Too often, children are not included in clinical trials for new drugs, even though children may eventually be prescribed those very same drugs. This forces physicians who treat children to try and extrapolate information collected from adult trials to determine if and how to use that medicine in kids. Children deserve better than that. To help address this problem, the Food and Drug Administration (“FDA”) recently published a draft guidance titled: “FDARA Implementation Guidance for Pediatric Studies of Molecularly Targeted Oncology Drugs: Amendments to Sec. 505B of the FD&C Act Guidance for Industry.”
The purpose of this guidance is to facilitate the development of molecularly targeted therapies for the treatment of pediatric cancers. The guidance addresses the early planning needed for the eventual submission of New Drug Applications (NDAs) and Biologics License Applications (BLAs) expected to be submitted to the FDA on or after August 18, 2020 (and in accordance with section 505B of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (also referred to as the Pediatric Research Equity Act, or PREA) as amended by the FDA Reauthorization Act of 2017 (FDARA)).
There are now requirements for pediatric investigations to be conducted for certain targeted cancer drugs with new active ingredients, based on the molecular mechanism of action rather than clinical indication. In other words, products being developed that are directed towards a specific molecule in the cancer cells that may be involved in the growth, progression, or spread of the cancer. These molecular targets may be related to numerous cancers rather than only a specific type of cancer. Original NDAs or BLAs for treatment of adult cancers and directed at a molecular target that is relevant to the growth or progression of a pediatric cancer must now include reports on the investigations of the molecularly targeted pediatric cancer.
The intent of this change is to accelerate early pediatric evaluation of these new products and help get these new products to market for kids with cancer. Many cancers that occur in children and adolescents may have the same molecular abnormalities that are seen in adult cancers. The 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.
Gröbner SN, et al. The landscape of genomic alterations across childhood cancers. 2018. Nature, Mar 15;555(7696):321-327
The guidance defines several terms for regulatory purposes. A molecular target is a “molecule in human cells (normal or cancer cells) that is intrinsically associated with a particular malignant disease process such as etiology, progression, and/or drug resistance.” Relevance refers to the determination if a molecular target is substantially related to the growth or progression of pediatric cancer. The guidance outlines some of the criteria to determine if a molecular target is relevant. Categories include the following:
- Targets Related to Specific Gene Abnormalities
- Targets Associated with Cell Lineage Determinants
- Targets on Normal Immune Cells and Cellular Components of the Tumor Microenvironment
- Other Targets Associated with Specific Pathways or Functional Mechanisms of Normal and/or Malignant Cells
Additionally, FDA maintains two molecular target lists (relevant and non-relevant) for pediatric cancers.
The Pediatric Research Equity Act (PREA) had required that initial pediatric study plans (iPSP) were required prior to submission of an NDA or BLA. For oncology products, the iPSPs were frequently waived due to the type of cancer not occurring, or rarely occurring in children, which would make conducting pediatric studies impossible or highly impractical to conduct. iPSPs, however, will be required after August 18, 2020 if an adult cancer indication is directed at a molecular target relevant to pediatric cancer. The guidance goes into detail about the content of an IPSP. Sponsors of these products can request a meeting with the Oncology COE Pediatric Oncology Program and Oncology Subcommittee of PeRC to assist with development of the iPSP.
The guidance offers additional considerations for Rare Cancers. These include considering including a pediatric cohort in adult trials. This can prevent the need for developing and conducting a separate pediatric trial. Another consideration is to imbed pediatric trials in an adult trial, especially if the molecular target is rare in the pediatric population. Increasing the enrollment of adolescent patients can be augmented by lowering the enrollment age for the trial. Tissue agnostic studies can help in development of treatment for multiple pediatric cancers that share the same genetic aberrations (e.g., MSI-H/dMMR tumors, NTRK-fusion positive tumors). Finally, master protocols (basket or umbrella trials) may be considered to minimize the number of pediatric patients exposed to therapies. These types of protocols will usually require a lot of planning and coordination.
Deferrals and waivers of doing pediatric studies are still appropriate in some cases such as when there is suspected serious toxicity in pediatric patients, when it may be prudent to wait until a clinical effect (in adults) is demonstrated, or if there are challenges in developing a pediatric formulation.
The guidance closes with a section on global implications and international collaboration which encourages drug developers to take a global approach when developing oncology treatments for pediatric patients.
Children with cancer may face additional risks when treated with drugs that were never specifically studied in pediatric clinical trials. Kids are way more complicated than being just small adults, and many things need to be considered when treating children e.g. age, rate of development and different metabolism. This new guidance is a great step in helping to see that new oncology drugs with molecular targets will be studied in children.
The docket for comments is open until February 20, 2020.