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OBJECTIVE: Nipocalimab is a neonatal Fc receptor (FcRn)-blocking monoclonal antibody that inhibits placental immunoglobulin G (IgG) transfer and lowers circulating maternal IgG levels. In an open-label, single-arm, phase 2 study, nipocalimab demonstrated evidence of safety and efficacy that support further investigation in a pivotal phase 3 trial of recurrent hemolytic disease of the fetus and newborn (HDFN). The phase 3 AZALEA study aims to evaluate the efficacy and safety of nipocalimab in a larger population at risk for severe HDFN, defined as HDFN associated with poor fetal outcomes or neonatal death. STUDY DESIGN: AZALEA is a multicenter, randomized, placebo-controlled, double-blind, phase 3 study enrolling alloimmunized pregnant individuals (N≈120) at risk for severe HDFN based on obstetric history. Participants are randomized 2:1 to receive intravenous 45 mg/kg nipocalimab or placebo weekly from 13-16 to 35 weeks gestational age (GA). During the double-blind treatment period, participants receive standard-of-care weekly monitoring for fetal anemia until planned delivery at 37 to 38 weeks GA. Postnatal follow up periods are 24 weeks for maternal participants and 104 weeks for neonates/infants. RESULTS: The primary endpoint is the proportion of pregnancies that do not result in IUT, hydrops fetalis, or fetal loss/neonatal death from all causes. Key secondary endpoints include the severity of HDFN as measured by a composite HDFN severity index, the earliest time to occurrence of IUT or hydrops fetalis, the modified neonatal mortality and morbidity index in liveborn neonates, and the number of IUTs received. Other endpoints are safety, patient- and caregiver-reported outcomes, pharmacokinetics, pharmacodynamics (eg, IgG, FcRn receptor occupancy), and immunogenicity of nipocalimab. CONCLUSION: AZALEA, the first placebo-controlled, randomized, multicenter, prospective trial in severe HDFN, is designed to evaluate the safety and efficacy of nipocalimab, a potential preventive and noninvasive intervention, in at-risk HDFN pregnancies.
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Recent reports related to in utero exposure of marketed immunosuppressive biologics led to clinical recommendations to delay live vaccinations for infants due to the concern of reduced vaccine effectiveness and/or increased risk of vaccine-related disease. These delays can increase the risk of children contracting vaccine preventable diseases, yet the alternative cessation of biologics during pregnancy may result in increased autoimmune disease activity for the pregnant person, raising complex benefit-risk (B-R) considerations and trade-offs. Our goal is to develop a conceptual framework for B-R assessment based on the key benefits and risks pregnant people would consider for themselves and their children when continuing (vs. discontinuing) a biologic during pregnancy. The proposed framework defines the decision contexts, key domains and attributes for potential benefits, and risks of biologic use during pregnancy, informed by a literature review of indications for biologics and refined with key clinical stakeholders. The framework includes both the pregnant person taking the biologic and the infant potentially exposed to the biologic in utero, with potential benefit and risk domains and attributes for each participant. To advance this conceptual framework, there are considerations of potential biases and uncertainty of available data that will be imperative to address when quantifying the B-R framework. For these reasons, we recommend the formation of a consortium to ensure development of a robust, validated framework that can be adopted in the healthcare setting.
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Productos Biológicos , Humanos , Embarazo , Femenino , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Medición de Riesgo , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Vacunación/efectos adversos , Efectos Tardíos de la Exposición Prenatal/prevención & controlRESUMEN
OBJECTIVE: Stakeholders met to address persistent challenges facing the development of therapeutics for polyarticular juvenile idiopathic arthritis (pJIA), which result in fewer approved therapies for children with pJIA than adults with rheumatoid arthritis (RA) and long lag times from adult RA approval to pediatric labeling. Ensuring that new medications are authorized in a timely manner to meet the needs of JIA patients worldwide is critically important to multiple stakeholders. METHODS: The Food and Drug Administration in collaboration with the University of Maryland Center for Regulatory Science and Innovation held a public workshop entitled "Accelerating Drug Development for pJIA" on October 2, 2019, to address challenges surrounding access to new medications for children and adolescents with pJIA. Regulatory, academic, and industry stakeholders, as well as patient representatives, participated in the workshop, which consisted of 4 sessions, including panel discussions. RESULTS: The workshop facilitated broad public discussion of challenges facing the development of pJIA therapeutics, highlighting areas of need and outlining opportunities to expedite development, while underscoring the necessity of close collaboration between all stakeholders, including patients and families. CONCLUSION: This report summarizes key aspects of the workshop, including the appropriate application of innovative approaches to the development of pJIA therapeutics, including extrapolation, to address current challenges and provide timely access to newer safe and effective treatments. Long-term safety assessment is of pressing concern to stakeholders and cannot be fully extrapolated from adult studies but requires consistent postmarketing long-term follow-up.
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Artritis Juvenil , Artritis Reumatoide , Adulto , Adolescente , Humanos , Niño , Artritis Juvenil/tratamiento farmacológico , Ensayos Clínicos como Asunto , Resultado del Tratamiento , Desarrollo de MedicamentosRESUMEN
BACKGROUND: Historically, pediatric medicines are developed after adult trials are completed, even when identical drug targets and disease similarities exist across the populations. This has resulted in significant delays in the authorization of medicines for adolescent use, limiting access to beneficial drugs. This study sought to understand how adolescent inclusion in adult trials is positioned in regulatory guidance documents as they set critical expectations for trial design and regulatory decision-making. METHODS: This study utilized a qualitative analysis approach. Guidance documents were identified via Food and Drug Administration and European Medicines Agency websites. Utilizing a blinded adjudication process, the documents were classified as permissive, exclusionary, or silent regarding recommendations about adolescent inclusion in adult clinical trials. A post hoc analysis of similarities and differences between the Food and Drug Administration and European Medicines Agency guidance documents was conducted to assess the possible role of regional pediatric research laws on age-inclusive trial methodologies as well as emergent themes by therapeutic area. RESULTS: In total, 96 Food and Drug Administration (1977 to 2019) and 106 European Medicines Agency (1987 to 2019) guidance documents were identified for analysis. The guidance contained explicit or implicit recommendations supporting adolescent inclusion in adult trials in 32% of Food and Drug Administration and 15% of European Medicines Agency documents, while 14% and 21%, respectively, were found to be exclusionary. A large number of guidance documents were silent regarding the applicability of adolescent-inclusive trial designs (53% and 64%, Food and Drug Administration and European Medicines Agency, respectively). Analysis by therapeutic area revealed the most permissive of adolescent inclusion in Food and Drug Administration guidance for infectious diseases and conditions requiring blood products in European Medicines Agency guidance. A more holistic approach to age-inclusive trial design was identified in disease guidance published by the Food and Drug Administration Oncology Center of Excellence. DISCUSSION: There are many influences on the development and/or revision of regulatory guidance documents. Substantial scientific knowledge and regulatory precedence for the inclusion of adolescents within adult trials are available to inform research approaches. Our study has identified important opportunities for the enhancement of guidance. For example, contextualization of developmental factors influencing adolescent disease progression provides insights into the role of adolescent inclusion. If addressed, guidance documents can facilitate broader acceptance of age-inclusive trial methodologies and accelerate adolescent access to medicines.
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Accesibilidad a los Servicios de Salud , Niño , Adulto , Estados Unidos , Humanos , Adolescente , United States Food and Drug AdministrationRESUMEN
OBJECTIVES: To describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA. METHODS: Pharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg). RESULTS: In the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed. CONCLUSIONS: These three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible. CLINICAL TRIAL REGISTRATION: GO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016.
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Anticuerpos Monoclonales , Artritis Juvenil , Artritis Psoriásica , Adulto , Niño , Humanos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Artritis Juvenil/tratamiento farmacológico , Artritis Psoriásica/tratamiento farmacológico , Ustekinumab/efectos adversos , Administración Intravenosa , Inyecciones Subcutáneas , Preescolar , Adolescente , Ensayos Clínicos Fase III como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Master protocols are innovative clinical trial designs that enable new approaches to analytics and operations, creating value for patients and drug developers. To date, the use of master protocols in pediatric drug development has been limited, focused primarily on pediatric oncology with limited experience in rare and ultra-rare pediatric diseases. This article explores the application of master protocols to pediatric programs required by FDA and EMA based on adult developmental programs. These required programs involve multiple assets developed in limited pediatric populations for registrational purposes. However, these required programs include the possibility for extrapolation of efficacy and safety from the adult population. The use of master protocols is a potential solution to the challenge of conducting clinical trials in small pediatric populations provided that such use would improve enrollment or reduce the required sample size. Toward that end, Janssen and Lilly have been working on a collaborative cross-company pediatric platform trial in pediatric Crohn's disease using an innovative Bayesian analysis. We describe how two competing companies can work together to design and execute the proposed platform, focusing on selected aspects-the usefulness of a single infrastructure, the regulatory submission process, the choice of control group, and the use of pediatric extrapolation. Master protocols offer the potential for great benefit in pediatrics by streamlining clinical development, with the goal of reducing the delay in pediatric marketing approvals when compared to adults so that children have timelier access to safe and effective medications.
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Desarrollo de Medicamentos , Pediatría , Adulto , Teorema de Bayes , Niño , HumanosRESUMEN
Pediatric drug development lags adult development by about 8 years (Mulugeta et al. in Pediatr Clin 64(6):1185-1196, 2017). In such context, many incentives, regulations, and innovative techniques have been proposed to address the disparity for pediatric patients. One such strategy is extrapolation of efficacy from a reference population. Extrapolation is currently justified by providing evidence in support of the effective use of drugs in children when the course of the disease and the expected treatment response would be sufficiently similar in the pediatric and reference population. This paper's position is that, despite uncertainties, pediatric drug development programs should initially assume some degree of extrapolation. The degree to which extrapolation can be used lies along a continuum representing the uncertainties to be addressed through generation of new pediatric evidence. In addressing these uncertainties, the extrapolation strategy should reflect the level of tolerable uncertainty concerning the decision to expose a child to the risks of a new drug. This judgment about the level of tolerable uncertainty should vary with the context (e.g., disease severity, existing therapeutic options) and can be embedded into pediatric drug development archetypes to ascertain the extent of studies needed and whether simultaneous development for adults and adolescents be considered.
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Desarrollo de Medicamentos , Adolescente , Niño , Humanos , PediatríaRESUMEN
Including adolescents in adult clinical trials can play an important role in making innovative new medicines available to children in a timelier fashion. Stakeholders involved in the processes leading to regulatory approval and labeling of new drugs recognize that challenges exist in involving adolescents and older children in clinical trials before the safety and efficacy of these drugs are established for adults. However, it has been possible to design and execute phase 3 trials that combine adults with adolescents which are medically and scientifically sound and ethically justified. Based on this experience and considerations of the medical and scientific, ethical, and operation-related matters, the 2019 Pediatric Innovation Research Forum advocated for the position that adolescents routinely be considered for enrollment in phase 3 clinical trials. The Forum also concluded that exclusion of adolescents in adult pivotal trials occur only when a thorough evaluation of the target disease and the potential benefit and risks of the study intervention supports a delay in their involvement until after completion of clinical trials in adults.
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Ensayos Clínicos como Asunto , Adolescente , Adulto , Niño , HumanosRESUMEN
The conduct of pediatric clinical trials is legally required, monitored, and encouraged in major geographic areas such as the United States and Europe. However, because pediatric patients are considered vulnerable populations, they should only be enrolled as research subjects in a clinical trial if enrolling adult subjects will not be able to answer the scientific question related to the health and welfare of children. Thus, there is an ethical obligation to build the foundation for the use of pediatric extrapolation and related innovative analytical strategies with appropriately designed pediatric and adult clinical trials to reduce the amount of, or general need for, additional information needed from children to reach conclusions. This manuscript discusses innovative applications of clinical trial designs, analytic strategies to more efficiently leverage prior information, and modeling approaches that impact the data required to determine efficacy of an investigational drug in pediatrics. The planning of pediatric trials and regulatory interactions related to required pediatric studies and the expectations for innovative analytics are also discussed.
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Ensayos Clínicos como Asunto/métodos , Desarrollo de Medicamentos/métodos , Adolescente , Teorema de Bayes , Niño , Aprendizaje Profundo , Humanos , Pediatría , Proyectos de Investigación , Estados UnidosRESUMEN
US regulations allow institutional review boards to approve pediatric clinical trials only when the risks are minimal or (in some cases) a minor increase over minimal, or when the risks are justified by a potential for direct benefit to the participants. But how should an institutional review board determine if the risks of pediatric clinical trials are justified by a potential for participant benefit? In this Ethics Rounds article, we consider which potential benefits can justify which research risks with a focus on randomized clinical trials.
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Investigación Biomédica/métodos , Investigación Biomédica/normas , Comités de Ética en Investigación/normas , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Administración Intravenosa , Atresia Biliar/diagnóstico , Atresia Biliar/tratamiento farmacológico , Niño , Glucocorticoides/administración & dosificación , Humanos , Metilprednisolona/administración & dosificación , Estudios Prospectivos , Medición de RiesgoRESUMEN
Despite significant additions to the HIV prevention toolbox, infection rates across the United States continue to rise among vulnerable adolescents and young adults. Access to these interventions by youth at risk for HIV is limited by the lack of data about their safety and use, compounding the myriad contextual barriers to effectively preventing HIV in this group. The NIH-funded Adolescent Trials Network implemented an innovative approach to the inclusion of adolescents at risk for HIV infection who consented for their own participation in the first adolescent study of HIV pre-exposure prophylaxis (PrEP). This model of mature minor consent was supported by state-based adolescent treatment statutes that extend an adolescent's ability to consent to participation in research with a sufficient prospect of clinical benefit from the intervention to justify the potential risks, and a balance of benefits and risks that is at least as favorable as available evidence-based alternatives. Important data on the safety and patterns of PrEP use by at-risk adolescents prompted the FDA to revise the label. The expanded indication of PrEP for HIV prevention in adolescents is hoped to inform clinical guidelines and provides a powerful tool to reduce new infections in the United States among vulnerable at-risk adolescents. Lessons learned from this years-long iterative endeavor have implications for improving access to the rapidly evolving landscape of HIV prevention modalities, including recently implemented studies of long-acting PrEP formulations designed to reduce the burden of daily adherence required by oral PrEP, a major clinical pitfall for adolescent clinicians and their patients.
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Fármacos Anti-VIH/administración & dosificación , Investigación Biomédica/tendencias , Quimioprevención/métodos , Infecciones por VIH/prevención & control , Profilaxis Pre-Exposición/métodos , Adolescente , Humanos , Estados Unidos , Adulto JovenRESUMEN
Despite more than thirty years of debate, disagreement persists among research ethicists about the most appropriate way to interpret the U.S. regulations on pediatric research, specifically the categories of "minimal risk" and a "minor increase over minimal risk." Focusing primarily on the definition of "minimal risk," we argue in this article that the continued debate about the pediatric risk categories is at least partly because their conceptual status is seldom considered directly. Once this is done, it becomes clear that the most popular strategy for interpreting "minimal risk"-defining it as a specific set of risks-is indefensible and, from a pragmatic perspective, unlikely to resolve disagreement. Primarily this is because judgments about minimal risk are both normative and heavily intuitive in nature and thus cannot easily be captured by reductions to a given set of risks. We suggest instead that a more defensible approach to evaluating risk should incorporate room for reflection and deliberation. This dispositional, deliberative framework can nonetheless accommodate a number of intellectual resources for reducing reliance on sheer intuition and improving the quality of risk evaluations.
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Investigación Biomédica , Comités de Ética en Investigación , Pediatría/ética , Niño , Humanos , Medición de RiesgoAsunto(s)
Cardiología , Control de Medicamentos y Narcóticos/organización & administración , Hipertensión Pulmonar , Pediatría , Ensayos Clínicos Controlados Aleatorios como Asunto , Citrato de Sildenafil , Cardiología/métodos , Cardiología/normas , Niño , Defensa del Niño , Salud Infantil/legislación & jurisprudencia , Relación Dosis-Respuesta a Droga , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/normas , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/mortalidad , Mortalidad , Uso Fuera de lo Indicado/legislación & jurisprudencia , Evaluación de Resultado en la Atención de Salud/ética , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Pediatría/métodos , Pediatría/normas , Ensayos Clínicos Controlados Aleatorios como Asunto/ética , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , Citrato de Sildenafil/administración & dosificación , Citrato de Sildenafil/efectos adversos , Vasodilatadores/administración & dosificación , Vasodilatadores/efectos adversosAsunto(s)
Desarrollo de Medicamentos/legislación & jurisprudencia , Política de Salud/legislación & jurisprudencia , Hipertensión Pulmonar/tratamiento farmacológico , Pediatría/legislación & jurisprudencia , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Citrato de Sildenafil/uso terapéutico , Vasodilatadores/uso terapéutico , Adolescente , Factores de Edad , Niño , Preescolar , Aprobación de Drogas/legislación & jurisprudencia , Regulación Gubernamental , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/fisiopatología , Lactante , Seguridad del Paciente/legislación & jurisprudencia , Inhibidores de Fosfodiesterasa 5/efectos adversos , Formulación de Políticas , Medición de Riesgo , Factores de Riesgo , Citrato de Sildenafil/efectos adversos , Resultado del Tratamiento , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudencia , Vasodilatadores/efectos adversosRESUMEN
The ability of adolescents to access safe and effective new products for HIV prevention and treatment is optimised by adolescent licensure at the same time these products are approved and marketed for adults. Many adolescent product development programmes for HIV prevention or treatment products may proceed simultaneously with adult phase III development programmes. Appropriately implemented, this strategy is not expected to delay licensure as information regarding product efficacy can often be extrapolated from adults to adolescents, and pharmacokinetic properties of drugs in adolescents are expected to be similar to those in adults. Finally, adolescents enrolled in therapeutic HIV prevention and treatment research can be considered adults, based on US Food and Drug Administration (FDA) regulations and the appropriate application of state law. The FDA permits local jurisdictions to apply state and local HIV/sexually transmitted infection minor treatment laws so that adolescents who are HIV-positive or at risk of contracting HIV may be enrolled in therapeutic or prevention trials without obtaining parental permission.
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Fármacos Anti-VIH/uso terapéutico , Investigación Biomédica/ética , Infecciones por VIH/tratamiento farmacológico , Consentimiento Informado de Menores , Consentimiento Paterno , Adolescente , Adulto , Investigación Biomédica/legislación & jurisprudencia , Ética en Investigación , Objetivos , Regulación Gubernamental , Infecciones por VIH/prevención & control , Humanos , Consentimiento Informado/ética , Consentimiento Informado/legislación & jurisprudencia , Concesión de Licencias , Estados UnidosRESUMEN
The natural history of spinal muscular atrophy type I (SMA-I) has changed as improved medical support has become available. With investigational drugs for spinal muscular atrophy now in clinical trials, efficient trial design focuses on enrolling recently diagnosed infants, providing best available supportive care, and minimizing subject variation. The quandary has arisen whether it is ethically appropriate to specify a predefined level of nutritional and/or ventilation support for spinal muscular atrophy type I subjects while participating in these studies. We conducted a survey at 2 spinal muscular atrophy investigator meetings involving physician investigators, clinical evaluators, and study coordinators from North America, Europe, and Asia-Pacific. Each group endorsed the concept that having a predefined degree of nutritional and ventilation support was warranted in this context. We discuss how autonomy, beneficence/non-maleficence, noncoercion, social benefit, and equipoise can be maintained when a predefined level of supportive care is proposed, for participation in a clinical trial.
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Ensayos Clínicos como Asunto/ética , Ensayos Clínicos como Asunto/normas , Atrofias Musculares Espinales de la Infancia/terapia , Humanos , Lactante , Internacionalidad , Proyectos de InvestigaciónRESUMEN
The critical need for pediatric research on drugs and biological products underscores the responsibility to ensure that children are enrolled in clinical research that is both scientifically necessary and ethically sound. In this chapter, we review key ethical considerations concerning the participation of children. We review a basic ethical framework to guide pediatric research, and suggest how this framework might be operationalized in linking science and ethics. Topics examined include: the status of children as a vulnerable population; the appropriate balance of risk and potential benefit in research; and parental permission and child assent to participate in research.