Summary of ASA BIOP Section’s Virtual Discussion with Regulators on Trial Considerations in Indolent Cancers with Overall Survival as a Safety Endpoint
Rajeshwari Sridhara (FDA), Olga Marchenko (Bayer), Qi Jiang (Pfizer), Elizabeth Barksdale (LUNGevity Foundation), Yiyi Chen (Pfizer), Marc Theoret (FDA)
On June 11, 2024, the American Statistical Association (ASA) Biopharmaceutical Section (BIOP) and LUNGevity Foundation hosted a virtual forum to discuss Trial Considerations in Indolent Cancers with Overall Survival as a Safety Endpoint. This forum was part of a series conducted under the guidance of the U.S. FDA Oncology Center of Excellence’s Project SignifiCanT (Statistics in Cancer Trials) and the third discussion on Overall Survival (OS) considerations in indolent cancer trials. The goal of Project SignifiCanT is to advance cancer drug development through collaboration and engagement among various stakeholders in the design and analysis of cancer clinical trials. The discussion was organized jointly by the ASA BIOP Statistical Methods in Oncology Scientific Working Group, the FDA Oncology Center of Excellence (OCE), and LUNGevity Foundation.
Progression-free Survival (PFS) is generally considered the primary endpoint for regulatory decision-making in indolent or chronic cancers. In randomized clinical trials for these conditions, OS is commonly evaluated as a secondary efficacy endpoint. However, due to the long course of such chronic diseases, a limited number of OS events are typically observed at the time of PFS analysis. Therefore, when assessing the benefit-risk profile of a treatment, it is crucial to evaluate OS as a safety endpoint to ensure there is no detrimental effect on survival. This open forum discussion among multi-disciplinary experts explored design considerations for randomized trials that incorporate OS as a safety endpoint, as is often done for indolent cancers.
The speakers/panelists* for the discussion included members of the BIOP Statistical Methods in Oncology Scientific Working Group representing pharmaceutical companies, representatives from international regulatory agencies (Food and Drug Administration (FDA), Health Canada (HC), Medicines and Healthcare products Regulatory Agency (MHRA), Therapeutic Goods Administration (TGA), and Brazilian Health Regulatory Agency (ANVIS)), clinicians, academicians, and expert statisticians. In addition, over 100 participants attended the virtual meeting, including representatives from other international regulatory agencies (Health Sciences Authority (HAS), European Medicines Agency (EMA), Singapore; Ministry of Health, Israel; Pharmaceuticals and Medical Devices Agency (PMDA), Japan). The discussions were moderated by the BIOP Statistical Methods in Oncology Scientific Working Group co-chairs, Dr. Olga Marchenko from Bayer and Dr. Qi Jiang from Pfizer; Dr. Elizabeth Barksdale from LUNGevity Foundation; and Dr. Rajeshwari Sridhara, consultant from OCE, FDA.
In the introductory presentation, OCE leadership discussed the challenges and considerations surrounding OS as an endpoint in clinical trials for indolent or chronic cancers. In these cancers, where patients often survive for 5-10 years or more, using OS as a primary endpoint is impractical due to time constraints. Instead, PFS or disease-free survival (DFS) are commonly used as primary efficacy endpoints. Recent discussions, including the Oncologic Drugs Advisory Committee (ODAC) meeting in April 2022 and subsequent panels, raised concerns about potential detrimental effects on OS in some trials and emphasized the need for pre-planned OS interim analysis at the time of final PFS analysis, with pre-set criteria for detrimental OS effect. Questions posed to panelists from academia, industry, and regulatory bodies included the following: Is it reasonable to evaluate OS as a safety endpoint in indolent cancers? And, if so, what are the critical considerations, minimum data requirements, and potential challenges in establishing detrimental effect criteria?
The speaker, from industry, introduced a noninferiority approach to ensure that new treatments do not have an unacceptably detrimental effect on OS, acknowledging the challenges of limited OS data in cancers with typically long survival times (Fleming et al, 2024). The method uses clinically informed parameters, such as hazard ratios for unacceptable detriment (HR null) and plausible benefit (HR alt), and the number of deaths feasible to accrue in a reasonable time to set thresholds at interim and final analyses. These thresholds help balance the risks of both false negative and false positive errors, while recognizing the need for decision-making under high uncertainty. The guidelines are flexible, allowing for tailoring to specific indications and disease settings. By providing a structured framework, this approach aims to facilitate transparent discussions between stakeholders about acceptable risk trade-offs in drug development for indolent cancers. An R package, monitOS (https://cran.r-project.org/web/packages/monitOS/index.html), is publicly available for implementing the guidelines.
The key points raised in the panel discussion following the presentation were:
OS remains a critical endpoint for evaluating both efficacy and safety, even when it is not the primary endpoint.
Like previously set guidelines for monitoring safety in diabetes clinical trials, Fleming et al proposed monitoring guidelines balancing false positive and negative error rates; unlike group sequential guidelines, these are not anticipated to prompt trial termination.
Results presented by industry suggest that it is not possible to have a procedure that protects against OS detrimental effect without rejecting a large proportion of treatments.
Pre-specifying OS thresholds and criteria for ruling out harm is essential for interpreting early OS data; this will require prospective discussions between sponsors and regulators.
Alternative statistical methods, such as repeated confidence intervals, restricted mean survival time (RMST) test, or Bayesian methods, may be useful in certain scenarios.
The challenge of achieving targeted death events in a relevant timeframe (e.g., 5 years) needs to be anticipated and addressed with appropriate methods.
Comprehensive OS analysis should incorporate safety considerations (e.g., dose modifications, toxicities) and quality of life measures. The willingness to accept safety risks may depend on disease severity and available treatment options, with less tolerance for risk in indolent cancers.
Capturing exposure to effective agents, including subsequent therapies, is important for understanding OS effects.
Designs with control arm crossover to the experimental agent (that is not approved in the subsequent line) confound OS safety signal.
To capture the relevant OS safety signal in the population of interest, trials should be restricted to countries with comparable standard of care.
Interpretability of OS analyses rely on longer term data integrity. Long-term follow-up is crucial for detecting OS detriments in indolent cancers.
This forum provided an opportunity to have open scientific discussion among a diverse multidisciplinary stakeholder group – clinicians, epidemiologists, and statisticians from academia, pharmaceutical companies, patient advocates, and international regulators- focused on emerging statistical issues in cancer drug development.
Acknowledgement: Authors thank Joan Todd (FDA) and Syed Shah (FDA) for technical support.
* Speakers/ Panelists:
Dr. Keaven Anderson (Merck), Dr. Elizabeth Barksdale (LUNGevity Foundation), Dr. Michael Coory (TGA, AU), Dr. Leonardo Costa (ANVIS, BR), Prof. Thomas Fleming (University of Washington), Dr. Boris Freidlin (National Cancer Institute), Prof. Tim Friede (University Medical Center Göttingen), Dr. Xin (Cindy) Gao (FDA), Dr. Nicole Gormley (FDA), Dr. Lisa Hampson (Novartis), Dr. Qi Jiang (Pfizer), Dr. Olga Marchenko (Bayer), Dr. Richard Pazdur (FDA), Prof. Martin Posch (Center for Medical Statistics, Informatics, and Intelligent Systems at the Medical University of Vienna), Dr. Khadija Rantell (MHRA, UK), Mr. Andrew Raven (Health Canada), Dr. Minghua (Michael) Shan (Bayer), Dr. Steve Snapinn (Independent Consultant), Dr. Rajeshwari Sridhara (FDA), Dr. Marc Theoret (FDA), Dr. Jonathon Vallejo (FDA)
Reference:
Fleming, T. R., Hampson, L. V., Bharani, B.-D., Bretz, F., Chakravartty, A., Coroller, T., Koukouli, E., Wittes, J., Yateman, N. and Zumber, E. (2024), ‘Monitoring overall survival in pivotal trials in indolent cancers’, Statistics in Biopharmaceutical Research . doi: 10.1080/19466315.2024.2365648.