Chadi Nabhan, MD, Hematologist and Oncologist, Chief Medical Officer at Ryght AI, and Vivek Subbiah, MD, Professor of Medicine at Stanford University and Executive Medical Director of Novel Therapies & Clinical Trial Network at Stanford Health Care, discuss the need for better classification systems in precision oncology.
The 1983 Orphan Drug Act (ODA) defined rare diseases as those affecting fewer than 200,000 Americans, resulting in regulatory incentives that transformed drug development. Since then, oncology has accounted for 38% of all orphan designations and approvals sanctioned by the US Food and Drug Administration (FDA).
An editorial published in the Journal of Clinical Oncology seeks to address the implications this framework and definition have on modern precision oncology and its original intention to enable and advance progress. Drs. Nabhan and Subbiah propose in their thesis that every cancer is effectively a rare disease and should be recognized as such, fundamentally challenging how malignancies are classified, studied, regulated, and treated.
In oncology today, cancers are grouped by subtype, often depending on the specific gene mutations involved. Each of these subtypes have their own unique natural history, treatment responses, and outcomes. When defined at this level, nearly all cancers could be defined as a rare disease, thus requiring new systems of treating cancer.
While drug development often focuses on these rare populations, there is a disconnect in how these diseases are framed in clinical practice, health care delivery, and public discourse. This results in misaligned expectations in clinical trials, inadequate molecule biomarker testing, and misaligned investment incentives for pharmaceutical development.
One concern in labeling most or all cancers are rare is that could weaken the current framework that was designed to advance orphan drug development. Defining all diseases as rare because of their molecular subdivisions may render the term “rare” meaningless. Treating every cancer as rare could also overwhelm regulatory systems and orphan designation reviews could take years. Additionally, this classification would exacerbate already struggling health care delivery to stay current with genomic testing and targeted therapies. Finally, taking this mindset to its logical conclusion every patient can be labeled as having a rare disease based on their unique molecular profile, ultimately defeating the purpose of disease classification entirely.
To overcome these concerns, Drs. Nabhan and Subbiah propose a new way to define and classify rare cancers. They propose a Tiered Rarity Classification System (TRCS) which defines diseases as: Common (prevalence threshold of less than 50 per 100,000), Uncommon (10-50 per 100,000), Rare (less than 6 per 100,000 (US/EU), Ultra-Rare (less than 1 per 100,000), Exceptionally Rare (less than 0.1 per 100,000; Case reports/series level; molecular subsets), and Compounded Rarity (less than 0.1 per 100,000; Ultra-rare cancer plus ultra-rare biomarker).
However, it is stressed that the real solution is not formally reclassifying all cancers as rare diseases, but in building systems that effectively respond to molecular rarity, clinical trial design, regulation of therapies, and delivery of care.
To learn more about rare cancers, visit https://checkrare.com/diseases/cancers/