FDA Approvals for Pediatric Cancer Indications using Children’s Oncology Group Associated Trials Data

Abstract

Background:

The Children’s Oncology Group (COG), formed in 2000, is a large international trial network that has conducted over 330 clinical trials for pediatric, adolescent, and young adult cancers. The role of COG trial data for Food and Drug Administration (FDA) approval of pediatric oncology indications was assessed since 2000.

Methods:

All FDA approvals for pediatric oncology indications between January 1, 2000, and December 31, 2024, were reviewed. Data were collected from the FDA website, clinicaltrials.gov and COG database.

Results:

Twenty-five (47%) of the 53 FDA pediatric indication approvals for 37 different drugs or biologics utilized COG clinical trial data for the approval of the pediatric indication. The 21 COG studies used for approvals were supported by three different partnership models, with 14 indications (26% of all pediatric approvals) supported by data from 15 trials utilizing the COG cooperative agreement award from the National Cancer Institute (NCI).

Conclusion:

Almost half of FDA approved pediatric indications for oncology therapeutics were supported by data from COG trials, highlighting the effectiveness of this public–private partnership model in producing the level of clinical evidence required for regulatory success.

Introduction

Despite continued improvements in therapy and 5-year survival rates for many patients, pediatric cancer remains the leading cause of non-accidental death in children.[1] Those who survive are often burdened with significant long-term sequelae from treatment.[2, 3] With the increase in ability to identify molecular tumor alterations, targeted therapies are increasingly being studied in children and adolescents. However, the relative rarity of pediatric cancer compared to adults, the differences in the molecular genetic alterations found in tumors in adults compared to those in children, and the economic costs of developing a therapeutic agent specifically for a rare patient population negatively affect the number of agents which are studied and subsequently approved for pediatric oncology indications. A recent review of approval data demonstrated that only 16% of oncology trials which included pediatric patients were industry-sponsored in contrast to at least twice that for trials for adults with cancer.[4]

Changes in legislation in both US and Europe have moved to promote early submission of pediatric development plans. The 2002 US Best Pharmaceutical for Children Act (BCPA; Public Law 107-109) grants a 6-month extension of patent exclusivity to sponsors who develop pediatric appropriate drug formulations and complete pediatric clinical studies as previously agreed upon in a Written Request. The Pediatric Research Equity Act (PREA) then allowed the Food and Drug Administration (FDA) to require pediatric studies of biologics or drugs if the agent could be used in a substantial number of pediatric patients or provide benefit over existing treatments. However, PREA-required studies could be deferred until post-approval or waived if the drug was indicated for a rare disease in adults, even if it could benefit a substantial number of pediatric patients.[5] The Research to Accelerate Cures and Equity (RACE) for Children Act was passed in 2017 and enacted in 2020. The RACE Act allows the FDA to require pediatric studies for an oncology drug that has a molecular target relevant to pediatric oncology and no longer allows an automatic waiver for orphan drug designation. While industry sponsorship has increased in pediatric oncology trials with these legislative acts[6], pediatric oncology trials are still much less likely to be industry-sponsored compared to oncology trials for patients 18 years and older.[4]

The National Cancer Institute (NCI)-supported pediatric clinical trial organization, the Children’s Oncology Group (COG), was formed in 2000 through a merger of four legacy cancer cooperative groups. COG is a large international trial network with more than 220 member sites across the United States, Canada, Australia, New Zealand and Saudi Arabia, and most children with cancer in those countries are treated at a COG member institution. Since its formation, COG has conducted well over 330 therapeutic clinical trials for pediatric, adolescent, and young adult cancers, supporting high quality study conduct, data and specimen collection, processing, and banking.[7] COG therapeutic trials include phase 1, 2, 3, and pilot studies, but do not include COG’s studies of biology, epidemiology, and observational supportive care or late effects. While COG is supported through grant awards from the NCI, there exist three distinct models of industry-COG partnership for the conduct of clinical trials. Some trials are exclusively sponsored and supported through the NCI/Cancer Therapy Evaluation Program (CTEP) with the investigational drug supply provided by NCI, most commonly through a Cooperative Research and Development Agreement (CRADA) for an Investigational New Drug (IND) agent or Clinical Trials Agreement (CTA) with NCI/CTEP serving as sponsor and COG serving as coordinating center. Additional support from the industry partner may be provided either through the CRADA or through a separate contract between the industry partner and COG, outside of the CRADA.

A second approach is a shared or “hybrid” model which entails COG leveraging NCI funding and the NCI/CTEP clinical trials infrastructure to partner with an industry collaborator for a trial with an agent that is not included in the CTEP IND agent portfolio. In this scenario, COG usually is the sponsor of the trial, assuming responsibility for the IND, and the industry partner is accountable for supplying and distributing the investigational agent. As with the first model, additional support from the industry partner may be negotiated with COG to supplement support provided by CTEP/NCI. Examples of support in this model may include funding for additional per patient capitation, electrocardiograms, echocardiograms, research -specific tests, specimen submission, and pharmacokinetic and pharmacodynamic assessments, data management and analysis. In this model, COG with CTEP/NCI oversees data collection, study conduct, and monitoring. Terms for data sharing are established as part of the trial agreement.

A third model involves COG facilitating the implementation of industry-sponsored trials conducted with COG member institutions, whereby the industry partner assumes full responsibility for trial management, data collection, and oversight, providing all necessary funding. The trial is managed entirely by the industry partner and conducted at selected COG institutions; however, the NCI-supported clinical trials infrastructure is not utilized, and NCI does not participate in the review or oversight of the study.

To evaluate the impact of COG-associated clinical trial data in recent pediatric oncology FDA approvals, we reviewed how often these COG and industry collaborations were successful in generating multi-center data to support these pediatric approvals since the inception of COG in 2000. We reviewed the number of agents receiving FDA approval for pediatric oncology indications and determined how many of these indications were supported by data generated from COG clinical trials taking into consideration which partnership model was utilized for each approval.

Methods:

The FDA Oncology (Cancer)/Hematologic Malignancies Approval Notification website and the Pediatric Oncology Drug Approval website were reviewed for all FDA approvals for an indication in pediatric oncology between January 1, 2000, and December 31, 2024. This included primary approvals for a drug or biologic, any supplementary approvals, and any subsequent additional indications for which the drug or biologic was approved. Approvals for non-oncology pediatric indications were not included. (e.g., pediatric oncology data to support pediatric rheumatologic indications). Approvals based on adult-focused studies which included a lower age limit of 12 years of age where the study data and analysis including pharmacokinetics were extrapolated to include pediatric dosing or those for tumors not occurring in pediatrics were also not included. Seven indications which only included patients 12 years of age and older were excluded as there were limited pediatric patients (no more than 3 patients 12 to 17 years were enrolled by any study). The approval letters, labels, and any review documentation available were obtained from the Drugs@FDA website and reviewed for the approval indication, dates of the pediatric oncology-specific approval, and the citation(s) or reference(s) within the documents to any pediatric clinical trial. All trials were then reviewed on the clinicaltrials.gov website to determine the primary sponsor and trial sites as well as reference to COG study numbers. All trials involving COG were cross-referenced to the COG database to confirm sponsor and industry/trial model relationship.

Defining the “Funding Model” category, clinical trials were characterized as “NCI only” when there was no industry support for the study’s conduct other than provision of investigational agent to CTEP/NCI for distribution to participating COG institutions. Alternatively, trials were designated as ‘NCI + industry partner’ when an industry partner contributed support beyond supplying the investigational agent to CTEP/NCI for study execution.

Results

Between 2000 and 2024, there were 53 FDA approvals for 37 different drugs or biologics with indications in pediatric oncology. (Figure 1 and Table S1) Seventeen of the 37 drugs approved for pediatric oncology indications (46%) used data from a total of 21 different COG trials. Twenty-five (47%) of these approvals utilized COG clinical trial data for safety, dosing, and/or efficacy for those labels (Table 1). The COG trials used for approvals were supported in all three of the partnership funding models. Eleven (44%) of the approved indications were supported with data from 6 fully industry sponsored trials, developed and implemented with the intent for regulatory filing. The remaining 14 indications (56%) were based on results from 15 trials: 2 (14%) indications utilized data from clinical trials that were solely NCI/CTEP supported; 11(79%) indications utilized data from clinical trials conducted with support from both NCI/CTEP and industry partners; 1 (dinutuximab for neuroblastoma) used data from 2 trials (1 solely NCI/CTEP supported and a second trial with support from both NCI/CTEP and the industry partner. The IND sponsor for these 14 trials was most commonly NCI/CTEP (n=9, 64%) or COG (n=3, 21%). The IND sponsor was the industry partner for 2 trials, both for new formulations of asparaginase. A single trial (also an asparaginase formulation) used commercial agent with no IND.

Figure 1.

Consort diagram of FDA pediatric approvals reviewed. Non-cancer therapy indications were chemotherapy-associated hearing loss, hemophagocytic lymphohistocytosis, plexiform neurofibroma, and bone marrow transplant conditioning regimen. Non-pediatric cancer indications were Merckel cell carcinoma and colorectal cancer.

Table 1. FDA Agents with Approved Pediatric Indication supported by COG Clinical Trial Data.

Date of FDA Approval of Pediatric Indication	Agent	Indication	COG associated study (NCT, phase of study, age*)	IND holder	Funding Model
10/28/05	Nelarabine	R/R Tcell-ALL, T-LBL	P9673 (NCT00002970, phase 2, <21y)	NCI	NCI + industry partner
7/24/06	PEG aspargase	ALL	CCG 1962 (NCT0001689, phase 2, 1y - 9y)**	Non-IND study	NCI only
9/27/06 1/25/13	Imatinib	Ph+CML	AAML0123 (NCT00030394, phase 2, <22y)	NCI	NCI + industry partner
		Ph+ALL	AALL0031 (NCT00022737, pilot, 1y - <22y)	NCI	NCI only
11/18/11	Asparaginase erwinia chrysanthemi	ALL allergic to E.coli derived asparaginase	AALL07P2 (NCT00537030, pilot, 1y - <31y)	Industry partner	NCI + industry partner
3/10/15	Dinutuximab	Neuroblastoma	ANBL0032 (NCT00026312, phase 3, <31 y)	NCI	NCI only
			ANBL0931 (NCT01041638, phase 3, any age)	NCI	NCI + industry partner
8/30/16 3/29/18	Blinatumomab	R/R CD19 + Bcell-ALL	AALL1121 (NCT01471782, phase 1/2, <18 y)	Industry partner	Industry partner only
		MRD+ ALL	AALL1331 (NCT02101853, phase 3, 1y – 30 y)	NCI	NCI + industry partner
3/15/17 5/23/17 6/13/18 6/16/20 12/3/21	Pembrolizumab	R/R cHL MSI-H/dMMR ST PMBCL TMB-H Stage IIb, IIIC melanoma	ADVL1621 (NCT02332668, phase 2, 6m -17y)	Industry partner	Industry partner only
3/22/18	Nilotinib	Ph+CML R/R Ph+CML resistant or intolerant of prior TKI	AAML1321 (NCT01844765, phase 2, 1y-17)	Industry partner	Industry partner only
12/20/18	Calaspargase pegol-mknl/SC PEG asparaginase	ALL	AALL07P4 (NCT00671034, pilot, 1y - 30y)	Industry partner	NCI + industry partner
12/21/18	Dasatinib + chemotherapy	Ph+ ALL	AALL1122 (NCT01460160, phase 2, 1y - 17)	Industry partner	Industry partner only
6/16/20	Gemtuzumab ozogamicin	CD33+AML	AAML0531 (NCT01407757, phase 3, 1m - 29)	NCI	NCI + industry partner
1/14/21 7/14/22	Crizotinib	ALCL ALK+ IMT	ADVL0912 (NCT00939770, phase 1, >12m – 21y)	COG	NCI + industry partner
3/30/21	Liposomal daunorubin/cytarabine	t AML or AML-MRC	AAML1421 (NCT02642965, phase 2, 1y – 21y)	COG	NCI + industry partner
7/1/21	Recombinant Erwinia asparaginase	ALL, LBL	AALL1931 (NCT04145531, phase 2/3, any age)	Industry partner	Industry partner only
12/2/21	Rituximab+ chemo	CD20+ NHL	ANHL1131 (NCT01516580, phase 3, 6m – 17y)	COG	NCI + industry partner
11/10/22	Brentuximab + chemo	cHL	AHOD1221 (NCT01780662, phase 1/2, >12m – 30y) AHOD1331 (NCT02166463, phase 3, 2y - 21y)	NCI NCI	NCI + industry partner NCI + industry partner
9/26/23	Bosutinib	CML	AAML1921 (NCT04258943, phase 1/2, 1y - 17y)	COG	Industry partner only

R/R (relapsed/refractory); ALL (acute lymphoblastic leukemia), LBL (lymphoblastic lymphoma); Ph+ (Philadelphia chromosome positive); CML (chronic myeloid leukemia); cHL (classical Hodgkin lymphoma); MSI-H (microsatellite instability- high), dMMR (mismatch repair deficiency), ST (solid tumor); PMBCL (primary mediastinal B-cell lymphoma AML (acute myeloid leukemia); ALCL (anaplastic large cell lymphoma); ALK+ (anaplastic lymphoma kinase), IMT (inflammatory myofibroblastic tumor); NHL (non-Hodgkin lymphoma); TKI (tyrosine kinase inhibitor)

^*age – age range for inclusion per eligibility criteria; m (months), y (years)

^**CCG1962 does not have an NCT as was a substudy of CCG 1952 (NCT00001689)

For both overall approved pediatric indications (n=53) and those supported by COG data (n=25), leukemia was the most common disease indication with 23 (43%) and 14 (56%) approved indications, respectively. (Table 1 and Table S1). Approved indications for specifically patients with acute lymphoblastic leukemia (ALL) were the most common, 2 of which also included lymphoblastic lymphoma. However, there were also several approvals for acute myelogenous leukemia and chronic myelogenous leukemia as well as one for juvenile myelomonocytic leukemia. There were 6 pediatric approvals for lymphomas (Hodgkin lymphoma (n=3), and one each of anaplastic large cell lymphoma (ALCL), CD20+ non-Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. There were 4 approvals for specific central nervous system (CNS) tumors, none of which were supported by COG trial data. Tumor-agnostic approvals were granted in 8 pediatric indications, 2 of which were supported by the same industry-funded COG trial. There were 9 extracranial solid tumor indications in pediatrics, 3 (33%) of which were supported by COG trial data (dinutuximab for neuroblastoma, pembrolizumab for melanoma, and crizotinib for anaplastic lymphoma kinase (ALK)+ inflammatory myofibroblastic tumor (IMT)).

The approval of dinutuximab (Unituxin^™, United Therapeutics) highlights the pathway for agent development occurring through NCI support of COG. This agent was developed without a pharmaceutical sponsor using an antibody manufactured by NCI, thereby allowing COG to conduct the ANBL0032 (NCT00026312) phase 3 clinical trial of dinutuximab for children with high-risk neuroblastoma. When the early results of ANBL0032 demonstrated significantly improved outcomes with post-consolidation dinutuximab in combination with cis-retinoic acid, NCI competitively selected an industry partner with which to collaborate in seeking regulatory approval of dinutuximab. NCI and United Therapeutics collaborated with COG to design and support the subsequent study ANBL0931 (NCT01041638) that was needed to collect the additional safety, toxicity, and efficacy data necessary to support the biological license application and subsequent filing for approval of dinutuximab in pediatric patients with high risk neuroblastoma.[8, 9]

COG trial ADVL0912 (NCT00939770) was a shared or “hybrid” partnership that used the NCI-supported clinical trials infrastructure and support from Pfizer for a phase 1/2 study for children and young adults with relapsed or refractory solid tumors and ALCL with specific cohorts for patients with confirmed ALK alterations or those with neuroblastoma. COG developed this trial, held the IND and acted as the coordinating center.[10] This trial provided the safety and efficacy data for crizotinib to be approved for two separate relatively rare indications: pediatric patients 1 year of age and older with unresectable, recurrent or refractory ALK+ IMT and those with relapsed or refractory ALK+ ALCL. This illustrates the ability of COG to hold INDs for agents that are not in the CTEP investigational agent portfolio and sponsor trials for these agents that lead to FDA approvals.

The COG trial AHOD1331 (NCT02166463) further illustrates the role of the NCI-COG-industry partnership in the conduct of trials for regulatory approval. AHOD1331 was a phase 3 trial of brentuximab vendotin (Seattle Genetics) with chemotherapy in children and young adults with newly diagnosed high-risk classical Hodgkin lymphoma (cHL).[11] COG developed the trial and acted as the coordinating center while NCI was the IND sponsor for brentuximab vedotin. Seattle Genetics supplied brentuximab vedotin to NCI for AHOD1331 through a CRADA. Separately, Seattle Genetics provided additional support to COG to offset research costs not covered by NCI grant funding. This trial, in combination with the pharmacokinetic data from AHOD1221 (NCT01780662), provided the pediatric safety and efficacy data that supported the FDA approval of brentuximab vedotin in combination with chemotherapy for patients 2 years and older with previously untreated high-risk cHL.

AALL1931 is an example of a fully industry-sponsored partnership with COG that led to the approval of recombinant Erwinia asparaginase Rylase (Jazz Pharmaceuticals). AALL1931 (NCT0414531) was developed by Jazz Pharmaceuticals with intent for regulatory filing, with scientific contributions provided by COG ALL content experts. [12] The study was opened at 70 COG institutions, but all study conduct, data management and oversight were run by Jazz Pharmaceuticals which also provided financial support for and sponsorship of the trial. The trial opened in December 2019 and completed enrollment in 2021. Rylase^™ received initial FDA approval in July 2021 based on data generated from AALL1931.

Discussion

These findings demonstrate that utilization of the NCI-supported COG infrastructure, including trial sites and centralized trial coordination, is a successful model of partnership for a pathway to regulatory approval of new therapies in pediatric oncology. Notably, COG clinical trial data supported almost half of the pediatric oncology therapeutic drug approvals in the past 24 years.

In a prior analysis of oncology trial sponsorship in the United States, industry sponsorship of pediatric oncology trials including patients less than 18 years of age was noted at 16% compared to 33% in oncology trials for patients 18 years or older.[4] However, despite this disparity in available industry supported trials, annual pediatric oncology enrollments to industry sponsored trials has doubled from 2013-2017 while enrollments to NIH sponsored trials decreased.[6] Similarly, nearly all the COG trials used for FDA approval since 2013 involved industry collaboration, however the majority were not sponsored by industry alone. Over half of the COG-supported FDA approvals (56%) used data from trials that utilized NCI-supported COG trial infrastructure for clinical trial operations and data collection and industry providing supplementary support to address specific research costs or enhanced trial monitoring and data collection to meet expectations for clinical trials supporting licensing applications. This success of public-private collaboration in advancing practice changing trials for pediatric cancer is noteworthy and challenges the perception that fully industry-sponsored trials need to be the primary route to achieving FDA drug approvals in pediatric oncology.[13]

Partnership with COG offers access to more than 220 institutions and to most patients in a given state, region, or country. This increases the opportunity for improved trial enrollment, access, and shorter trial times, a particularly important factor for rare cancers or for pediatric cancers in which molecular subtyping leads to further division of already small patient populations. There have been increasing numbers of pediatric oncology indication approvals for cancers harboring specific genetic mutations in already rare cancers. The extensive COG network is one way that industry partners can increase access to and enrollment on clinical trials of these targeted agents for patients with rare tumor genetic alterations.

The numerous FDA approved pediatric indications obtained using COG data from NCI supported trials demonstrate that COG data quality and reliability are sufficient to gain FDA approval. This collaboration between pediatric oncology leaders in COG and industry can generate well-designed trials where those with a positive result in either phase 2 or 3 trials can provide compelling evidence of efficacy to support approval. Additionally, the ability of COG to hold an IND and successfully sponsor trials is important, as it is not possible for CTEP’s agent portfolio to include all the investigational agents that the COG prioritizes to evaluate in clinical trials. A successful industry and COG partnership involves early engagement to determine which partnership model is best and including NCI/CTEP if anything other than a fully-industry sponsored trial is envisioned. These collaborations should involve the FDA and other regulatory bodies during trial design to help ensure the clinical trial results, if positive, can be used to meet regulatory objectives.

The data reviewed and reported herein were obtained using publicly available databases and not all private or internal sponsor documents were available for review. We excluded 7 indications which only included patients 12 years of age and older. While including adolescents in adult trials and extrapolation of data from adult patients can improve access to agents in adolescents, these studies did not separate dosing or efficacy data for the pediatric population specifically and often the cancer type indicated was extremely rare in the pediatric oncology population, limiting the information available for younger patients. Additionally, trials were not always identified by NCT number or consortium study name in the documentation, making it challenging to identify whether the data used were from a COG trial or included other trials. In these instances, if there was not a clear relationship to COG/COG trial, it was assumed the data were not generated through a COG trial. As trials were not always identified in the labeling, we were unable to identify a definitive total number of non-COG supported trials that were used to obtain the 53 pediatric indications, which limits the ability to draw conclusions regarding the overall success of pediatric trials leading to FDA approvals. This paper also did not analyze the role of cooperative group or academic trial data in supporting European Medical Agency and Medicine and Healthcare Regulatory Agency approvals which may further support the role of COG and other academic consortia in global regulatory approvals.

Our analysis highlights the feasibility, reliability, and capacity of the COG consortium, an NCI-funded cooperative group, to effectively conduct and complete trials that generate data sufficient to support FDA approvals for pediatric oncology indications. The three described models of COG collaboration with industry partners have each been successful in generating fit-for-filing data for 25 FDA pediatric approvals over the 25-year history of the Group. There is an ongoing need to efficiently identify effective new therapies for children and adolescents with cancer and move these treatments forward to regulatory approval. COG, through its NCI-supported clinical trials infrastructure and expansive international catchment areas, is uniquely positioned to lead the pediatric clinical trials needed to meet regulatory requirements. We are optimistic that continued public-private partnerships like those described in this report will lead to timely advances in providing safer, more effective therapies for children facing cancer.

Data Sharing:

The data used in this article were derived from the following sources in the public domain:

• Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm

• The FDA Oncology (Cancer)/Hematologic Malignancies Approval Notification website: https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancerhematologic-malignancies-approval-notifications

• The Pediatric Oncology Drug Approvals website: https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology-drug-approvals

• Clinicaltrials.gov: https://clinicaltrials.gov