Clinical Cancer Research Publishes a Systematic Review of Regulatory Real-World Evidence in Successful Oncology Product Approvals

Analysis Group research distills insights directly from the FDA’s commentary on submissions

Date:November 5, 2021
Location:Boston, MA
Contact:Eric Seymour
+1 978 273 6049

Analysis Group, a global leader in health economics and outcomes research (HEOR) and regulatory epidemiology, today announced the publication of research examining the US 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 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 contributes to an accelerated or full drug approval.

“Drug developers have hundreds of decisions to make for using RWE, and our research can be used to quickly hone in on the most effective choices for their submissions. The FDA’s comments are an invaluable resource to navigate the vagaries found in the official guidance documents,” said coauthor Mei Sheng Duh, M.P.H., Sc.D., a Managing Principal with Analysis Group. “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.”

Drug developers may prepare stronger submission dossiers for RWE studies by drawing on the research’s key insights:

  • 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. A hybrid study design to combine trial with external control data through Bayesian or frequentist methods, and ambi-directional RWE data collection (both prospective and retrospective) are study designs worth considering.  
  • Select appropriate data sources to ensure that real-world data (RWD) are high quality and fit for purpose. Although chart review was the most common source for RWE, the FDA also commented that data from such studies could have limited generalizability and are subject to selection bias.
  • 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, such as inverse probability treatment weighting. Critically, the study protocol needs to be developed a priori.
  • Describe methods to minimize residual confounding and unmeasured confounding, including appropriate index date and reduction in missing values. If imputation methods are used to address missing values, validation of the imputation algorithms is recommended. The impact of unmeasured confounding should be evaluated through quantitative bias analysis.

“It’s clear from analyzing the FDA comments that the agency believes high-quality RWD are paramount. 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,” said coauthor and Analysis Group Vice President Maral DerSarkissian, Ph.D. “Moreover, we found that inclusion of RWE helped accelerate oncology drug development timelines by 1–3 years. That directly relates to getting urgently needed treatments into the hands of patients with difficult-to-treat cancers.”

The analysis, “Real-world Evidence in Support of Oncology Product Registration: A Systematic Review of New Drug Application and Biologics License Application Approvals from 2015-2020,” was published in Clinical Cancer Research, an American Association of Cancer Research journal. Coauthors include Bhakti Arondekar, Bryon Wornson, and Alexander Niyazov of Pfizer; and George D. Demetri of the Dana-Farber Cancer Institute and the Ludwig Center at Harvard Medical School.  Funding for the work was provided by Pfizer.

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About Analysis Group’s HEOR Practice

Founded in 1981, Analysis Group is one of the largest international economics consulting firms, with more than 1,000 professionals across 14 offices. Analysis Group’s health care experts apply analytical expertise to health economics and outcomes research, clinical research, drug safety, epidemiology, market access and commercial strategy, and health care policy. Analysis Group’s internal experts, together with its network of affiliated experts from academia, industry, and government, provide our clients with exceptional breadth and depth of expertise and end-to-end consulting services globally.