Ushering in the next generation of precision trials for pediatric cancer

Science ◽  
2019 ◽  
Vol 363 (6432) ◽  
pp. 1175-1181 ◽  
Author(s):  
Steven G. DuBois ◽  
Laura B. Corson ◽  
Kimberly Stegmaier ◽  
Katherine A. Janeway
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Pediatric Cancer ◽  
Case Reports ◽  
Precision Oncology ◽  
Genomic Profile ◽  
Key Factors ◽  
Pediatric Drug ◽  
The Past ◽  
Pediatric Cancers

Cancer treatment decisions are increasingly based on the genomic profile of the patient’s tumor, a strategy called “precision oncology.” Over the past few years, a growing number of clinical trials and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors.

scholarly journals Pediatric Clinical Trials in Mainland China Over the Past Decade (From 2009 to 2020)

2021 ◽  
Vol 8 ◽  
Author(s):  
Wen-Wen Wu ◽  
Xing Ji ◽  
Hao Wang ◽  
Feng Chen ◽  
Qian Ding ◽  
...  
Keyword(s):  
Resource Allocation ◽  
Clinical Trials ◽  
Drug Development ◽  
Mainland China ◽  
Developed Countries ◽  
Chinese Government ◽  
Pediatric Drug ◽  
Development Environment ◽  
Pediatric Drug Development ◽  
The Past

In mainland China, there remains a shortage of pediatric drugs. The Chinese government has recently launched policies and incentives to encourage pediatric drug development and clinical trials. However, data on the characteristics or development trends of these trials are limited. In this review, we extracted source data from the Chinese Clinical Trials Registry and Information Transparency Platform and systematically reviewed the pediatric clinical trials conducted in mainland China from 2009 to 2020, a comprehensive process evaluation of the pediatric drug clinical trials development in the past decade, providing data support to policy makers and industry stakeholders. We included 487 pediatric clinical trials. Over the past decade, the number of pediatric trials has increased, especially since 2016. The most common therapeutic areas were infectious diseases (n = 108, 22.2%), agents for preventive purpose (n = 99, 20.3%), and neurological and psychiatric diseases (n = 71, 14.6%). The number of clinical trials involving epilepsy (39, 10.1%), asthma (33, 8.5%), and influenza (24, 6.2%) were the highest. The distribution of leading institutions is unbalanced in mainland China, with most units in East China (34.0%) and few in Southwest China (6.9%). China has made progress in improving the research and development environment of pediatric drugs and increasing pediatric trials. However, a wide gap in pediatric drug development and clinical trials quality exists between China and the developed countries. The pharmaceutical industry in China has faced grim setbacks, including study duplication, lack of innovation, poor research design, and unbalanced resource allocation. Thus, we suggest that the Chinese government should adjust their policies to improve innovation and clinical design capacity, and optimize resource allocation between regions.

scholarly journals Application of Real-World Data to External Control Groups in Oncology Clinical Trial Drug Development

2022 ◽  
Vol 11 ◽  
Author(s):  
Timothy A. Yap ◽  
Ira Jacobs ◽  
Elodie Baumfeld Andre ◽  
Lauren J. Lee ◽  
Darrin Beaupre ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Real World ◽  
External Control ◽  
Control Group ◽  
Precision Oncology ◽  
Efficacy And Safety ◽  
Control Groups ◽  
Real World Data ◽  
World Data

Randomized controlled trials (RCTs) that assess overall survival are considered the “gold standard” when evaluating the efficacy and safety of a new oncology intervention. However, single-arm trials that use surrogate endpoints (e.g., objective response rate or duration of response) to evaluate clinical benefit have become the basis for accelerated or breakthrough regulatory approval of precision oncology drugs for cases where the target and research populations are relatively small. Interpretation of efficacy in single-arm trials can be challenging because such studies lack a standard-of-care comparator arm. Although an external control group can be based on data from other clinical trials, using an external control group based on data collected outside of a trial may not only offer an alternative to both RCTs and uncontrolled single-arm trials, but it may also help improve decision-making by study sponsors or regulatory authorities. Hence, leveraging real-world data (RWD) to construct external control arms in clinical trials that investigate the efficacy and safety of drug interventions in oncology has become a topic of interest. Herein, we review the benefits and challenges associated with the use of RWD to construct external control groups, and the relevance of RWD to early oncology drug development.

scholarly journals Letter from the Editors

2020 ◽  
Vol 2 ◽  
pp. 1
Author(s):  
Editorial Office
Keyword(s):  
Clinical Trials ◽  
Medical Journal ◽  
Open Access ◽  
Drug Development ◽  
Orphan Drug ◽  
Rare Diseases ◽  
Case Reports ◽  
Orphan Drugs ◽  
Original Research ◽  
Orphan Drug Development

Last year we successfully introduced a new journal: The Journal of Rare Diseases and Orphan Drugs (JRDOD) is a peer-reviewed open-access medical journal that publishes original research, reviews, case reports, and letters covering a broad field of its specialty. We intend to publish articles stimulating to read, educate, and inform readers with the most up-to-date research in genetics, rare diseases, and new orphan drug development in different stages of clinical trials. Journal topics are centered on patients living with undiagnosed rare diseases, the importance of a diagnosis, individual approaches to treatments. We hope that this journal will increase awareness of many difficult to diagnosed and treat medical conditions.

scholarly journals Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Feras Khalil ◽  
Stephanie Läer
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Age Groups ◽  
Modeling Technique ◽  
Pbpk Modeling ◽  
Pediatric Drug ◽  
Pediatric Drug Development ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

The concept of physiologically based pharmacokinetic (PBPK) modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”.

scholarly journals Trial Design Challenges and Approaches for Precision Oncology in Rare Tumors: Experiences of the Children’s Oncology Group

2019 ◽  
pp. 1-13
Author(s):  
Lindsay A. Renfro ◽  
Lingyun Ji ◽  
Jin Piao ◽  
Arzu Onar-Thomas ◽  
John A. Kairalla ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Risk Stratification ◽  
Pediatric Cancer ◽  
Trial Design ◽  
Intensive Therapy ◽  
The United States ◽  
Precision Oncology ◽  
Cancer Type ◽  
Oncology Group ◽  
Operating Characteristics

In the United States, cancer remains the leading cause of disease-related death in children. Although survival from any pediatric cancer has improved dramatically during past decades, a number of cancers continue to yield dismal prognoses, which has motivated the continued study of novel therapeutic strategies. Furthermore, even patients cured of pediatric cancer often experience severe adverse effects of treatment and other long-term health implications, such as cardiotoxicity or loss of fertility. For these patients, improved risk stratification to identify those who could safely receive alternate or less-intensive therapy without affecting prognosis is a key objective. Fortunately, pediatric cancers are rare overall, but even among patients with the same narrow cancer type, there is often broad heterogeneity in terms of prognosis, molecular features or pathology, current treatment strategies, and scientific objectives. As a result, the design of clinical trials in the pediatric cancer setting is challenged by a number of practical issues that must be addressed to ensure trial feasibility for this vulnerable group of patients. In this review, we discuss some of the unique trial design considerations often encountered in any rare tumor setting through the lens of our experiences as faculty statisticians for the Children’s Oncology Group, the largest organization in the world dedicated exclusively to pediatric cancer research and clinical trials. These topics include risk stratification within individual trials, relaxation of trial operating characteristics and parameters, use of historical controls, and address of noninferiority-type objectives in small cohorts. We review each in terms of practical motivation, present challenges, and potential solutions described in the literature and implemented in selected example trials from the Children’s Oncology Group.

Changes in numbers of randomized (RCT) versus non-randomized (NRCT) clinical trials from 2004-2016: Evidence of shifting cancer drug development pathway.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2543-2543
Author(s):  
Laura Vidal Boixader ◽  
Kelly Kevelin Curtis ◽  
Jim Wahl ◽  
Nicholas Kenny ◽  
Keren Rachel Moss
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Cancer Biology ◽  
Drug Approval ◽  
Cancer Drug ◽  
Phase 2 ◽  
The Past ◽  
Anti Cancer ◽  
High Antitumor Activity ◽  
Drug Approval Process

2543 Background: Trials using randomized designs have been conducted for decades to demonstrate efficacy of novel anti-cancer drugs (NACD). Recently, several NACD have shown high antitumor activity in early phase studies, prompting suggestions that NRCT could expedite drug development. We sought to determine what changes have occurred in numbers of NACD RCT vs NRCT conducted from 2004-2016. Methods: We reviewed a database of NACD clinical trials conducted by INC (excluding phase I and I/II trials) and classified them by RCT vs NRCT, grouped by year (≤ 2010 or > 2010). We queried Citeline Trialtrove database for industry sponsored, phase 2 trials (P2T) initiated from 2006-2016 and examined numbers of RCT vs NRCT by year.A more detailed analysis of non-small cell lung cancer (NSCLC) clinical trials based on drug type category - Immunooncology (IO) vs. all other mechanims of action (NIO) was performed. Results: 190 INC-conducted trials were reviewed. 58 trials (31%) were performed ≤ 2010 and 132 trials (69%) > 2010. Over this period, NRCT (n = 107, 56%) outnumbered RCT (n = 83, 44%). Whereas RCT outnumbered NRCT from 2004-2010 (74% vs 52%), after 2010, NRCT outnumbered RCT (58% vs 42%). Citeline Trialtrove search revealed 4776 industry sponsored P2T initiated from 2006-2016. The total number of P2T started annually was highest in 2007 (n = 621), decreasing to a low of 375 in 2016. The proportion of phase 2 RCT demonstrated an increase from 27% (n = 166) in 2006 to a peak plateau of 37-39% from 2011-2014, followed by a drop to 33% in 2015 and 29% in 2016. Among IO studies, RCT declined in 2015-6 vs. previous years, and a decreased for all NACD in 2016 vs. previous years also was noted. For studies in NSCLC, declines in RCT were evident from 2015-6 vs. previous years ( 45% in 2007-14 vs. 25% in 2015-6). Conclusions: Our data indicate a trend toward fewer trials of NACD using randomized designs and more studies using non-randomized designs, with overall fewer P2T initiated in the past year. This change reflects shifts in NACD development pathways, related to a better understanding of cancer biology, drive to develop personalized treatment and a more flexible regulatory drug approval process.

scholarly journals 5-Methylcytosine and 5-Hydroxymethylcytosine Signatures Underlying Pediatric Cancers

Epigenomes ◽  
2019 ◽  
Vol 3 (2) ◽  
pp. 9 ◽  
Author(s):  
Shalu Jhanwar ◽  
Ajinkya Deogade
Keyword(s):  
Pediatric Cancer ◽  
Therapeutic Potential ◽  
The Past ◽  
Pediatric Cancers ◽  
Genome Wide ◽  
Recent Developments ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Shed Light

In addition to the genetic variations, recent evidence has shown that DNA methylation of both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) underlies the pathogenesis of pediatric cancer. Given the high mortality rate, there is an urgent need to study the mechanisms contributing to the pathogenicity of pediatric cancer. Over the past decades, next-generation sequencing (NGS) has enabled us to perform genome-wide screening to study the complex regulatory mechanisms of 5mC and 5hmC underlying pediatric tumorigenesis. To shed light on recent developments on pediatric cancer predisposition and tumor progression, here we discuss the role of both genome-wide and locus-specific dysregulation of 5mC and 5hmC in hematopoiesis malignancy and neuroblastoma, the most common types of pediatric cancer, together with their therapeutic potential.

Trends in paediatric, neonatal, and adult cardiology publications over the past 10 years

2013 ◽  
Vol 24 (2) ◽  
pp. 297-302 ◽  
Author(s):  
Samuel Menahem ◽  
Daniel Fink ◽  
Francis B. Mimouni
Keyword(s):  
Clinical Trials ◽  
Practice Guidelines ◽  
Case Reports ◽  
Linear Increase ◽  
Publication Type ◽  
The Past ◽  
Rate Of Increase ◽  
Randomised Control Trials ◽  
Number Of Publications ◽  
Meta Analyses

AbstractObjective:Medline classifies publications as clinical trials, randomised control trials, meta-analyses, practice guidelines, reviews, case reports, editorials, and letters. We tested the hypothesis that cardiology-related publications have increased with a shift in the type of publications over the past 10 years by age category.Methods:To retrieve from Medline the cardiology articles, we used the keyword “heart disease”, but limited the search to articles in English from 2000 to 2009. We repeated the search using one limit according to the publication type and using age tags. We used regression analysis to determine the effect of the year of publication on the number of publications of each type.Results:During the 10-year period, Medline registered 152,849 cardiology articles, doubling from 10,452 in 2000 to 20,841 in 2009, of which 8.5% were tagged as both paediatric and adult. There was a linear increase in the number over the study period in the total number of publications and in all categories, except for practice guidelines. There was almost a twofold increase in adult and neonatal articles, but ∼70% in paediatric articles. The rate of increase was 66% for randomised control trials, 73% for clinical trials, 124% for meta-analyses, 117% for editorials, 36% for reviews, and 103% for case reports. Practice guidelines remained very low, increasing significantly for paediatric and neonatal articles.Conclusions:There was a substantial increase in cardiology articles over the past 10 years, being greater for adult and neonatal articles compared with paediatric articles. The increase varied according to the type of article.

scholarly journals Trends in clinical development of pediatric cancer for PD-1 and PD-L1 inhibitors: an analysis of ClinicalTrials.gov

2021 ◽  
Vol 9 (9) ◽  
pp. e002920
Author(s):  
Yi Que ◽  
Yang Hu ◽  
Dongchun Hong ◽  
Yizhuo Zhang
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Pediatric Cancer ◽  
Checkpoint Inhibitors ◽  
Pediatric Population ◽  
Vascular Endothelial ◽  
Inhibitory Effects ◽  
The Past ◽  
Endothelial Growth Factor ◽  
Cell Death Protein

Compared with cytotoxic chemotherapy, radiotherapy, and surgery, positive findings have been acquired through the approach of blocking the programmed cell death protein 1 (PD-1) pathway with antibodies that exert inhibitory effects on PD-1 or cell death protein ligand 1 (PD-L1). Results from clinical trials showed great potential in adult patients with cancers, such as melanoma, non-small cell carcinoma, and nasopharyngeal carcinoma. However, studies of checkpoint inhibitors specifically targeting PD-1/PD-L1 in pediatric patients are limited. We evaluated ongoing clinical trials using PD-1 or PD-L1 inhibitors alone or in combination with other therapies to treat pediatric cancer. The proportion of PD-1/PD-L1 combination clinical trials has increased since 2018; the three most common trials over the past 2 years used CTLA-4 monoclonal antibodies, chemotherapy, and therapies that target the vascular endothelial growth factor axis. This commentary aimed to provide trends and specific insights into methods for conducting clinical trials of immunotherapy in the pediatric population.

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