Real-World Evidence Complements Randomized Clinical Trials to Enhance Drug Safety and Effectiveness
Randomized clinical trials (RCTs) serve as the regulatory gold-standard for demonstrating the safety and efficacy of treatments. Despite the many strengths of the RCT, including the ability to randomly assign treatments, the design also has important limitations. For example, RCTs are resource intensive, so they can require many years to complete before a therapy is approved or labeling is revised.
The U.S. Food and Drug Administration 21st Century Cures Act recognizes the potential for RWE to support the approval of new indications for approved medications and to potentially accelerate the availability of scientific information to support regulatory decisions. Real-world evidence (RWE) offers insights into current medical practice in large populations unrestrained by RCT study protocols, with the ability to reliably observe important rare outcomes in sensitive segments of the population. Real-world studies conducted after regulatory approval using automated data routinely collected by administrative insurance claims and electronic medical records can provide new insights into drug safety and effectiveness.
Traditionally, real-world studies have most commonly been conducted to understand drug safety, and HealthCore has conducted many real-world safety studies that have been successfully submitted by our clients to regulatory authorities such as the FDA. Recently, researchers from the Safety and Epidemiology team at HealthCore conducted one of the first real-world studies investigating the safety of palbociclib, the most widely prescribed CDK4/6 inhibitor in the treatment of HR+/HER2- advanced stage breast cancer.
When used in combination with breast cancer medications (letrozole or fulvestrant), randomized clinical trials have demonstrated that palbociclib prolonged progression-free survival for women with HR+/HER2- advanced breast cancer. In the same studies, palbociclib had higher rates of adverse events than the prior standard of care, including elevations of alanine amino aminotransferase, a marker of acute liver injury (ALI) which can be difficult to detect in RCTs. In addition to supporting many of the findings from RCTs, our recently published real-world study found palbociclib users had an increased risk of ALI.
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.