposed “amount of drug within the respirable range” is not enough to ensure equivalence from an in vitro point of view since the whole aerodynamic particle size distribution has to be compared.3 If comparative in vitro determination using a validated method does not show equivalence, a clinical comparison is required. This clinical comparison must include an assessment of systemic safety through investigation of equivalence based on pharmacokinetic data or pharmacodynamic data.3

From an efficacy viewpoint the study must be sensitive enough to discriminate between spacers. For a study to have assay sensitivity at least two non-zero levels need to be studied and one dose level needs to be shown to be superior to the other. Consequently, the proposed study design to assess “improvement of spirometric parameters” does not comply with the regulatory requirements3-5 and the state of the art,2 consisting of the estimation of the relative potency. Furthermore, the authors have neither compared the results statistically nor predefined the acceptance range to conclude that both VHCs are equivalent. Therefore, it is not possible to conclude that “both of the VHCs tested were suitable for use in the delivery of salbutamol.”1 The new VHC should be compared properly to be used and it should be used only with those pMDIs investigated.

Di Berardino F, Forti S, Piatti G, Fasano V. A comparative study of two different metered-dose inhaler-valved holding chambers in the administration of salbutamol. Chest. 2010;1372:502-503. [CrossRef] [PubMed]
 
Ahrens RC. On comparing inhaled beta adrenergic agonists. Ann Allergy. 1991;673:296-298. [PubMed]
 
Committee for Human Medicinal Products (CHMP) EMACommittee for Human Medicinal Products (CHMP) EMA 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. http://www.ema.europa.eu/pdfs/human/ewp/415100enfin.pdf. Accessed March 28, 2010.
 
Division of Bioequivalence, Office of Generic Drugs, FDADivision of Bioequivalence, Office of Generic Drugs, FDA Interim Guidance for Documentation of In Vivo Bioequivalence of Albuterol Inhalation Aerosols. Metered Dose Inhalers. 1994; Silver Spring, MD US FDA
 
Therapeutic Products Directorate. Health CanadaTherapeutic 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 (MDI). http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/mdi_bad-eng.pdf. Accessed March 28, 2010.
 

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References

Di Berardino F, Forti S, Piatti G, Fasano V. A comparative study of two different metered-dose inhaler-valved holding chambers in the administration of salbutamol. Chest. 2010;1372:502-503. [CrossRef] [PubMed]
 
Ahrens RC. On comparing inhaled beta adrenergic agonists. Ann Allergy. 1991;673:296-298. [PubMed]
 
Committee for Human Medicinal Products (CHMP) EMACommittee for Human Medicinal Products (CHMP) EMA 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. http://www.ema.europa.eu/pdfs/human/ewp/415100enfin.pdf. Accessed March 28, 2010.
 
Division of Bioequivalence, Office of Generic Drugs, FDADivision of Bioequivalence, Office of Generic Drugs, FDA Interim Guidance for Documentation of In Vivo Bioequivalence of Albuterol Inhalation Aerosols. Metered Dose Inhalers. 1994; Silver Spring, MD US FDA
 
Therapeutic Products Directorate. Health CanadaTherapeutic 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 (MDI). http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/mdi_bad-eng.pdf. Accessed March 28, 2010.
 
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