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Imiquimod, Molluscum, and the Need for a Better “Best Pharmaceuticals for Children” Act -- Main article

Imiquimod, Molluscum, and the Need for a Better “Best Pharmaceuticals for Children” Act -- Main article

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Published by Kenneth Katz
Main article

Published online June 24, 2013, doi: 10.1542/peds.2013-0116
PEDIATRICS June 24, 2013
Main article

Published online June 24, 2013, doi: 10.1542/peds.2013-0116
PEDIATRICS June 24, 2013

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Published by: Kenneth Katz on Jun 24, 2013
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DOI: 10.1542/peds.2013-0116; originally published online June 24, 2013;
Kenneth A. Katz and Glenda L. Swetman
Children'' ActImiquimod, Molluscum, and the Need for a Better ''Best Pharmaceuticals for
located on the World Wide Web at:The online version of this article, along with updated information and services, is
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academypublished, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned,PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
 at Kaiser Permanente Clinical Library on June 24, 2013pediatrics.aappublications.orgDownloaded from 
Imiquimod, Molluscum, and the Need for a Better
Best Pharmaceuticals for Children
It was the best research Emily
s doctor had never heard about.*Emily was a delightful 6-year-old with molluscum contagiosum (MC).Characteristic dome-shaped umbilicated papules, some of them itchy,peppered her chest and buttocks. Emily had returned to the clinic,where one of us (KAK) saw her, after she failed treatment with imi-quimod 5% cream.Coincidentally, Emily was born just as 2 rigorously conducted ran-domized controlled trials (RCTs) of imiquimod for treatment of MC inchildren were concluding. In both studies, imiquimod proved in-effective. Six years later, and 5 years after imiquimod
s package insert(PI) had been updated to include those RCT results, no studies hadshown otherwise.So why was Emily prescribed imiquimod? It would be easy to blameEmily
s doctor.But it
s not that simple.The real problem lies in a federal law that allows data from pediatricdrug studies requested by the federal government and subsidized by taxpayers to escape meaningful dissemination to physicians. As a re-sult, children like Emily are needlessly exposed to ineffective and/orunsafe medicines.Imiquimod was
rst approved by the Food and Drug Administration(FDA) for treatment of genital warts in adults in 1997. Physicians soonbegan using it off-label to treat MC in children.There were good reasons for that. First, other treatments were in-convenient and/or poorly tolerated. Second, imiquimod had proveneffective for genital warts, which like MC are caused by a virus. Third,numerous observational studies and review articles, as well as 2 smallRCTs, suggested that imiquimod might work.But the evidence was not overwhelming, and imiquimod is not benign.It can cause application site reactions and, rarely,
ulike symptomsand other systemic adverse effects.To address questions about imiquimod
s safety and ef 
cacy in treating MCin children, the FDA stepped in, using its authority under the BestPharmaceuticals in Children Act (BPCA). Signed into law in 2002 and
*The name of the child discussed in the manuscript has been changed to protect herprivacy.
Kenneth A. Katz, MD, MSc, MSCE, and Glenda L.Swetman, MD
The Permanente Medical Group, Inc., Pleasanton, California 
molluscum contagiosum, imiquimod, clinical trials, public policy
Best Pharmaceuticals for Children ActFDA
Food and Drug AdministrationMC
Molluscum contagiosumPI
package insertRCT
randomized controlled trialDr Katz conceptualized the manuscript and drafted the initialmanuscript; Dr Swetman helped conceptualize the manuscriptand reviewed and revised the manuscript; and both authorsapproved the
nal manuscript as submitted.The views expressed in this manuscript are those of the authorsand do not necessarily represent the views of The PermanenteMedical Group, Inc.www.pediatrics.org/cgi/doi/10.1542/peds.2013-0116doi:10.1542/peds.2013-0116Accepted for publication Apr 17, 2013Address correspondence to Kenneth A. Katz, MD, MSc, MSCE, ThePermanente Medical Group, Inc., 7601 Stoneridge Dr, SecondFloor, Pleasanton, CA 94588. E-mail:kenneth.katz@gmail.comPEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).Copyright © 2013 by the American Academy of Pediatrics
Dr Katz is a contributor to several of  the publications listed in Supplemental Table 1, including 
Decision Support in Medicine
, and 
sDermatology in General Medicine
. He is a shareholder in Synta Pharmaceuticals Corp. Dr Swetman has indicated she has no 
nancial relationships relevant to this article to disclose.
No external funding.PEDIATRICS Volume 132, Number 1, July 2013
 at Kaiser Permanente Clinical Library on June 24, 2013pediatrics.aappublications.orgDownloaded from 
made permanent in 2012, BPCA isa major pillar of the federal govern-ment
s efforts to promote pediatric drugresearch.The need formore researchstems from the existence of potentially dangerousgaps in knowledge about prescriptiondrug use in children. Although childrenoften respond to drugs differently fromadults, drug companies often lac
-nancial incentives to study drugs inchildren.
The BPCA enables the FDA to offer drugcompanies a quid pro quo. The FDAgets data from speci
cally requestedpediatric studies of drugs used forconditions deemed of public healthimportance. In return, FDA rewardscompanies with 6-month marketingexclusivity extensions for a drug, worthup to $500 million.
The BPCA has spurred substantialpediatric drug research and rewards:
300 study requests,
44 000 childrenenrolled in studies,
100 PI amend-ments, and
100 marketing exclusivityextensions granted.
Regarding imiquimod, FDA requested 2RCTs and 1 pharmacokinetic study, allin children aged 2 to 12 years with MC.
In 2006, 3M, imiquimod
s original man-ufacturer, received a marketing exclu-sivity extension after having completed the RCTs and the pharmacokinetic study,which enrolled 702 and 22 children,respectively.
The study results were clear: imiquimoddid not work. In both studies, a similarproportion (
25%) of both imiquimod-and vehicle-treated children cleared their MC after 18 weeks.
However, imiquimod might harm chil-dren.IntheRCTsmoreimiquimod-treatedchildren experienced application-site re-actions (by far the most commonly re-ported adverse effect of imiquimod, inboth children and adults) as well as otitismedia, conjunctivitis, leukopenia, andlymphadenopathy.
In the pharmacokinetic study, in whichimiquimod was applied to at least 10%of body surface area (
maximal useconditions
), systemic absorption wasdetected after just 1 dose.
White bloodcell (WBC) and absolute neutrophilcounts decreased; 40% and 25% of subjects, respectively, experienced leu-kopenia or neutropenia.
the FDA reviewer wrote,
may bedue to systemic effects of imiquimod.
As a result, imiquimod
s PI was amendedin 2007 to state that
cacy was notdemonstrated for MC in children aged2
and to present additionalpharmacokinetic and safety informa- tion, including effects on white bloodcell and absolute neutrophil counts.
In accordance with BPCA requirements, the FDA posted its review of the studieson its Web site.
For its part, 3M and its coinvestigatorspublished the pharmacokinetic studyin a peer-reviewed, PubMed-indexed journal, proving a more favorable in- terpretation of the results than that in the FDA review or the PI amendment.The drug
s effects on blood counts, theauthors wrote, were
not considered to be clinically meaningful,
and per-cutaneous absorption was judged
minimal or very low.
In passing, in the second-to-last paragraph of thediscussion section, the article men- tioned the 2 RCTs and also, interestingly,hypothesized that characteristics of theMC virus genome could explain imiqui-mod
s lack of ef 
3M also postedsummaries of all 3 studies on a now-defunct industry-sponsored Web site.3M never published the RCTs them-selves in a journal. The BPCA does notrequire companies to do so.Not that they would have been dif 
cult topublish. Many journals likely would havebeen interested in publishing the RCTs.MC is acommon conditionand thereforeof substantial interest to clinicians. TheRCTs upended conventional thinkingabout imiquimod
s effectiveness whileraising pediatric safety concerns.However, failure to have published theRCTs in a peer-reviewed, PubMed-indexed journal means, practically, that doctorslike Emily
s are unlikely to know about them. Practicing physicians generally donot peruse PIs for updates, scour phar-macokinetic study reports, or search theFDA Web site for BPCA-related reviews.Rather, when looking to the medical lit-erature to solve clinical problems,physicians might search for clinical tri-als on PubMed or, more likely, for reviewarticles in medical journals, textbook chapters, or online reference guides.Yet no major dermatology or pediatrics textbooks or online references, all pub-lished since 2007, even mention the 2negative imiquimod RCTs (SupplementalTable 1). Nor does an exhaustivelyresearched Cochrane Collaboration sys- tematic review on MC, updated in 2009(Supplemental Table 1). Nearly all in-clude imiquimod as a reasonable treat-ment option. (The sole exception isa dermatology textbook that recom-mends against imiquimod on the basisof an alleged lack of trial data.)Moreover, RCTs of imiquimod for MC inchildren continue to be designed,conducted, and reported without ref-erence to the 2 BPCA RCTs.
This is not the
rst time that publicationof studies conducted under BPCA orsimilar programs has been found lack-ing. One study found that only 44% of such studies were published in anindexed, peer-reviewed journal.
sexperience illustrates the continuinghazard to evidence-based practice posedby lack of publication of BPCA studies.It
s time to
x the problem.Congress should amend BPCA by re-quiring publication of studies in peer-reviewed medical journals as anadditional condition for marketingexclusivity extensions, as others haveadvocated.
Acceptable journals should
 at Kaiser Permanente Clinical Library on June 24, 2013pediatrics.aappublications.orgDownloaded from 

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