While real-world studies have many strengths, they also carry important limitations. Without a placebo group, RWE investigators rely on epidemiologic and statistical methods to identify appropriate comparison groups. When palbociclib first became available, it quickly became the standard of care for most women with HR+/HER2- advanced stage breast cancer – which limited the availability and suitability of a contemporaneous comparator drug. Therefore, we selected new users of the standard of care prior to palbociclib approval (new users of fulvestrant monotherapy) as the comparator. Analyses showed the comparator group to be similar in measured characteristics (e.g. age, presence of metastases, other medication use) to new users of palbociclib-fulvestrant both before and particularly after they were propensity score-matched.
Real-world studies often use administrative data developed for billing, not research purposes. These records can lack clinical details needed to accurately identify safety outcomes, and if the outcomes identified by billing records are inaccurate, they could distort the drug-outcome relationship. To mitigate this limitation, we collaborated with expert hepatologists, who reviewed medical records to validate our ALI algorithm and support its validity.
While RWE studies can balance measured covariates between treatment groups using methods such as propensity score matching, these methods do not directly address potential differences between treatment groups in unmeasured variables. This concern can be addressed in RWE by conducting additional analyses, such as sensitivity analyses and quantitative bias analyses, which can provide information on the amount of confounding or differential outcome misclassification that would be required to explain the observed drug-safety outcome association. After completing numerous analyses, we concluded these sources of error were unlikely to impact our conclusions, and larger studies in diverse populations could further improve precision regarding the safety of palbociclib and other CDK4/6 inhibitors, particularly in their hepatic risks.
The epidemiologic methodology to support and improve real-world drug studies continues to grow and improve, as does the availability of robust clinical data. We are in an era in which the benefits and risks of medications can be continuously updated and improved upon so that medications can be used more effectively to improve public health.
The full study, “Real-world safety of palbociclib in breast cancer patients in the United States: a new user cohort study,” can be accessed here.