The Challenges of Pediatric Drug Development

Abstract

Introduction and Background “Pediatric Drug Development” is being used to describe not the development of drugs for children, but rather the planning & conducting separate efficacy and safety (E&S) studies requested/demanded by regulatory authorities designed to produce pediatric labels. Pediatric studies required for drug approval enroll “children”; defined as <17 years of age (US Food and Drug Administration [FDA])/ <18 years (European Union [EU]). The medical rationale for study designs was examined. Material & Methods International industry-sponsored pediatric E&S studies registered in www.clinicaltrials.gov were analysed along with the history of US/EU laws, published literature, internet-retrieved regulatory documents, and regulatory/ American Academy of Pediatrics (AAP) justifications for doing separate pediatric E&S studies. Results US/EU regulators utilize an official, but non-physiological definition of childhood based on an age limit of 17/18 years. This definition, which blurs the interface between medicine and law, emerged after clinical studies became required for drug approval in 1962 prompting drug manufacturers to insert pediatric warnings into product information. Intended largely as legal protection against liability, they were interpreted medically. Absorption, distribution, metabolism, excretion mature rapidly. Drug toxicities seen in newborns during the first months of life were cited by AAP/FDA in warnings of dangers of drugs in all "children" including in adolescents who are physiologically no longer children. Warnings were/are exaggerated, exploit/ed parents' protective instincts and fears, and increase/d pediatric clinical trial activity. Conflicts of interest created by this increased activity involve research funding, career status & advancement, commercial profits. Discussion FDA/EMA-requested/demanded "pediatric" studies were identified which lack medical sense at best, others actually harm young patients by impeding use of superior, effective treatments. Separate labels for different indications make medical sense; separate approval in persons above/below 17/18 years of age does not. Conclusions Pediatric medical research should be restricted to studies which meet important medical needs of all recruited young patients, which generate information that cannot be obtained by other study designs, and do not limit access to superior alternative therapies. Clinical centers, investigators, and IRBs/ECs should more carefully examine studies for unjustified regulatory demands, prevention of subjects' access to superior treatments, and undeclared COI's. Questionable studies should not be approved and ongoing ones should be suspended.

Too Many Avoidable Suicides Occur Worldwide in Young Patients

“…In the 1950s, toxicities had been observed in preterm newborns treated with antibiotics 26. Consequently companies inserted pediatric warnings into drug labels to prevent damage lawsuits in the litigious US 17,18,20. The first chairman of the AAP’s committee on drugs soon thereafter declared that these warnings denied children the use of many modern drugs and characterized children as “therapeutic orphans.”19…”

“…It blurs two meanings of the word “child”: (1) all underage persons are legally “children”: they cannot give informed consent to participate in a study; and (2) physiologically, “children” are young, pre-pubertal, vulnerable persons. Adolescents and older pre-pubertal minors are physiologically no longer “children.” Justifications for separate “pediatric” studies switch between these meanings and confer an apparent physiological characteristic to the age limit of <17 (FDA)/<18 years (EMA) 17,18,20,22. These age limits are administrative, not physiological.…”

“…The concept of “pediatric drug development” did not evolve with scientific data in depression, but semantically as a blur between different meanings of the word “child” and furthermore from society’s desire to do “more” for “children,” as well as conflicts of interest that so far are little acknowledged 18,22. It originated from toxicities observed in preterm newborns treated with antibiotics 17,18,20,22,27. The FDA-rewarded “pediatric” trials in oncology, neurology, psychiatry, and other diseases did not emerge from clinical questions arising from hands-on clinical work, but from the concept that children-are-therapeutic-orphans 17,18,20,22…”

“…It originated from toxicities observed in preterm newborns treated with antibiotics 17,18,20,22,27. The FDA-rewarded “pediatric” trials in oncology, neurology, psychiatry, and other diseases did not emerge from clinical questions arising from hands-on clinical work, but from the concept that children-are-therapeutic-orphans 17,18,20,22…”

“…The concept that children are “therapeutic orphans” was the intellectual basis of the US pediatric legislation 19,20. In our opinion, we need an analysis of this concept and of the resulting demand for “pediatric drug development.”21 This concept was also the basis of the pediatric studies undertaken with antidepressants.…”