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

Abstract

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 18^th 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.

Key Words: Epilepsy; Pediatric drug development; Therapeutic orphans; Antiseizure medications; Pediatric investigation plan; Clinical pharmacology

Core Tip: For young people with epilepsy, the framework of drug development has stalled. The misconception emerged that for people < 18 years drugs, including antiseizure medications (ASMs), need separate proof of efficacy and safety, overall called "pediatric drug development". For ASMs, the authorities require "extrapolation of efficacy", as if minors were another species. Relevant parts of pediatric epilepsy research were pointless, and research on meaningful goals was hampered. ASMs work also before the 18^th birthday. We should learn to prevent brain damage in young patients by preventing seizures and by optimize ASMs’ use.

INTRODUCTION

Antiseizure medications (ASMs) have changed epilepsy from the dramatic connotation of "falling sickness" in the past to a chronic condition that can often be prevented and managed. ASMs prevent seizures in many, but unfortunately not all patients[1,2]. In the United States, about 1.2% of the total population had active epilepsy in 2015, corresponding to 3.4 million persons, i.e. 3 million adults and 470000 minors. About 0.6% of persons aged 0-17 years had active epilepsy, i.e. about 6 out of every thousand minors[3]. Epileptic seizures affect patients of all ages. Most seizures resolve on their own, but the younger a child is at diagnosis, the higher the danger that frequent seizures or status epilepticus (SE) will cause lasting brain damage; furthermore, disease progression is not limited to more seizures[4-6]. Even if we can only prevent brain damage in a small percentage of young patients, that would be worth the effort.

A century ago there was no ASM, so drug development has been excellent. However, it is counterproductive that there is a demand for additional approval of all medications for chronologically defined children, including ASMs. This has resulted in recent decades in numerous clinical studies to prove again efficacy and safety of ASMs in legally and chronologically defined minors, as if they represent a different species. Epileptology was the first academic clinical discipline to distance itself from this basic assumption[7-9]. However, several major challenges remain. First, the awareness that research efforts during the last decades could have been used much better in the treatment of epilepsy in minors is not widespread in the clinical world. Second, there is a lack of awareness that this is a challenge far beyond epilepsy. Third, the waste of research energy over the last decades was based on massive conflicts of interests, the addressing of which has until now been largely taboo. In our opinion, this represents a fundamental challenge to modern science and medicine.

Over the last decades, the pharmaceutical industry's alleged greed served as a welcome scapegoat to force companies to carry out supposedly "good" clinical studies in minors. Sadly, the reality was different and included: (1) The combination of a society-wide illusion in the clinical value of separate drug approval in minors; (2) the desire for funds, careers, and reputation of some academics, and their supporters in the regulatory authorities; and (3) the Western academic world accepted an unfortunate social issue.

Acceptance while not paying attention to potential warning signs and dangers in science or political events can be perilous. When Russia developed the first anti-corona virus infectious disease 2019 (COVID-19) vaccine and tried to use it to gain diplomatic advantages and greater prestige around the world[10], few were paying attention that Russia was also preparing the invasion of Ukraine. COVID-19 was a medical challenge, while the invasion of Ukraine was a military aggression. Both were carried out by the same government. It was much more convenient to ignore warning. In our view, ignoring the conflicts of interest behind "pediatric drug development" (PDD) and resulting pointless ASM studies in minors is a similar scenario.

We analyzed characteristics and impact of separate pediatric clinical studies on ASMs with the background of the history of United States and European Union (EU) pediatric legislation, which resulted in "PDD"[11-13]. On this basis, we describe how the PDD requirements for ASMs evolved from the 1990s to today; how academic criticism has changed the demand profile of the regulatory requirements and how, in hindsight, many pediatric epilepsy studies should be classified as pointless. We conclude that excessive demands for "pediatric" ASM studies should be replaced by meaningful studies with the potential to improve the care of pediatric epilepsy patients.

ASMS, PDD, AND EVIDENCE-BASED MEDICINE

Drug approval is today based on regulatory clinical and other studies within an elaborate bureaucratic process. The United States introduced the obligation to prove the efficacy and safety of new drugs in 1962 as a response to the thalidomide disaster. The resulting procedure has become standard worldwide in the following decades[14]. This framework requires, inter alia, a functional public administration, social trust, and a societal balance of influence of the classical healthcare professions, drug manufacturers, regulatory authorities, public opinion, patients, and for underage patients' caregivers/parents. Two additional factors have in the last decades come into play for young patients that need to be considered when reflecting about future epilepsy research. (1) PDD assumes that in chronologically defined "children" separate drug approval is needed, resulting in separate "pediatric" labels. The requirement for PDD is set out in United States and EU laws[11-17]. "Children" and "pediatric" are in quotation marks because the globally used age limit of < 18 years does not even come close to the end of puberty when the child's body becomes mature. The process of puberty has accelerated over the past 100 years[18,19]. Clinical studies in adolescents are physiologically and scientifically not pediatric studies, but the regulatory authorities are maintaining this illusion. This is of specific relevance for epilepsy in young patients as epilepsy was the first broad clinical area where the Food and Drug Administration (FDA) and European Medicines Agency (EMA) halfway accepted that drugs work after and before the 18^th birthday[20-22], triggered by critical review of "pediatric" research by academic neurologists[7-9]. However, even the term "extrapolation of efficacy" from adults to minors is misleading. Minors are not another species[14-16]. The PDD concept is best expressed by the mantra of children as "therapeutic orphans"[23], taken up by the American Academy of Pediatrics and the historically new discipline of developmental pharmacology[11,12,14-16]; and (2) the concept of evidence-based medicine (EBM). From 1962 onwards, in the wake of the United States processing of the thalidomide disaster and the resulting modification of pharmaceutical law, randomized clinical trials to prove drug’s efficacy and safety became widespread[17].

Based on the awareness of the limitations of traditional determinants of clinical decisions, EBM became in the view of clinicians a new paradigm. EBM was a step forward in replacing traditional personal authority by the dictate of independently produced data[24-26]. EBM with young people defines a group of people according to chronological, not physiological criteria. These chronological criteria are administrative in nature, not scientifically based. Clinicians may overlook that most large clinical trials were and are registration studies for new drugs, not simply independent data. An exception was pediatric oncology, where chemotherapeutic agents had already existed for decades but were systematically tested for malignancies in minors only since the 1960s[14,27]. These studies and the resulting treatment protocols resulted in saving the lives of hundreds of thousands of minors, but not in drug labels, which representatives of the EMA criticized seriously[28].

The 18^th birthday is an administrative age limit and does not correspond to a physiological change. Drugs treat the body, not the legal status. Amplifying the original United States PDD approach, EU law and the EMA demand a "pediatric investigation plan" (PIP) for all new drugs[13], except those that target a disease the EMA recognizes as non-existing in "children". Companies have to commit to "pediatric" studies, resulting in a repetition of clinical development in minors < 18 years, subdivided into the subgroups defined by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use: Preterm neonates; neonates; infants and toddlers; children; and adolescents[29]. EU-PIP-demanded studies recruit worldwide.

In 1994 the United States National Institute of Health organized a conference on drug treatment of children with epilepsy as part of the emerging PDD movement. Clinicians then used ASMs in minors irrespective of separate "pediatric" approval. Nevertheless, the regulators now wanted separate proof of efficacy and safety also in "children“. The non-government participants opined that drug efficacy for focal seizures in adults justified their approval in young patients provided safety and pharmacokinetic were proven, an appropriate and "common sense" approach in contrast to the strict regulatory approach that has dominated the next 30 years and which we consider "dogmatic". Sheridan et al[30] did not address the difference between the physiological and legal/administrative meanings of the term "child"[30,31].

DOGMATIC REGULATORY PDD APPROACH

Since 2019 the FDA accepts extrapolation of efficacy for focal-onset seizure (FOS) epilepsy in young patients down to two years[20], justified by advances in understanding disease pathophysiology and progression in epilepsy research[21]. In its official justification, the FDA uses what is considered by some as an outdated term "partial onset seizure (POS)"[20]. The EMA accepts this extrapolation at present down to 4 years. A review of all studies from 1970-2010 on adjunctive therapy in FOS in adults and children concluded that ASMs are effective for FOS in children as well, once efficacy is proven in adults[7-9]. Under 2 years there were not enough patients and trials. In our view, the term "extrapolation" of the efficacy of ASMs from adults to "children" is misleading. "Extrapolation" implies a fundamental difference between adults and "children". There are real differences between infants and adults, but they are the same species. Furthermore, children grow and do not remain newborn and vulnerable until they reach the official age of maturity.

Extrapolating observed toxicities in preterm newborns to all "children" (and silently switching the use of the term "child" from its physiological to its legal/administrative meaning), the advocates of PDD managed to convince lawmakers that separate "pediatric" labels would resolve a major healthcare crisis and would allow a fundamental step forward in pediatric healthcare[32]. What clinicians had advised in 1994 was decades later accepted by the FDA and eventually also the EMA: Regarding ASMs, it is legitimate to call "pediatric" patients small adults: The underlying pathophysiological process is the same in all patients > 2 years. Young patients will respond similarly to ASMs, provided an equivalent serum concentration-time profile. Neurology was one of the first clinical disciplines to openly challenge the children-are-therapeutic-orphans concept[31]. However, it is not sufficient to "just" accept that ASMs are effective before and after the 18^th birthday. It is necessary to candidly address the misconception that separate labels in patients < 18 years have any substantial clinical benefit. The formulas and dosing tables used by pediatricians and family doctors in the 1960s were largely sufficient, except for preterm. In our opinion, the PDD movement was a regulatory exercise with much official success but no real clinical progress.

Several other clinical areas face the same dilemma. There is no such thing as separate "pediatric" and "adult" rheumatoid arthritis[33]. The conditions summarized under "juvenile idiopathic arthritis" (JIA) are disorders that begin early and persist into adulthood[34-37]. They were first described when diseases in young people were systematically studied in the second half of the 20^th century, including childhood cancer, childhood joint inflammation, childhood skin inflammation, and the like. It was thought at the time that these were separate "pediatric" diseases. They had not been observed before because most of these diseases are so rare that an individual family doctor may see them once or twice in their entire professional life (and there was no internet in these times). Patients with systemic JIA (sJIA) diagnosed early do not switch to classical rheumatoid arthritis later. Only the patient’s administrative status changes. Conventional malignant melanoma in adolescents and adults is the same disease and needs the same treatment[38,39]. There are extremely rare forms of a distinctive variant of melanoma that is diagnosed in very young children and infants, not adolescents.

Another good example from neurology is amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease, leading to progressive paralysis, and eventually to death. Most cases are sporadic, but some are familial with a wide variety of genetic mutations. No definitive diagnostic test or biomarker exists so far. The diagnosis is made by clinical observations. The peak age at onset is 58–63 years for sporadic and 47–52 years for familial disease. From the age of 80 years on the incidence decreases rapidly. Symptomatic multidisciplinary treatment can slow down disease progression[40]. In a small subgroup of patients, onset is described as < 25 years; in even rarer cases, symptoms start before the 18^th birthday. A literature research found twenty-nine such pediatric cases reported in the literature[41], while a European survey identified thirty-nine such patients[42]. The literature discusses both juvenile ALS, starting < 25 years, and pediatric ALS, even more rare, beginning < 18 years of age[43]. The more genetic mutations that are identified, the more ALS in young patients appears to be less a uniform disease and more an overlapping of degenerative motor neuron deficits based on different genetic mutations. After the EU pediatric regulation had been enacted, the EMA had issued a "waiver" for various predominantly adult diseases, including malignant melanoma, ALS, and more, meaning that no PIPs were needed. But in 2015, the EMA declared that from now on it classified several predominantly adult diseases also as "pediatric", including ALS, liver carcinoma, kidney carcinoma, Parkinson disease, Huntingdon chorea, and more[44]. For ALS it claims that there is no criterion other than age to distinguish juvenile from adult onset ALS forms, referring to three publications[45-47]. However, these publications do not support the EMA’s claims. Orban et al[45] describe familial neurodegenerative diseases based on various genetic mutations. The paper’s title is "Juvenile ALS", but the syndromes also have various other names. Juvenile onset ALS is defined as beginning < 25 years[45]. Finsterer et al[46] discuss the genetics of motor neuron diseases. Several genetic mutations are found in syndromes described as "juvenile" beginning at < 20 years of age[46]. Bertini describes juvenile ALS as a very rare severe motor neuron disease beginning at < 25 years of age. Bertini 2014 is not peer-reviewed, but a 1-page orphanet entry by a single author[47].

In 2020, 58 ALS clinical experts affiliated with the European Network to Cure ALS[48], participated in a survey on PIP-demanded pediatric ALS studies. All questions had been reviewed by the executive board of Treatment Research Initiative to Cure ALS[49], comprising neurologists from eight European countries. Thus, the survey represents the best clinical ALS knowledge in Europe. It concluded that pediatric ALS as a disease entity does not exist, patients < 18 years are extremely rare, and that the pediatric studies demanded by the EMA and its Pediatric Committee (PDCO) would be unfeasible and a waste of money and resources[42].

Thus, in several clinical areas the regulatory claim of two forms of the same disease, an adult one (> 18 year) vs a "pediatric" one (< 18 year) is no longer supported.

THE DOGMATIC REGULATORY APPROACH TO "CHILDREN" IS FAR FROM OVER

For heads of medical departments, raising funds for clinical research is a key responsibility. Industry-paid funds triggered by regulatory demands were and are a temptation. The number of ongoing "pediatric" studies has diminished, but clinicians have not yet processed sufficiently the fundaments of the temptations of "pediatric" clinical studies.

The flawed belief that the 18^th birthday corresponds to a physiological change has resulted in superfluous clinical studies in adolescents and studies in younger minors, where dose-finding would have been clinically required. The main conclusions by Pellock, Arzimanoglou et al[8,9] were eventually accepted by FDA/EMA, but large international clinical studies in "children" that often were physiologically no longer children continued worldwide. Also the formal–and flawed-distinction between adult and "pediatric" patients continues. The division of the medical world into "pediatric" and "adult" disciplines is administrative, not scientific. Whether a 15-year-old casualty is placed in a pediatric or adult surgical ward is medically irrelevant. It is an administrative question. But the same disease before or after the 16^th, 17^th or 18^th birthday should neither have different names nor should be treated differently. This is the case when there is a pediatric and an adult rheumatology department in the same hospital, and where adult and "pediatric" rheumatology use different names for the identical disease, e.g. sJIA[37].

A NECESSARY PARADIGM SHIFT

"Pediatric" ASM drug studies were performed worldwide in up to 118 medical centers[14-16,50-52]. Parents have become reluctant to allow the participation of their loved ones in "pediatric" epilepsy studies[53]. The studies demanded by regulatory authorities would need more "pediatric" patients than exist worldwide[54]. The EMA knows this, the PIPs continue, and FDA and EMA continue to publish common statements that explain "pediatric" requirements even for vaccines and drugs against COVID-19[55].

Well-intended but flawed regulatory requirements in the name of EBM, PDD and "better medicines for children" led to many pointless studies and publications. The EMA has issued PIPs for most modern ASMs, demanding studies in "children" < 18 years. Some PIPs have translated into studies, others are in various stages of preparation, many are ongoing, and some PIPs have silently been converted into waivers, i.e. no "pediatric" studies are required any more[14-16]. The EMA continues to call PDD "better medicines for children"[56]. In our view, the current focus of pediatric epilepsy research is too focused on drug approval in minors. Such studies require complex and expensive logistics but do not improve treatment. Instead, we propose a shift away from clinically pointless, but formally regulatorily justified "pediatric" studies to clinically meaningful studies. Such studies will not prove again that ASMs work before and after the 18^th birthday. Instead, we propose to simply accept their efficiency and instead explore how they can be better used.

In young children, self-management means the administration of emergency ASMs by parents/caregivers. Patel et al[57] initiated a regional project to involve parents. This reduced the number of SE emergency admissions by 28%[58]. A paper on acute seizure action plans compares the self-management guides for patients and caregivers in asthma and diabetes to SE. Stredny et al[59] emphasize infrequent or restricted use of home rescue medications by caregivers[59]. Buchhalter aims at recommendations from a broad stakeholder group including caregivers[60]. The pediatric SE research group investigated the timing and escalation of ASM administration in pediatric SE both in the prehospital and in-hospital settings[61,62]. Training of caregivers is addressed by several authors[4,63,64].

A further dimension is the patient's quality of life (QoL). Today, seizure control is considered the primary goal but when a patient is treated with many drugs, other QoL issues are impacted, including weight gain or altered mentation. Parents, doctors and older patients should decide together on balancing priorities. This might include the acceptance of occasional seizures in return for a better overall QoL. Better integrating parents into the prospective care of children at risk for epileptic seizures or those who have already had seizures is recommended[65]. Hopefully, parents' advocative groups for Dravet syndrome, Lennox Gastaut Syndrome, Sturge Weber Syndrome, and more will contribute to funds, coordination, and intellectual processing of such a new strategy. In 1994, reimbursement of drugs not approved for "children" was not a problem[30]. Today, administrative aspects have acquired a stronger role in medical care. Nonetheless, the lack of "pediatric" approval is no valid clinical justification for separate studies.

A CHALLENGE BEYOND EPILEPSY

Overall, this is a gigantic challenge for the next decades. Only since the public administration issued identity documents for all is the precise date of birth immediately available in an officially certified form, and hence the conceptual creation of a chronologically and administratively defined "pediatric population" [66]. The 20^th century also brought the discovery and industrial production of effective drugs. The triangle of (1) Initially chemical, then pharmaceutical, and now life sciences industry; (2) academia and clinical care; and (3) regulatory authorities emerged as a framework for drug development. With the globalization of economy and drug development, an additional international framework emerged, operating alongside and above national drug approval. All institutions of public administration became stronger and developed their own self-interests.

Drug development, public administration and the new discipline of developmental pharmacology met the new institution of regulatory authorities and increased public interest in children's well-being. When it was recognized that absorption, distribution, metabolism, excretion (ADME) of drugs in premature infants is different from ADME in older people, this developed into the children-are-not-small-adults and children-are-therapeutic-orphans mantras, reflected in the PDD legal codes. Using the history of "pediatric" epilepsy studies, we traced how the demand for separate approval of ASMs in "children" emerged, "children" defined legally/administratively, not scientifically and physiologically. It took almost half a century until Pellock et al[7] questioned the legitimacy of these pediatric efficacy and safety studies[7-9,31]. Unforunately, the first systematic criticism of PDD, first in peer-reviewed journals and then in medical textbooks, only began in 2014[14-16,39,67].

Epilepsy is investigated and treated in the context of neurology. The challenge goes far beyond neurology. It is a challenge for humanity in the 21^st century to distinguish in medicine between the legal and administrative definition of minors and the physiological definition of premature infants and children.

The EMA demands "pediatric" studies on underage mothers with postpartum depression and on underage athletes with cartilage injuries in the knee joint between the physiological end of puberty, as evidenced by the closure of the growth plates, and the 18^th birthday[14-16]. Such studies are scientifically and medically unnecessary. We identify the extent of the abuse of young people in clinical research only when we look beyond individual medical disciplines. All the discussed "pediatric" studies are in direct violation of the Declaration of Helsinki[68]. They are a blatant abuse of power, based on conflicts of interest that are not captured by the control mechanisms currently in use[69].

Medicine has made great progress in the last decades and centuries. But it has also become a comfortable professional field in which individual young participants compete to rise in the hierarchy of power and influence. The origin of PDD lies in developmental pharmacology, the emergence of organized pediatrics, and the contemporary emergence of regulatory authorities. We are of the opinion that it is a task for every neurologist to check which questionable "pediatric" studies are being carried out at their workplace. In distinguishing between "pediatric" and adult research in neurology and other medical disciplines, administrative matters must be separated from those that are truly medically justified. This is a task not only for pediatric neurology, but for the entire medical profession.

FUTURE PEDIATRIC EPILEPSY RESEARCH

The avenue of the future should not be to ask for additional and larger, multicenter, pediatric-specific randomized clinical trials, nor more standardized diagnostic and treatment algorithms along with prospective multicenter studies; nonetheless. Such studies and research targets continue to be advocated[64,70-72].

Regulatory authorities support the narrative that only on-label drugs are safe for children and adults[73]. However, the entire discipline of pediatrics with the sub-disciplines of pediatric neurology, oncology, and neonatology emerged decades before the term "off-label" emerged in 1988[74]. There is a respect for the regulatory authorities as they have an important role in drug approval, but they are not scientific authorities.

A recent paper reviews the current international literature on management protocols for SE in the pediatric emergency room[75]. In our view, it would be desirable that fewer children with SE reach the pediatric emergency room if their caregivers were able to intervene earlier[4,64,76,77]. Self-management of epilepsy has in the last years been discussed, but in contrast to asthma or diabetes mellitus, it is still in its infancy[58,78,79].

REMAINING OPEN QUESTIONS

Pellock et al[7,8] accepted the age limit of two years for pragmatic reasons[7-9]. Novotny et al[50] confirmed that adjunctive topiramate does not reduce the daily rates of FOS in infants aged 1-24 months[50]. What is the true age limit? Parents might be too enthusiastic to administer emergency medication. There will never be a perfect scheme regarding decisions on the balance of QoL vs intake of multiple drugs. For such discussions and decisions, EBM does not provide any valid guidance.

DISCUSSION

Table 1 summarizes our overview over historical events. It shows how the clinical development of all new drugs since 1962 has taken place in an interplay between drug developers, now mostly industrial companies; clinicians; and the regulatory authorities. With the concept of PDD, the FDA began to actively intervene in drug development, which was continued and expanded by the EU and its EMA. The concept that children are completely different from adults led to the requirement of separate pediatric efficacy and safety studies despite the fact that the regulatory authorities define children administratively, i.e. chronologically, not scientifically and/or physiologically. On the night of the 18^th birthday, the body does not fundamentally change even though the legal status does. The clinical analyzes from Pellock et al[8] in 2012 onwards showed that, at least in POS epilepsy, medications that work after the 18^th birthday also work before that birthday[8].

Table 1 Key events in the tension between pediatric drug development and epilepsy clinical research.

Ref.	Year	Event
[23]	1950	Toxicities are reported in preterm newborns treated with antibiotics
[17]	1962	United States pharmaceutical legislation (Keifauver-Harris Amendment)
[23]	1968	Shirkey coins the term “therapeutic orphans“
[8,30]	1996	United States National Institutes of Health “pediatric“ antiseizure medications workshop in Bethesda, MD, United States
[32]	1997	United States pediatric legislation
[13]	2006	European Union pediatric legislation
[80]	2010	European Medicines claims fundamental difference in pediatric vs adult epilepsy, demands studies in > 100 children for new drugs
[7]	2012	Efficacy of antiseizure medications in adults predicts efficacy in minors
[22]	2016	Proposal for a new paradigm
[8]	2017	Proof that antiseizure medications work both in adults and minors
[11]	2018	Justification of “pediatric drug development“ repeated
[20]	2019	Food and Drug Administration accepts extrapolation for antiseizure medications adults to minors
[80]	2019	European Medicines authors equate antiseizure medications approval with "availability," as if without approval they would not exist for patients before their 18th birthday
[81]	2023	EMA accepts extrapolation from adults to “children“

The hands-on running of clinical regulatory studies is done by clinicians, albeit not in a vacuum. The clinicians overestimate their own role and underestimate the two other sides in the triangle in which drug development has taken place since 1962: The life science companies and the regulatory authorities. The concept that the 18^th birthday corresponds to a physiological change is maintained, reflected in the expression "extrapolation". Does extrapolation from an 18 years old adult to a 17 years old teenager make sense? No. Are they fundamentally different from each other? Medically no, but administratively yes. In 2019 the FDA accepted that ASMs work also before the 18^th birthday but used the term "extrapolation of efficacy"[80]. The EMA continues to defend "extrapolation of efficacy" for ASMs, equating approval of ASMs before the 18^th birthday with their alleged "availability", as if they would not exist and could not be used before the 18^th birthday[81]. Now, at least, the EMA accepts extrapolation from adults to young patients[82].

CONCLUSIONS

Regarding PDD, we refer to a recent publication in which authors representing regulatory authorities from around the world describe PDD as an ecosystem[83], which we regard as a Freudian slip. Ecosystems have inflows and outflows. The inflow of the PDD ecosystem is the payments from the life sciences industry. The outflow of PDD studies are "pediatric" labels, careers in "pediatric" research, "pediatric" publications, and a further expansion of academic and clinical research activism that has become, to a large extent, a self-purpose, sold to the general public, politicians, and young researchers early in their career as an essential path to scientific and medical progress and better care for children.

Medicine in the 21^st century will have to learn that neither the regulatory authorities nor the World Health Organization are white knights who represent nothing but the truth and the interests of patients. Our world has become more complex and conflicts of interest are increasingly hidden beneath the surface. Science has had to overcome other major obstacles in the past. The consequence for the individual disciplines will be that they will have to learn to think outside the box again. The conduct of purportedly pediatric clinical trials is overall the greatest abuse of patients in the history of medicine, going well beyond the classic, often-cited examples of the published studies criticized by Beecher in 1966 and the Tuskegee study terminated in 1972[84,85]. Conferences of all major medical disciplines will have to address and discuss this issue.

Epilepsy research will hopefully direct itself to new, truly innovative goals. Self-management of diseases is not a radically new concept. Herein, we have put our thoughts into the context of flawed demands for ASMs efficacy and safety studies in "children". Involving and training parents will have many new challenges. In our view, our conclusions are to some degree obvious: ASMs work in young person equally well before and after the 18^th birthday. The time has come to candidly address alleged pediatric research in neurology and beyond that is not really pediatric; to suspend ongoing questionable trials; to reject questionable studies newly submitted to Institutional Review Boards/ethics committees; and to focus on ways to better engage caregivers and parents.