Pediatric Melanoma and Drug Development.

Klaus Rose,Jane Grant-Kels

doi:10.3390/children5030043

Abstract

Importance—Pediatric melanoma occurs, albeit rarely. Should patients be treated by today’s medical standards, or be subjected to medically unnecessary clinical studies? Observations—We identified international, industry-sponsored pediatric melanoma studies triggered by regulatory demands in www.clinicaltrials.gov and further pediatric melanoma studies demanded by European Union pediatric investigation plans. We retrieved related regulatory documents from the internet. We analyzed these studies for rationale and medical beneficence on the basis of physiology, pediatric clinical pharmacology and rationale. Regulatory authorities define children by chronological age, not physiologically. Newborns’ organs are immature but they develop and mature rapidly. Separate proof of efficacy in underage patients is justified formally/regulatorily but lacks medical sense. Children—especially post-puberty—and adults vis-a-vis medications are physiologically very similar. Two adolescent melanoma studies were terminated in 2016 because of waning recruitment, while five studies in pediatric melanoma and other solid tumors, triggered by European Union pediatric investigation plans, continue recruiting worldwide. Conclusions and Relevance—Regulatory-demanded pediatric melanoma studies are medically superfluous. Melanoma patients of all ages should be treated with effective combination treatment. Babies need special attention. Children need dose-finding and pharmacokinetic studies but adolescents metabolize and respond to drugs similarly to adults. Institutional Review Boards/ethics committees should suspend ongoing questionable pediatric melanoma studies and reject newly submitted questionable studies.

Highlights

Metastatic malignant melanoma, once incurable, can today be treated, even in some cases with durable responses [1]
We identified further pediatric melanoma studies demanded by the European Medicines Agency (EMA) in pediatric investigation plans (PIPs)
Two PIP decisions that originally demanded pediatric studies [32,33] were later changed into waivers

Summary

Introduction

Metastatic malignant melanoma, once incurable, can today be treated, even in some cases with durable responses [1]. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) promote and require pediatric studies [4,5,6] In melanoma, such studies appear to recruit predominantly patients with adult-type conventional melanoma [7]. The American Academy of Pediatrics (AAP) defines children in the context of healthcare as ≤21 years but accepts pediatric healthcare for older patients with special needs [18]. These age ranges are appropriate for hands-on pediatric clinical care, they should not be used to limit access to pharmacological treatment. From 1962 onwards, drug developers included pediatric warnings on drug labels to avoid potential lawsuits As a result, these drugs could not be advertised for children. The AAP guideline of 1995 [25] explicitly referenced the toxicities reported in the 1950s [21,22]

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Conclusion