Have Children Truly Ever Been ‘Therapeutic Orphans?’


Imposing the FDA on-label/off-label framework on administratively defined "children" resulted in a regulatory demand for pediatric studies that had no basis in clinical medicine, with the exception of the small group of preterm newborns.

Dr. Harry Shirkey, chairman of the American Academy of Pediatrics (AAP) committee on drugs, talked of children as “therapeutic orphans” for the first time in 1963 at a conference and published his toughts in 1968.1,2 This concept looks back on a remarkable success story. It was adopted by the AAP, endorsed by the emerging discipline of developmental pharmacology, taken up by the FDA, and resulted in US pediatric legislation in 1997.

Credit: ibreakstock - stock.adobe.com.

Credit: ibreakstock - stock.adobe.com.

As if that were not enough, it inspired comparable legislation in the European Union (EU) and became the backbone of what is now called "pediatric drug development" (PDD).3,4

Shirkey cited as evidence the pediatric warnings that drug developers had inserted into labels since 1962, when new US pharmaceutical legislation had been enacted in response to the thalidomide catastrophe: "not to be used in children;…not recommended for use in infants and young children, since few studies have been carried out in this age group;…clinical studies have been insufficient to establish any recommendations for use in infants and children;…should not be given to children.“

Shirkey also complained that despite these warnings, many physicians continued to prescribe. He asked what a jury would decide if a defendant physician admitted to have prescribed a drug despite such clear warning.

He argued that children were now deprived of the use of safe medicines. And he used examples of treatment that had been considered as harmless but had been associated with unexpected adverse effects (AEs), such as oxygen in newborns. In conclusion, he demanded separate clinical efficacy and safety (E&S) studies also in children.1

The US legislation of 1962 had demanded proof of E&S in adequate and well-controlled studies. Drug developers had inserted pediatric warnings into labels for legal reasons to avoid damage lawsuits in the litigatious US legal environment.5-8

Shirkey's concept appears to be logical and coherent. But should physicians really have followed the warnings and not have used life-saving medicines in young patients? Shirkey argued medically that in newborns, treatments previously considered as harmless later showed negative AEs.

Many preterm newborns treated with oxygen developed retinopathy of prematurity—for awhile the largest single cause of infant blindness. When oxygen administration to preterm newborns was eventually reduced, retinopathy of prematurity decreased worldwide.9,10

But should physicians have let babies die because treatments were not yet approved? In the 1960s, drug development and drug approval were still emerging. Toxicities of antibiotics in preterm newborns had been reported in the 1940/50s.11-13

Shirkey used really observed toxicities but switched to discuss “children” in the legal sense: minors. Could a physician really have been charged for prescribing a drug despite a pediatric warning? In the 1960s, physicians used formulas and dosing tables to adapt doses for minors.14 They worked well in general, but not in premature newborns.

Shirkey used the nightmare of every physician: to be accused of malpractice. But what might be dangerous in a baby is not dangerous in all minors until they come of age.

Shirkey’s argument was legal and formal only, without any medical evidence. No public prosecutor would have charged a physician for saving the life of a patient of 15 years because the drug was not approved. No jury would have found him guilty.

Neonatology emerged in 1960s, but the dangers of antibiotics were already well known.15,16 No family physician would have dared to routinely treat a preterm baby. For example, in an emergency such as a hurricane, nobody would have expected the same level of treatment as in a neonate intensive care unit.

In several official statements, the AAP claimed a dilemma that the physician must often either not treat children or treat them with drugs based on adult studies or anecdotal empirical experience in children.13,17,18 In 1995, the AAP defined children as persons not yet of age,13 a legal definition.

The concept of children as “therapeutic orphans” uses medical technical terms, moral pressure, threat with litigation, and different meanings of the term “child” to create the impression that minors are bodily different from adults. In this exercise, the AAP successfully used its scientific authority. From a public relations point of view, this worked rather well.

In the 1960s and later, no major pediatric drug disasters occurred. But a group of influential pharmacologists and pediatricians conjured such an alleged crisis. A subheading in a lecture from 1999 was "CONTINUED PEDIATRIC THERAPEUTIC DISASTERS."19 But all listed problems had occurred in preterm neonates.

Clinical pharmacology measures absorption, distribution, metabolism, and excretion (ADME) of food and drugs. In short, what the body does to drugs and what drugs do to the body.20,21 Developmental clinical pharmacology investigates how ADME develops and changes over time.22

Biologically, there are not 2 human species of children before and adults after the 18th birthday.7,8,23 This distinction is legal,5,8 but such a static view is expressed in the literature until today.24-30

Developmental pharmacology was strongly involved in the intellectually justifying the “therapeutic orphans” concept. The lament about alleged continued pediatric therapeutic disasterswas given at a meeting where representatives of today’s European Society for Perinatal and Pediatric Pharmacology,31 the Japanese Society for Pediatric Clinical Pharmacology,32 and the US Pediatric Pharmacology Research Unit Network33 discussed how to resolve the therapeutic orphan problem.34,35

Some publications that claim that in “children” everything is different, and that pediatric drug development is essential to pediatric health care are rather differentiated. Others allege crudely a lack of availability of appropriate drugs for children.36,37

A comparable accusation is that children are a neglected group.25 The European Medicines Agency (EMA) complains that the use of unlicensed and off-label medicines in children is widespread, that in the EU 50% or more of medicines used in children have never actually been studied in this population, and warns that this lack of information may expose them to unwanted AEs or underdosing.38,39

The “pediatric population” is not a medically defined human group. The narrative of children as neglected therapeutic orphans is a tall tale without scientific basis—it is pseudo-science.

On a general level, there is off-label use of drugs, their off-label prescription, and their off-label promotion. The FDA does not regulate off-label use by patients or off-label prescription by physicians. It regulates the marketing of drugs.

If a company would register a new drug in a rare disease and promote it in a frequent disease, this would be off-label promotion. The FDA has issued fines of billions of dollars to companies for off-label promotion.40 The on-label/off-label discussion is a neverending story.41,42

Imposing the on-label/off-label framework on administratively defined "children" resulted in a regulatory demand for pediatric studies that had no basis in clinical medicine, with the exception of the small group of preterm newborns. But this imposition resulted in the requirement for clinical drug studies in all administratively defined minors.

The main beneficiary of these studies was academic research, supported by developmental pharmacology organizations, the AAP, and the regulatory authorities.A new kind of conflict of interest in the 21st century.5,8 Will a drug work better in a 17-year-old if it has a pediatric label? No, labels do not have magic power.

The AAP supports studies in “children” with the aim to get “pediatric” labels, but accepts off-label use if is based on sound expert medical judgment.43 It defends reasonable pediatricians’ decisions, but supports “pediatric” research irrespectively if the minors are bodily still children.5-8

The key advances in pediatrics were achieved by clinicians who used whatever was available, often by trial and error. There was no major involvement of the regulatory authorities.

See the development of the iron lung for children with polio, the development of the incubator for preterm babies, or the antibiotic treatment of preterm newborns to prevent or treat bacterial infections.15,16 Pediatric oncology and neonatology developed without interventions by the regulatory authorities.5-8

The first US pediatric legislation in 1997 represented an alleged compromise between drug developers, pediatric researchers, and the FDA, as companies could propose “pediatric” studies for patented drug. If the FDA agreed, it issued a “pediatric request.”

When the company had fulfilled its requirements, it got 6 months patent extension (“pediatric exclusivity”). A list of granted pediatric exclusivities is public and44 many, but not all written requests are published online.6

Six months patent extension can be rather rewarding, which has been discussed in depth in the literature.45-47 The other side is that pediatric researchers profited as well, because now companies had to consider studies. “Pediatric” drug studies are expansive, but unfortunately, most are medically pointless and many even cause harm.48,49

The FDA has stepped back in several clinical areas from the “children are not small adults” mantra, such as for drugs that treat or prevent epilepsy. For crisaborole ointment for neurodermatitis, the FDA accepted patients aged 2-79 years in the pivotal studies. In adolescents with malignancies, the FDA now recommends inclusion into promising adult studies.6

Children were never therapeutic orphans.A clever choice of words, if you blindly believe the authorities.7 A closer look reveals the gaps in this pseudo-scientific argument.It is time for the life science industry, which achieves top scientific and technical achievements, to take a closer look at this challenge and the interface between medicine and law.5,8

About the Authors

Earl B Ettienne, BScPharm, MBA, LPD,Assistant Dean of Graduate Programs and Industrial Partnerships, Howard University, College of Pharmacy, Washington, DC; and Klaus Rose, MD, MS, klausrose Consulting, Riehen (BS), Switzerland.


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