Although childhood cancer is rare, it is the leading cause of disease related death in children.1 2 The diagnosis of cancer in children may be delayed due to the non-specific nature of the symptoms which may allow the disease to progress, and treatment may be more complex or less likely to result in a cure.3 Certain genetic changes and molecular targets associated with adult cancers are seen in childhood presentations, but these are often for different cancers than those that occur in adults. As a result, evaluating genetic changes and molecular targets in children requires separate pediatric studies. For adults, the available treatment landscape and in select cancer indications response rates have significantly benefited from research. However, development of targeted therapies for pediatric cancers lags. Given the rarity of cancer in children, developing targeted treatments for small numbers of children will be challenging, yet these treatments are likely to improve outcomes and survival like the success we have seen with targeted therapies in adults.4 5
To include children in a clinical trial, the ethical requirements under 21 CFR 50, subpart D, the Additional Safeguards for Children in Clinical Investigations, must be considered. Clinical investigations that include an investigational product generally must offer a prospect of direct benefit to the individual child, the risk must be justified by the benefit, and the balance of the risk and benefit must be at least as favorable as any available alternative treatments. Often, by the time a child is offered an investigational product for cancer, the child has exhausted approved treatments and has limited options. The prospect of direct benefit to the individual child in the trial may be assessed through non-clinical studies rather than having confirmation from adult trials, especially if the cancer does not exist or differs in adults. Benefits may be justified by a greater risk to the child since the purpose of the study is to extend survival.6
Companies sponsoring clinical trials often focus on adult product development first as establishing potential clinical benefit to support studying the product in children.6 Legislation exists to require and foster pediatric studies for products being developed for adult indications. Studies are required for indications relevant to children under the Pediatric Research and Equity Act (PREA). Under the Best Pharmaceuticals for Children Act (BPCA), a company may voluntarily elect to conduct studies in children to gain additional product exclusivity (or patent extension).7 8
Many products developed for cancer indications in adults are not applicable to children because the condition may not be present in children. Consequently, pediatric studies are waived under PREA at the time of FDA approval. However, in 2017, the RACE for Children Act was enacted. The RACE Act amended PREA to add a requirement for companies with an approved product for an adult cancer that targets a molecular target relevant to children. Starting on August 18, 2020, these companies must assess what studies should be conducted in children, if the product could be used in a substantial number of pediatric patients, or the product will have a meaningful therapeutic benefit over existing therapies.9 The law also eliminated the exemption from PREA for products that have orphan drug status; products with orphan drug status with a relevant molecular target in children must now develop a plan for studies in children.
For the purposes of the RACE Act, for a molecule to be considered a target, there must be evidence that the product interacts with the target and is anticipated measurable effect on a cancer to result in a clinically favorable objective change in the disease process.10 The FDA posts a list of relevant and non-relevant molecular targets on their website, reviews it periodically, and updates it as more information becomes available.
As noted above, safety information will be collected in adults; information to assess potential benefit of the targeted therapy will likely be evaluated in non-clinical studies using a pediatric specific tumor model. The pediatric studies evaluate dose limiting toxicities, pharmacokinetics and preliminary assessment of activity measured by overall response rate, or other agreed upon endpoints.10 If these initial studies look promising, the FDA may issue a written request for additional studies under the BPCA process.11
In early 2023, the Government Accounting Office (GAO) issued a report summarizing the progress that the RACE Act had made on pediatric oncology product development.11 The GAO reviewed pediatric study plans submitted to the FDA over a two-year period starting on August 18, 2020, and interviewed various stakeholders, such as patient advocates, drug industry representatives and pediatric cancer researchers. After enactment of the RACE Act, thirty-two initial pediatric study plans were submitted to the FDA that otherwise would not have been proposed. However, because of the long timeline associated with completion of studies, at the time of GAO publishing their report, the planned studies were still in early phases or had not started.
There are many well-known challenges in conducting pediatric research and these are amplified when evaluating oncologic indications. The number of patients available can be highly limited for pediatric cancers and when evaluating molecular targets, only children who have already failed therapy might be considered for enrollment, further narrowing the pool. Additionally, these rigors of oncology trials place a significant burden on parents and children to maintain protocol required assessments and follow-up. Both the parent and the child must be aware of the time commitments and constraints on parental work schedules and scholastic activities. Although the parent has final decisional authority on study participation, the decision to participate in the trial should be a shared responsibility between the provider and the family given the complexities of cancer trials and therapy.12
Guidance is being developed by the FDA on methods to evaluate same-in-class products with the same molecular target, to reduce the number of studies needed to assess potential benefit. The FDA is collaborating with the European Medicines Agency (EMA) to coordinate studies through the International Pediatric Cluster.13 A global pool will increase the number of patients available and address both the FDA and EMA’s requirement for studies.
In summary, the leading cause of disease related deaths in children is cancer. New legislation requires companies to conduct studies in children if a molecular target being evaluated in an adult cancer may be relevant to a childhood cancer. These studies may offer additional promise for treatment of pediatric cancer, especially for children who have exhausted other options. Companies should be aware of the requirements for studies and work with the FDA to develop pediatric study plans as the FDA develops guidance to help companies make those plans more efficient.
AUTHOR BIOs
Brant Nicks, senior vice president of Clinical Solutions & Strategic Partnering, WCG, provides support and oversite for hematology/oncology trials. Brant has worked in clinical research for 28 years in various capacities with biotechnology companies and contract research organizations with an emphasis on hematology/oncology research.
Donna Snyder, MD, MBE, executive physician, WCG, provides guidance on medicine, research, and regulations. Prior to WCG, Dr. Snyder served as senior pediatric ethicist, the Office of Pediatric Therapeutics, U.S. FDA. She is a board-certified pediatrician with experience in pediatric practice and research ethics.
References
1. 21 CFR 50.3(o). Children are "persons who have not attained the legal age of consent to treatments or procedures involved in clinical investigations under the applicable law of the jurisdiction in which the clinical investigation will be conducted.”
2. Centers for Disease Control. Deaths: Leading Causes for 2020. National Vital Statistics Reports. 2020, Vol. 72, 13.
3. Dang-Tan T, Franco EL. Diagnosis delays in childhood cancer: a review. Cancer. August 15, 2007, Vol. 110, 4, pp. 703-13.
4. National Cancer Institute. Research on Childhood Cancers. cancer.gov. [Online] March 21, 2022. [Cited: April 22, 2024.] https://www.cancer.gov/research/areas/childhood.
5. FDA. Approved Cellular and Gene Therapy Products. fda.gov. [Online] April 26, 2024. [Cited: April 30, 2024.] https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.
6. FDA. fda.gov. Ethical Considerations for Clinical Investigations of Medical Products Involving Children. [Online] September 2022. [Cited: April 23, 2024.] https://www.fda.gov/media/161740/download.
7. FDA. fda.gov. Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act Guidance for Industry. [Online] May 2023. [Cited: April 30, 2024.] https://www.fda.gov/media/168201/download.
8. FDA. Pediatric Drug Development Under the Pediatric Research Equity Act and the Best Pharmaceuticals for Children Act: Scientific Considerations Guidance for Industry. fda.gov. [Online] May 2023. [Cited: April 30, 2024.] https://www.fda.gov/media/168202/download.
9. H.R.1231 - RACE for Children Act. Congress.gov. Research to Accelerate Cures and Equity for Children Act or the RACE for Children Act. [Online] February 27, 2017. [Cited: April 23, 2024.] https://www.congress.gov/bill/115th-congress/house-bill/1231.
10. FDA. fda.gov. FDARA, Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to sec. 505B of the FD&C Act. [Online] May 2021. https://www.fda.gov/media/133440/download.
11. US Government Accounting Office (GAO). Pediatric Cancer Studies: Early Results of the Research to Accelerate Cures and Equity for Children Act. gao.gov. [Online] January 31, 2023. [Cited: April 23, 2024.] https://www.gao.gov/assets/gao-23-105947.pdf.
12. Whitney, SN. Decision Making in Pediatric Oncology: Who Should Take the Lead? The Decisional Priority in Pediatric Oncology Model. JCO. 24, 2006, pp. 160-165.
13. FDA. fda.gov. International Collaboration / Pediatric Cluster. [Online] February 16, 2024. [Cited: April 25, 2024.] https://www.fda.gov/science-research/pediatrics/international-collaboration-pediatric-cluster.