Kenneth A. Katz, MD,
Department of
Dermatology, Kaiser
Pleasanton, California.

author: Kenneth A.
Katz, MD, MSc, MSCE,
Department of
Dermatology, The
Permanente Medical
Group Inc, 7601
Stoneridge Dr, South
Building, Second Floor,
Pleasanton, CA 94588

Dermatologists, Imiquimod, and Treatment
of Molluscum Contagiosum in Children
Righting Wrongs
“Half of what we’re teaching you is wrong,” one of my
medical school deans would often say. “The problem,”
he would continue, “is that we don’t know which half.”
The dean was wise. Consider the case of imiquimod, long widely considered beneficial for treatment of molluscum contagiosum. It actually is not, as 2
large randomized clinical trials (RCTs) showed.1,2 The
catch is that those 2 RCTs were never published. As a result, physicians—including, especially, dermatologists—
continue to prescribe the drug for molluscum contagiosum in children. It’s time we stopped doing that.
The story begins in 1997, when imiquimod first received US Food and Drug Administration (FDA) approval for treatment of genital warts in adults. Soon physicians began prescribing imiquimod off-label to treat
molluscum contagiosum in children. That off-label use
was supported by the observation that genital warts and
molluscum contagiosum are both viral diseases, by the
lack of convenient therapies for molluscum contagiosum in children, and by the promising results of small observational studies and RCTs.
But the FDA was not convinced. To further address
the question, the FDA invoked authority conferred by the
Best Pharmaceuticals for Children Act (BPCA). Initially
enacted in 2002, the BPCA aims to promote pediatric
drug research by enabling the FDA to offer 6-month marketing exclusivity extensions, worth up to $500 million, to pharmaceutical companies that conduct FDArequested pediatric studies.3
In the case of imiquimod, the FDA requested that
3M, the drug’s then-manufacturer, conduct 2 RCTs and
1 pharmacokinetic study in children ages 2 to 12 years
with molluscum contagiosum. In 2006, 3M completed
the studies and received a marketing exclusivity extension for imiquimod.1
Neither RCT demonstrated evidence of imiquimod’s effectiveness, according to the FDA’s publicly
available review of both RCTs and to data contained in
imiquimod's package insert (PI).1,2 In one RCT,1,2 which
enrolled 323 children, complete clearance at 18 weeks
occurred in 24% of imiquimod-treated children and 26%
of vehicle-treated children; in the other,1,2 which enrolled 379 children, complete clearance occurred in 24%
and 28%, respectively. Moreover, imiquimod-treated
children were more likely to experience applicationsite reactions, otitis media, conjunctivitis, leukopenia,
and lymphadenopathy.1,2
In the pharmacokinetic study, according to the FDA
review,1 imiquimod application,1 imiquimod application to at least 10% of body surface area led to leukopenia or neutropenia in 40% and 25% of patients, respec-

tively, and to systemically detectable drug levels after
single and multiple doses.
Finding from all 3 studies led to changes, adopted
in 2007, in imiquimod’s FDA-approved PI.2 “Efficacy was
not demonstrated for molluscum contagiosum in children aged 2 to 12,” the amended PI states.2 The PI also
incorporated concerns raised by the studies about adverse events and systemic absorption.2
But few physicians know about those data. Critically, as with many BPCA studies—and particularly those
leading to unfavorable PI changes4—the 2 RCTs have
never been published. The BPCA does not require pharmaceutical companies to publish studies to receive marketing exclusivity extensions.3,4 The pharmacokinetic
study was published.5
The indexed medical literature has nearly entirely
ignored evidence of imiquimod’s lack of effectiveness
for molluscum contagiosum in children. As a colleague
and I documented,3 as of 2013 no major online references or textbooks—or even a Cochrance Collaboration
systematic review of treatments for molluscum contagiosum—mentioned the 2 RCTs. Nor were the 2 RCTs
referenced in a recent dermatology journal article
reviewing management of molluscum contagiosum in
children.6 All of those sources (with 1 exception)3 continued to include imiquimod as a treatment option for
molluscum contagiosum.
The upshot is that physicians continue to prescribe
imiquimod for children with molluscum contagiosum. In
a 2009 survey7 of health care providers (including 250
dermatologists) about treatment of molluscum contagiosum, 67 percent of dermatologists—more than twice
the percentage of any other specialty—reported prescribing imiquimod. Even among internists, the group
least likely to report prescribing imiquimod, 17% reported prescribing it.7 Although reported treatments
were not stratified by patient age, it is likely that many
physicians were prescribing imiquimod for children.
Physicians’ enthusiasm for prescribing imiquimod to
treat children with molluscum contagiosum would likely
dramatically decrease if they knew about the 2 RCTs.1,2
The RCT investigators should publish the results of the
2 RCTs. Even better—as has been advocated3,4—the
BPCA should be amended to make marketing exclusivity extensions conditional on publication of study data.
We should not wait. As experts in treating skin disease, we dermatologists must not continue prescribing
a medicine for children with molloscum contagiosum
that has been shown to be neither safe nor effective. It’s
time we shift our practice to reflect that knowledge.
The dean would be proud.

(Reprinted) JAMA Dermatology Published online January 14, 2015

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archderm.jamanetwork.com/ by a Kaiser Permanente User on 01/15/2015


Opinion Viewpoint

Published Online: January 14, 2015.
Conflict of Interest Disclosures: Dr Katz has stock
ownership or options in Arrowhead Research Corp
and Synta Pharmaceuticals Corp.
Disclaimer: The views expressed in this article do
not necessarily reflect those of Kaiser Permanente.
1. Papadopoulos EJ. Clinical executive summary
[Imiquimod]. http://www.fda.gov/downloads
/DevelopmentResources/UCM162961.pdf. Accessed
August 11, 2014.


2. Aldara (imiquimod) cream for topical use.
Dailymed. http://dailymed.nlm.nih.gov/dailymed
-8f78a5804ed3. Accessed August 11, 2014.
3. Katz KA, Swetman GL. Imiquimod, molluscum,
and the need for a better “best pharmaceuticals for
children” act. Pediatrics. 2013;132(1):1-3.
4. Benjamin DK Jr, Smith PB, Murphy MD, et al.
Peer-reviewed publication of clinical trials
completed for pediatric exclusivity. JAMA. 2006;

6. Berger EM, Orlow SJ, Patel RR, Schaffer JV.
Experience with molluscum contagiosum and
associated inflammatory reactions in a pediatric
dermatology practice: the bump that rashes. Arch
Dermatol. 2012;148(11):1257-1264.
7. Hughes CM, Damon IK, Reynolds MG.
Understanding U.S. healthcare providers’ practices
and experiences with molluscum contagiosum.
PLoS One. 2013;8(10):e76948.

5. Myhre PE, Levy ML, Eichenfield LF, Kolb VB,
Fielder SL, Meng TC. Pharmacokinetics and safety
of imiquimod 5% cream in the treatment of
molluscum contagiosum in children. Pediatr
Dermatol. 2008;25(1):88-95.

JAMA Dermatology Published online January 14, 2015

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archderm.jamanetwork.com/ by a Kaiser Permanente User on 01/15/2015