Rho experts recently attended the FDA-AACR-ASA Workshop on the use of overall survival as an endpoint in oncology trials.  In a series of five blogposts, they will discuss key topics to consider when designing such a study as presented at the workshop. These topics will include study design, endpoint construction, subgroup considerations, and analysis interpretation.

Overall survival (OS) is both an important efficacy & safety endpoint for oncology trials. Often when study results are submitted for regulatory consideration, OS results are often “immature”/still in their early stages which makes them difficult to evaluate. Understanding how to place these results into a proper benefit-risk framework for consideration is therefore important when assessing a potential treatment’s viability.

When assessing the benefit-risk tradeoffs, the context surrounding the analysis results and treatment landscape is critical. Keeping this in mind, being able to think through these questions will be of assistance when drafting your clinical report:

1) What are “immature” results?

The level of ambiguity that can be tolerated depends heavily on what the current treatment space looks like and the specifics of the proposed treatment. For example, treatments for aggressive and/or severe cases of disease will tend to accept more uncertainty to provide patients access to treatments while indolent diseases have time on their side to wait for more certain results. Similarly, if there are no available treatments for patients there is more urgency as compared to when there are alternative treatments. Looking at the treatment in question, examination of its side effects vis-à-vis its efficaciousness will play a role in decision making. Severe side effects may be acceptable for a product with curative intent but are less likely if treatment has limited improvement in survival. Likewise, understanding how long it will take to obtain more data to sharpen trial results will play a role in decision framing (i.e., if more data can come quickly, it is likely best to wait).

2) What type of picture do the study analyses portray? How does this fit into the pre-existing treatment space? Other drugs in class?

When examining results from your development program, the narrative generated by trials results will be a critical factor in how to understand benefit/risk. If the candidate treatment has consistent results across multiple analyses, there’s greater confidence that the finding is accurate whereas uncertainty will creep in if there are conflicting analysis results. Likewise, fitting the candidate treatment into the current therapeutic space and comparing/contrasting its benefits & safety profile against other products in the same space will be of value.

3) What type of approval is the drug trying to obtain?

Assuming eligibility, the benefit/risk framework for treatments will differ between accelerated approval vs. full approval. While the goal of any approval is the same, demonstration of safe & efficacious treatments ready for the marketplace, the level of certainty for these approvals can differ. Accelerated approval provides a pathway for treatments addressing an unmet need to reach the market faster while additional data collection is ongoing. If your product is addressing such a need, the level of certainty required in your study results may be less as the benefit of having an available treatment would outweigh the risk of disease progression and/or death.

There are many types of cancer that are actively being researched with the hope of bringing about cures. Understanding what treatments are out there, how your proposed treatment fits into this space, and what story your trial analyses are telling will be critical to providing a proper benefit-risk framework for your product. Working with a CRO, like Rho, that routinely conducts these analyses and wrestles with these questions can help give the proper context for your product and help navigate the regulatory waters.

Scott Mollan, Associate Director, Biostatistics, has more than 17 years of experience in clinical and non-clinical statistics across the CRO & pharmaceutical industry. Having led studies of all phases (pilot, pivotal, post-market, phases I-IV) and assisting clients during both the pre-submission phase and FDA approval via the NDA/PMA process (2 NDAs/10 PMAs), he has a wealth of experience to draw upon to support clients. Armed with graduate degrees in business and statistics, Mr. Mollan has been able to leverage his understanding of the clinical trial process via a diverse range of indications to publish on the medical device trial process, lung cancer diagnostics, and women’s health while similarly offering industry presentations on missing data analysis strategies and the use of adaptive trial designs within medical devices studies.