The world-wide market share of biologic drugs is advancing at a staggering pace, with some estimates ranging from $ 300 billion to $452 billion in revenue within the next five years.,, The treatment costs for patients administered biologic drugs are very high relative to historic drug prices. The one year average treatment costs for patients ranges from $20,000 – $30,000, but can be as much as $100,000 per year.
The high cost of biologic drugs has motivated governments and regulatory agencies to facilitate entry of biosimilars – generic versions of biologic drugs – into the respective markets in order to increase competition and reduce costs. However, as reported here in our post tracking ongoing biosimilar approvals in the U.S. and Europe, as of October 12, 2020, the U.S. had approved only 28 biosimilar drugs compared to 70 approved biosimilars in Europe. While European biosimilar approvals outpace those in the U.S., biologic drug prices remain high throughout the world.
To understand the key challenges limiting biosimilar entry, a recent study published in Nature Biotechnology provides a qualitative study of biosimilar manufacturer and regulator perceptions on intellectual property and abbreviated approval pathways through a series of interviews with various stake-holders and regulatory officials in the U.S. and Europe. Participants in the study identified regulatory hurdles and patent thickets as the two most significant factors impacting biosimilar development and market entry.
Although the branded biologic product provides biosimilar manufacturers with a starting point for development of a biosimilar version, biosimilar development remains a substantial challenge for drug manufacturers. For example, in the U.S., biosimilar product sponsors must show that, to the extent the scope of the mechanism of action of the reference product are known, the biosimilar candidate drug utilizes the same mechanism of action for the approved conditions using the same route of administration, dosage form, and strength of the reference product. The regulatory requirements must be met amidst the backdrop of greater complexity in the manufacturing process. In particular, different cell lines and variations in cell feed/growth conditions can result in a final product that varies both in structure and purity from the reference product. Moreover, numerous downstream purification and stabilization requirements enhance the complexity of the process needed to produce an approved product. As a result, a significant number of developmental and regulatory steps are needed for marketing approval of biosimilar versions of biologic drugs.
Biosimilar manufacturers report being encumbered by uncertainty about what studies are required to show biosimilarity and how regulators expect those studies to be conducted to satisfy the various regulatory agencies. Yet, such ambiguity may be intentionally baked into the regulatory process. On the other hand, interviews with regulatory officials explain that ambiguity in the guidelines prevents manufacturers from repeating old methods that may be outdated and instead allow room for innovative new methods to meet approval guidelines.
Biosimilar manufacturers often concurrently seek approval in both the U.S. and Europe and must navigate differing regulatory requirements and expectations. The U.S. and Europe, in some cases, require different analyses, including distinct statistical treatments, which can affect study outcomes. A recent study of U.S. biosimilar approvals found that most comparative efficacy trials conducted to obtain FDA approval for a biosimilar had a tendency to be larger, longer, and more costly than clinical trials required for originator products. Moreover, the FDA requires animal studies whereas the EMA does not require animal studies to approve a biologic product. As a result, biosimilar manufacturers are forced to meet different study requirements and stringency between regulatory agencies and often heightened standards compared to standards required for originator manufacturers. Thus, even though biosimilar manufacturers avoid a significant portion of the basic research costs, challenges still reside in developing and refining chemistry, manufacturing, and control (CMC) processes, as well as in conducting studies to establish that the biosimilar drug has sufficiently similar efficacy, animal and clinical pharmacology, and stability profile as the reference product.
The other key challenge cited by biosimilar manufacturers is navigating the large patent portfolios that are often built around biologic drugs. So-called “patent thickets” arise when drug manufacturers take advantage of numerous aspects, including, to name just a few, aspects of processes for manufacturing, different treatment indications, delivery methods, delivery devices, excipients, and aspects relating to side effects, impurities, and pharmacology to create a web of patents that deter biosimilar manufacturers from developing competing versions. Famously, AbbVie protected its adalimumab biologic (Humira®) with over 100 patents directed to the biologic itself along with numerous parts of the manufacturing process, formulation, and uses, and has enjoyed a monopoly in marketing adalimumab in the United States since 2002.,
A recent study comparing the three best-selling biologic drugs in 2018, i.e., Humira®, Enbrel®, and Rituxan®, versus the three best-selling small molecule drugs in 2018, i.e., Revlimid®, Eliquis®, and Lyrica®, found that the biologics were each covered by an average of 93 patents, while, in contrast, the small molecule drugs were each covered by an average of 41 patents. In fact, the study found that in comparing core patents, i.e., patents that are most likely to block entry of a generic drug maker, for example, an FDA approved use of the drug, the biologic drugs were each covered by an average of 47 core patents whereas the small molecule drugs were each covered by an average of only 13 core patents.
Creating patent thickets surrounding biologic drugs is viewed as a deliberate attempt to block generic/biosimilar competition for as long as possible. As an example, the price of Humira® in the U.S. doubled from about $19,000 in 2014 to about $38,000 in 2018 after applying available drug rebates. Moreover, AbbVie successfully thwarted biosimilar entry for years and eventually settled litigations with numerous biosimilar manufacturers to delay biosimilar competition until 2023. As a result, AbbVie became the first company to face a “patent thicket” antitrust lawsuit over its patenting practices and assertions of its patents. While the complaint alleged that AbbVie improperly extended its exclusivity out to 2023, which is the earliest expected entry date of generic versions of Humira® to enter the U.S. market, the district court judge sided with AbbVie and held that “even when considered broadly and together for their potential to restrain trade – [the Plaintiffs’ allegations] fall short of alleging the kind of competitive harm remedied by antitrust law.”
Biosimilar manufacturers note that some of the cost and uncertainty involved in navigating patent thickets could be addressed by requiring reference product sponsors to list all patents protecting their biologic products in the FDA’s purple book, an analog of the Orange Book, which would also make it easier to identify the patents that would need to be overcome or avoided in order to launch a biosimilar product. By providing a searchable patent list, biosimilar manufacturers would be better situated to develop manufacturing and control (CMC) processes that can avoid process claims that protect manufacturing of the reference product. Such lists would also clarify exclusivity timelines, making it easier and cheaper for biosimilar manufacturers to decide when and how to enter the regulatory process.
A bill introduced in the U.S. House of Representatives and Senate aims to require licensed biologic drug manufacturers to disclose all patents believed to be covering the drug. Both versions of the bill would require the list to provide (1) the official and proprietary name of the biological product; (2) the patents the license holder holds that would be infringed by making, using, offering to sell, selling, or importing into the United States of the biological product; (3) whether various market exclusivity periods apply to the product; and (4) information about whether the product is interchangeable with another biologic product. Each bill would also require the Department of Health and Human Services (HHS) to make the information available to the public. Notably, the current versions stipulate that if a patent that should have been listed was not timely disclosed to HHS, the patent holder would be estopped from asserting that patent in litigation.
Increasing market participation by biosimilar manufacturers is a critical component of the overall price reduction strategy for biologic drugs. Comments from regulatory officials and stakeholders suggest that steps to achieve greater clarity and guidance for the biosimilar marketing approval process and requiring lists of patents protecting biologic products will help to achieve this goal. Regulatory officials need to take steps to streamline and expedite the approval process and provide much needed guidance to biosimilar manufacturers without diminishing the flexibility needed to adequately assess each biosimilar seeking approval. Likewise, policy makers can enhance efficiency and transparency by mandating patent lists as in the proposed Biologic Patent Transparency Act to facilitate entry of biosimilar versions of approved biologic drugs. These foundational improvements will make the biosimilar approval and commercialization pathway more efficient and predictable.
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