Using real‐world data to evaluate biosimilar switching

We read with interest the review by Desai et al on “Methodologic considerations for non-interventional studies of switching from reference biologic to biosimilars. ” Following the Biologics Price Competition and Innovation Act that created an abbreviated approval pathway in the United States for biosimilar and interchangeable biological products in 2010, biosimilars have been approved to treat a variety of conditions, including neutropenia, rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, psoriatic arthritis, anemia, and various malignancies. Product-specific information, including a summary of the US Food and Drug Administration's (FDA) review of the data used to support approval, can be found at the Drugs@FDA website. As the number of biosimilars approved in the United States continues to grow, an increasing number of patients and their physicians will be making the decision to use a reference biologic or a biosimilar. A biosimilar is defined as a biological product that is “highly similar to the reference product,” with “no clinically meaningful differences . in terms of safety, purity and potency. ” An interchangeable biosimilar must provide additional evidence to show that “the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch. ” Prospective, controlled switching studies offer the most straightforward data on the clinical impacts of switching, as randomization helps minimize potential confounding. Also, prospective switching studies can be designed to evaluate alternation (eg, multiple switches between a reference product and a proposed biosimilar), which may not be readily available in observational data. However, postmarketing data on a licensed biosimilar product may be helpful as a factor when considering the data necessary to support a demonstration of interchangeability, and appropriately designed observational studies may help address uncertainty around an interchangeability determination. The paper by Desai et al provides a guide for applying good research practices to observational studies that evaluate safety and effectiveness following switching between reference biologic and biosimilar medications. Many of these recommendations are in line with the FDA guidance on “Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data. ” For biologics and biosimilars, there are unique challenges when designing observational switching studies. Here, we comment on several aspects of the proposed recommendations by Desai et al, including exposure identification, minimizing bias due to confounding, accounting for complex patient utilization patterns, and considerations for source data when assessing biologics and biosimilars. Switching studies can take different forms, including (a) studies in which switching itself is an outcome of interest, which may also identify factors associated with switching and (b) studies comparing safety or effectiveness outcomes, for example, between patients who continue a reference product and patients who switch from a reference product to a different product. Factors associated with switching to a biosimilar identified in the first type of study may represent potential confounders and can inform comparative studies. For both types of studies, it is critical that investigators understand prescribing, dispensing, and billing patterns of the reference biologic and biosimilar prior to operationalizing exposure definitions. For instance, Desai et al discuss the use of billing procedure (administration) or dispensing codes to identify exposure. However, definitions will be dependent on the specific product(s) under study and how they are intended for use, and in some cases, it may be necessary to include both types of codes. In addition, while National Drug Codes include information on the dispensed product's strength, it may be challenging to get dosage information when using procedure codes. Therefore, extensive biosimilar utilization studies should be conducted prior to comparative safety or effectiveness assessments to understand billing and administration or refill patterns and aid decisions on building exposure episodes. This is critical for products with nonoral formulations and those dosed based on patient response. We agree with Desai et al on the need for careful selection of appropriate confounders. When considering confounders for Received: 6 August 2019 Accepted: 26 August 2019