Paediatric Investigation Plan Research Articles

Approved medicines for paediatric solid tumours in Europe: Lessons from the life cycle of a paediatric investigation plan

BackgroundDespite the positive changes brought by the Paediatric Regulation in the European Union (EU) in 2007, drug development in children remains challenging. MethodsTo better understand the issues encountered to reach an authorisation for paediatric patients, we reviewed the pathway of the 11 Paediatric Investigational Plans (PIPs) with indications targeting paediatric solid tumours granted by the Committee for Medicinal Products for Human Use (CHMP) between 2007 and 2022. ResultsOn average 5,5 years were necessary to reach approval after a PIP was agreed. All the PIPs underwent at least one modification (median 3 modifications per PIP). The use of single arm trials, in the context of refractory/relapsed disease in absence of standard of care treatment, was supportive for granting a paediatric indication in the majority of the cases. In 6 out of 11 approved products, extrapolation from adults was used. For 2/11 the approval focused on an older population first compared to the initial age group agreed in the PIP due to the development of a suitable formulation for younger children still ongoing at the time of first approval. Scientific advice sought on paediatric development use of extrapolation from adults, major objections raised by CHMP and post-marketing requirements were examined. ConclusionAnalysing the process necessary to reach an authorisation for paediatric patients, we highlight the major challenges faced in the paediatric approval process and the positive examples of successful drug development that reached final approval. Our analysis is expected to provide useful insights to drug developers, investigators and regulators.

Evolution of the Innovative Therapies for Children With Cancer Consortium Trial Portfolio for Drug Development for Children With Cancer.

The aim of the Innovative Therapies for Children with Cancer (ITCC) consortium is to improve access to novel therapies for children and adolescents with cancer. The evolution of the ITCC clinical trial portfolio since 2003 was reviewed. All ITCC-labeled phase I/II trials opened between January 1, 2003 and February 3, 2018 were analyzed in two periods (2003-2010 and 2011-2018), and data were extracted from the ITCC database, regulatory agencies' registries, and publications. Sixty-one trials (62% industry-sponsored) enrolled 3,198 patients. The number of trials in the second period increased by almost 300% (16 v 45). All biomarker-driven trials (n = 14) were conducted in the second period. The use of rolling six and model-based designs increased (1 of 9, 11% v 21 of 31, 68%), and that of 3 + 3 designs decreased (5 of 9, 55% v 5 of 31, 16%; P = .014). The proportion of studies evaluating chemotherapeutics only decreased (5 of 16, 31% v 4 of 45, 9%), the proportion of single-agent targeted therapies did not change (9 of 16, 56.2% v 24 of 45, 53.3%), the proportion of combination targeted therapies trials increased (2 of 16, 12%, v 17 of 45, 38%), the proportion of randomized phase II trials increased (1 of 7, 14% v 8 of 14, 57%). More trials were part of a pediatric investigation plan in the second period (4 of 16, 25% v 21 of 45, 46%). The median time for Ethics Committees' approvals was 1.7 times longer for academic compared with industry-sponsored trials. This study reports a shift in the paradigm of early drug development for childhood cancers, with more biologically relevant targets evaluated in biomarker-driven trials or in combination with other therapies and with more model-based or randomized designs and a greater focus on fulfilling regulatory requirements. Improvement of trial setup and recruitment could increase the number of patients benefiting from novel agents.

A multicohort platform trial to improve drug access for pediatric cancer patients in Japan: The PARTNER trial (NCCH2220).

TPS10079 Background: In Japan, there are no pediatric regulations that encourage drug development for pediatric cancer, such as Pediatric Investigation Plans (PIPs) which are mandated in Europe, or the RACE Act in the U.S. Therefore, there are fewer early-phase clinical trials and approved drugs for pediatric cancer than in Western countries. In addition, because there is no rapid compassionate use program, there are delays when using an unapproved drug. According to a report from the Japanese cancer genome profiling (CGP) testing data center, C-CAT, 51.3% of pediatric patients with solid tumors had targetable genetic abnormalities. However, only 5.8% of them had access to the recommended molecular targeted therapy (Tanimura K. et al., presented at the Japanese Society of Pediatric Hematology and Oncology annual meeting 2022). Thus, Japanese pediatric patients with relapsed or refractory solid tumors have limited access to novel drugs, even if they have druggable mutations. Therefore, we designed a platform study (NCCH2220, PARTNER trial) to rapidly deliver molecularly targeted drugs based on CGP testing. Methods: This study has two objectives: first, to administer some drugs to pediatric patients that are not approved for pediatric cancer in Japan. These drugs have been shown to be safe in pediatric patients in foreign countries and are expected to be effective. Second, to evaluate the safety and efficacy of the drug in Japanese pediatric patients and, if necessary, its pharmacokinetics. These data will be used for potential future regulatory filings. This is an open-label, multicenter, multicohort study. Eligible patients are aged 0–29 years with diseases having no standard therapy, which are refractory, or when there is intolerance to standard therapy. The study drug must be recommended for the patient by CGP testing or approved for pediatric use for their disease in the U.S. or Europe, or approved in Japan for use in adults only. The drugs are used as monotherapy in the study. The study schedules follow a master protocol. Up to 30 patients can be enrolled in each cohort. The primary endpoint is the incidence of dose-limiting toxicity in each cohort. The secondary endpoints are the incidence of adverse events, the overall response rate, and, if necessary, the pharmacokinetics in each cohort. As of January 2024, the study had five treatment cohorts with the following agents: imatinib, pazopanib, ruxolitinib, trametinib, and atezolizumab. Additional cohorts will be added. We started planning the study in November 2022, and enrollment began on January 18, 2024. This platform trial has enabled us to deliver drugs to patients more quickly and efficiently than by conducting individual early-phase trials for each drug. Clinical trial information: jRCTs031230544 .

Safety and effectiveness of Evicel® fibrin sealant as an adjunct to sutured dural repair in children undergoing cranial neurosurgery

PurposeCerebrospinal fluid (CSF) leakage is a challenging complication of intradural cranial surgery, and children are particularly at risk. The use of dural sealants confers protection in adults, but pediatric studies are scarce. We evaluated the safety and efficacy of Evicel® fibrin sealant as an adjunct to primary dural suturing in children undergoing cranial surgery.MethodsA multicenter trial prospectively enrolled pediatric subjects (< 18 years) undergoing cranial neurosurgery who, upon completion of primary sutured dural repair, experienced CSF leakage. As agreed by the EMA Evicel® Pediatric Investigation Plan, 40 subjects were intra-operatively randomized 2:1 to Evicel® or additional sutures (‘Sutures’). Data analysis was descriptive. The efficacy endpoint was treatment success rate, with success defined as intra-operative watertight closure after provocative Valsalva maneuver (primary endpoint). Safety endpoints were postoperative CSF leakage (incisional CSF leakage, pseudomeningocele or both) and surgical site complications (secondary endpoints).ResultsForty subjects (0.6–17 years) were randomized to Evicel® (N = 25) or Sutures (N = 15) (intention-to-treat). Intracranial tumor was the most common indication and procedures were mostly supratentorial craniotomies. Success rates were 92.0% for Evicel® and 33.3% for Sutures, with a 2.76 estimated ratio of success rates (Farrington-Manning 95% CI [1.53, 6.16]). Sensitivity analyses in per-protocol and safety sets showed similar results. Despite a higher rescue treatment rate, the frequencies of postoperative CSF leakage and wound complications were higher for Sutures than for Evicel®.ConclusionThis small-scale prospective study shows Evicel® treatment to be safe and effective as an adjunct to primary sutured dura mater closure in a pediatric population. Compared to additional sutures, Evicel® was associated with reduced postoperative CSF leakage and surgical site complications. (Trial registration: The trial was registered as NCT02309645 and EudraCT 2013-003558-26).

A Study of Safety and Effectiveness of Evicel Fibrin Sealant as an Adjunctive Hemostat in Pediatric Surgery.

Data on the use of fibrin sealants to control intraoperative bleeding in children are scarce. Evicel Fibrin Sealant (Ethicon Inc., Raritan, New Jersey, United States) was found safe and effective in clinical trials of adults undergoing various surgery types. We evaluated the safety and efficacy of Evicel versus Surgicel Absorbable Hemostat (Ethicon Inc.) as adjunctive topical hemostats for mild/moderate raw-surface bleeding in pediatric surgery. A phase III randomized clinical trial was designed as required by the European Medicines Agency's Evicel Pediatric Investigation Plan: 40 pediatric subjects undergoing abdominal, retroperitoneal, pelvic, or thoracic surgery were randomized to Evicel or Surgicel, to treat intraoperative mild-to-moderate bleeding. Descriptive analyses included time-to-hemostasis and rates of treatment success (4, 7, 10 minutes), intraoperative treatment failure, rebleeding, and thromboembolic events. Forty of 130 screened subjects aged 0.9 to 17 years were randomized 1:1 to Evicel or Surgicel. Surgeries were predominantly open abdominal procedures. The median bleeding area was 4.0 cm2 for Evicel and 1.0 cm2 for Surgicel. The median time-to-hemostasis was 4.0 minutes for both groups. The 4-, 7-, and 10-minute treatment success rates were 80.0% versus 65.0%, 100.0% versus 80.0%, and 95.0% versus 90.0%, whereas treatment failure rates were 5.0% versus 25.0%, for Evicel and Surgicel, respectively. No deaths or thrombotic events occurred. Re-bleeding occurred in 5.0% of Evicel and 10.0% of Surgicel subjects. In accordance with adult clinical trials, this randomized study supports the safety and efficacy of Evicel for controlling mild-to-moderate surgical bleeding in a broad range of pediatric surgical procedures.

Target therapy for high-risk neuroblastoma treatment: integration of regulatory and scientific tools is needed.

Several new active substances (ASs) targeting neuroblastoma (NBL) are under study. We aim to describe the developmental and regulatory status of a sample of ASs targeting NBL to underline the existing regulatory gaps in product development and to discuss possible improvements. The developmental and regulatory statuses of the identified ASs targeting NBL were investigated by searching for preclinical studies, clinical trials (CTs), marketing authorizations, pediatric investigation plans (PIPs), waivers, orphan designations, and other regulatory procedures. A total of 188 ASs were identified. Of these, 55 were considered 'not under development' without preclinical or clinical studies. Preclinical studies were found for 115 ASs, of which 54 were associated with a medicinal product. A total of 283 CTs (as monotherapy or in combination) were identified for 70 ASs. Of these, 52% were at phases 1, 1/2, and 2 aimed at PK/PD/dosing activity. The remaining ones also included efficacy. Phase 3 studies were limited. Studies were completed for 14 ASs and suspended for 11. The highest rate of ASs involved in CTs was observed in the RAS-MAPK-MEK and VEGF groups. A total of 37 ASs were granted with a PIP, of which 14 involved NBL, 41 ASs with a waiver, and 18 ASs with both PIPs and waivers, with the PIP covering pediatric indications different from the adult ones. In almost all the PIPs, preclinical studies were required, together with early-phase CTs often including efficacy evaluation. Two PIPs were terminated because of negative study results, and eight PIPs are in progress. Variations in the SmPC were made for larotrectinib sulfate/Vitrakvi® and entrectinib/Rozlytrek® with the inclusion of a new indication. For both, the related PIPs are still ongoing. The orphan designation has been largely adopted, while PRIME designation has been less implemented. Several ASs entered early phase CTs but less than one out of four were included in a regulatory process, and only two were granted a pediatric indication extension. Our results confirm that it is necessary to identify a more efficient, less costly, and time-consuming "pediatric developmental model" integrating predictive preclinical study and innovative clinical study designs. Furthermore, stricter integration between scientific and regulatory efforts should be promoted.

Changing incentives to ACCELERATE drug development for paediatric cancer.

More effective incentives are needed to motivate paediatric oncology drug development, uncoupling it from dependency on adult drug development. Although the current European and North-American legislations aim to promote drug development for paediatrics and rare diseases, children and adolescents with cancer have not benefited as expected from these initiatives and cancer remains the first cause of death by disease in children older than one. Drug development for childhood cancer remains dependent on adult cancer indications and their potential market. The balance between the investment needed to execute a Paediatric Investigation Plan (PIP) in Europe and an initial Paediatric Study Plan (iPSP) in the US, coupled with the potential financial reward has not been sufficiently attractive to incite the pharmaceutical industry to develop drugs for rare indications such as childhood cancer. We propose changes in the timing and nature of the rewards within the European Paediatric Medicine Regulation (PMR) and Regulation on Orphan Medicinal Products (both currently under review), which would drive earlier initiation of paediatric oncology studies and provide incentives for drug development specifically for childhood indications. We suggest modifying the PMR to ensure mechanism-of-action driven mandatory PIP and reorganization of incentives to a stepwise and incremental approach. Interim and final deliverables should be defined within a PIP or iPSP, each attracting a reward on completion. A crucial change would be the introduction of the interim deliverable requiring production of paediatric data that inform the go/no-go decisions on whether to take a drug forward to paediatric efficacy trials. Additionally, to address the critical gap in the current framework where there is a complete lack of incentives to promote paediatric-specific cancer drug development, we propose the introduction of early rewards in the Orphan Regulation, with a variant on the US-Creating Hope Act and its priority review vouchers.

AIT in pediatric allergology: Opportunities and difficulties on the home stretch of the Therapy Allergen Ordinance.

Allergen immunotherapy (AIT) is the only causal therapy for allergic diseases and therefore particularly important. Allergen preparations have been classified as medicinal products since 1989 (Directive 89/342/EEC) and were taken over into Directive 2001/83/EC in 2001. In addition, in 2008 the Therapy Allergen Ordinance (TAO) came into force to stricter regulate the exception for named patient products (NPP) by exclusion of common therapy allergens from the exception to be marketed as NPP. The TAO regulates the requirements for testing safety and efficacy for these common therapy allergens. Due to the long transitional provisions, the last deadlines for solving clinical shortcomings will end in 2026. The advantage of this regulation is that the market for common allergens has been cleared of products without proof of efficacy, and new preparations with an optimal dose range are developed through dose-finding studies. The demand for long-term pediatric studies has been outlined by the standard Pediatric Investigation Plan (PIP) on allergen products from the Pediatric Committee of the EMA (PDCO). This is particularly problematic, as it is foreseeable that recruitment of patients will be limited and ethical problems arise from the prolonged use of placebo. Furthermore, many newly approved preparations will not be used in pediatrics for the foreseeable future, as no marketing authorization has yet been granted for this age group. This will result in a serious supply gap for children.

Registration of medicinal products for pediatric use and Pediatric Investigation Plan

Registration of medicinal products for pediatric use and Pediatric Investigation Plan

Letermovir for Prophylaxis and Pre-emptive Therapy of Cytomegalovirus Infection in Paediatric Allogeneic Haematopoietic Cell Transplant Patients.

Cytomegalovirus (CMV) infection is a frequent event in patients undergoing allogeneic haematopoietic cell transplantation (HCT) and is associated with increased morbidity and mortality due to eventual progress to end-organ disease. Letermovir prophylaxis for CMV infections has become a standard of care in adult HCT recipients due to its efficacy and high tolerability. However, itis not yet approved for paediatric patients. In a retrospective single-centre observational study we evaluated the use of letermovir for prophylaxis or pre-emptive treatment of cytomegalovirus (CMV) infection in seropositive paediatric HCT recipients receiving the compound outside of clinical trials. The primary endpoint was CMV reactivation requiring a change of medication. A total of 17 patients (seven female/ten male; median age 12.2 [range3.5-19] years, median body weight 39.5 [range15-63] kg; median follow-up time 463.7 [range41-1022] days) were identified who were started on oral (14) or intravenous (3) followed by oral (2) letermovir shortly after neutrophil engraftment at doses determined on the basis of age, weight, and concomitant cyclosporine use. Five patients had no evidence of viral replication (prophylactic use), while 12 patients had varying extents of viral replication (pre-emptive therapy). A change of therapy was required in one patient due to a sustained increase in CMV viral load, and in two patients, letermovir was stopped without later reactivation after initiation of palliative care for recurrent leukaemia. Of the 14 patients who completed treatment, 3 had evidence of transient viral replication after end of treatment that required no further antiviral treatment. No patients (of 17) discontinued letermovir dueto an adverse event. Letermovir was effective in controlling CMV infection in seropositive paediatric allogeneic HCT recipients and wasoverall well tolerated. Pending completion of the still ongoing paediatric investigation plans, letermovir will be an important adjunct to our options for control of infectious complications in this special population.

ITCC-101/APAL2020D: A Randomized Phase 3 Trial of Fludarabine/Cytarabine/Gemtuzumab Ozogamycin with or without Venetoclax in Children with Relapsed Acute Myeloid Leukemia

Background Despite improvements in the therapy of children with acute myeloid leukemia (AML) over the last decades with overall survival (OS) rates approaching 70%, the outcome after relapse remains poor. Outcomes are particularly poor for patients unable to receive anthracyclines due to prior cardiac toxicity or those beyond first relapse, e.g., the AML-Berlin-Frankfurt-Mu¨nster Study Group reported a 5-year OS rate in second relapse of 15+/-4%, and 31+/-9% following hematopoietic stem cell transplantation (HSCT) (n=25/73). Additional therapeutic options for these groups of children are needed. Venetoclax is a selective, potent, orally bioavailable, small molecule inhibitor of B-cell lymphoma-2 (BCL-2) that restores programmed cell death in cancer cells, and is approved for the treatment of adult patients with newly diagnosed AML in combination with hypomethylating agents or low-dose cytarabine, who are ineligible for intensive chemotherapy (Venetoclax Summary of Product Characteristics and United States Prescribing Information). The single arm VENAML trial (NCT03194932) assessed the safety and activity of venetoclax in combination with cytarabine and idarubicin in pediatric patients with relapsed or refractory (R/R) AML with encouraging response rates. In 20 evaluable patients treated at the recommended phase II dose (RP2D), there were 13 CRs and 1 CRi. Two additional patients achieved a PR. For patients treated at the RP2D, 10/14 achieved minimal residual disease (MRD) negative (<0.1% by flow cytometry) CR/CRi. Among patients treated at the RP2D, 5/6 patients in untreated first relapse achieved a CR while 9/14 patients beyond first relapse achieved a CR (N=8) or a CRi (N=1). These encouraging preliminary results in children on the safety and anti-tumor activity of venetoclax led to the development of our study: ITCC-101/APAL2020D trial, within the framework of a Pediatric Investigational Plan and Written Request agreement. The Pediatric Acute Leukemia (PedAL)/European Pediatric Acute Leukemia (EuPAL) initiative is a master protocol with sub-trials with the goal of establishing new standards of care for children with R/R AML in order to improve the outcome and increase the long-term survival of these patients. This is the first sub-trial under the ITCC-101 master protocol in the PedAL/EuPAL project. Study Design and Methods This is an open-label randomized phase 3 trial of fludarabine, high dose cytarabine (FLA)+gemtuzumab ozogamicin (GO) with or without venetoclax in children with relapsed AML. This study will enroll children, adolescents, and young adults with AML without FLT3/ITD mutation in second relapse, who are sufficiently fit to undergo intensive chemotherapy, or in first relapse, who cannot tolerate additional anthracycline containing chemotherapy. There are two cycles of treatments and as backbone chemotherapy, the Cycle 1 consists of FLA+GO and the Cycle 2 FLA. In the experimental arm, venetoclax will be administered at 300 mg adult equivalent dose on Cycle 1 Day 1 and 600 mg adult equivalent dose on subsequent days of each 28 day cycle. Responding patients after the first two cycles can undergo allogeneic HSCT. Patients who have responded to protocol therapy but who cannot tolerate HSCT will receive maintenance therapy consisting of azacitidine or combination azacitidine-venetoclax as per the randomized arm. In maintenance therapy, a lower dose of venetoclax is applied in combination with azacitidine, i.e., 400 mg adult equivalent dose. The primary objective is to compare the OS of venetoclax in combination with FLA+GO compared with FLA+GO alone. Secondary objectives include the assessment of response, safety, pharmacokinetics and rate of transition to HSCT. A comprehensive study of correlative biomarkers such as BCL-2 homology profiling or venetoclax drug sensitivity will also be carried out. Morphology and MRD by flow cytometry assessments will be centralized. For statistical analysis, 72 death events need to be observed for which 98 patients will randomized. The primary analysis will be performed approximately 5 years after the first patient is randomized. Recruitment is ongoing. This trial is registered on clinicaltrials.gov: NCT05183035 and EudraCT Number is 2021-003212-11.

General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children.

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well-designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state-of-the-art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.

ODP426 SPIOMET4HEALTH: a 4-Arm Trial to Test the Effects of Lifestyle Intervention plus either Placebo, or Pioglitazone (PIO), or Spironolactone-Pioglitazone (SPIO), or Spironolactone-Pioglitazone-Metformin (SPIOMET) in Adolescent Girls and Young Women with PCOS

Abstract Introduction PCOS in adolescent girls and young women is nowadays thought to be, in essence, an epiphenomenon of ectopic fat accumulation. By definition, "adolescent PCOS" is characterized by androgen excess (as well clinical as biochemical) and oligo-anovulation (often judged by oligo-amenorrhea) (1) presenting between 2 and 8 years after menarche. There is no FDA-approved treatment for "adolescent PCOS". In SPIOMET4HEALTH (a project funded by the European Commission under Grant Agreement 899671), we aim at reducing ectopic fat in an early phase of PCOS, with a standardized lifestyle intervention plus a pharmacological addendum consisting of either placebo, or PIO, or SPIO, or SPIOMET. In "adolescent PCOS", low-dose pioglitazone (7.5 mg/d) may exert insulin-sensitizing and gonadotropin-normalizing effects, in part by raising the circulating concentrations of high-molecular-weight adiponectin; low-dose spironolactone (50 mg/d) may not only act as an anti-androgen but also exert anti-mineralocorticoid effects that raise energy expenditure by activating brown adipose tissue; low-dose metformin (850 mg/d) is known to act through multiple mechanisms and was recently shown to be capable of changing the relative deficit of GDF15 into an abundance that is thought to contribute to reduce liver fat. Subjects &amp; Methods In the SPIOMET4HEALTH trial, patients with "adolescent PCOS" (age range 12. 0–23.9 years; BMI &amp;lt;35 kg/m 2) will be recruited in seven centers across Europe. A total of 364 patients are expected to engage into a lifestyle intervention, and to receive either placebo, or PIO, or SPIO, or SPIOMET once daily (1: 1: 1: 1 randomization; single tablets; double blinding) for 12 months. Post-treatment follow-up will span 6 months. The primary endpoint is ovulation rate, as judged by a combination of menstrual data and progesterone concentrations in saliva; the analysis will start by testing for superiority between placebo and SPIOMET. Secondary endpoints include pre-treatment, on-treatment and post-treatment measures of androgen excess, body composition and insulin sensitivity, as well as measures of quality of life, and of adherence to treatment. The design of this trial has been endorsed by the European Medicines Agency, as part of a "Paediatric Investigation Plan". Expected Results/Discussion The SPIOMET4HEALTH project is expected to deliver the first results of an international, randomized, double-blind, active-controlled/placebo-controlled trial evaluating the safety, efficacy, and tolerability of the fixed dose combination SPIOMET in adolescent girls and young women with PCOS. Favorable results of this Phase 2 trial may advance SPIOMET into Phase 3. Reference: Ibáñez L, et al. An International Consortium Update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr 2017;88: 371-395. Presentation: No date and time listed

European regulatory strategy for supporting childhood cancer therapy developments

IntroductionRegulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs. ObjectiveRegulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development. ConclusionAn agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings.

The Pediatric Pharmacy Association and Members Threaded Through a Career and the Impact on Pediatric Drug Development.

The Pediatric Pharmacy Association and Members Threaded Through a Career and the Impact on Pediatric Drug Development.

New Information on Old Medicinal Products: A Cross-Sectional Analysis of Guidance for Paediatric Use for Substances on the European Priority List of Off-Patent Medicinal Products.

As part of the European Paediatric Regulation, the European Medicines Agency (former European Medicines Evaluation Agency) and the Paediatric Working Party (precursor for the Paediatric Committee) revised a priority list for studies on off-patent medicinal products in 2007 where a need for studies on paediatric medicinal products was emphasised. We aimed to evaluate the status of guidance for paediatric use in the Summary of Product Characteristics for medicinal products on the priority list as well as the presence and status of Paediatric Investigation Plans for these medicinal products. We included active pharmaceutical ingredients on the priority list authorised through the centralised procedure and/or marketed in Denmark. The status of guidance for paediatric use (indication, posology and/or contraindication) was reviewed from the most recent Summary of Product Characteristics uploaded on the European Medicines Agency or the Danish Medicines Agency website as of November 2020. Information on Paediatric Investigation Plans status (Paediatric Committee opinion, completion and waivers granted) was retrieved from the European Medicines Agency website. A total of 121 active pharmaceutical ingredients were included in this study. Seventy-one percent had guidance for paediatric use in the Summary of Product Characteristics for at least one paediatric subpopulation, more often concerning adolescents (70%) and children (70%) as compared with neonates (41%) and infants (49%). The guidance included a paediatric indication in 46% of the cases, but less often a contraindication (13%). Thirty-three active pharmaceutical ingredients had an agreed Paediatric Investigation Plan, six of these were completed. Most active pharmaceutical ingredients from the priority list had guidance for paediatric use in the Summary of Product Characteristics. However, there is still an unmet need in relation to guidance for use for the youngest paediatric subpopulation.

New Developments in Pediatric Antifungal Pharmacology.

New Developments in Pediatric Antifungal Pharmacology.

Paediatric Allergen-Specific Immunotherapy Studies Required by the European Medicines Agency: Is It Time for a Reassessment?

Allergen-specific immunotherapy (AIT) works well both in children and adults. An often-alleged gap between the level of evidence of AIT efficacy in adults versus children is based upon the flawed ‘children-are-not-small-adults’ and ‘children-are-therapeutic-orphans’ mantras, both of which emerged in the 1960s. These mantras led to paediatric legislation in the USA in 1997 and the European Union (EU) paediatric regulation 10 years later. Although preterm newborns and newborns are vulnerable, during the first year of life their organs mature. Young children are no longer physiologically newborns; their immune system can overreact and cause allergic reactions, and AIT works for them just like it does in adults. Young patients need dosing recommendations and safety observations, rather than repetition of proof of efficacy. Placebo-controlled efficacy studies withhold effective treatment, increase the risk of asthma in the placebo group and are, therefore, in the authors’ opinion, unethical as well as in breach of the declaration of Helsinki. Individuals under the age of 18 years are not offered AIT treatments that are available to adults that are 18 years or older, but AIT treatment would be a suitable option. Since 2007, there were &gt;100 EMA paediatric investigation plans that demanded ‘paediatric’ AIT studies involving tens of thousands of minors. Almost none were successfully undertaken and those that were done were unnecessary. It is time for the specialty of allergy to face this challenge.

Comprehensive review and enhancing approaches for Pediatric investigation plan in USA, EU and India

Several various regulations connected to paediatric clinical investigations characterise the regulatory framework in the United States, EU and INDIA. Regulations that govern the requirements for conducting paediatric studies or provide incentives for sponsors to perform such studies have been implemented in these countries. The Food and Drug Administration in the United States has a comprehensive set of paediatric rules. It has established a distinct department for paediatric medication regulations, known as the Pediatric Therapeutics Offices. The FDA Modernization Statute was passed in the United States of America as the first act for paediatric population clinical trials (1997). These laws govern the incentives for drug developers to do paediatric research (after receiving a written request from the FDA) as well as the standards for conducting paediatric clinical trials. In Europe, the 'Pediatric Regulation (EC) No 1901/2006' was adopted in January 2007 to improve the protection of children in research, while India has no special standards for pediatric investigation. In order to promote better medicines for children, regulatory bodies in the United States and Europe have done a terrific job. There is presently no specific rule for paediatric clinical trials in India, however some provisions are included in Schedule Y. For the safety of children, the Indian health authorities must enact separate legislation for clinical trials. Enhancing approaches are needed for all conceivable indications will be assessed based on the product's mechanism of action, data from other development programmes, proof of concept studies, and so on. Pediatric experts will be consulted to examine each indication.

Clinical trials in pediatric ALS: a TRICALS feasibility study

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.