Questionable Drug Studies in Minors Enforced by Regulatory Authorities

Since 1997, the FDA has rewarded pediatric drug studies with patent extensions. Since 2003, US legislation demands pediatric studies also without a reward.

Image Credit: Adobe Stock - Minerva Studio

US legislation encouraged the European Union (EU) to create a comparable law that even goes further. Pharmaceutical companies must commit to pediatric studies in a "pediatric investigation plan" (PIP), which must cover all pediatric age groups. Without a PIP approved by the European Medicines Agency (EMA), the EMA will not process approval applications for new drugs.¹

Pediatric drug development (PDD) has fundamental catches. The authorities define children by age, the United States initially as <17 years of age, the EU as <18 years of age; however, both now use the 18th birthday. But the human body matures with puberty, not overnight before a birthday. Drugs treat the body, not the administrative and/or legal status.

Furthermore, the onset and end of puberty have shifted significantly to younger ages over the past hundred years.^2-4

The consequence is that young people who are already physically mature enough to be treated with adult doses are still formally children. To demand "pediatric" studies from such people is not based on science.

The FDA has backed away from over-the-top studies on minors in many areas. It now recognizes that antiseizure medications (ASMs) also work for partial onset seizures in young people,⁵ and now "only" requires studies to extrapolate the efficacy of adults to children.⁶ But even the notion of extrapolation is incorrect because young people with a mature body are not a different species.

FDA authors have shown that the doses found in alleged "child" studies across all clinical areas were, in virtually all cases, identical to the adult doses.⁷ In many other areas, the FDA is now accepting pivotal studies across a wide range of age groups, including minors, where this makes medical sense.⁸ For example, the pivotal studies for the approval of Crisaborol ointment for atopic dermatitis were conducted in patients aged 2 to 79 years.⁹

On the other hand, the EMA is more fundamental in its demands for "pediatric" studies and now also demands pediatric studies for malignant melanoma, amyotrophic lateral sclerosis (Lou Gehrig disease), multiple sclerosis, and Parkinson disease.¹⁰ Perhaps the most absurd and bizarre EMA-demanded study is a placebo-controlled, randomized, double-blind "pediatric" study in young mothers with perinatal depression below 18 years of age.¹¹

These depressed young mothers are administratively still minors, but physiologically no longer children. Medicines treat the patient, not the administrative status.

For drug developers, the pediatric study requirements have become an additional burden. Initially, the patent extension offered US companies financial rewards, so the industry supported the concept and funded many such studies. In the EU, the financial reward is negligible, but since drug approval is no longer possible without an approved PIP, all companies developing a new drug must comply.

The EU itself estimates that the costs of planning, negotiating, and implementing a PIP are around 20 million euros.¹² Large companies have come to terms with this situation. They can afford the additional costs. Many now have their own pediatric function to coordinate regulatory pediatric requirements. It is different for smaller companies.

The sticking point of PDD is that the study participants are often physically no longer children at all. Adolescents are young, physically adult people who are not yet of legal age.⁷

But the authorities demand separate efficacy and safety (E&S) studies as if they were a different species.PDD has a complex background and history—on one hand, it goes back to the 1950s with observations of toxicity in preterm infants treated with antibiotics.^13-15

Added to this was the processing of the thalidomide catastrophe, a tranquillizer that caused severe birth defects in thousands of babies worldwide.¹⁶ Since 1962, the FDA requires E&S studies to prevent further such catastrophes.¹⁷

As a protection against damage lawsuits, drug manufacturers included warnings into drug labels that the drug had not been tested in children.^8,18 This in turn was used by the chairman of the American Academy of Pediatrics (AAP) committee on drugs to characterize children as "therapeutic orphans" who were constantly being treated with drugs whose E&S was unknown.¹⁹

Scientifically, this claim is mostly not true—as children grow and mature. For the vast majority of minors at the time, physicians used formulas to calculate the dose required. These formulas were good, but not for the very small babies.

The observations of toxicity in preterm newborns and babies had now become the claim that in “children” everything is different, but now with legal, and not physical characteristics being used to define them. PDD is, in this regard, a blur at the interface of medicine and law.

PDD hit a nerve of the time and concern for children occupied a large space in the public consciousness. This was after better hygiene, diet, clothing, housing, and advances in medicine had prevented or allowed to treat infectious diseases. Supported by the American Academy of Pediatrics (AAP) and the new discipline of developmental pharmacology, PDD advocates managed to persuade US lawmakers that the non-approval of drugs for (now chronologically defined) "children" showed that they represented a neglected population group.

The great successes in pediatric medicine had occurred long before the regulatory debate about drugs for children. Childhood cancer had gone from being a death sentence to an often treatable and curable condition.

Many other fields of illness in pediatrics had emerged, such as the treatment of minors with rheumatic diseases, children with kidney diseases, multiple sclerosis, depression, and more. But the excitement of having found something that would further improve child health care was not to be marred by contrary facts.

A health crisis in the pediatric population was claimed and now the legislature had to step in.^20-22 One element was that the pharmaceutical industry had become the target of critical attacks.A whole generation of writers characterized the industry as evil and greedy,^23-26 further aided by academics who stressed the sanctity of their position against worldly interests.^27-32

This criticism may have peaked by now, but the industry’s negative image has become ingrained in the public consciousness.Who of us remembers that in the COVID-19 pandemic it was the life science industry that created a way out?

Countries such as Russia and China had developed the first vaccines and hoped to collect diplomatic Brownie points worldwide, until it became clear thattheir vaccines were not effective enough.³³ Ironically, under Trump's presidency, Operation Warp Speed provided massive financial support for the development of really effective vaccines.³⁴ The vaccine development against the coronavirus disease would not have been possible without the expertise, infrastructure, and experience of the life science industry.

There was never a health care crisis in children. It was an alleged crisis, conjured up against a backdrop of strengthened regulatory agencies and the growing importance of the new discipline of developmental pharmacology.^20-22

It was not a real crisis, but the belief that separate drug approvals before the 18th birthday would make a huge difference in pediatric medicine. The FDA mentioned such hopes in its 2001 Report to Congress, including quicker recoveries from childhood illnesses, fewer attendant hospital stays, physician visits, and parental work days lost.³⁵ Fifteen years later, these clinical expectations were replaced by regulatory endpoints, such as number of label changes and pediatric studies.³⁶

PDD is a phenomenon of our increasingly complex society, in which the demands of the regulatory authorities, the new discipline of developmental pharmacology, the economic interests of pediatric researchers, and other currents have been brought under one roof for the time being. PDD has provided the infrastructure for many pediatric studies.³⁷ But many of these studies are neither pediatric nor scientifically based.^8,18 PDD is a regulatory challenge falsely sold as a clinical crisis.

Just knowing that the demands of the authorities have a weak scientific basis is of little help for companies alone but it is no reason to hang your head. PDD is currently supported by a coalition of academic pediatric researchers, regulatory authorities, and some employees from large pharmaceutical companies.

Very few clinical pediatricians are aware of the regulatory context.They want to help young people. The "pediatric" epilepsy studies were brought down by epilepsy specialists who examined the studies of the past 40 years and concluded that they had been unjustified.^38,39 There are comparable examples in several other clinical areas.^8,18,40

Regulatory authorities fear a public dispute with clinicians and/or institutional review boards (IRBs)/ethics committees (ECs). PDD is an ethical challenge so far overlooked by IRBs/ECs.⁴¹ The better the respective company is prepared in the pediatric negotiations and knows the arguments of the other side, the better it can argue.

It is equally important to have clinical specialists on your side who are not intimidated by the authorities. Another reason to take this matter seriously is that institutions and companies that run studies that harm young people can be sued for damages.

The EMA-demanded "pediatric" studies often require comparison to placebo or to treatment below standard-of-care. This directly harms the young patients. The authorities themselves cannot be sued, but companies, researchers, and research centers can.

It is a question of time until when this will happen a first time. As EMA-demanded “pediatric” studies recruit patients worldwide, such a first lawsuit will probably happen in the United States with a questionable EMA-demanded study. US judges will not be impressed by EMA justifications if the parents are represented by a good lawyer.⁴²

About the Author

Klaus Rose, MD, MS, is Founder and Managing Director, klausrose Consulting, Pediatric Drug Development & More, Riehen, Switzerland.

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