Review Focuses on Regulatory Real-World Evidence in Successful Oncology Product Approvals

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Mei Sheng Duh, MPH, ScD, Managing Principal, Analysis Group

Analysis Group, which specializes in health economics and outcomes research and regulatory epidemiology, has published research examining the U.S. Food and Drug Administration’s (FDA’s) commentary on the use of real-world evidence (RWE) in successful oncology product approvals between 2015 and 2020. The group says that the analysis, published in Clinical Cancer Research, is the first of its kind to systematically aggregate detailed regulatory feedback to provide practical insights to drug developers.

While existing FDA guidance documents provide a theoretical framework for conducting regulatory RWE studies, the details of how to actually design and analyze adequate real-world studies remain largely unaddressed. To meet this critical knowledge gap for drug developers, a team of researchers from Analysis Group, Pfizer, and the Dana-Farber Cancer Institute analyzed 133 original and 573 supplemental oncology New Drug Application and Biologics License Application approvals to identify the attributes of a successful RWE study that contribute to an accelerated or full drug approval. Funding for the work was provided by Pfizer.

“Drug developers have hundreds of decisions to make for using RWE, and [the findings of this review] can be used to quickly hone in on the most effective choices for their submissions,” said coauthor Mei Sheng Duh, MPH, ScD, a managing principal with Analysis Group. “The FDA’s comments are an invaluable resource to navigate the vagaries found in the official guidance documents. For example, the most common primary endpoint as an external control to contextualize or compare with the pivotal trial was overall response rate. The most commonly used statistical method to adjust for differences in patient characteristics was inverse probability of treatment weighting.”

Among other insights for preparing stronger submission dossiers for RWE studies were the following:

  • Engage the FDA early to confirm appropriate data sources and whether the RWE study should be designed as a natural history study for contextualization, or as an external control study for comparison with the pivotal trial.
  • Ensure that the real-world data (RWD) used are high quality and fit for purpose.
  • Align the RWE and pivotal trial populations by matching on trial inclusion and exclusion criteria to the extent possible and adjusting for the remaining imbalance in baseline characteristics with propensity score weighting methodology.
  • Describe methods to minimize residual confounding and unmeasured confounding, including appropriate index date and reduction in missing values.

“It’s clear from analyzing the FDA comments that the agency believes high-quality RWD are paramount,” said coauthor and Analysis Group Vice President Maral DerSarkissian, PhD. “The accuracy of the primary endpoints, key covariates such as prior lines of therapy, and imputation models for missing values all need to be validated. Moreover, we found that inclusion of RWE helped accelerate oncology drug development timelines by one to three years. That directly relates to getting urgently needed treatments into the hands of patients with difficult-to-treat cancers.”

Edited by Gary Cramer