Biologics Price Competition Research Articles

Biosimilars Striving for US Uptake

Though biosimilars have to go through an abbreviated regulatory pathway for approval, it is quite challenging given the scientific and technical complexities associated with these products. As an increasing number of biologics face patent expiration, biosimilars offer an attractive opportunity. While companies would be desiring to have a footing in the developed markets like US and EU, considerable opportunities exist in developing/emerging markets. With more number of biosimilars making their commercial foray, starting to gain acceptance across formularies, the leading biologic players have started taking a hit on price, volume and market share of their blockbuster drugs. The pace of sales erosion due to biosimilars is expected to be gradual yet relentless. Since the enactment of Biologics Price Competition and Innovation (BPCI) Act, 12 biosimilars have been approved by the US Food and Drug Administration (FDA) till September 2018. However, only a small percentage have seen the light of the day in terms of commercial launches. These are primarily driven by legal challenges and hesitancy from insurers and healthcare providers. While originators have been trying all the means at their disposal to thwart competition by posing challenges, the biosimilar players are striving to take them head on with the anticipated revenues in mind. Stakeholders have made key recommendations to increase the uptake of biosimilars in US market. Regulatory agencies have to play a key role in promoting confidence in biosimilars among healthcare practitioners and patients. The FDAs much awaited Biosimilars Action Plan (BAP) is expected to revive the sedentary biosimilar market in the US. The medical community, payers, and the FDA should work together for ensuring the approved biosimilars are adopted and prescribed in a manner to bring down overall healthcare costs.

FDA's Approval of the First Biosimilar to Bevacizumab.

Passage of the Biologics Price Competition and Innovation Act of 2009 created an abbreviated licensure pathway for biosimilar products. The FDA approved ABP215 (MVASI, bevacizumab-awwb; Amgen) as a biosimilar to U.S.-licensed Avastin (bevacizumab; Genentech) based on an extensive comparative analytic characterization, data obtained in a pharmacokinetic similarity study in healthy subjects, and a comparative clinical study in patients with non-small cell lung cancer. The totality of the evidence for biosimilarity supported extrapolation of the data to support licensure as a biosimilar for other approved indications of U.S.-licensed Avastin, without the need of additional clinical studies. Clin Cancer Res; 24(18); 4365-70. ©2018 AACR.

Pricing of Monoclonal Antibodies in the United States

Pricing of Monoclonal Antibodies in the United States

Biosimilars and federal preemption in the USA

Summary This article reports on the recent decision by the Court of Appeals for the Federal Circuit (“Federal Circuit”) in Amgen v. Sandoz on remand from the U.S. Supreme Court. The Supreme Court held that a biosimilar applicant cannot be compelled under federal law to provide a copy of its abbreviated biologics license application (“aBLA”) and manufacturing information to the reference product sponsor (“RPS”) as required by the Biologics Price Competition and Innovation Act (“BPCIA”). The Supreme Court remanded the case to the Federal Circuit to determine whether there was any remedy under California state law available to Amgen, and if so, whether such remedy is preempted by the BPCIA. The Federal Circuit held that the BPCIA preempts state law remedies for a biosimilar applicant’s failure to comply with the BPCIA. This article also briefly discusses three other recent cases involving situations where the biosimilar applicant initiates the BPCIA information exchange process but provides only partial or no manufacturing information to the RPS or fails to complete the process by opting out at some later stage of the process.

PHP38 - Biosimilar Regulatory Policies Issues and Implications: Where are we Headed?

Eight biosimilars are currently approved in the United States, accounting for $446 billion alone and is anticipated to grow exponentially by 2020. The goal of this review was to assess the regulatory policy issues and legislative interplay regarding biosimilars in the United States, providing potential insights into possible implications and remedies. A targeted literature review was conducted in PubMed and Google Scholar to identify studies that provided a scientific backbone for the regulatory and legislative issues. An additional targeted search of Westlaw databases was conducted to identify case studies for legislative issues concerning biosimilars. Searches were supplemented with manual citation review of the selected studies and for landmark cases. Regulatory issues impact processes regarding development, approval, manufacturing, and marketing of biosimilars. The regulatory issues identified in this review impact all aspects of the US biosimilar market. Key regulatory policy issues concerning biosimilars included interchangeability with the innovator biologic, extrapolation to another therapeutic area, and reimbursement. We identified 27 cases that directly (16 cases related to biosimilar or pharmaceutical patents) or indirectly (11 cases) affect regulatory process for biosimilars. Biosimilars with structural variability had regulatory and legislative advantages over their innovator biologic, unlike generic drugs. In the patent infringement cases, the court rulings generally upheld the Biologics Price Competition & Innovation Act, favoring biosimilar approval and marketing. Biosimilars hold promise for patients, reducing both patient and national burden of diseases and promoting further research for better healthcare. This review takes a novel approach in the light of the biosimilar patent infringement cases and the corresponding court rulings to better understand the regulatory framework for biosimilar marketing. There is a need for rigorous policy framework from Congress and Food and Drug Administration that promote biosimilar safety, improve patient access, and reduce the cost of biosimilars.

Ensuring Expeditious Entry: Korea and the U.S. Regulatory Pathway for Bringing Biosimilars to Market

Biosimilar products are expected to encounter substantial barriers in their efforts to compete with branded biologics. Current biosimilar regulatory regimes in both Korea and the U.S. raise questions about the viability of successfully bringing competition, innovation, and affordability into the biological products market as intended. Thus, bringing a biologic to market presents significant challenges that necessitate complex situations and subsequent legal regimes. This article will discuss the bilateral implications of each respective biosimilar regulatory pathway and the procedures each regime uses to resolve patent disputes. In particular, key amendments in pharmaceutical intellectual property provisions pursuant to the Korea-U.S. Free Trade Agreement suggest that select bilateral regulatory principles can enhance biosimilar market involvement. As a corollary, Korea's first invalidation action and several related cases in the U.S. in which courts interpreted some of the important provisions of the Korean Pharmaceutical Affairs Act and the Biologics Price Competition and Innovation Act of 2009 are analyzed using a comparative approach. Finally, future developments and exogenous factors that may impact the expeditious entry of the future first biosimilars into the two countries are applied to these legal regimes.

Basaglar: A Hypersensitivity Reaction.

The human insulin molecule is composed of a specific sequence of amino acids built in such a way that any change or modification will affect its primary, secondary, or tertiary structure, which in turn can affect the safety and efficacy of the therapeutic protein. As patents on currently available basal insulins begin to expire, biosimilar products will emerge and quickly replace many of these products owing to their favorable pricing profiles. However, biosimilar products are not 100% identical to their reference products because of their complex manufacturing processes from living cells or organisms (1). For that reason, the regulatory requirements for biosmiliars are more complex than for generic molecules. The Biologics Price Competition and Innovation Act of 2009, passed as part of the Patient Protection and Affordable Care Act, allows biosimilar products to be approved by the U.S. Food and Drug Administration (FDA) via an abbreviated pathway (2). Biosimilars must demonstrate no clinically meaningful differences from their reference products in safety, purity, and potency, but they do not have to complete a therapeutic equivalence study. Yet, a major concern with biosimilars is the risk of immunogenicity resulting from variations in manufacturing, and thus clinical studies must be conducted before FDA approval to evaluate potential differences in the incidence and severity of immune responses (3). However, such FDA approval studies may not be sufficient, and post-marketing monitoring of biosimilars is essential for patient safety. Hypersensitivity reactions to insulin analogs are rare, with only one published case report of a reaction caused by a biosimilar product in China (4). In 2016, Basaglar was the first “follow-on” insulin glargine approved for use in the United States, with an amino acid sequence identical to that of insulin glargine (Lantus) (5). In Europe, this agent is referred to as a “biosimilar,” but because of …

Overview of Biosimilars

Biosimilar is a biologic product that is similar to the original innovator product that has been manufactured by a different company.Though, biosimilar and biologics are analogous to each other, biosimilar is the generic version of biologics. Unlike generics where the active ingredients are identical to the reference drug, biosimilar is not identical, rather similar to the reference biologics. Due to post-transcriptional changes, the manufacture of biosimilar is difficult. These complexities that occur in the manufacture of biosimilar make it hard to claim patent. The Patient Protection and Affordable Care Act vindicate the future for granting biosimilars in the U.S through its subtitle, the Biologics Price Competition Innovation Act (BPCIA). 351 (a) application is used for getting approval of new biosimilar while 351 (k) is the biologic license application. For Europe, approval of biosimilars occurs through EMA via centralised procedure. The pilot study can be conducted by the sponsor for scientific advice needed in the filing of biosimilar. The GCC (Gulf Cooperation Council) is an economic and political confederation of six Middle Eastern countries- Kuwait, Oman, Saudi Arabia, UAE (United Arab Emirates), Qatar, Bahrain.Therefore, technically, patent infringement is no big concern as there are no patents for these products in India.

A Systematic Review of U.S. Biosimilar Approvals: What Evidence Does the FDA Require and How Are Manufacturers Responding?

Biosimilars undergo an abbreviated licensure pathway called 351(k), which was created by the Biologics Price Competition and Innovation Act of 2009. This approval process is different from the 351(a) pathway for original biologic approval and, as of August 2017, has been used to approve 5 biosimilars in the United States. To identify the types and quantities of evidence required by the FDA for biosimilar approval and the corresponding evidence manufacturers have provided in their 351(k) biosimilar approval applications. To collect data for this review, we searched through drug-specific FDA approval documents and approval-related FDA webcasts for approval indications and dates; reference product names; formulations; postmarketing requirements and commitments; evidence used for extrapolation claims; advisory committee votes; and evidence on similarity in analytical and functional characteristics, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. All biosimilars approved in the United States provided a large evidence base to demonstrate similarity in analytical and functional characteristics-3 to 5 clinical studies showed similarity in pharmacokinetics and pharmacodynamics, and 1 to 2 clinical studies demonstrated efficacy. Safety and immunogenicity were evaluated across all clinical studies. All biosimilars were compared with either the U.S.-licensed reference product or the reference product licensed by the European Union. Extrapolation allowed biosimilars to be approved for indications in which clinical studies were not conducted. The few indications for which biosimilars did not share approval with the reference product were due to market exclusivity protection. None of the 5 biosimilars have been approved as interchangeable in the United States. The approval process for the first 5 biosimilars on the market in the United States provides a baseline understanding of what type and degree of evidence is required for biosimilar approval. There was no external funding for this study. Hung reports employment as a pharmacist for CVS Health, an AHRQ F32 grant, and meeting/accommodation/travel support from AACP, DIA, and ISPOR, all outside the submitted work. Vu and Mostovoy have nothing to disclose. Study concept and design were contributed by Hung and Mostovoy, along with Vu. Hung and Vu collected the data, and data interpretation was performed primarily by Hung, along with Mostovoy. The manuscript was written by Hung and Vu and revised by all the authors. Some of the study results were previously presented as a poster at the ISPOR 22nd Annual International Meeting; May 20-24, 2017; in Boston, Massachusetts.

Integrating Biosimilars Into Oncology Practice: Implications for the Advanced Practitioner

Biosimilar agents are biologic products that have been shown to be "highly similar" to an already approved reference biologic product. Their integration into clinical practice has the potential to significantly decrease costs for patients, health-care systems, and insurance companies. Through legislation, the US Food and Drug Administration (FDA) approved the Biologics Price Competition and Innovation (BCPI) Act in 2009. In 2010, it was signed into law, allowing for an abbreviated pathway for biosimilar approval. This law implemented a framework for development and regulation of biosimilars for manufacturers and provided guidance for the key submission components necessary to achieve final FDA approval. Many factors will influence how biosimilars are integrated into health-care systems and oncology clinics. As biosimilar utilization in the United States expands beyond supportive care, unique challenges will emerge. Patient and staff education will be at the forefront of the successful application of biosimilar agents in oncology, and advanced practitioners will be in a unique position to lead change. The goal of this article is to describe the chemical and clinical nature of biosimilars, review focus areas of interest for biosimilar development in oncology, discuss implementation strategies for biosimilars, and provide techniques for patient education on biosimilars.

Perspectives on the Current State of the Biosimilar Regulatory Pathway in the United States.

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated licensure pathway in the United States that allows for the development and approval of biologic products shown to be biosimilar to or interchangeable with a US Food and Drug Administration (FDA)-licensed reference product (Table 1). Here we discuss implementation of the US biosimilar approval pathway and the role of various types of data, including clinical pharmacology data, in biosimilar development.

Aace/ace Position Statement on the use of follow-on Biologics and Biosimilars for Endocrine Diseases

BPCIA = Biologics Price Competition and Innovation Act; FDA = Food and Drug Administration; FFDC = Federal Food Drug and Cosmetics Act; PHS = Public Health Services Act; TE = therapeutic equivalence.

FDA's Approach to Regulating Biosimilars.

The Biologics Price Competition and Innovation (BPCI) Act, enacted as part of the Affordable Care Act, created a new licensure pathway for biological products demonstrated to be biosimilar with or interchangeable with an FDA-licensed biological product (the "reference product"). The FDA's approach to the regulation of biosimilars is based on the requirements set forth in the BPCI Act. A biosimilar product is highly similar to the reference product, notwithstanding minor differences in clinically inactive components, and there are no clinically meaningful differences between products in terms of safety, purity, and potency. The foundation of a biosimilar development program is an analytic similarity assessment that directly compares the structural/physiochemical and functional properties of the proposed biosimilar with the reference product. Data from clinical studies, which include an assessment of immunogenicity and pharmacokinetics/pharmacodynamics, are used to assess for clinically meaningful differences and not to independently establish the safety and effectiveness of the biosimilar. Like all products that the FDA regulates, the FDA requires that biosimilar products meet the agency's rigorous standards of safety and efficacy for approval. That means patients and health care professionals are able to rely upon the safety and effectiveness of biosimilar products in the same manner as for the reference product. Clin Cancer Res; 23(8); 1882-5. ©2016 AACR.

Brief of 11 Professors as Amici Curiae in Support of Amgen in Amgen v. Sandoz

The Federal Circuit ruled in Amgen v. Sandoz that the premarket information exchange process in the Biologics Price Competition and Innovation Act (sometimes known as the “patent dance”) — which begins when a biosimilar applicant complies with section 351(l)(2)(A) of the Public Health Service Act (the applicant “shall provide” a copy of its marketing application) — is optional for biosimilar applicants. This amicus brief explains why the discovery and development of new biological medicines is expensive, time-consuming, and risky. It notes that the United States has led the world for decades in the development of important new biologics for serious and life–threatening diseases, and it explains that this innovation is made possible by robust patent protection. The brief then describes the importance of permitting patent enforcement prior to market launch of infringing medicines. It also explains that the Federal Circuit misunderstood the purpose of the artificial act of infringement where biosimilar applicants fail to comply, because the court failed to take account of the difference (particularly in FDA’s role) between this statute and the Hatch-Waxman generic drug statute. Finally, the brief describes the process culminating in enactment of the BPCIA, noting the many arguments and proposals to make the premarket information exchange and patent litigation processes optional. As Sandoz noted publicly right after enactment, Congress chose instead to make participation mandatory.

An FDA perspective on the assessment of proposed biosimilar therapeutic proteins in rheumatology.

Biologic products have revolutionized the management of many rheumatic diseases, but access to these products might be limited by their relatively high costs. The US Biologics Price Competition and Innovation Act of 2009, which is contained within the Patient Protection and Affordable Care Act, established an abbreviated pathway for licensure by the FDA of biologic products that are demonstrated to be biosimilar to or interchangeable with FDA-licensed biologic products, termed reference products. This law allows for the approval of biosimilar biologic products, which are expected to increase access to treatment for patients, and ensuring the implementation of this Act is a high priority for the FDA. In this Perspectives article we describe the considerations for approval of proposed biosimilar products, including those to treat rheumatological conditions, by describing the FDA's rigorous approach to assessment of biosimilarity.

Midyear Commentary on Trends in Drug Delivery and Clinical Translational Medicine: Growth in Biosimilar (Complex Injectable Drug Formulation) Products Within Evolving Collaborative Regulatory Interagency (FDA, FTC, and DOJ) Practices and Enforcement

Before the 2009 Biologics Price Competition and Innovation Act that enabled the U.S. Federal Drug Administration (FDA) to create the 351(k) Biologic License Application–an abbreviated biosimilar approval process, FDA approved follow-on biomolecule products such as beta-interferon, glucagon, hyaluronidase, and somatropin (human growth hormone) under varying and evolving rules. With the 351(k) Biologic License Application biosimilar approval process in place, currently, there are 4 (licensed in 2015-2016) biosimilars available, namely Neupogen (filgrastim; $1 B/y), Humira (adalumumab; $14.2 B/y), Enbrel (etanercept; $8.7 B/y), and Remicade (infliximab; $6.5 B/y). With well-established product market capitalization of these and other top income producers—such as Rituxan (rituximab; $6.8 B/y), Herceptin (trastuzumab; $6.5 B/y), and Avastin (bevacizumab; $5.8 B/y), and a price differential of 15%-30% compared to branded products, there is an intense interest in development of biosimilars by established pharmaceutical companies. Currently, there are 160 biosimilar candidates in clinical studies, many of which are sponsored by large pharmaceutical companies known for product innovation. This trend will likely continue. Additional information on a biomolecule platform is presented in the Journal of Pharmaceutical Sciences Drug Delivery Clinical Trials Database (jpharmscidatabase.org). There are 44,789, 18,456, and 12,897 clinical trials registered to evaluate (1) drug delivery technology, (2) biomolecule platform, and (3) drug metabolism and pharmacokinetic-pharmacodynamic interactions; representing 19%-60% increase over the last 3 years.

Statistical Considerations in Evaluating a Biosimilar Product in an Oncology Clinical Study

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) established an abbreviated approval pathway for biosimilar and interchangeable biological products that was intended to balance innovation and consumer interests. The FDA has published several guidance documents to facilitate implementation of the BPCI Act. Here we discuss the role of comparative clinical studies in the assessment of clinically meaningful differences and illustrate the underlying scientific concepts with a hypothetical example of a clinical study comparing a product to US-licensed bevacizumab. Clin Cancer Res; 22(21); 5167-70. ©2016 AACR.

Biosimilars: The US Regulatory Framework

With the passage of the Biologics Price Competition and Innovation Act of 2009, the US Food and Drug Administration established an abbreviated pathway for developing and licensing biosimilar and interchangeable biological products. The regulatory framework and the technical requirements of the US biosimilars program involve a stepwise approach that relies heavily on analytical methods to demonstrate through a "totality of the evidence" that a proposed product is biosimilar to its reference product. By integrating analytical, pharmacological, and clinical data, each of which has limitations, a high level of confidence can be reached regarding clinical performance. Although questions and concerns about the biosimilars pathway remain and may slow uptake, a robust scientific program has been put in place. With three biosimilars already licensed and numerous development programs under way, clinicians can expect to see many new biosimilars come onto the US market in the coming decade. [Note added in proof: Since the writing of this article, a fourth biosimilar has been approved.].

“Shall” We Dance? Interpreting the BPCIA’s Patent Provisions

This Note examines the Federal Circuit's decision in Amgen Inc. v. Sandoz Inc. where the court ruled that the described in the Biologics Price Competition and Innovation Act (BPCIA) for biosimilar drug approval was not mandatory. After reviewing the BPCIA's language, structure, and legislative history, this Note concludes that Congress intended the patent dance to be mandatory to maintain an efficient and effective patent dispute resolution process for biosimilar and original biologic drug makers.

Are biosimilars patentable?

ABSTRACTIntroduction: This paper explores whether, and under what circumstances, a biosimilar approved in the United States under the Biologics Price Competition and Innovation Act (hereafter ‘BPCIA’) can be patented. The possibility that a biosimilar product could have meaningful patent protection arises from specific requirements for biosimilarity under the BPCIA, which account for the fact that manufacturing processes of biologics are inherently imprecise. The requirements for biosimilar approval may provide sufficient leeway to a biosimilar applicant to patent structural or formulation differences that provide non-clinical but business-relevant advantages over the reference molecule, such as improved shelf-life or ease of manufacture, without compromising clinical biosimilarity.Areas covered: Examination of the BPCIA and related Acts, Food and Drug Administration (FDA) guidance papers, case law, patent database searching, and relevant scholarly articles.Expert opinion: Legislative and regulatory requirements for the approval of a biosimilar under the BPCIA are focused on clinical results and allow a degree of leeway for differences to exist between a biosimilar’s structure and non-clinical components and those of the biosimilar’s reference molecule. This leeway can be exploited to provide the biosimilar with potentially patentable business-relevant advantages over its reference product while maintaining clinical biosimilarity to the reference product.