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Ethical Issues in Pediatric Regulatory Studies Involving Placebo Treatment

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  • klausrose Consulting
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Abstract

Separate pediatric studies for antiepileptic drugs (AEDs) emerged with general separate drug approval in children and were defined by the U.S. Food and Drug Administration (FDA) as <17 years and by the European Union (EU) as <18 years. These administrative age limits are necessary in pediatrics, but they correspond variably with the physiological maturity of young patients and are not helpful for therapeutic decisions or as study inclusion criteria. AEDs are often effective for partial onset seizures (POS) in 2 to 17-year-olds as well as in ≥18-year-olds, if dosed correctly. Separate pediatric AED studies assume no difference between the legal and the physiological meaning of the word “child.” While the FDA now accepts efficacy of AEDs in POS in children ≥2 years, the EU still requires separate “pediatric” studies. For retigabine it waived all pediatric studies after having required 20 such studies over several years. We feel the current regulation creates a situation where many studies in children are done unnecessarily; we question the ethics of such an approach, which in our view, is morally wrong. Critical publications contributed to the FDA's shift of opinion for AEDs in POS but did not address the blur of different meanings of the word “child.”

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... Antiepileptic drugs work in both adults and children. 65 Other clinical areas still use "pediatric," e.g. the International Pediatric Multiple Sclerosis Study Group (IPMSSG). 66 While the term "pediatric" is incorrect for adolescents, the IPMSSG speaks out against "pediatric" placebo-controlled studies. ...
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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.
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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.
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Objective: The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety. Methods: The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population. Results: In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span. As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency. There are also ethical considerations on conducting clinical trials in this age group including the use of placebo owing to highly active disease. It is imperative to reconsider study design and implementation based on what information is needed. Are studies needed for efficacy or should safety be the primary goal? Further, there have been major recruitment challenges in recently completed and ongoing pediatric MS trials. Phase 3 trials for every newly approved therapy for adult MS in the pediatric MS population are simply not feasible. Conclusions: A primary goal is to ensure high-quality evidence-based treatment for children and adolescents with MS, which will improve our understanding of the safety of these agents and remove regulatory or insurance-based limitations in access to treatment.
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The secular trend in the height of the US population has been almost neglected in a comparative perspective, despite its being a useful indicator of early-life biological conditions. The study estimated the height of the US population and compared it to Western European trends after World War II. The complete set of NHES and NHANES data were analyzed, collected between 1959 and 2004 by the National Center for Health Statistics, in order to construct trends of the physical stature of US-born men and women limited to non-Hispanic blacks and whites. Also analyzed was the trend in the height of US military personnel whose parents were also born in the USA. The trends and levels were compared with those of several European populations. The increase in the physical stature of US adults slowed down by mid-century concurrent with a substantial acceleration in height attainment in Western and Northern Europe. Military data corroborate this finding in the main. After being the tallest population in the world ever since colonial times, Americans are now shorter than most Western and Northern Europeans and as much as 4.7-5.7 cm shorter than the Dutch, who are the tallest in world today. Given the well-established relationship between adult stature and early-life biological welfare, it was hypothesized that either American diets are sub-optimal or that the universal health care systems and social safety net of the European welfare states are providing a more favorable early-life health environment than does the American health care system.
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Most antiepileptic drugs (AEDs) receive regulatory approval for children years after the drug is available in adults, encouraging off-label use of the drug in children and hindering attempts to obtain quality pediatric data in controlled trials. Extrapolating adult efficacy data to pediatrics can reduce the time between approval in adults and that in children. To extrapolate efficacy from adults to children, several assumptions must be supported, such as (1) a similar disease progression and response to interventions in adults and children, and (2) similar exposure response in adults and children. The Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE) addressed these assumptions in focal-onset seizures (FOS), the most common seizure type in both adults and children. PEACE reviewed the biological and clinical evidence that supported the assumptions that children with FOS have a similar disease progression and response to intervention as adults with FOS. After age 2 years, the pathophysiological underpinnings of FOS and the biological milieu in which seizures are initiated and propagated in children, seizure semiology, electroencephalographic features, etiology and AED response to FOS in children are similar to those in adults with FOS. PEACE concluded that extrapolation of efficacy data in adults to pediatrics in FOS is supported by strong scientific and clinical evidence. However, safety and pharmacokinetic (PK) data cannot be extrapolated from adults to children. Based on extrapolation, eslicarbazepine is now approved for children with FOS, down to age 4 years. Perampanel, lacosamide and brivaracetam are now undergoing PK and safety studies for the purposes of extrapolation down to age 2 or 4 years. When done in conjunction with PK and safety investigations in children, extrapolation of adult data from adults to children can reduce the time delay between approval of effective and safe AEDs in adults and approval in children.
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A series of government actions have evolved since the 1990s to facilitate the development of medicinal products for pediatric use using a combination of incentives and mandates. The initiatives have been successful in stimulating activity and interest in products developed for pediatric use. The initiatives continue to evolve as experience accumulates and regulatory agencies develop robust cooperative programs. A multidimensional program is necessary to achieve the necessary goal of aligning pediatric therapeutics with adult therapeutics and providing children the most favorable opportunity to benefit and minimize risk to vulnerable populations.
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More than 30 percent of patients with epilepsy have inadequate control of seizures with drug therapy, but why this happens and whether it can be predicted are unknown. We studied the response to antiepileptic drugs in patients with newly diagnosed epilepsy to identify factors associated with subsequent poor control of seizures. We prospectively studied 525 patients (age, 9 to 93 years) who were given a diagnosis, treated, and followed up at a single center between 1984 and 1997. Epilepsy was classified as idiopathic (with a presumed genetic basis), symptomatic (resulting from a structural abnormality), or cryptogenic (resulting from an unknown underlying cause). Patients were considered to be seizure-free if they had not had any seizures for at least one year. Among the 525 patients, 333 (63 percent) remained seizure-free during antiepileptic-drug treatment or after treatment was stopped. The prevalence of persistent seizures was higher in patients with symptomatic or cryptogenic epilepsy than in those with idiopathic epilepsy (40 percent vs. 26 percent, P=0.004) and in patients who had had more than 20 seizures before starting treatment than in those who had had fewer (51 percent vs. 29 percent, P<0.001). The seizure-free rate was similar in patients who were treated with a single established drug (67 percent) and patients who were treated with a single new drug (69 percent). Among 470 previously untreated patients, 222 (47 percent) became seizure-free during treatment with their first antiepileptic drug and 67 (14 percent) became seizure-free during treatment with a second or third drug. In 12 patients (3 percent) epilepsy was controlled by treatment with two drugs. Among patients who had no response to the first drug, the percentage who subsequently became seizure-free was smaller (11 percent) when treatment failure was due to lack of efficacy than when it was due to intolerable side effects (41 percent) or an idiosyncratic reaction (55 percent). Patients who have many seizures before therapy or who have an inadequate response to initial treatment with antiepileptic drugs are likely to have refractory epilepsy.
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The ethical approach to experimentation in man has several components; two are more important than the others, the first being informed consent. The difficulty of obtaining this is discussed in detail. But it is absolutely essential to strive for it for moral, sociologic and legal reasons. The statement that consent has been obtained has little meaning unless the subject or his guardian is capable of understanding what is to be undertaken and unless all hazards are made clear. If these are not known this, too, should be stated. In such a situation the subject at least knows that he is to be a participant in an experiment. Secondly, there is the more reliable safeguard provided by the presence of an intelligent, informed, conscientious, compassionate, responsible investigator. Ordinary patients will not knowingly risk their health or their life for the sake of "science." Every experienced clinician investigator knows this. When such risks are taken and a considerable number of patients are involved, it may be assumed that informed consent has not been obtained in all cases. The gain anticipated from an experiment must be commensurate with the risk involved. An experiment is ethical or not at its inception; it does not become ethical post hoc - ends do not justify means. There is no ethical distinction between ends and means. In the publication of experimental results it must be made unmistakably clear that the proprieties have been observed. It is debatable whether data obtained unethically should be published even with stern editorial comment.
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Children, at least in the United States andin Western Europe, have been growing taller and have been reaching biologic maturity at an earlier age as evidenced by available growth data for the past 100 years. This secular accelerative trend shows no sign of slackening. Possible causes for this acceleration of growth are briefly discussed; no single factor seems responsible. Finally, this secular trend would appear to be yet another but important biologic variable in planning future growth studies.
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In 1960, the terms "neonatology" and "neonatologist" were introduced. Thereafter, an increasing number of pediatricians devoted themselves to full-time neonatology. In 1975, the first examination of the Sub-Board of Neonatal-Perinatal Medicine of the American Board of Pediatrics and the first meeting of the Perinatal Section of the American Academy of Pediatrics were held. One of the most important factors that improved the care of the neonate was the miniaturization of blood samples needed to determine blood gases, serum electrolytes, glucose, calcium, bilirubin, and other biochemical measurements. Another factor was the ability to provide nutrition intravenously, and the third was the maintenance of normal body temperature. The management of respiratory distress syndrome improved with i.v. glucose and correction of metabolic acidosis, followed by assisted ventilation, continuous positive airway pressure, antenatal corticosteroid administration, and the introduction of exogenous surfactant. Pharmacologic manipulation of the ductus arteriosus, support of blood pressure, echocardiography, and changes in the management of persistent pulmonary hypertension, including the use of nitric oxide and extracorporeal membrane oxygenation, all have influenced the cardiopulmonary management of the neonate. Regionalization of neonatal care; changes in parent-infant interaction; and technological changes such as phototherapy, oxygen saturation monitors, and brain imaging techniques are among the important advances reviewed in this report. Most remarkable, a 1-kg infant who was born in 1960 had a mortality risk of 95% but had a 95% probability of survival by 2000. However, errors in neonatology are acknowledged, and potential directions for the future are explored.
Article
Direct-to-consumer advertising (DTCA) of prescription drugs in the United States is controversial. Underlying the debate are disagreements over the role of consumers in medical decision making, the appropriateness of consumers engaging in self-diagnosis, and the ethics of an industry promoting potentially dangerous drugs. Drug advertising and federal policy governing drug advertising have both responded to and reinforced changes in the consumer's role in health care and in the doctor-patient relationship over time. This article discusses the history of DTCA in the context of social movements to secure rights for health care patients and consumers, the modern trend toward consumer-oriented medicine, and the implications of DTCA and consumer-oriented medicine for contemporary health policy debates about improving the health care system.
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