Abstract
On October 16, 2018, FDA expanded the adalimumab dosing regimen to adolescent hidradenitis suppurativa (HS) patients 12 years and older, weighing at least 30 kg without new clinical data. This approval was mainly supported by the model-informed drug development approach. Population pharmacokinetic simulations suggest body weight-tiered dosing regimens in adolescent patients will achieve similar exposure to adult patients across all weight range. Adalimumab has a well-established, 16-year long-term safety profile in various diseases in adult and pediatric populations. Current data of adalimumab in the pediatric population demonstrate no exposure-response relationship for adverse events. The effectiveness in adolescent patients was extrapolated from two adequate and well-controlled phase 3 studies in adult patients, assuming similar positive exposure-efficacy relationships in adults and adolescents. This article provides the insight of the application of MIDD on the adalimumab approval in adolescent HS patients and its implication on drug development and regulatory decision especially for pediatrics or rare diseases.
This is a preview of subscription content, log in via an institution to check access.
References
Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35–45.
Drug label for adalimumab BLA 125057, Oct 16 2018 <https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s409lbl.pdf>.
Humira : EPAR- Product Information. Aug 2018.
Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med. 2012;366:158–64.
Garg A, Wertenteil S, Baltz R, Strunk A, Finelt N. Prevalence estimates for hidradenitis suppurativa among children and adolescents in the United States: a gender- and age-adjusted population analysis. J Invest Dermatol. 2018;138:2152–6.
Wang Y, Zhu H, Madabushi R, Liu Q, Huang SM, Zineh I. Model-informed drug development: current US regulatory practice and future considerations. Clin Pharmacol Ther. 2019;105:899–911.
Bi Y, Liu J, Furmanski B, Zhao H, Yu J, Osgood C, et al. Model-informed drug development approach supporting approval of the 4-week (Q4W) dosing schedule for nivolumab (Opdivo) across multiple indications: a regulatory perspective. Ann Oncol. 2019;30:644–51.
Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med. 2016;375:422–34.
Kimball AB, Sobell JM, Zouboulis CC, Gu Y, Williams DA, Sundaram M, et al. HiSCR (Hidradenitis Suppurativa Clinical Response): a novel clinical endpoint to evaluate therapeutic outcomes in patients with hidradenitis suppurativa from the placebo-controlled portion of a phase 2 adalimumab study. J Eur Acad Dermatol Venereol. 2016;30:989–94.
Yao LP. Extrapolation in pediatric drug development: an evolving science. 2018 ASA biopharmaceutical section regulatory-industry statistics workshop. Sep 2018.
Guidance for industry: how to comply with the pediatric research equity act. Draft Guidance. Sep 2005.
Federal Food, Drug, and Cosmetic Act (FD&C Act) U.S. Food and Drug Administration.
Liy-Wong C, Pope E, Lara-Corrales I. Hidradenitis suppurativa in the pediatric population. J Am Acad Dermatol. 2015;73:S36–41.
FDA clinical pharmacology and biopharmaceutic review: treatment of active moderate to severe hidradenitis suppurativa in adult patients. 2015.
Van Steenbergen S, Bian S, Vermeire S, Van Assche G, Gils A, Ferrante M. Dose de-escalation to adalimumab 40 mg every 3 weeks in patients with Crohn’s disease - a nested case-control study. Aliment Pharmacol Ther. 2017;45:923–32.
Dubinsky MC, Rosh J, Faubion WA Jr, Kierkus J, Ruemmele F, Hyams JS, et al. Efficacy and safety of escalation of adalimumab therapy to weekly dosing in pediatric patients with Crohn’s disease. Inflamm Bowel Dis. 2016;22:886–93.
Ryan C, Sobell JM, Leonardi CL, Lynde CW, Karunaratne M, Valdecantos WC, et al. Safety of adalimumab dosed every week and every other week: focus on patients with hidradenitis suppurativa or psoriasis. Am J Clin Dermatol. 2018;19:437–47.
2 to 20 years: Boys, Stature-for-age and Weight-for-age percentiles. Centers for Disease Control and Prevention.
Acknowledgments
The data presented in this article are based on analysis results by the review team of Office of Clinical Pharmacology and the Office of New Drugs at the FDA. The original datasets and codes used for the analyses were provided by the AbbVie. PopPK analyses were conducted by the AbbVie and modified by FDA. Exploratory E-R analyses for safety and efficacy were conducted by the AbbVie.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
All listed authors are employees of the Food and Drug Administration of the United States. The authors indicated no potential conflicts of interest.
Disclaimer
The views expressed in this article are those of the authors and do not necessarily reflect the official views of the FDA.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bi, Y., Liu, J., Wang, J. et al. Model-Informed Drug Development Approach Supporting Approval of Adalimumab (HUMIRA) in Adolescent Patients with Hidradenitis Suppurativa: a Regulatory Perspective. AAPS J 21, 91 (2019). https://doi.org/10.1208/s12248-019-0363-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1208/s12248-019-0363-5