Strategies to facilitate adolescent access to medicines: Improving regulatory guidance.

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.

Intravenous Golimumab in Patients with Polyarticular Juvenile Idiopathic Arthritis and Juvenile Psoriatic Arthritis and Subcutaneous Ustekinumab in Patients with Juvenile Psoriatic Arthritis: Extrapolation of Data from Studies in Adults and Adjacent Pediatric Populations.

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.

The Role of Master Protocols in Pediatric Drug Development.

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.

Advancing HIV Biomedical Prevention Research for At-Risk Adolescents.

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.

Factors related to voluntary parental decision-making in pediatric oncology.

OBJECTIVE: The aim of the current study was to examine demographic and contextual correlates of voluntariness in parents making research or treatment decisions for their children with cancer. METHODS: Participants included 184 parents of children with cancer who made a decision about enrolling the child in a research or treatment protocol within the previous 10 days. Parents completed questionnaires that assessed voluntariness, external influence by others, concern that the child's care would be negatively affected if the parent did not agree, time pressure, information adequacy, and demographics. RESULTS: Lower perceived voluntariness was associated with lower education, male gender, minority status, and not having previous experience with a similar decision. Parents who reported lower voluntariness also perceived more external influence and time pressure, had more concern about the child's care being negatively affected if they declined, and perceived that they had either too much or not enough information about the decision. In a multivariate regression, education, minority status, gender, external influence, and too little information remained significantly associated with voluntariness. CONCLUSIONS: Several groups of parents appear to be at risk for decreased voluntariness when making research or treatment decisions for their seriously ill children, including fathers, nonwhite parents, and those with less education. Parental voluntariness may be enhanced by helping parents to mitigate the effects of unhelpful or unwanted influences by others and ensuring that their information needs are met.

Relationship of external influence to parental distress in decision making regarding children with a life-threatening illness.

OBJECTIVE: To examine the relationship of external influence to parental distress when making a decision about research or treatment for a child with a life-threatening illness and to test potential moderators of this relationship. METHODS: Parents (n = 219) who made a decision about research or treatment for a child completed measures of external influence, distress, decision-making preference, and coping. RESULTS: More external influence was associated with more hostility, uncertainty, and confusion. Decision-making preference and coping style moderated the relationship between external influence and distress: More external influence was associated with more distress when decision-making preference was low and task-focused coping was high. CONCLUSIONS: External influence appears to be related to distress in parents making research and treatment decisions for children with life-threatening illnesses. However, it is important to consider parent characteristics, such as decision-making preference and coping style, when examining the effects of contextual factors on distress during decision making.

Assessment of parental decision-making in neonatal cardiac research: a pilot study.

OBJECTIVE: To assess parental permission for a neonate's research participation using the MacArthur competence assessment tool for clinical research (MacCAT-CR), specifically testing the components of understanding, appreciation, reasoning and choice. STUDY DESIGN: Quantitative interviews using study-specific MacCAT-CR tools. HYPOTHESIS: Parents of critically ill newborns would produce comparable MacCAT-CR scores to healthy adult controls despite the emotional stress of an infant with critical heart disease or the urgency of surgery. Parents of infants diagnosed prenatally would have higher MacCAT-CR scores than parents of infants diagnosed postnatally. There would be no difference in MacCAT-CR scores between parents with respect to gender or whether they did or did not permit research participation. PARTICIPANTS: Parents of neonates undergoing cardiac surgery who had made decisions about research participation before their neonate's surgery. METHODS: The MacCAT-CR. RESULTS: 35 parents (18 mothers; 17 fathers) of 24 neonates completed 55 interviews for one or more of three studies. Total scores: magnetic resonance imaging (mean 36.6, SD 7.71), genetics (mean 38.8, SD 3.44), heart rate variability (mean 37.7, SD 3.30). Parents generally scored higher than published subject populations and were comparable to published control populations with some exceptions. CONCLUSIONS: The MacCAT-CR can be used to assess parental permission for neonatal research participation. Despite the stress of a critically ill neonate requiring surgery, parents were able to understand study-specific information and make informed decisions to permit their neonate's participation.

Variation in standards of research compensation and child assent practices: a comparison of 69 institutional review board-approved informed permission and assent forms for 3 multicenter pediatric clinical trials.

OBJECTIVE: To systematically compare standards for compensation and child participant assent in informed permission, assent, and consent forms (IP-A-CFs) approved by 55 local institutional review boards (IRBs) reviewing 3 standardized multicenter research protocols. METHOD: Sixty-nine principal investigators participating in any of 3 national, multicenter clinical trials submitted standardized research protocols for their trials to their local IRBs for approval. Copies of the subsequently IRB-approved IP-A-CFs were then forwarded to an academic clinical research organization. This collection of IRB-approved forms allowed for a quasiexperimental retrospective evaluation of the variation in informed permission, assent, and consent standards operationalized by the local IRBs. RESULTS: Standards for compensation and child participant assent varied substantially across 69 IRB-approved IP-A-CFs. Among the 48 IP-A-CFs offering compensation, monetary compensation was offered by 33 as reimbursement for travel, parking, or food expenses, whereas monetary or material compensation was offered by 22 for subject inconvenience and by 13 for subject time. Compensation ranged widely within and across studies (study 1, $180-1425; study 2, $0-500; and study 3, $0-100). Regarding child participant assent, among the 57 IP-A-CFs that included a form of assent documentation, 33 included a line for assent on the informed permission or consent form, whereas 35 included a separate form written in simplified language. Of the IP-A-CFs that stipulated the documentation of assent, 31 specified > or =1 age ranges for obtaining assent. Informed permission or consent forms were addressed either to parents or child participants. CONCLUSION: In response to identical clinical trial protocols, local IRBs generate IP-A-CFs that vary considerably regarding compensation and child participant assent.

Weighing the risks of G-CSF administration, leukopheresis, and standard marrow harvest: ethical and safety considerations for normal pediatric hematopoietic cell donors.

BACKGROUND: Granulocyte colony stimulating factor (G-CSF) is used for collection of hematopoietic cells in most adult and a smaller but significant percentage of pediatric normal donor harvests. Short and long-term risks of G-CSF administration and leukopheresis are not well understood in the pediatric population. PROCEDURE: Literature review including observations from the IBMTR, NMDP, EBMT, German Donor Registry, and the authors' work. RESULTS: G-CSF causes temporary discomfort in a minority of younger donors. Rare serious side effects of G-CSF have yet to be reported in children. To date, an increase in hematological malignancies after short-term G-CSF use has not been detected in adult donors and no cases have been reported in children. Reported complications of leukopheresis in children are rare and minor, but donors <20 kg may be exposed to allogeneic blood products. Pediatric aged donors vary widely in their ability to assent or consent to the risks of a donation procedure. There are key regulations and ethical imperitives, which must be addressed in deciding which donation procedures are appropriate for minors. CONCLUSIONS: While short term administration of G-CSF and leukopheresis appear to be safe and effective procedures when used to assist in collection of a hematopoietic cell graft from a normal pediatric donor, institutions adding or substituting one or both of these procedures for standard marrow donation must decide whether the donor should be considered a research subject, and if so, whether the new procedures are a minor increase over minimal risk. Because these procedures are being performed on and off study at many pediatric centers, a comprehensive study addressing donor safety could help clarify risks of rare adverse events.

Parental decision-making in congenital heart disease.

OBJECTIVE: To explore whether prenatal diagnosis of congenital heart disease is associated with lower levels of parental distress and greater satisfaction with decisions about cardiothoracic surgery when compared to postnatal diagnosis. METHODOLOGY: A combined quantitative-qualitative design was used. Participants included the parents of 31 neonates (30 mothers and 22 fathers) admitted to the cardiac intensive care unit between 1 November 2001 and 1 May 2002 for repair of congenital cardiac malformations. Participants completed self-report measures of anxiety, optimism, and life events pre-operatively, and semi-structured qualitative interviews assessing satisfaction with decision-making within 1 week of the operation. RESULTS: At the time of surgery, mothers of neonates receiving the diagnosis prenatally did not differ from mothers of neonates receiving the diagnosis postnatally on measures of anxiety, optimism, and life events. Fathers of neonates receiving the diagnosis prenatally, however, reported more optimism, lower state and trait anxiety, and fewer negative life events than fathers of neonates receiving the diagnosis postnatally. When we analyzed the interviews, we found that, regardless of the timing of the diagnosis, parents felt as though they made a genuine choice for their baby to have surgery. CONCLUSIONS: In this pilot study, fathers who learned prenatally that their child had a congenital cardiac malformation were less distressed than those who discovered this fact only postnatally. From the parental perspective, nonetheless, distress and urgency do not impair their ability to make decisions about neonatal cardiac surgery.

Multicenter analysis of platelet transfusion usage among neonates on extracorporeal membrane oxygenation.

OBJECTIVE: Multiple platelet transfusions are invariably given to neonates on extracorporeal membrane oxygenation (ECMO), and no alternative to repeated transfusions exists. Before any alternatives, such as administration of thrombopoietic stimulators, could be contemplated, data regarding the number of platelet transfusions received by neonatal ECMO patients is needed, and the mechanisms that cause the thrombocytopenia of these patients must be better defined. As a step toward determining this, we analyzed the use of platelet transfusions in this group of neonates. We conducted a historic cohort study of neonates who were treated with ECMO to determine the number of platelet units received as a function of 1) days on ECMO, 2) medical diagnosis for which ECMO was instituted, and 3) type of ECMO used (venovenous [VV] vs venoarterial [VA]). METHODS: We reviewed the hospital records of all neonates who were admitted to the neonatal intensive care units at Shands Children's Hospital, Arnold Palmer Hospital for Children and Women, and Tampa General Hospital and treated with ECMO between January 1, 1995, and June 30, 2000. Data were expressed as the number of platelet transfusions versus number of days on ECMO, diagnosis for which ECMO was instituted, and type of ECMO used. RESULTS: Of the 234 ECMO patients, 81 were placed on VV, 138 were placed on VA, and 15 were converted from VV to VA. The average number of platelet transfusions received per day was 1.3 and varied by diagnosis and by type of ECMO. Neonates with meconium aspiration and sepsis required more platelet transfusions per day than neonates with other conditions. Infants who were converted from VV to VA required more transfusions per day (mean: 1.57) than did patients on VA (1.47) or VV (1.06). CONCLUSIONS: Platelet transfusions among neonates on ECMO are dependent of their medical diagnosis; they average 1.3 transfusions per day and are higher on VA than VV ECMO.