RACE Act: A Promising Catalyst for Improved Pediatric Cancer Treatments

Pediatric oncology development is set for tremendous innovation due to the recent enactment in the U.S. of the Research to Accelerate Cure and Equity (RACE) for Children Act. There is a significant gap between cancer treatments approved for children and those approved for adults. Pediatric patients have not benefited from major advances in molecular medicine, even though pediatric cancer remains the main medical cause of death in this population.¹ Clearly the need is great.

Listen to Dr. Timothy Miller, global VP and lead of PPD’s Rare Disease & Pediatric Center of Excellence, briefly discuss the importance of the RACE Act on developing targeted therapies to benefit pediatric oncology development.

In this blog post, Charity Schuller, senior director of country solutions at PPD, and Laura Garcia-Davenport, associate director of U.S. regulatory solutions at PPD, outline the changes in regulatory strategy brought about by the enactment of the RACE Act and discuss its implications for pediatric oncology clinical development programs.

Why the RACE Act

The RACE Act is designed to address the need for investigation of oncology therapeutics in pediatric populations to drive better outcomes for children with cancer. Why? Despite the enactment in 2003 of the Pediatric Research Equity Act (PREA), there has been a significant gap in FDA required studies in pediatric cancers because these studies have received waivers or orphan exemption. It is now incumbent on sponsors to prepare to address this new requirement.

Any sponsor developing treatments for adult cancer indications directed at a molecular target that the FDA determines to be “substantially relevant” to the growth or progression of a pediatric cancer is now required to do pediatric investigations.

The RACE Act shifts the development focus from indications to molecular targets and supersedes previous exemptions. As such, it requires sponsors to conduct pediatric studies for novel drugs and biologics intended for the treatment of adult cancers.

Understanding what’s required

The top takeaway for any sponsor advancing a molecularly targeted oncology medication is to begin planning as early as possible. This means early engagement in identifying relevant pediatric populations with the FDA and early planning for the potential inclusion of pediatric populations in your trial design.

Four ways the RACE Act impacts patients, trial design and sponsor compliance

Molecular targets: The FDA has worked with experts in government, academia and industry to determine and establish a list of molecular targets that are substantially relevant and a non-relevant molecular target list, with the latter warranting waivers. These lists have more than 200 targets and are maintained by the FDA.

Recommendation: Sponsors of molecularly targeted oncology medications should consult early with the FDA about their planned development and Initial Pediatric Study Plan (iPSP), as these lists are helpful but are considered nonbinding.

New Drug Applications (NDA): Any NDAs or Biologics License Applications (BLAs) for oncology treatments in the aforementioned category must provide reports on the pediatric cancer investigation. This also now applies to medications with orphan drug designations.^2,3

Recommendation: To avoid delays of targeted NDA/BLA filings, sponsors of molecularly targeted oncology medications must plan as early as possible for the inclusion of pediatric patients in their clinical development programs.

Initial Pediatric Study Plan (iPSP): The iPSP should include a well-constructed pediatric plan based on the current knowledge of the drug and disease epidemiology. Once the iPSP is agreed upon with the FDA, it can be amended at any time based on additional data. Moreover, waiver or deferral requests must be included in the iPSP. It is critical to secure agreement on the iPSP or an amended PSP, as it must be included in the NDA/BLA or supplemental application when a deferral of pediatric studies is requested. Failure to submit an agreed iPSP when a deferral is requested may be grounds for refusal to file the application.

Recommendation: Sponsors should plan to submit early, no later than 60 calendar days after the end of their Phase II meeting or at the pre-IND stage for INDs opening with a Phase III study.

Inclusion Strategies for Your Compound: The FDA guidance offers suggestions to comply with the RACE Act by including the following in adult trials:

• Pediatric cohorts: FDA’s July 2020 guidance, Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for Inclusion of Pediatric Patients⁴ recommends an evaluation of all available evidence, including in vivo and in vitro data, particularly when conducted using pediatric tumor model systems, in order to determine if pediatric expansion cohorts might be included in adult studies. The FDA guidance, Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics⁵ discusses FDA’s current thinking on assessing a reasonably safe dose in a special population, such as pediatrics. Opportunities may exist to use real-world data and knowledge from the literature and adult studies to bridge the data gap for pediatric populations.
  
• Adolescents: Early pediatric data can be obtained in some cases, if adequate pharmacokinetics and toxicology data is available and the adolescent patients have recurrent cancers or no other treatment option, by enrolling adolescents with adults in Phase III trials and per FDA’s 2019 guidance, Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials⁶.
  
• Use of Master Protocols: This strategy, including basket and umbrella trials, may allow for the minimization of the number of pediatric patients exposed to potentially ineffective treatments. This is particularly advantageous when the population sizes are small as in rare diseases. FDA’s guidance, Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics⁷, addresses the use of the master protocols in pediatric oncology indications. Dose range finding should be presented to the FDA prior to any efficacy evaluation. As with any global pediatric trial, consideration should be given to local laws and regulations.

Recommendation: Effective strategic planning for molecularly targeted oncology medications should identify trigger data points that have been prospectively agreed with FDA for early pediatric evaluation within adult studies. These trigger data points could result in efficiencies during clinical development and generate much needed pediatric data.

Promising Catalyst for Change

The passage and now enactment of the RACE Act offers a promising catalyst to advance the development of treatments for many pediatric cancers. The FDA’s guidance states, “Up to 50% of pediatric cancers have been reported to harbor a potentially druggable event, i.e., a molecular abnormality which can be potentially addressed by a targeted drug already approved for use in adults.”⁸ While the RACE Act is specific to the U.S., this legislation will affect the development of medicines for children worldwide and as such coordination and collaboration with regulatory authorities globally is vital. Careful planning and consideration need to be taken by biotech and pharma companies developing molecularly targeted cancer treatments.