Q. When it comes to oncology, what is one specific example of how the system is not performing well for patients, in other words, a Slow Zone?
A. Pediatric oncology is a space in which technological and performance enhancements greatly benefit the patient population, but implementation is often slower due to the very challenges that make such advancements important. Biomarker development and implementation is one such enhancement. Biomarkers are measurable indicators that can be helpful in evaluating the most effective therapeutic regimes for a particular cancer type. As such, they have significant potential to predict an outcome, enable quick and accurate diagnosis, improve clinical trial design, and drive the development and use of targeted therapy. These are all areas that would greatly benefit the small pediatric patient population.
Q. What makes it a “Slow Zone?
A. A relative paucity of validated biomarkers in pediatric oncology is a slow zone. A systematic literature search in PubMed, assessing publication of pediatric clinical studies on biomarkers identified 1,126 publications in the years 2012-2016 [1], compared to nearly 25,000 publications in adults in 2010. Several additional publications address this slow zone [2], [3], [4], [5].
Q. What is the challenge?
A. The primary population affected by this slow zone is pediatric cancer patients. Biomarkers enable therapy selection and stratification, earlier and more accurate diagnosis, design and proper use of targeted therapeutics [6], and earlier assessment of the negative effects of therapeutics [7], to name a few. In addition to patients, pharmaceutical companies and oncologists are impacted. Biomarkers can increase the efficiency and accuracy of patient selection, reducing the trial size and ensuring that oncologists select the most promising trials for their patients. As a specific example, without companion biomarkers, clinical trials are often larger, reducing the patients available for other trials. Prioritization in clinical trials is a huge concern right now as pharmaceutical companies prepare to address the requirements of Title V of the FDA Reauthorization Act [8]. A biomarker that allows for the selection of the proper population for treatment and enables response measurement contributes more efficient clinical trials that require fewer patients [9].
Q. What difference does this make for an individual patient? What is the “before and after” for a patient if the Slow Zone is resolved OR what is the difference for an individual patient if the Hotspot solutions did not exist?
A. Addressing this slow zone would mean increased efficiency in terms of diagnosis, treatment selection, determination of treatment effectiveness, and assessment of tumor burden. The anticipated result would be more quick and effective cancer management and decreased treatment-related side-effects and late-effects due to increased implementation of targeted therapy. Importantly, for patients and their families, this means difficult treatment decisions are simplified resulting in increased confidence in the treatment plan and certainty regarding clinical trial selection.
Q. Which domains from the FasterCures model for the health system are relevant for this example?
A. The challenges to identifying, assessing, and implementing biomarkers in pediatric patients will take a concerted effort to overcome. The most relevant domains are:
Capacity:
The successful translation of a biomarker from discovery to clinical application is generally challenging. When considering the limited pediatric cancer patient population as well as restrictions to the types and quantities of biological samples that can be collected from pediatric patients, biomarker discovery becomes especially difficult. Large clinical trials and easily accessible biorepositories could greatly benefit biomarker development and utilization in pediatric cancer by increasing capacity.
Efficiency:
Without sufficient biomarkers, both clinical trials and targeted drug development efficiencies are decreased. In terms of clinical trials, enrichment trial designs, which are reliant on companion biomarkers, often enable faster approvals with smaller patient numbers [9]. Biomarker measurements are pivotal in ensuring that clinical trials are testing the proper biological hypotheses and that those drugs that do address their targets are appropriately dosed to the correct patient population.
Patient Centricity:
Addressing efficient trial design and enabling targeted therapeutic design will greatly benefit pediatric patients and could serve as a model for increased efficiency in patients with other cancer types. When considering drug development, we recognize the promise personalized medicine holds for young cancer patients hoping to avoid late-effects of therapy. Pediatric patients are especially in need of clinical trials that take into account their specific molecular subtypes, and with fewer patients, trials would benefit from biomarker incorporation.
References
[1] D. R. Shores and A. D. Everett, "Children as Biomarker Orphans: Progress in the Field of Pediatric Biomarkers," J Pediatr., vol. 193, no. 31, pp. 14-20, 2018.
[2] W. J. Savage and A. D. Everett, "Biomarkers in pediatrics: Children as biomarker orphans," Proteomics Clin. Appl., vol. 4, pp. 915-921, 2010.
[3] N. Shukla, J. D. Schiffman, D. Reed, I. J. Davis, R. B. Womer, S. L. Lessnick and E. R. Lawlor, "Biomarkers in Ewing sarcoma: the promise and challenge of personalized medicine. A report from the Children's Oncology Group," Front. Oncol., vol. 3, p. 141, 2013.
[4] M. D. Russell, A. M. H. Young and S. K. Karri, "Biomarkers of Pediatric Brain Tumors," Frontiers in Pediatrics, vol. 1, no. 7, 2013.
[5] T. H. Tran, A. T. Shah and M. L. Loh, "Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies," Clinical Cancer Research, vol. 23, no. 18, pp. 5329-38, 2017.
[6] S. J. Forrest, B. Geoerger and K. A. Janeway, "Precision medicine in pediatric oncology," Current Opinion in Pediatrics, vol. 30, no. 1, pp. 17-24, 2018.
[7] S. E. Lipshultz, T. L. Miller, R. E. Scully, S. R. Lipsitz, N. Rifai, L. B. Silverman, S. D. Colan, D. S. Neuberg, S. E. Dahlberg, J. M. Henkel, B. L. Asselin, U. H. Athale, L. A. Clavell, C. Laverdiere, B. Michon, M. A. Schorin and S. E. Sallan, "Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes," J. Clin. Oncol., vol. 30, no. 10, pp. 1042-9, 2012.
[8] "S.3239 - RACE for Children Act," 14 July 2016. [Online]. Available: https://www.congress.gov/bill/114th-congress/senate-bill/3239. [Accessed 13 January 2020].
[9] J. T. Jorgensen, "A paradigm shift in biomarker-guided oncology drug development," Annals of Translational Medicine, vol. 7, no. 7, p. 148, 2019.