Quantifying Challenges to Development of Generics and Biosimilars in Non-Hodgkin's Lymphoma Therapeutics: The Future of Low-Cost Alternatives from Monoclonal Antibodies to CAR-T

Abstract

Background: There are numerous monotherapies and combination therapies available to treat Non-Hodgkin lymphoma's (NHL), however relatively few of these varied antineoplastics agents have commercially available, lower-cost generic forms in the United States. High cancer drug prices, in particular for socioeconomically vulnerable and underinsured patients, pose challenges to affordable cancer treatment in the United States. In 2017, FDA initiated the Drug Competition Action Plan (DCAP) that aimed to ensure timely market competition by enabling generic drug development, review, and approval, and streamlining regulatory complexities. This regulatory program was designed to limit so-called “gaming” recognized as a cause of delay to generic drug approvals, a phenomenon that has the further deleterious effect of extending brand monopolies beyond what Congress intended with Hatch-Waxman Amendments (1984) establishing modern generic drug regulatory processes. In 2018, FDA announced analogous Biosimilars Action Plan (BAP). However, to date the efficacy of these measures has not been comprehensively assessed in the NHL development landscape. Methods: A model was created by surveying the FDA Orange Book (drug approval database) and Purple Book (biologic product approval database) for initial approval of drugs/biologics with their initial generic/biosimilar approval. Approvals were classified by drug class and availability of generic/biosimilar for the innovator product with approval from 2002 to 2023 (Fig. 1) and t-test were used to determine significance. Results: Of small molecule drug NHL therapeutics approved in the last two decades, only 37% (19/52; Fig. 2) have available, lower-cost generics, with use in more than one indication and time on market both positively and significantly corresponding with availability of generics for the original innovator drug (P < 0.05). Notably, while generic drug approvals dropped during the 2020-2021 period (possibly due to impact of the COVID-19 pandemic), after 2017 implementation of DCAP more generics for common NHL antineoplastics were approved. Conversely, there are relatively few biologic drugs (total of 41 approvals; Fig. 2) with biosimilars, in part due to retained patents and exclusivity, and perhaps indicating a lack of efficacy in BAP among NHL antineoplastics therapies. For off-patent innovator monoclonal antibodies (mAbs), which make up the majority of these therapies, development of biosimilars is effectively blocked by secondary or “process-related” patents which effectively extend the period of non-competition for complex biologic therapies. It is expected that novel bispecific antibody (biAb) therapeutics and novel therapies, such as CD19 CAR-T will also have a delayed time to low-cost biosimilar availability following a similar trend. Conclusions: With drug price and ever-rising insurance and patient payments a critical area of public health, in particular in the United States, availability of lower cost generics and biosimilars is a critical issue for NHL patients. As we move into the maturation of gene therapies and CAR-T therapeutics, it merits consideration of that additional regulatory programs may be needed to incentivize the development of efficacious and lower cost biosimilars. However, it is critical that controlling competition be carefully balanced with investment in both biologic drug entity and process-related innovations among these relatively complex therapeutic entities.