Cognivia recently initiated a discussion with the FDA through the “Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program” process. A Letter of Intent (LOI) was submitted outlining Placebell’s methodology and seeking to explore Placebell’s applicability within the ISTAND for a wide range of statistical models. In response to the LOI, the FDA acknowledged that Placebell operates as a “special case” of covariate adjustment. This confirms that Placebell is already covered under its guidance for adjusting covariates in clinical trials, meaning it does not need further qualification under the ISTAND program.
Placebell is a statistical methodology that leverages individual patient’ psychology to produce powerful predictors of patient response in randomized controlled trials (RCTs). These predictors, used as prognostic covariates, enhance the precision of treatment effect estimation and boosts the study’s power.
The Placebell methodology can be applied with most statistical models typically used in RCTs, including linear regression, ANCOVA, generalized linear models, and Cox proportional hazards models. By incorporating Placebell into these models, researchers can adjust for baseline characteristics to enhance the precision of treatment effect estimation while ensuring statistical robustness (without inflating the type I error rate).
By categorizing Placebell as a methodology aligned with traditional covariate adjustment techniques, the FDA confirmed that its correct use might improve study precision and power, contingent on the prognostic value of the composite covariate within the study population. This recognition positions Placebell as a practical and scientifically grounded tool for enhancing the analysis of treatment effects in clinical trials.
FDA response confirms that Placebell’s methodology may be a viable tool in advancing clinical drug development. The FDA’s guidance and subsequent communications reinforce the notion that Placebell can be used alongside other covariates in targeted statistical models, as long as it is correctly applied within the context of a specific trial.
Cognivia’s future efforts will focus on assisting sponsors in implementing Placebell and maximizing its benefits in optimizing clinical trial outcomes.
Direct Quotes from FDA’s Response
- “ The proposed Context of Use (COU) aims to create a composite prognostic covariate to adjust the efficacy model in randomized controlled trials, including linear and Analysis of Covariance (ANCOVA) models, generalized linear models, and Cox models.”
- “We appreciate your interest in statistical methodology intended to improve the efficiency of clinical trials by using trial subjects’ predicted outcomes on placebo (prognostic scores) in covariate adjustment with linear models to increase the precision of treatment effect estimation and statistical power.”
- “This likely will depend on the prognostic value of the Placebell covariate in its intended study population.”
- Considering that: “Based on our review of your LOI, Placebell® Methodology is in principle a special case of an ANCOVA.”
- “ Any future requests related to the use of this methodology should be product or trial specific and directed by a sponsor to the appropriate review division.”
Conclusion
The FDA’s response indicates that the Placebell methodology aligns with current guidance on covariate adjustment in clinical trials. Placebell can be utilized like any other covariate in statistical models. Its application is already addressed by existing FDA guidance, ensuring unbiased estimates of treatment effects.
This feedback supports the methodology’s validity and highlights its potential to enhance study power, driven by Placebell prognostic performance in the target population
