"Pediatric" Drug Studies Might Be the Largest Abuse in Medical Research in History. It Is Time for Lawyers to Step In.

A new type of research has emerged with United States and European Union pediatric laws that request/demand separate clinical studies for vaccines and drugs in minors less than 18 years of age. Physiologically, minors mature before their 18th birthday. Medicine treats the body, not the administrative status. Many "pediatric" studies are performed in minors that bodily are no longer children, which makes them pointless. Traditional malpractice litigation in clinical research involves patients that were harmed in clinical studies. In the new type of "pediatric" studies, drugs known to work in humans are retested, pretending that "children" are uniquely different, which is incorrect. Minors are not another species. Patients are not treated at all (placebo group) or below standard-of-care (comparison to outdated treatment). Pediatric laws are the law, but not a free pass for harming patients. Where "pediatric" studies violate accepted norms of medical practice, lawyers should be aware of this challenge at the interface of medicine and law.

The Challenges of Pediatric Drug Development.

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.

Questionable Industry-Sponsored Postneonatal Pediatric Studies in Slovenia.

BACKGROUND: US and EU pediatric laws promote industry-sponsored pediatric studies, based on the therapeutic orphans concept that claims discrimination of children in drug treatment and drug development. OBJECTIVE: We investigated the medical validity of international pediatric studies with centers in Slovenia, an EU member state, and challenge their medical utility. METHODS: We analyzed international industry-sponsored pediatric studies with centers in Slovenia, listed in www.ClinicalTrials.gov, for their medical value. RESULTS: Most pediatric studies triggered by the US Food and Drug Administration and by the European Medicines Agency were/are without medical or scientific value. They were/are formally and regulatorily justified, but lack medical sense and thus were/are unethical. Several even harm children and/or adolescents with serious diseases by exposing them to placebo or substandard treatment. CONCLUSIONS: Pediatric studies triggered by US and EU regulatory demands are a serious abuse of nonneonatal children and adolescents in Slovenia and worldwide. They are medically redundant at best and often deter patients from effective innovative personalized therapy. They also exclude young patients from reasonable studies. Institutional review boards/ethics committees should be alerted, should critically review all ongoing pediatric studies, should suspend those found to be questionable, and should reject newly submitted questionable ones.

Current state and future of pediatric allergology in Europe: A road map.

The history of pediatric allergology (PA) in Europe is relatively youthful, dating back to 1984, when a small group of pediatricians founded the European Working Group on Pediatric Allergy and Immunology-later giving rise to ESPACI (European Society on Pediatric Allergology and Clinical Immunology). In 1990, the first dedicated journal, Pediatric Allergy and Immunology (PAI), was founded. There are striking differences across Europe, and even within European countries, in relation to the training pathways for doctors seeing children with allergic disease(s). In 2016, the EAACIClemens von Pirquet Foundation (CvP) organized and sponsored a workshop with the European Academy of Allergy and Clinical Immunology (EAACI) Pediatric Section. This collaboration focussed on the future of PA and specifically on education, research, and networking/ advocacy. The delegates representing many countries across Europe have endorsed the concept that optimal care of children with allergic diseases is delivered by pediatricians who have received dedicated training in allergy, or allergists who have received dedicated training in pediatrics. In order to meet the needs of children and families with allergic disease(s), the pediatric allergist is highly encouraged to develop several networks. Our challenge is to reinforce a clear strategic approach to scientific excellence to across our member base and to ensure and enhance the relevance of European pediatric research in allergy. With research opportunities in basic, translational, clinical, and epidemiologic trials, more trainees and trained specialists are needed and it is an exciting time to be a pediatric allergologist.

Pediatric investigation plans for specific immunotherapy: Questionable contributions to childhood health.

Allergen-specific immunotherapy (SIT) is the only disease-modifying treatment for children, adolescents, and adults with allergic diseases. The EU has a combined system of national and EU-wide marketing authorization for all medicines. Germany introduced a new therapy allergen ordinance in 2008. Allergen products manufacturers had to apply for marketing authorization application for the major allergen groups (grass group, birch group, mites group, bee/wasp venom). Due to the EU pediatric regulation, in force since 2007, manufacturers had also to submit a pediatric investigation plan (PIP) for each allergen product. We investigated the allergic rhinoconjunctivitis (ARC) standard PIP, developed jointly by the European Medicines Agency (EMA) and the German Paul Ehrlich Institut (PEI). We analyzed the 118 EMA PIP decisions, looked for SIT trials in children in www.clinicaltrials.gov, and further analyzed EMA/EU justifications. The PIPs request a 1-year dose-finding study in adults, a 5-year placebo-controlled (PC) efficacy & safety (E&S) study in adults, and a 5-year PC E&S study in children. Fifty-eight PIP development programs will have to be performed until 2031. But children benefit even more from SIT for ARC than adults. There is no convincing medical/scientific justification for PC E&S studies in children in the relevant EMA documents. The PIP requirement to withhold effective treatment to thousands of children in the placebo group over a 5-year period raises profound concerns. The EMA justifications are formalistic and lack scientific foundation. A critical academic review of the ARC PIPs and the entire PIP system is urgently needed.

Drug development: EU paediatric legislation, the European Medicines Agency and its Paediatric Committee--adolescents' melanoma as a paradigm.

The European Medicines Agency (EMA) website lists all diseases that officially exist in adults only. The class waiver for juvenile melanoma was revoked in 2008 referring to US SEER statistics. This statistical justification is misleading. Melanoma in adolescents is much rarer than claimed by EMA/Paediatric Committee; < 1 ∕ 4 of adolescents with melanoma need systemic treatment; separate efficacy studies are neither medically justified nor feasible. The scarce adolescent patients should be allowed to participate in adult trials. To force companies to investigate them separately turns them into paediatric hostages, to adapt the term therapeutic orphans coined in 1968 by Shirkey. There are now five melanoma Paediatric Investigation Plans (PIPs). Probably none of the PIP-triggered clinical studies will ever be completed; we propose to call them ghost studies. An oncology research network considering a reasonable trial in melanoma, including adolescents, will compete for recruitment with the PIP-triggered trials designed by regulatory tunnel vision and sponsored by companies under EMA-imposed pressure. EMA/Paediatric Committee's territorial enthusiasm ("our patients") damages oncology research.

Did pediatric drug development advance epilepsy treatment in young patients? It is time for new research goals.

Modern drugs have changed epilepsy, which affects people of all ages. However, for young people with epilepsy, the framework of drug development has stalled. In the wake of the thalidomide catastrophe, the misconception emerged that for people < 18 years of age drugs, including antiseizure medications (ASMs), need separate proof of efficacy and safety, overall called "pediatric drug development". For ASMs, this has changed to some degree. Authorities now accept that ASMs are effective in < 18 years as well, but they still require "extrapolation of efficacy," as if minors were another species. As a result, some of the pediatric clinical epilepsy research over the past decades was unnecessary. Even more importantly, this has hampered research on meaningful research goals. We do not need to confirm that ASMs work before as they do after the 18th birthday. Instead, we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs' uses. Herein we discuss how to proceed in this endeavor.

Neurology's vital role in preventing unnecessary and potentially harmful pediatric studies.

INTRODUCTION: Regulatory authorities recognize two human populations: adults and children defined as <18 years. For drug approval, they demand separate studies. But humans mature slowly during puberty. The 18th birthday is an administrative limit that does not correspond to a physiological change. Separate drug approval before/after the 18th birthday reflects the children-are-therapeutic-orphans concept that emerged after 1962. The Food and Drug Administration (FDA) has backed away from this concept for antiepileptic drugs, but sticks to it in other areas. In contrast, the European Medicines Agency (EMA) is continuously expanding its demand for 'pediatric' studies. Parents hesitate increasingly to let their children participate in questionable studies. AREAS COVERED: Neurologists challenge the children-are-therapeutic-orphans mantra. Young patients do not need separate proof of efficacy & safety, but appropriate dosing recommendations. Minors should be treated as human beings, instead of being abused in questionable studies. EXPERT OPINION: Young patients with multiple sclerosis and other neurological diseases deserve studies with therapeutic intentions. 'Pediatric' careers have emerged in academia, regulatory authorities, and pharmaceutical companies. Institutional Review Boards/ Ethics Committees should suspend questionable 'pediatric' studies and reject newly submitted ones. The medical professions should distance themselves from questionable 'pediatric' research that reflects massive conflicts of interest.

Pharmacokinetic considerations surrounding the use of levetiracetam for seizure prophylaxis in neurocritical care - an overview.

INTRODUCTION: Levetiracetam (LEV) is one of the most widely used anti-seizure medications (ASMs) in clinical practice. This is due both to a different mechanism of action when compared to other ASMs and its easy handling. Indeed, because of its interesting pharmacokinetic properties, it is often used outside of the labeled indications, notably in the neurocritical setting as prophylaxis of epileptic seizures. AREAS COVERED: A literature search was conducted and the most relevant studies on the pharmacokinetic properties of LEV were selected by two independent investigators. Current evidence on the use of ASM prophylaxis in the neurocritical setting was also reviewed, highlighting and discussing the strengths and limits of LEV as drug of choice for anti-epileptic prophylaxis in this scenario. EXPERT OPINION: LEV has a 'near-ideal' pharmacokinetic profile, which makes it an attractive drug for ASM prophylaxis in neurocritical care. However, current recommendations restrict ASMs prophylaxis to very selected circumstances and the role of LEV is marginal. Moreover, studies are generally designed to compare LEV versus phenytoin, whereas studies comparing LEV versus placebo are lacking. Further, randomized trials will be needed to better elucidate LEV utility and its neuroprotective role in the neurocritical setting.

The value of juvenile animal studies: a pediatric clinical perspective.

With the emphasis of US American and European legislators on consideration of children in the drug development process regulatory authorities ask increasingly for additional non-clinical data to elucidate the safety of a given drug in development in future pediatric use. Juvenile animal studies are increasingly requested. These requests should never be tick box requests. Companies, academic toxicologists, clinicians, and regulatory authorities need a dialogue to differentiate between the perceived need to do "something" and the request for studies that have clinically meaningful results.

Development of paediatric medicines: concepts and principles.

The term "off-label use of drugs in children" is common to current medical practice. A look into the historical context helps to elucidate the framework for the use of medicines in children. Proper drug labels are relatively new in history. They emerged half a century ago when U.S. legislation forced manufacturers to prove the safety and efficacy of drugs by adequate clinical trials. Today pharmaceutical progress is so obvious and well established that the discrepancy between its benefit for adults as compared to children started to be perceived by champions in different institutions. There is an increased understanding of the child's physiology during developmental growth, of the maturation of enzyme systems, of the pharmacokinetics and pharmacodynamics and of the differences in disease processes. The involved institutions include legislators, government, regulatory authorities, academic scientists, pharmaceutical companies, the WHO, to name just the most prominent ones, but there are many more. Driving forces for the improvement of medicines for children include societal priorities, the involvement of science, the mission of regulatory authorities the role of clinical pharmacologists, paediatricians, and the characteristics of our market-driven economy with its chaotic, contradictory and lively elements. We do not live in an ideal world, but there is progress, and children are likely to benefit from it.

COVID-19 and Treatment and Immunization of Children-The Time to Redefine Pediatric Age Groups is Here.

Children are infected with coronavirus disease 2019 (COVID-19) as often as adults, but with fewer symptoms. During the first wave of the COVID-19 pandemic, multisystem inflammatory syndrome (MIS) in children (MIS-C), with symptoms similar to Kawasaki syndrome, was described in young minors testing positive for COVID-19. The United States (US) Centers for Disease Control and Prevention (CDC) defined MIS-C as occurring in <21-year-olds, triggering hundreds of PubMed-listed papers. However, postpubertal adolescents are no longer children biologically; the term MIS-C is misleading. Furthermore, MIS also occurs in adults, termed MIS-A by the CDC. Acute and delayed inflammations can be triggered by COVID-19. The 18th birthday is an administrative not a biological age limit, whereas the body matures slowly during puberty. This blur in defining children leads to confusion regarding MIS-C/MIS-A. United States and European Union (EU) drug approval is handled separately for children, defined as <18-year-olds, ascribing non-existent physical characteristics up to the 18th birthday. This blur between the administrative and the physiological meanings for the term child is causing flawed demands for pediatric studies in all drugs and vaccines, including those against COVID-19. Effective treatment of all conditions, including COVID-19, should be based on actual physiological need. Now, the flawed definition for children in the development of drugs and vaccines and their approval is negatively impacting prevention and treatment of COVID-19 in minors. This review reveals the necessity for redefining pediatric age groups to rapidly establish recommendations for optimal prevention and treatment in minors.

Challenges in pediatric drug development: a pharmaceutical industry perspective.

A paradigm change is taking place from protecting children against clinical research to protecting them through research. It is based on a better scientific understanding of the child's physiology, on the increasing potential of biomedical interventions, and on an evolving conviction of children's right to benefit from scientific and pharmaceutical progress. The WHO campaign 'Make medicines child size' is contributing to expand this to a global vision of the health of all children. Research-based pharmaceutical industry develops innovative new medicines for serious and life-threatening diseases. It has built up competency in pediatric drug development and has welcomed US and EU pediatric legislation as well as the WHO campaign. More diseases without effective therapy in the past will become treatable conditions. Eventually these advances will also be reflected in the medical care in developing countries. Research-based pharmaceutical industry can support specific pediatric aspects of drug development in neglected diseases by sharing its learning. The way forward will be a constructive dialog among the key stakeholders to ensure continuing improvement in worldwide child healthcare.

The Meanings of "Pediatric Drug Development".

Pediatric drug development (PDD) became an industry goal when the Food and Drug Administration (FDA) granted patent extensions. This was later expanded to obligations for pediatric studies and to the European Medicines Agency's (EMA's) strict pediatric investigation plans (PIPs). Industry now sponsors many often international studies in young patients that are difficult or impossible to recruit. PDD's intellectual foundations characterize children as "therapeutic orphans," allegedly discriminated in drug treatment and development. While toxicities occured in newborns, demanding separate efficacy and safety (E&S) studies in all age groups is wasteful and reflects hidden conflicts of interest. The American Academy of Pediatrics (AAP) successfully procured pediatric research funds; the FDA dislikes pediatric off-label use and envisions labels as instructions for physicians. Pediatricians have continuously improved child health care by careful use of available drugs. Instead of physiologically defining children vis-à-vis drug treatment, the FDA defines children as ≤16 years old, offering convincing pretense for the need for mostly senseless "pediatric" studies in young adults, adolescents, and children. Although these studies may help advance pediatric academic careers, they do not improve pediatric health care. The EMA defines children as <18 years old and demands even more senseless and potentially harmful "pediatric" studies. Young patients need pharmacokinetic/pharmacodynamic and dose finding, but not separate E&S, studies. Institutional review boards and ethics committees should suspend or reject questionable FDA/EMA-demanded "pediatric" studies. Industry and science need repositioning towards "PDD"; US/EU pediatric laws need revision. We hope this will not take decades.

Too Many Avoidable Suicides Occur Worldwide in Young Patients.

United States (US) and European Union (EU) laws attempt to counterbalance the presumed discrimination of children in drug treatment and drug development. The US Food and Drug Administration (FDA)-rewarded pediatric studies with antidepressants triggered in 2004 an FDA black-box warning of suicidality in young patients. Fewer antidepressants were prescribed, and the number of completed suicides of young persons increased. The dilemma between this warning and the need to adequately treat young depressed patients remains unsolved. We analyzed the history of drug development, the evolving view of diseases in young patients, US/EU pediatric laws, and pediatric studies triggered by FDA/European Medicines Agency (EMA) in depression and other diseases on the background of developmental pharmacology; financial, institutional, and other interests; and the literature. The FDA/EMA define children administratively, not physiologically, as <17 (FDA)/<18 years old (EMA). But young persons mature physiologically well before their 17th/18th birthday. Depression occurs in young persons, has special characteristics, but is not fundamentally different from adult depression. Young persons are not another species. Regulatory requirements for "pediatric" studies focus on "pediatric" labels. Many "pediatric" studies, including those in depression, lacked and lack medical sense and harm patients by placebo treatment although effective drugs exist. The FDA has partially abandoned separate "pediatric" efficacy studies, but not in psychiatry. Clinicians, parents, institutional review boards, and ethics committees should become aware of questionable "pediatric" studies, should re-evaluate ongoing ones, consider to suspend them, and to reject new ones. The concept of separate "pediatric" drug approval needs to be abandoned.

Rational Use of Medicine in Children-The Conflict of Interests Story. A Review.

BACKGROUND: United States (US) and European Union (EU) legislation attempts to counterbalance the presumed discrimination in pediatric drug treatment and development. METHODS: We analyzed the history of drug development, US/EU pediatric laws, and pediatric studies required by US/EU regulatory authorities and reviewed relevant literature. RESULTS: The US and EU definitions of a child are defined administratively (rather than physiologically) as being aged <17 years and <18 years, respectively. However, children mature physiologically well before their seventeenth or eighteenth birthdays. The semantic blur for these differing definitions may indicate certain conflicts of interest. CONCLUSIONS: Pediatric healthcare today is better than ever. Regulatory-related requirements for "pediatric" studies focus on labeling. Most of these studies lack medical usefulness and may even harm "pediatric" patients through administration of placebo and/or substandard treatment, despite the resultant publications, networking, patent extensions, and strengthened regulatory standing. Clinicians, parents, and ethics committees should be aware of these issues. New rules are needed to determine new pharmaceutical dose estimates in prepubescent patients, and when/how to clinically confirm them. Internet-based structures to divulge this information should be established between drug developers, clinicians, and regulatory authorities. A prerequisite for the rational use of pharmaceuticals in children would be to correct the flawed concept that children are discriminated against in drug treatment and development, and to abandon separate "pediatric" drug approval processes.