Performance of the Population Bioequivalence (PBE) Statistical Test Using an IPAC-RS Database of Delivered Dose from Metered Dose Inhalers
- 37 Downloads
This article reports performance characteristics of the population bioequivalence (PBE) statistical test recommended by the US Food and Drug Administration (FDA) for orally inhaled products. A PBE Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) assembled and considered a database comprising delivered dose measurements from 856 individual batches across 20 metered dose inhaler products submitted by industry. A review of the industry dataset identified variability between batches and a systematic lifestage effect that was not included in the FDA-prescribed model for PBE. A simulation study was designed to understand PBE performance when factors identified in the industry database were present. Neglecting between-batch variability in the PBE model inflated errors in the equivalence conclusion: (i) The probability of incorrectly concluding equivalence (type I error) often exceeded 15% for non-zero between-batch variability, and (ii) the probability of incorrectly rejecting equivalence (type II error) for identical products approached 20% when product and between-batch variabilities were high. Neglecting a systematic through-life increase in the PBE model did not substantially impact PBE performance for the magnitude of lifestage effect considered. Extreme values were present in 80% of the industry products considered, with low-dose extremes having a larger impact on equivalence conclusions. The dataset did not support the need for log-transformation prior to analysis, as requested by FDA. Log-transformation resulted in equivalence conclusions that depended on the direction of product mean differences. These results highlight a need for further refinement of in vitro equivalence methodology.
KEY WORDSpopulation bioequivalence inhalation products in vitro performance regulatory FDA
The authors would like to acknowledge IPAC-RS member companies, board of directors, and all members of the PBE working group for supporting this work through discussions and by providing the data.
- 1.FDA. Guidance for industry. Statistical approaches to establishing bioequivalence. 2001. http://www.fda.gov/downloads/Drugs/Guidances/ucm070244.pdf Accessed 9 Jul 2017.
- 2.FDA. Draft guidance for industry. Bioavailability and bioequivalence studies for nasal aerosols and nasal sprays for local action. 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070111.pdf. Accessed 9 Jul 2017.
- 3.FDA. Draft guidance on budesonide. 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM319977.pdf. Accessed 18 Sept 2017.
- 4.FDA. Draft guidance on azelastine hydrochloride and fluticasone propionate. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM452689.pdf. Accessed 9 Jul 2017.
- 5.FDA. Draft guidance on aclidinium bromide. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM460918.pdf. Accessed 9 Jul 2017.
- 6.FDA. Draft guidance on albuterol sulfate. 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346985.pdf. Accessed 9 Jul 2017.
- 7.FDA. Draft guidance on beclomethasone dipropionate. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM481768.pdf. Accessed 9 Jul 2017.
- 8.FDA. Draft guidance on budesonide; formoterol fumarate dihydrate. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM452690.pdf. Accessed 9 Jul 2017.
- 9.FDA. Draft guidance on ciclesonide (nasal). 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM319983.pdf. Accessed 9 Jul 2017.
- 10.FDA. Draft guidance on ciclesonide (inhalation). 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM481787.pdf. Accessed 9 Jul 2017.
- 11.FDA. Draft guidance on fluticasone furoate. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM495024.pdf. Accessed 9 Jul 2017.
- 12.FDA. Draft guidance on fluticasone furoate; vilanterol trifenatate. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM495023.pdf. Accessed 9 Jul 2017.
- 13.FDA. Draft guidance on fluticasone propionate. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM461051.pdf. Accessed 9 Jul 2017.
- 14.FDA. Draft guidance on fluticasone propionate; salmeterol xinafoate. 2013. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM367643.pdf. Accessed 9 Jul 2017.
- 15.FDA. Draft guidance on formoterol fumarate. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM461064.pdf Accessed 9 Jul 2017.
- 16.FDA. Draft guidance on formoterol fumarate; mometasone furoate. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM481824.pdf. Accessed 9 Jul 2017.
- 17.FDA. Draft guidance on indacaterol maleate. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM495054.pdf Accessed 9 Jul 2017.
- 18.FDA. Draft guidance on ipratropium bromide. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM436831.pdf. Accessed 9 Jul 2017.
- 19.FDA. Draft guidance on levalbuterol tartrate. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM452780.pdf. Accessed 9 Jul 2017.
- 20.FDA. Draft guidance on mometasone furoate. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM495387.pdf. Accessed 9 Jul 2017.
- 21.FDA. Draft guidance on mometasone furoate monohydrate. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM461141.pdf. Accessed 9 Jul 2017.
- 22.FDA. Draft guidance on umeclidinium bromide. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM520285.pdf. Accessed 9 Jul 2017.
- 23.FDA. Draft guidance on triamcinolone acetonide. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM520271.pdf. Accessed 9 Jul 2017.
- 24.FDA. Draft guidance on olopatadine hydrochloride. 2016. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM520248.pdf. Accessed 9 Jul 2017.
- 25.Anderson S, Hauk W. Consideration of individual bioequivalence. Pharmacometrics. 1990;18:259–73.Google Scholar
- 28.Davit BM, Nwaka PE, Buehler GJ, Conner DP, Haidar SH, Patel DT, et al. Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. Ann Pharmacother. 2009;43:1583–97. https://doi.org/10.1345/aph.1M141.CrossRefPubMedGoogle Scholar
- 30.IPAC-RS. A parametric tolerance interval tests for improved control of delivered dose uniformity of orally inhaled and nasal drug products. https://ipacrs.org/assets/uploads/outputs/IPAC-RS_DDU_Proposal_15_Nov_2001_Final-pdf.pdf. Accessed 25 Oct 2017.
- 32.Wasserstein RL, Lazar, NA. The ASA’s statement on p-values: context, process, and purpose. 2016;70:129–133.Google Scholar
- 33.IPAC-RS. Operating characteristic (OC) curves from simulation. Available at http://ipacrs.org/assets/uploads/outputs/Operating_Characteristic_(OC)_Curves_from_Simulation.pdf. Accessed 18 Sept 2017.
- 34.IPAC-RS. Summary data for operating characteristic curves from simulation. Available at http://ipacrs.org/assets/uploads/outputs/PBEsimresults_Sept2017.pdf. Accessed 18 Sept 2017.
- 35.FDA. Statistical information from the Jun 3 1999 draft guidance and statistical information for in vitro bioequivalence data posted on August 18, 1999. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070118.pdf. Accessed 11 Jul 2017.
- 38.EMA. Reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/03/WC500224995.pdf. Accessed 7 Jul 2017.