One doctor's opinion: BPCA should require publishing of studies

January 26, 2015

Physicians continue to prescribe imiquimod for children with molluscum contagiosum though study findings don't support efficacy and safety. One doctor calls for a shift in practice.

Writing in the Viewpoint online forum in the Jan. 14 JAMA Dermatology, dermatologist Kenneth Katz, M.D., recalls what his med-school dean would often say: “Half of what we’re teaching you is wrong - the problem is that we don’t know which half.”

Dr. Katz proves the dean’s wisdom by citing the example of imiquimod, which is widely accepted as en effective treatment for molluscum contagiosum.

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“It actually is not, as two large randomized clinical trials (RCTs) showed,” Dr. Katz explains. “The catch is that those two 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 Food and Drug Administration originally approved imiquimod in 1997 for treatment of genital warts in adults. It wasn’t long before physicians began prescribing the drug as an off-label treatment for molluscum contagiosum in children.

“That off-label use,” Dr. Katz writes, “was supported by the observation that genital warts and molluscum contagiosum are both viral diseases, by the lack of convenient therapies for molluscum contagiosumin children and by the promising results of small observational studies and RCTs.”

Soon the Food and Drug Adminstration (FDA), seeking to further address the question of whether imiquimod is appropriate for the off-label use, invoked the Best Pharmaceuticals for Children Act (BPCA). This law promotes pediatric drug research by allowing the FDA to offer six-month marketing exclusivity extensions, worth up to $500 million, to pharmaceutical companies that conduct FDA-requested pediatric studies.

“In the case of imiquimod, the FDA requested that 3M, the drug’s then-manufacturer, conduct two RCTs and one pharmacokinetic study in children ages two to 12 years with molluscum contagiosum,” Dr. Katz writes. “In 2006, 3M completed the studies and received a marketing exclusivity extension for imiquimod.”

But the RCTs did nothing to demonstrate 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).

“In one RCT, which enrolled 323 children, complete clearance at 18 weeks occurred in 24 percent of imiquimod-treated children and 26 percent of vehicle-treated children,” Dr. Katz explains. “In the other, which enrolled 379 children, complete clearance occurred in 24 percent and 28 percent, respectively. Moreover, imiquimod-treated children were more likely to experience application site reactions, otitis media, conjunctivitis, leukopenia and lymphadenopathy.”

The pharmacokinetic study showed that imiquimod application to at least 10 percent of body-surface area led to leucopenia or neutropenia in 40 percent and 25 percent of patients, respectively, and to systemically detectable drug levels after single and multiple doses.

The three studies’ findings led to changes in imiquimod’s FDA-approved PI. “Efficacy was not demonstrated for molluscum contagiosum in children aged 2 to 12,” the amended PI now reads. The PI also addresses concerns the studies raised about adverse events and systemic absorption.

“But few physicians know about those data,” Dr. Katz writes. “Critically, as with many BPCA studies - and particularly those leading to unfavorable PI changes - the two RCTs have never been published [though the pharmacokinetic study was]. The BPCA does not require pharmaceutical companies to publish studies to receive marketing exclusivity extensions.”

No surprise, then, that physicians continue to prescribe imiquimod for children with molluscum contagiosum.

“In a 2009 survey 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,” Dr. Katz writes, adding that if they were aware of the two RCTs, “physicians’ enthusiasm for prescribing imiquimod to treat children with molluscum contagiosum would likely dramatically decrease.”

Dr. Katz offers a simple solution to this serious oversight: The investigators should publish the results of the two RCTs. An even better solution-and one that’s been advocated-is amending the BPCA to make marketing exclusivity extensions conditional on the publication of study data.

“We should not wait” Dr. Katz writes. “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.”

Dr. Katz practices in Pleasanton, Calif.

Katz KA. Dermatologists, Imiquimod, and Treatment of Molluscum Contagiosum in Children: Righting Wrongs. JAMA Dermatol. 2015;