Pediatric Melanoma and Drug Development

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 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.

Pediatric melanoma—The whole (conflicts of interest) story

“…So far, more than 1000 PIPs have been issued (European Union, 2017), with each demanding one, few, or many pediatric studies. FDA-requested/demanded and PIP-demanded pediatric studies ask predominantly for separate proof of efficacy in minors (Field and Boat, 2012, Rose and Grant-Kels, 2018b) and often include young adults age ≤ 21 years. Many patients in these studies are physiologically no longer children but rather adolescents and young adults.…”

“…The pharmacokinetic and safety study was terminated with 14 enrolled patients, of whom 12 were treated with ipilimumab (U.S. Food and Drug Administration, 2017, Geoerger et al, 2017, Rose and Grant-Kels, 2018a, Rose and Grant-Kels, 2018b). Recruitment had waned because the superiority of ipilimumab plus nivolumab had resulted in FDA approval (FDA clinical review ipilimumab, 2017).…”

“…The study was not pediatric and should have been stopped in 2011 for patients age ≥ 18 years. A PIP-demanded phase 1 pediatric melanoma study with vemurafenib in adolescents was terminated because recruitment had waned (Rose and Grant-Kels, 2018b, Rose and Walson, 2017a).…”

“…Instead of applying the learnings of developmental pharmacology (Kearns et al, 2003) to drug approval and clinical practice, fears are amplified and used to justify questionable, label-focused, regulatory studies performed by clinicians (Turner et al, 2017) and coordinated by the FDA and EMA (Dunne et al, 2012, Saint-Raymond and Brasseur, 2005, Tomasi et al, 2017). These studies are paid for initially by pharmaceutical companies (Li et al, 2007, Rose and Grant-Kels, 2018b) but ultimately by patients, their families, and the tax payers. The highest price is paid by the young patients who are prohibited from already approved efficacious safe therapies because of these misconceptions.…”

“…Pediatric melanoma remains a paradigm of profound and unsolved challenges of innovative medicine because of the 1) contrast between how well young patients with melanoma could be treated versus how they are not given access to some of these new medications and are enrolled in questionable studies; 2) kafkaesque interference in medical treatment by the FDA and EMA; and 3) grudging and partial recognition by regulators and clinicians of committed errors in this arena (Geoerger et al, 2017, Rose and Grant-Kels, 2018b) To ethically and successfully advise and treat young patients with melanoma and their families, physicians need an intellectual compass to navigate the jungle of conflicting information, false promises, and useless studies (Rose and Grant-Kels, 2018b).…”