Acne vulgaris is an extraordinarily common skin condition in adolescents. The mainstays of acne treatment have remained largely unchanged over recent years. In the context of increasing antibiotic resistance worldwide, there is a global movement away from antibiotic monotherapy toward their more restrictive use. Classically reserved for nodulocystic acne, isotretinoin has become the drug of choice by dermatologists for moderate to severe acne. Given the virtually ubiquitous nature of acne in teenagers, there remains an appreciable need for novel therapies. In this article, we will cover the currently used acne treatments, evaluate the issues and data supporting their use, explore the issues of compliance and the mental health implications of acne care, and recommend directions for the field of acne management in adolescents in the years ahead.
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May 2020
Comments
RE: Trends in Isotretinoin-Exposed Pregnancies Pre- and Post-iPLEDGE
As researchers with interest in isotretinoin-exposed pregnancies, we write to offer some comment on trends in isotretinoin-exposed pregnancies as advanced by Habeshian and Cohen in their excellent review article.[1] The authors cite a recent (2019) analysis of adverse event reports submitted to FDA by Tkachenko et al. [2] to assert an “absolute decrease in pregnancy-related outcomes…after the implementation of iPLEDGE in 2006.” Indeed, by inspection of Figure 1 from the analysis by Tkachenko et al., it is easy to appreciate a marked decrease in reporting of pregnancies to the FDA Adverse Event Reporting System (FAERS) database since 2006. However, it should be stressed that iPLEDGE is designed to prevent isotretinoin-exposed pregnancies: it is not designed to identify and enumerate them. Therefore, we believe it is untenable to infer that a decrease in reporting of isotretinoin-exposed pregnancies actually represents a decrease in isotretinoin-exposed pregnancies (or the underlying pregnancy rate) in the recipient population at large.
Prior to iPLEDGE, Mitchel et al reported a pregnancy rate of 2.9 per 1,000 women exposed to isotretinoin based on the experience of Boston University’s Slone Survey (1989-99). [3] We reported a very similar pregnancy rate of 3.5 per 1,000 women in our evaluation of the Accutane SMART program (2002-03). [4] There have also been robust efforts to assess rates of isotretinoin-exposed pregnancies following the initiation of iPLEDGE in 2006. In a public presentation in 2012, 3 sponsors of generic isotretinoin reported a pregnancy rate of 1.2 per 1,000 based on 150 pregnancies captured by iPLEDGE year 5 (Mar 2010-Feb 2011).[5] Shin et al reported a rate of 2.7 pregnancies per 1,000 based on 11 pregnancies captured within patients enrolled in Kaiser of California during 2006 and 2007.[6] More recently, MacDonald et al advanced a rate of 3.0 per 1,000 pt-years (or approx. 1.5-2.0 per 1,000 patients based on a 4-6 month course of therapy by our calculations) from a claims-based analysis for years 2011-2014. [7] These estimates suggest a relatively stable rate over time. Since reporting can also be proportional to use, a decline in absolute report counts in the recent past could be due to decreasing utilization [7] assuming the underlying rate remains constant.
With a point of reference of cases reported to iPLEDGE 2008-2011, Collins et al [8] stated an opinion in 2014 that the absolute number of isotretinoin pregnancies in the United States was stable at approximately 150 per year. In our review of the literature, we could find no data that would support the supposition that the rate of isotretinoin-exposed pregnancies in the population at large has markedly changed in the recent past. To us, recent trends in reporting for isotretinoin-exposed pregnancies appear most consistent with stimulated reporting due to notoriety through 2006 and decreased reporting due to “reporting fatigue” thereafter, both known limitations of adverse event reporting. [9,10]
While there have been numerous specific interventions by drug sponsors and other stakeholders since the initial marketing of isotretinoin in 1982 that might impact the incidence of isotretinoin-exposed pregnancies, we argue that trends in adverse event reports offer no inference on the true rate of isotretinoin pregnancies in the recipient population at large.
Disclaimer
The views expressed are those of the authors and do not necessarily represent the position of, nor imply endorsement from, the U.S. Food and Drug Administration or the U.S. Government.
References
1. Habeshian KA, Cohen BA. Current Issues in the Treatment of Acne Vulgaris. Pediatrics
2020;145(Suppl 2):S225-S230.
2. Tkachenko E, Singer S, Sharma P, Barbieri J, Mostaghimi A. US Food and Drug Administration reports of pregnancy and pregnancy-related adverse events associated with isotretinoin. JAMA Dermatol 2019;155(10):1175-1179.
3. Mitchell AA, Van Bennekom CM. Comment on Pregnancy and pregnancy rates in association with isotretinoin (Accutane). J Am Acad Dermatol 2003;49(6):1201-1202.
4. Brinker A, Kornegay C, Nourjah P. Trends in adherence to a revised risk management program designed to decrease or eliminate isotretinoin-exposed pregnancies: evaluation of the Accutane SMART program. Arch Dermatol 2005;141(5):563-569.
5. Dermatologic and Ophthalmic Drugs Advisory Committee, Food and Drug Administration. Briefing document for iPLEDGE. https://wayback.archive-it.org/7993/20170405213524/https://www.fda.gov/d...
CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCo
mmittee/UCM281376.pdf. Accessed April 20, 2020.
6. Shin J, Cheetham TC, Wong L, Niu F, Kass E, Yoshinaga MA, Sorel M, McCombs JS, Sidney S. The impact of the iPLEDGE program on isotretinoin fetal exposure in an integrated health care system. J Am Acad Dermatol 2011;65(6):1117-1125.
7. MacDonald SC, Cohen JM, Panchaud A, McElrath TF, Huybrechts KF, Hernández-Díaz S.
Identifying pregnancies in insurance claims data: Methods and application to retinoid teratogenic surveillance. Pharmacoepidemiol Drug Saf 2019;28(9):1211-1221.
8. Collins MK, Moreau JF, Opel D, Swan J, Prevost N, Hastings M, Bimla Schwarz E, Korb Ferris L. Compliance with pregnancy prevention measures during isotretinoin therapy.
J Am Acad Dermatol 2014;70(1):55-59.
9. Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther 1998;20 Suppl C:C40-44.
10. Sachs RM, Bortnichak EA. An evaluation of spontaneous adverse drug reaction monitoring systems. Am J Med 1986; 81 Suppl 5B:49-55.