Lynne Georgopoulos

The Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA), have driven pediatric research efforts resulting in over 800 medicines being labeled for use in children. PREA gives FDA authority to require pediatric assessments (either filed with the initial application or deferred) for the “claimed indication” for any application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration, unless such assessments have been waived. When pediatric assessments (studies) are required, the sponsor must submit an initial pediatric study plan (iPSP) to FDA detailing its plan to fulfill its PREA requirements.

Unfortunately, PREA has failed to promote research for pediatric cancers. Most oncology products are developed for adult cancer indications that do not occur or rarely occur in children, making studies in children impossible or highly impracticable, resulting in studies being waived. Even if the rare adult cancer occurred in children, most will have orphan-drug designation and thus are exempt from PREA requirements.

The Research to Accelerate Cures and Equity (RACE) for Children Act, an amendment to PREA as part of the 2017 FDA Reauthorization Act, goes into effect on Aug. 18 and aims to change the landscape and promote pediatric cancer drug development.

This new Act requires sponsors to submit an iPSP with any original new drug application or biologics license application for an oncology product “intended for the treatment of adult cancers and directed at a molecular target substantially relevant to the growth or progression of a pediatric cancer.” This requirement applies even if the proposed cancer therapy has orphan-designated indications or is being developed for a cancer that only occurs in adults, if the molecular target (mode of action) is relevant to pediatrics.

The iPSP needs to include an outline of the planned pediatric investigation(s), any request for deferral or waiver with supporting documentation, and be submitted to FDA within 60 days of the end-of-Phase II meeting.

The RACE for Children Act is challenging because multiple indications may need to be investigated to address the entire pediatric population (i.e., children ages 0-2 years, 2-11 years, and adolescents ages 12-<17 years). There are significant differences between children and adults in disease physiology, pharmacokinetics (PK), and pharmacodynamics (PD), and they are especially evident in children under two years of age. As a result, different age groups may require different drug formulations and dosing.

Limited sample size, more complex PK sampling strategy, and lack of clinically meaningful and measurable endpoints are just a few of the pediatric issues that need to be addressed.

Furthermore, sponsors will likely need to plan their first study in children, define dose-finding and formulation strategies, and efficacy population and endpoints before they fully understand the drug’s activity in adults and have identified potential developmental toxicities.

Model-informed drug development (MIDD) can help address many of these challenges. Population PK models with adult data can be appropriately scaled to pediatrics, integrating maturation and disease factors using allometric scaling to determine the best dose for the first pediatric trial cohort. Physiologically-based pharmacokinetic (PBPK) modeling and simulation can also be used to model drug performance and assess drug-drug interactions in neonates and onwards.

Preparation is important for optimally managing this new regulatory requirement.

Review FDA guidance on implementing studies of molecularly targeted oncology drugs, the content and process for submitting an iPSP4, the Relevant Molecular Target list, and the Non-relevant Molecular Target list. While these target lists provide useful direction, they are not binding. Anticipate it taking 210 days to progress from iPSP FDA submission to either agreement or receipt of a non-agreed letter.

Ask for advice regarding iPSP development from the Oncology Center of Excellence Pediatric Oncology Program and the Oncology Subcommittee of the Pediatric Review Committee.

Consider requesting formal and parallel scientific advice from FDA and the European Medicines Agency (EMA) to avoid unnecessary duplication of pediatric studies.

Leverage real-world data and knowledge from the literature and adult studies to bridge the data gap for pediatric patient populations. In certain cases, it is permissible to enroll adolescents with adults in Phase III trials and obtain early pediatric data. FDA issued draft guidance in 2019 allowing this if sponsors have obtained PK and toxicity data and the adolescent patients have recurrent cancers or no other treatment option.

Use MIDD—which has been adopted by FDA and EMA—to support dose optimization, provide evidence of efficacy, and improve clinical trial designs. MIDD can also help reduce the size of trials or eliminate the need for trials in some circumstances.

Pediatric patients deserve safe and effective therapies that have been evaluated for their stage of development. MIDD can help sponsors to meet the RACE for Children Act’s endeavors to facilitate inclusion of more pediatric dosing information on new drug labels.

, RN, MSHS, RAC, is Vice President, Regulatory Strategy, at 

Articles

An amendment to Pediatric Research Equity Act, as part of the 2017 FDA Reauthorization Act, goes into effect soon aiming to change the landscape and promote pediatric cancer drug development.

The RACE for Children Act Takes Effect This Month

	The Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA), have driven pediatric research efforts resulting in over 800 medicines being labeled for use in children.

PREA gives the Food and Drug Administration (FDA) authority to require pediatric assessments (either filed with the initial application or deferred) for the “claimed indication” for any application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration, unless such assessments have been waived. When pediatric assessments (studies) are required, the sponsor must submit an initial pediatric study plan (iPSP), to FDA detailing its plan to fulfill its PREA requirements. 

	Unfortunately, PREA has failed to promote research for pediatric cancers. Most oncology products are developed for adult cancer indications that do not occur or rarely occur in children, making studies in children impossible or highly impracticable, resulting in studies being waived. Even if the rare adult cancer occurred in children, most will have orphan drug designation and thus are exempt from PREA requirements.

	The Research to Accelerate Cures and Equity (RACE) for Children Act, an amendment to PREA as part of the 2017 FDA Reauthorization Act, goes into effect on August 18 and aims to change the landscape and promote pediatric cancer drug development.  

	This new Act requires sponsors to submit an iPSP with any originalnew drug application or biologics license application for an oncology product “intended for the treatment of adult cancers and directed at a molecular target substantially relevant to the growth or progression of a pediatric cancer.”

This requirement applies even if the proposed cancer therapy has orphan-designated indications or is being developed for a cancer that only occurs in adults, if the molecular target (mode of action) is relevant to pediatrics.

	The iPSP needs to include an outline of the planned pediatric investigation(s), any request for deferral or waiver with supporting documentation, and be submitted to the FDA within 60 days of the end-of-Phase II meeting.

	The RACE for Children Act is challenging because multiple indications may need to be investigated to address the entire pediatric population (i.e., children ages 0-2 years, 2-11 years and adolescents ages 12-<17 years). There are significant differences between children and adults in disease physiology, pharmacokinetics (PK), and pharmacodynamics, and they are especially evident in children under two years of age. As a result, different age groups may require different drug formulations and dosing. 

	Limited sample size, more complex PK sampling strategy, and lack of clinically meaningful and measurable endpoints are just a few of the pediatric issues that need to be addressed. 

	Furthermore, sponsors will likely need to plan their first study in children, define dose finding and formulation strategies, and efficacy population and endpoints before they fully understand the drug’s activity in adults and have identified potential developmental toxicities.

	Model-informed drug development (MIDD) can help address many of these challenges. Population PK models with adult data can be appropriately scaled to pediatrics, integrating maturation and disease factors using allometric scaling to determine the best dose for the first pediatric trial cohort.  Physiologically-based pharmacokinetic (PBPK) modeling and simulation can also be used to model drug performance and assess drug-drug interactions in neonates and onwards.  

	Preparation is important for optimally managing this new regulatory requirement.

		Review the FDA guidance on implementing studies of molecularly targeted oncology drugs,

the content and process for submitting an iPSP

and the Non-relevant Molecular Target list.

While these target lists provide useful direction, they are not binding. Anticipate it taking 210 days to progress from iPSP FDA submission to either agreement or receipt of a non-agreed letter.

		Ask for advice regarding iPSP development from the Oncology Center of Excellence Pediatric Oncology Program and the Oncology Subcommittee of the Pediatric Review Committee.

		Consider requesting formal, parallel scientific advice from the FDA and EMA to avoid unnecessary duplication of pediatric studies. 

		Leverage real-world data and knowledge from the literature and adult studies to bridge the data gap for pediatric populations.

In certain cases, it is permissible to enroll adolescents with adults in Phase III trials and obtain early pediatric data. FDA issued draft guidance in 2019 allowing this if sponsors have obtained PK and toxicity data and the adolescent patients have recurrent cancers or no other treatment option.

		Use MIDD – which has been adopted by FDA and EMA – to support dose optimization, provide evidence of efficacy, and improve clinical trial designs.

MIDD can also help reduce the size of trials or eliminate the need for trials in some circumstances.

	Pediatric patients deserve safe and effective therapies that have been evaluated for their stage of development. MIDD can help sponsors to meet the RACE for Children Act’s endeavors to facilitate inclusion of more pediatric dosing information on new drug labels. 

RN, MSHS, RAC is Vice President, Regulatory Strategy at Certara. 

		Food and Drug Administration. New Pediatric Labeling Information Database. Changes as of March 2019. FDA website. https://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase, accessed July 12, 2020.

https://www.congress.gov/115/plaws/publ52/PLAW-115publ52.pdf

		FDA 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” (December 2019). FDA website, 

https://www.fda.gov/media/133440/download

		Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans Guidance for Industry DRAFT GUIDANCE March 2016 

		Candidate Pediatric Molecular Target List. 

https://www.fda.gov/media/120331/download

https://www.fda.gov/media/120329/download

		FDA Oncology Center of Excellence, FDA website, June 4, 2020, 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

		Food and Drug Administration. Framework for FDA’s Real World Evidence Program. December 2018. FDA website, 

https://www.fda.gov/media/120060/download

		FDA. Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials Guidance for Industry. March 2019. FDA website, 

https://www.fda.gov/media/113499/download

		Wang Y, Zhu H, Madbushi R, et al. Model-Informed Drug Development: Current US Regulatory Practice and Future Considerations. 

		Youwei B, LIuJ, Li L, et al. Role of Model-Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling. 

An amendment to Pediatric Research Equity Act, as part of the 2017 FDA Reauthorization Act, goes into effect soon aiming to change the landscape and promote pediatric cancer drug development.  

Author | Lynne Georgopoulos