Clinical Researcher—September 2020 (Volume 34, Issue 8)

RECRUITMENT & RETENTION

Lynne Georgopoulos, RN, MSHS, RAC; S. Y. Amy Cheung, PhD

 

Approximately 1.8 million new cases of cancer will be diagnosed in the U.S. in 2020.{1} Less than 1% of them will be diagnosed in pediatric patients.{2} Although pediatric cancer is rare, it is the second leading cause of death in children ages 1 to 14 in the U.S. after accidents, and the number of cases are steadily rising.{2}

It is a complex situation; there are more than 100 types of pediatric cancer, and their distribution varies by age. For example, the incidence of leukemias in children 1 to 4 years of age is more than twice that in adolescents (15 to 19 years of age).{3} In contrast, lymphomas rarely occur in children younger than 4, but comprise about a quarter of all cancers diagnosed in adolescents.{3}

While there are hundreds of approved cancer therapies, only about 40 have pediatric labeling, and only four have been developed specifically for pediatric cancer.{4,5}

RACE for Children Act

The Research to Accelerate Cures and Equity (RACE) for Children Act aims to advance more effective therapies for pediatric cancers.

The RACE for Children Act was incorporated as Title V in the 2017 U.S. Food and Drug Administration (FDA) Reauthorization Act and just went into effect on August 18 this year. It builds upon earlier advances made by the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA), which resulted in more than 800 medicines being labeled for pediatric use but had limited success with oncology drugs.

PREA was previously only triggered by an application for a new indication, dosage form, dosing regimen, route of administration, or active ingredient, unless the drug was for an indication with orphan designation. The RACE for Children Act amends PREA and requires the sponsor of an original New Drug Application (NDA) or Biologics License Application (BLA) for an adult cancer drug directed at a molecular target considered relevant to the growth or progression of a pediatric cancer to submit an initial Pediatric Study Plan (iPSP).

The Act applies to NDAs and BLAs for a new active ingredient, which may include biosimilars, filed on or after August 18, 2020. It applies even if the adult cancer does not occur in children or the adult indication was granted orphan designation.

The iPSP must contain an outline of the proposed molecularly targeted pediatric cancer investigation, “using appropriate formulations, regarding dosing, safety and preliminary efficacy to inform potential pediatric labeling.”{6} It should also include any planned request for a deferral or waiver together with supporting documentation.

Sponsors should leverage adult safety, pharmacokinetic (PK), and efficacy data to inform pediatric trial design and assess whether an age-appropriate pediatric formulation is required. The iPSP needs to be submitted to the FDA within 60 days of the end-of-Phase II meeting,{7} and it will take about 210 days to receive either an agreement or a non-agreed letter.

The iPSP must address the following areas:

• Safety: Determine tolerability and dose limiting toxicities in pediatric patients
• Exposure: Examine PK across different age groups as appropriate
• Dose/Exposure/Response (DER): Support the pediatric recommended Phase II dose (RP2D)
• Response: Assess the overall response rate across the entire study population in biomarker enriched population(s), pre-specified disease cohorts, or adaptive design settings
• Sample Size: This will vary, but should support the study objectives

As this is a new regulatory requirement, sponsors might want to consult the relevant guidance{8} and FDA’s lists of relevant and non-relevant pediatric molecular targets.{9} As these target lists are not binding, requesting a consultation with the Oncology Center of Excellence Pediatric Oncology Program and the Oncology Subcommittee of the Pediatric Review Committee might be valuable.{10} Requesting scientific advice from the FDA and European Medicines Agency (EMA) in tandem could also help avoid the need for duplicate pediatric studies. FDA also suggests that sponsors consider including adolescents in Phase II trials, which is a practice employed in other therapeutic areas.

Pediatric Challenges

Working with pediatric populations is complicated, because children are not small adults. Rapid changes due to growth and maturation, impact body composition, organ size, PK processes (such as absorption, distribution, metabolism [enzymes and transporters], and elimination), and pharmacodynamic (PD) processes (such as receptor responses).{11}

There are also practical and ethical reasons why it is not possible to collect all the requisite pediatric data from clinical trials. Overcoming these challenges requires the application of a quantitative framework that can use sparse pediatric samples or existing adult and pediatric data from drugs in the same class—or a similar class of compounds—to build a more complete picture of the new drug’s activity.

In addition, sponsors need to leverage all the available real-world and published clinical data to bridge knowledge gaps between adult and pediatric patient populations and understand the extent of disease similarity and, if different, the magnitude of disease progression or DER relationship.

Model-Informed Drug Development (MIDD) Benefits

MIDD approaches,{12} which have been widely adopted by global regulatory agencies including the FDA, the EMA, and Japan’s Pharmaceuticals and Medical Devices Agency, can help to achieve those goals. Population PK models can employ allometric scaling using body size metrics to scale adult data for pediatric purposes and support the optimal starting dose and schedule selection for the first pediatric trial.

Physiologically based PK (PBPK), which incorporates ontogeny, physiological changes, and disease progression, can be used to model drug performance, assess drug-drug interactions, simulate responses for different age groups, and conduct adult-to-pediatric extrapolations. MIDD can also support dose optimization, provide evidence of efficacy, improve clinical trial designs, and reduce the size or eliminate the need for clinical trials in certain circumstances. These quantitative MIDD strategies make optimal use of all the existing data and help sponsors to prepare the requisite elements for their iPSP efficiently.

Conclusion

Pediatric oncology patients need safer, more effective therapies. It is anticipated that the RACE for Children Act will help to make that goal a reality. When successfully applied, MIDD can support dose optimization, identify risks and benefits of the drug product under development, improve clinical trial efficiency, and reduce the burden of trial participation to enhance patient recruitment and retention, with the goal of increasing the probability of regulatory success. 

References

1. American Cancer Society. Cancer Facts & Figures 2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf
2. American Cancer Society. Key Statistics for Childhood Cancers. https://www.cancer.org/cancer/cancer-in-children/key-statistics.html
3. Source SEER Cancer Statistics Review 1975–2017, Table 29.1. https://seer.cancer.gov/csr/1975_2017/browse_csr.php?sectionSEL=29&pageSEL=sect_29_table.01
4. Coalition Against Childhood Cancer. Drug Development Section. https://cac2.org/interest-groups/awareness/childhood-cancer-fact-library/
5. Ye J. 2019. Statistical and Regulatory Considerations on Registration Trials in Pediatric Cancer (PowerPoint) The 3rd Stat4Onc Symposium. https://events.stat.uconn.edu/stat4onc/talk-slides/April27-1030-1200/Jingjing_Ye_Stat4Onc_2019.ppt
6. FDARA Title V Sec 504 (a)(3)(A) or Federal Food, Drug, and Cosmetics Act (FD&C Act) Sec. 505B (a)(3)(A).
7. Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans Guidance for Industry. 2020. https://www.fda.gov/media/86340/download
8. U.S. Food and Drug Administration. 2019. Draft Guidance: “FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act Guidance for Industry.” https://www.fda.gov/media/133440/download
9. U.S. Food and Drug Administration. Pediatric Molecular Target Lists. https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology
10. U.S. Food and Drug Administration. 2020. FDA Oncology Center of Excellence. Pediatric Oncology Product Development Early Advice Meeting (Type F)1, https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology-product-development-early-advice-meeting-type-f1
11. Corriol-Rohou S, Cheung SYA. 2019. Industry Perspective on Using MIDD for Pediatric Studies Requiring Integration of Ontogeny. Clinical Pharmacology. https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.1495
12. EFPIA MID3 Workgroup. 2016. Good Practices in Model-Informed Drug Discovery and Development: Practice, Application, and Documentation. CPT Pharmacometrics Syst Pharmacol 5(3):93–122. https://pubmed.ncbi.nlm.nih.gov/27069774

Lynne Georgopoulos, RN, MSHS, RAC, is Vice President of Regulatory Strategy at Certara and a founding member of the company’s Pediatric Practice, which provides integrated drug development, regulatory strategy, population PK modeling, and PBPK analysis with the Simcyp® Pediatric Simulator. Certara has contributed to more than 100 Pediatric Investigation Plans and Pediatric Study Plans.

Amy Cheung, PhD, is Senior Director of Integrated Drug Development at Certara and a project manager and core group member of the company’s Pediatric Practice. She has expertise in pediatric drug development, oncology trials, MIDD, PBPK, and extrapolation. She is a member of the IQ CPLG pediatric working group and co-chair of the TALG CPLG Pediatric PBPK group.