This article delves into the intricacies of biosynthetic insulin products, leveraging data from the Food and Drug Administration’s (FDA) Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book. Through a meticulous analysis, we explore the landscape of biosynthetic insulin, considering individual products, patents, and regulatory exclusivities.
Our primary focus is on understanding the duration of expected protection for these products, measured by the time interval between FDA approval and the expiration of relevant patents or regulatory exclusivities.
We adopted a systematic approach, treating individual products, even within the same New Drug Application (NDA), as separate entities to ensure a nuanced analysis. The Orange Book served as our primary data source, providing information on approved biosynthetic insulin products, patents, and regulatory exclusivities. Google Patents was utilized to extract details on patent application timing and the specific aspects of products covered by these patents, with a keen emphasis on delivery devices.
Primary Outcome: Duration of Expected Protection:
The crux of our analysis lies in determining the duration of expected protection for biosynthetic insulin products. This was achieved by subtracting the FDA approval date from the last-to-expire patent or regulatory exclusivity, whichever occurred later. Our findings reveal a median duration of expected protection across all insulin products of 16.0 years. Notably, manufacturers of nine products managed to extend their protection by a median of 6 years through post-approval patent filings.
Secondary Analysis: Overall Protection on Insulin Lines:
In addition to individual product analysis, we conducted a secondary examination, considering insulin lines. Insulin lines encompass groups of products approved under the same NDA, featuring identical active ingredients and manufactured by the same company. The median protection on insulin lines was found to be 17.6 years, providing a comprehensive overview of the extended protection granted to these groupings.
Competition from Follow-On Insulin Products:
To gauge market competition, we explored the landscape of follow-on insulin products. These are defined as products sharing active ingredients with originators but manufactured by different companies under a specific drug approval pathway outlined in section 505(b)(2) of the Food, Drug, and Cosmetic Act. Our analysis uncovered the approval of five follow-ons across three insulin lines, shedding light on the dynamics of market entry and competition in the biosynthetic insulin arena.
Patent Landscape and Device Focus:
A critical aspect of our investigation was the examination of patents related to biosynthetic insulin products. Manufacturers, particularly those of drug-device combinations, exhibited a notable focus on obtaining patents, with 63% of all patents associated with these combinations relating to delivery devices. This underscores the strategic importance of securing intellectual property rights over the various components of insulin delivery systems.
Discussion: Unraveling the Dynamics of Brand-Name Insulin Market Exclusivity
The period spanning 1986 to 2019 witnessed a landscape dominated by brand-name insulin products, shielded by extended periods of market exclusivity and minimal competition from follow-on products. The robust protection on insulin was not solely reliant on initial FDA approval but was significantly bolstered by the strategic acquisition of patents post-approval. In nine instances, manufacturers successfully prolonged their expected market exclusivity by a median of 6 years through the addition of patents after FDA approval. This maneuver allowed brand-name insulin manufacturers to enjoy a median protection period of 16 years, surpassing the 14 years observed in analogous studies on top-selling small-molecule drugs.
Device Patents as a Pivotal Factor in Market Protections:
The study underscores a pivotal role played by device patents, particularly in drug-device combinations, in extending market protections for brand-name insulin products. Approximately two-thirds of these combinations featured last-to-expire patents focused on delivery devices. Notably, these last-to-expire device patents contributed to a median extension of 5.2 years to the overall protection duration. The shift toward relying on device patents aligns with observations in other drug-device combination markets, such as inhalers for respiratory conditions and GLP-1 receptor agonist injector pens for diabetes and obesity. While innovations in delivery devices may enhance patient experience and safety, they concurrently serve as a mechanism for brand-name manufacturers to maintain high prices by avoiding direct competition.
Limited Follow-On Competition and the Dominance of Big Manufacturers:
Even the limited follow-on competition in the insulin market has been orchestrated by the major brand-name manufacturers. Examples include the approval of Lilly’s Basaglar as a follow-on for Sanofi’s Lantus and Sanofi’s Admelog as a follow-on for Lilly’s Humalog. Recent approvals of interchangeable biologics for Lantus, namely Mylan’s Semglee and Lilly’s Rezvoglar, may potentially impact insulin market dynamics in the future. However, current uptake of follow-on and biosimilar insulin products remains modest. Medicare Part D data from 2021 indicates a higher preference for brand-name Lantus over follow-on Basaglar. The limited market penetration of biosimilar Semglee further suggests that brand-name firms maintain market share through negotiations with pharmacy benefit managers (PBMs), despite efforts to expedite biosimilar availability.
Challenges in Lowering Insulin Prices and the Role of Legislation:
While manufacturers of some brand-name insulins have announced list price reductions in 2024, the impact is constrained to a select few insulin products. Negotiations under the Inflation Reduction Act may potentially lower costs in Medicare, but these negotiated prices do not extend to commercial markets. The study highlights the ongoing need for robust generic and biosimilar competition, coupled with payer reforms to ensure patient access to more affordable insulin products.
Antitrust Scrutiny on Device Patents and Regulatory Challenges:
The role of device patents in delaying competition has become a focal point in recent antitrust litigation. Cases, such as the class-action lawsuit against Sanofi, underscore the impact of improperly listing device patents in the Orange Book. Our analysis identified 17 cases where the last-to-expire patent on a drug-device combination was a device patent with claims unrelated to insulin, extending protection by a median of more than 4 years. Regulatory uncertainty persists concerning the types of device patents that should be listed in the Orange Book, prompting the Federal Trade Commission to scrutinize such patent listings.
Regulatory Shifts and Obstacles in the Biologic Classification:
The regulatory status of insulin, initially treated as a small-molecule drug despite its biologic properties, contributed to limited competition. The move to regulate insulin as a biologic introduces new challenges, including reduced requirements for manufacturers to list key patents. The shift to the Purple Book complicates matters for biosimilar manufacturers challenging new insulin products, potentially hindering competition.
Addressing Regulatory Barriers and Ensuring Quality Patents:
Reforming the patent and regulatory system is crucial to fostering a healthier pipeline of cost-effective and interchangeable insulin products. Manufacturers’ strategies, including filing patents post-FDA approval and the prevalence of device patents, necessitate legislative and regulatory interventions. Collaboration between Congress, the FDA, and the USPTO is imperative to address issues such as comprehensive patent listings for biologics, quality standards for device patents, and international collaboration to improve the patenting process.
Conclusion: Toward a Balanced and Competitive Insulin Market:
In conclusion, the complex interplay of patents, regulatory shifts, and market dynamics has contributed to the prolonged dominance of brand-name insulin products. While recent legislative actions and manufacturer-initiated price reductions represent positive steps, a multifaceted approach involving regulatory reforms, increased competition, and payer reforms is essential. The future trajectory of the insulin market will hinge on concerted efforts to strike a balance between innovation, affordability, and patient access.
reference link : https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004309