Questionable Drug Studies in Minors Enforced by Regulatory Authorities


Pediatric drug development, which has a complex background and history, has fundamental catches based around how children are defined in the context of clinical studies.

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

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.


  1. Hirschfeld S, Saint-Raymond A. Pediatric regulatory initiatives. Handb Exp Pharmacol. 2011;205:245-68
  2. Abreu AP, Kaiser UB. Pubertal development and regulation Lancet Diabetes Endocrinol. 2016 March ; 4(3): 254–264.
  3. Beunen GP, Rogol AD, Malina RM. Indicators of biological maturation and secular changes in biological maturation. Food Nutr Bull. 2006 Dec;27(4 Suppl Growth Standard):S244-56.
  4. Komlos J, Lauderdale BE. The mysterious trend in American heights in the 20th century. Ann Hum Biol. 2007;34(2):206–215.
  5. FDA 2019. Drugs for Treatment of Partial Onset Seizures: Full Extrapolation of Efficacy from Adults to Pediatric Patients 2 Years of Age and OlderGuidance for Industry.
  6. Sun H, Temeck JW, Chambers W, Perkins G, Bonnel R, Murphy D. Extrapolation of efficacy in pediatric drug development and evidence-based medicine: progress and lessons learned. Ther Innov Regul Sci 2017;2017:1–7.
  7. Momper JD, Mulugeta Y, Green DJ, et al. Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007. JAMA Pediatr. 2013 Oct;167(10):926-32.
  8. Rose K. Considering the Patient in Pediatric Drug Development. How good intentions turned into harm. Elsevier, London, UK, 2020.
  9. FDA 2020 EUCRISA (Crisaborole) label
  10. EMA 2015.EMA/PDCO Summary Report on the review of the list of granted Class Waivers.
  11. EMA Allopregnanolone/ brexanolone PIP EMEA-002051-PIP-02-16. EMA 2017
  12. EMA 2017. 10-year Report to the European CommissionGeneral report on the experience acquired as a result of the application of the Paediatric Regulation.
  13. Silverman WA, Andersen DH, Blanc WA, et al. A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 1956;18:6
  14. Burns LE, Hodgman JE, Cass AB. Fatal circulatory collapse in premature infants receiving chloramphenicol. N EngI J Med. 1959;261:1318-1321
  15. American Academy of Pediatrics (AAP) 1995 | Committee on Drugs |Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations Pediatrics 1995 Feb,95(2),286–294.
  16. Vargesson N. Thalidomide‐induced teratogenesis: History and mechanisms. Birth Defects Res C Embryo Today. 2015 Jun; 105(2): 140–156.
  17. Rägo L, Santo B: Drug Regulation: History, Present and Future. Uppsala, Sweden,2008
  18. Rose K, Neubauer D, Grant-Kels JM. Rational Use of Medicine in Children – The Conflict of Interests Story. A Review. Rambam Maimonides Med J. 2019 Jul 18; 10(3): e0018. Review. doi:10.5041/RMMJ.10371. 
  19. Shirkey H. Therapeutic Orphans. J Pediatr 1968 Jan; 72 (1), 119-120. 
  20. Ward RM, Benjamin DK Jr, Davis JM, et al. The Need for Pediatric Drug Development. J Pediatr 2018 Jan;192:13-21.
  21. van den Anker JN. Developmental Pharmacology. Dev Disabil Res Rev. 2010;16(3):233-8.
  22. Smits A, Annaert P, Cavallaro G, et al. Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper. Br J Clin Pharmacol 2022 Dec;88(12):4965-4984.
  23. Rosenthal, Elisabeth. An American Sickness: How Healthcare Became Big Business and How You Can Take it Back. Penguin, London, UK, 2017
  24. Gøtzsche PC. Deadly Medicines and Organised Crime: How Big Pharma Has Corrupted Healthcare. Routledge, London, UK, 2013
  25. Gøtzsche P. Deadly Psychiatry and Organized Denial. People's Press, København,Denmark 2015.
  26. Goldacre B. Bad Pharma: How drug companies mislead doctors and harm patients.HarperCollinsPublishers, London, UK, 2012
  27. Angell M. The Truth about the Drug Companies: How They Deceive Us and What to Do about It. Random House Publishers, New York, USA, 2004
  28. Angell M. Industry-sponsored clinical research: a broken system. JAMA. 2008 Sep 3;300(9):1069-71.
  29. Angell M. Conflicts in serving both non-profit and for-profit medical centres. BMJ. 2015 Oct 21;351:h5491. doi: 10.1136/bmj.h5491.
  30. Goldacre B. Bad Pharma: How drug companies mislead doctors and harm patients.HarperCollinsPublishers, London, UK, 2012 
  31. Goldacre B. Bad Science: Quacks, Hacks, and Big Pharma Flacks. Farrar, Straus and Giroux (FSG) Adult, NY, USA, reprint 2010
  32. Steinbrook R, Kassirer JP, Angell M. Justifying conflicts of interest in medical journals: a very bad idea. BMJ. 2015 Jun 2;350:h2942
  33. Rose K. The COVID-19 Pandemic: A Global High-Tech Challenge at the Interface of Science, Politics, and Illusions. Elsevier, London, UK, 2022
  34. Operation Warp Speed: Accelerated COVID-19 Vaccine Development Status and Efforts to Address Manufacturing Challenges.U.S. Government Accountability Office (GAO), 2021.
  35. FDA 2001. The Pediatric ExclusivityProvision. January 2001. Status Report to Congress.
  36. FDA 2016. BPCA and PREA Status Report to Congress July 9, 2012 – June 30, 2016.
  37. Boots I, Sukhai RN, Klein RH, et al. Stimulation programs for pediatric drug research - do children really benefit? Eur J Pediatr. 2007;166(8):849-55.
  38. Pellock JM, Carman WJ, Thyagarajan V, et al. Efficacy of antiepileptic drugs in adults predicts efficacy in children: a systematic review. Neurology. 2012 Oct 2;79(14):1482-9.
  39. Pellock JM, Arzimanoglou A, D'Cruz O, et al. Extrapolating evidence of antiepileptic drug efficacy in adults to children ≥2 years of age with focal seizures: The case for disease similarity. Epilepsia. 2017 Oct;58(10):1686-1696
  40. Rose K, Neubauer D, Grant-Kels JM. Ethical Issues in Pediatric Regulatory Studies Involving Placebo Treatment. J Pediatr Epilepsy 2020; 9(03): 073-079
  41. Rose K. Abuse of Minors in Clinical Studies: A Worldwide Ethical Challenge for the 21st Century. Ethics International Press, Bradford, UK, July 2023
  42. Rose K, Grant-Kels JM, Striano P, et al. “Pediatric” Drug Studies Might Be the Largest Abuse in Medical Research in History. It Is Time for Lawyers to Step In. J Law Med 2023,30(1),131-154
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