Abstract
Proper adhesion plays a critical role in maintaining a consistent, efficacious, and safe drug delivery profile for transdermal and topical delivery systems (TDS). As such, in vivo skin adhesion studies are recommended by regulatory agencies to support the approval of TDS in new drug applications (NDAs). A draft guidance for industry by the US Food and Drug Administration outlines a non-inferiority comparison between a test product and its reference product for generic TDS in abbreviated new drug applications (ANDAs). However, the statistical method is not applicable for evaluating adhesion of TDS for NDAs, because no reference product exists. In this article, we explore an alternative primary endpoint and a one-sided binomial test to evaluate in vivo adhesion of TDS in NDAs. Statistical considerations related to the proposed approach are discussed. To understand its potential use, the proposed approach is applied to data sets of in vivo adhesion studies from selected NDAs and ANDAs.
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References
FDA. Guidance for Industry (Draft Guidance): Transdermal and topical delivery systems - product development and quality considerations. 2019. https://www.fda.gov/media/132674/download. Accessed 1 Feb 2020
Singh I, Morris AP. Performance of transdermal therapeutic systems: effects of biological factors. Int J Pharm Investig. 2011;1(1):4–9.
Paudel KS, Milewski M, Swadley CL, Brogden NK, Ghosh P, Stinchcomb AL. Challenges and opportunities in dermal/transdermal delivery. Ther Deliv. 2010;1(1):109–31.
Pastore MN, Kalia YN, Horstmann M, Roberts MS. Transdermal patches: history, development and pharmacology. Br J Pharmacol. 2015;172(9):2179–209.
Jassim ZE, Sulaiman HT, Jabir SAH. Transdermal drug delivery system: a review. J Pharm Res. 2018;12(5):802.
Wiedersberg S, Guy RH. Transdermal drug delivery: 30+ years of war and still fighting! J Control Release. 2014;190:150–6.
Walter JR, Xu S. Therapeutic transdermal drug innovation from 2000 to 2014: current status and outlook. Drug Discov Today. 2015;20(11):1293–9.
Strasinger C, Raney SG, Tran DC, Ghosh P, Newman B, Bashaw ED, et al. Navigating sticky areas in transdermal product development. J Control Release. 2016;233:1–9.
Grissinger M. Fentanyl patch fatalities: we all have a role in prevention! Pharm Therapeut. 2016;41(7):405.
FDA. Guidance for Industry (Draft Guidance): Assessing adhesion with transdermal and topical delivery systems for ANDAs. 2018. https://www.fda.gov/media/98634/download. Accessed 1 May 2019
FDA. Approval package for ANDA 200910 (Xulane). 2014. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/200910Orig1s000.pdf. Accessed 1 May 2019
EMA. Draft guideline on quality of transdermal patches. 2012. https://www.ema.europa.eu/documents/scientific-guideline/draft-guideline-quality-transdermal-patches_en.pdf. Accessed 1 May 2019
EMA. Guideline on quality of transdermal patches. 2014. https://www.ema.europa.eu/documents/scientific-guideline/guideline-quality-transdermal-patches_en.pdf. Accessed 1 May 2019
Cai TT. One-sided confidence intervals in discrete distributions. J Stat Plan Infer. 2005;131(1):63–88.
Brown LD, Cai TT, DasGupta A. Interval estimation for a binomial proportion. Stat Sci. 2001:101–17.
Brown LD, Cai TT, Dasgupta A, et al. Confidence intervals for a binomial proportion and asymptotic expansions. Ann Stat. 2002;30(1):160–201.
Wilson EB. Probable inference, the law of succession, and statistical inference. J Am Stat Assoc. 1927;22(158):209–12.
Agresti A, Coull BA. Approximate is better than “exact” for interval estimation of binomial proportions. Am Stat. 1998;52(2):119–26.
Berger JO. Prior information and subjective probability.In: Berger JO, author. Statistical decision theory and Bayesian analysis. New York: Springer; 1985. pp. 74–117.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika. 1934;26(4):404–13.
Anscombe FJ. The transformation of Poisson, binomial and negative-binomial data. Biometrika. 1948;35(3/4):246–54.
Fleiss JL. Statistical methods for rates and proportions. 2nd ed. New York: Wiley; 1981.
Acknowledgments
The authors would like to thank Dr. Wanjie Sun at the US Food and Drug Administration for providing a list of abbreviated new drug applications that expedited the real data analysis and Dr. S. Edward Nevius at the US Food and Drug Administration for his proofreading and comments that improved the presentation of the paper. The authors also thank two peer reviewers whose suggestions have led to significant improvement of this paper.
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Wang, C., Strasinger, C., Shen, M. et al. Statistical Considerations in Assessing In Vivo Adhesion with Transdermal and Topical Delivery Systems for New Drug Applications. AAPS J 22, 137 (2020). https://doi.org/10.1208/s12248-020-00519-z
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DOI: https://doi.org/10.1208/s12248-020-00519-z