RE:RE:Clinical Trial Size in Orphan and Rare Diseases Phase II/III trials that are adaptive in design, randomized controlled, and using surrogate clinical endpoints to predicitively determine treatment outcome were considered valuable alternatives to a relatively small sample size and overall survival in orphan diseases and rare cancers by 80% of oncologists.
‘FDA guidance states that where a potential surrogate endpoint exists that is correlated with the primary endpoint, and the primary endpoint itself is difficult or slow to ascertain, an adaptive design can be based on the potential surrogate endpoint.
For example, in a trial with a primary endpoint of overall survival in which median survival time and tumor response (e.g. complete or partial response) is anticipated to predict clinical benefit, adaptive features such as sample size reassessment could be based on tumor response rather than mortality. ‘
‘Adaptive designs offer many important advantages including an earlier selection of the most promising patient characteristics or therapeutic options. Interim analysis allows the trial to be stopped early, for example, for futility, which, in turn, can help limit patient exposure to ineffective treatments. ‘
‘ Adaptive trials can also be used for a variety of development opportunities from dose finding to expanding indications and offer the opportunity for a seamless switch to a Phase III confirmatory trial if early results are favorable. Such improved value for pharmaceutical companies may subsequently encourage greater involvement in research in rare cancers and other diseases. For physicians and researchers, participation offers access to a valuable data set in terms of outcomes, imaging and biomarkers and opportunities for continuous learning. For patients and advocates, adaptive trials and surrogate endpoints increase the likelihood that patients receive the most beneficial treatment for their cancer subtype at an earlier point in their disease. Strategies to individualize treatment, for example by the identification of biomarkers to better predict treatment response, also offer value-based treatment, which is increasingly demanded by payers when making prescribing decisions. ‘
‘In the era of personalized medicine, adaptive designs may also prove beneficial in more common cancers with specific markers that allow them to be classed as orphan subsets. ‘
ONCYs Phase 1/2 Goblet study was randomized, adaptive, biomarker driven and involving the surrogate endpoints of ORR, PFS and mOS that I have presented beforehand ... which satisfy the FDA and 80% of oncologists surveyed on an accelerated appproval pathway for rare cancers.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982798/
The Orphan Drug Act of 1983 incentivizes development of drugs not only for rare diseases but also for ultra-rare diseases and subsets of common diseases. These orphan indications fill significant unmet needs, yet their approval is based on small trials.
Although there is no universally accepted definition for a rare cancer, the Orphan Drug Act defines a rare disease or condition as one which affects less than 200,000 people in the United States (U.S). The National Institute of Health defines rare cancers as those that affect fewer than 40,000 people in the U.S., and many cancer types are even rarer. Additionally, there are also rare subsets of some more common cancers, such as lung cancer or breast cancer.
In the past few years, the less common cancers have started to receive more attention and the top-performing orphan drugs are in oncology. As researchers have been able to understand more about molecular profiles, they have been able to develop impactful treatments for many rare cancers. Basket trials (like ONCYs Phase 1/2 Goblet study ) in particular (also called histology-agnostic) have highlighted this and fueled the development of tumor-agnostic treatments. In other words, they are treating the mutations that create tumors at a molecular level, so it doesn’t necessarily matter what type of cancer, just that the genetic mutation is the same.
https://www.obroncology.com/article/rare-cancers-are-no-longer-orphans