Biologics Price Competition Research Articles

Regulatory requirements for approval and Registration Procedure of Biosimilar in US and European Union (EU)

The market for biotechnology-derived medicinal products is evolving rapidly with the imminent entry of biosimilars. The development and approval of biosimilars represent a critical pathway to expanding access to biological therapies while maintaining high standards of safety, efficacy and immunogenicity profile because biosimilars are made in living organisms there may be some minor differences from the reference medicines.
 In the US, biosimilars are regulated under the Biologics Price Competition and Innovation Act (BPCIA), which is part of the Affordable Care Act. The regulatory pathway emphasizes a stepwise approach, involving analytical studies, preclinical assessments, and comparative clinical trials to establish biosimilarity with a reference product. The FDA assesses the totality of evidence provided by the biosimilar applicant to make a determination on safety, purity, and potency.
 In the EU, the approval process for biosimilars is governed by the European Medicines Agency (EMA). The regulatory framework relies on a robust comparability exercise, emphasizing extensive analytical studies and well-designed clinical trials to establish biosimilarity. The EMA assesses the comprehensive data package submitted by the biosimilar applicant, considering the totality of evidence before granting marketing authorization.
 While the overall approach is similar, there are nuanced differences in the regulatory processes. The US typically requires a more prescriptive approach to clinical trials, with the expectation of conducting at least one confirmatory comparative clinical trial. In contrast, the EU may allow for a more tailored approach to clinical development, recognizing that the need for extensive clinical trials may vary depending on the nature of the biosimilar and the reference product.
 As the biosimilar landscape continues to evolve, ongoing collaboration and harmonization efforts between regulatory authorities aim to streamline global access to high-quality ,cost-effective biologic therapies.

A Critical Analysis of the FDA's Omics-Driven Pharmacodynamic Biomarkers to Establish Biosimilarity.

Demonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.

The availability of gonadotropin therapy from FDA-approved pharmacies for men with hypogonadism and infertility.

Recent changes to the Biologics Price Competition and Innovation Act of 2009 have created barriers to accessing therapy for men utilizing gonadotropins for hypogonadism and infertility. In this study we sought to investigate ways to decrease disparities in the treatment of male hypogonadism by increasing access to gonadotropin therapy by identifying 503b outsourcing pharmacies which currently provide gonadotropin therapy. A review of 503b compounding pharmacies was performed using the online published registry available from the US Food and Drug Administration (FDA). Each pharmacy was contacted regarding their ability to provide gonadotropin therapy. Pharmacies were also queried regarding the impact of FDA-related legal changes and cost considerations. The study outcomes were the number and location of FDA-approved 503b compounding pharmacies supplying human chorionic gonadotrophin (hCG) and/or follicle-stimulating hormone (FSH) for the treatment of male hypogonadism and infertility. The 81 503b-compounding pharmacies approved by the FDA to produce hCG and FSH therapy were identified using the FDA registry. Seventy-five of the 81 pharmacies responded to the survey (response rate92.6%). Of the contacted pharmacies, 5 provided hCG (6.67%). Of the pharmacies offering compounded hCG, 4 offered FSH. No additional pharmacies offered compounded FSH. Eight pharmacies had previously provided hCG and FSH. Six of the 8 pharmacies that stopped making hCG and FSH cited the 2020 FDA mandate as the reason for halting compounding services. Of the 75 pharmacies that responded, only 1 pharmacy provided the cost for FSH ($287 per 100-IU vial), and 3 pharmacies provided the cost for hCG ($50-$83 per 10 000-IU vial). There are few FDA-approved outsourcing pharmacies currently providing male gonadotropin therapy, and increasing awareness of these pharmacies may decrease barriers to care for patients with male hypogonadism and infertility. The strengths of this article are the clinical utility of the data presented, as this article may serve as a tool for clinicians to increase patient access to therapy. All FDA-approved 503b outsourcing pharmacies were contacted, and 92.6% participated in this project. Limitations of this article were the following: no non-FDA-approved compounding pharmacies such as 503a pharmacies were contacted, participant-reported outcomes were utilized, and only 3 contacted outsourcing pharmacies provided a cost for FSH or hCG, allowing for an unknown degree of cost variability between outsourcing pharmacies. There currently exists limited access to FDA-approved compounded gonadotropin therapies for hypogonadism and male infertility, and these results demonstrate the barriers to hCG and FSH access and the need for additional treatment options for this vulnerable patient population.

An Evaluation of the Biologics Price Competition and Innovation Act and its Impact on Innovation in the Pharmaceutical Industry

An Evaluation of the Biologics Price Competition and Innovation Act and its Impact on Innovation in the Pharmaceutical Industry

Generics and Biosimilars: Barriers and Opportunities

Generics and Biosimilars: Barriers and Opportunities

Biosimilars: Novel Emerging Field of Biomedicine


 A biosimilar is the new emerging drug product of the sector of Biologics that comes under speedily evolving area of pharmaceutical industry. It is the generic substitute for original research-based drugs. Since the Biologics are produced by a variety of products more commonly including cells extracted from humans, animals, microorganisms which varies phenotypically therefore they are “similar but not same” to the original product. Being a new product, it produces several challenges in the market including its regulation guidelines, production efficiency, quality management, and safety factors etc. The quality of these products along with its effectiveness and reduced costs are making them more and more popular. Different research is still being going on for enhancing the efficacy of biosimilars due to its more and more usage in the market. Several countries have developed their separate norms for the production and clinical usage of these biosimilars constituting Canada, Japan, Korea, and United States of America etc. The more biologics grab the attention of the eminent scientists for better innovations, the less marketing approval it gets. To enhance such a situation U S Congress passed the Biologics Price Competition and Innovation act 2009 and US FDA allowed “abbreviated pathway” for their approval and India being the most suited manufacturing area has also prepared certain guidelines stated as “Draft Guidelines on Similar Biologics” which were announced in June 2012, by Department of Biotechnology at Boston bio. The regulatory environment for biosimilars continues to evolve, both in recognition of advances in technology/ analytical methods and the availability of new targets for biosimilar development. With the advent of such efforts biosimilars are trying to surround the market. The demanding sector of biosimilars reveals the challenging gateway towards the nanomedicines also which shows that with the advancing biotechnology after these biosimilars, we are heading towards other newly biologically derived products.

Nothing Permanent Except Change: Trade-Offs and the Substitution Paradox.

Inimitability and non-substitutability make a competitive advantage sustainable; however, they can also have trade-offs between them. The more inimitable a resource is, the more competitors will feel pressure to substitute around it. At the same time, we do not know if this trade-off is dynamic or static, nor do we know the contingencies as to when this trade-off occurs. We study this paradox using a natural experiment – the Biologics Price Competition and Innovation Act of 2009. We find that the substitution paradox is dynamic, and it is also subject to important boundary conditions. While firm characteristics help determine whether there is a trade-off, resource characteristics are unaffected by the exogenous shock. These results support our hypotheses while drawing important implications about the applicability of the VRIN framework.

Barriers To US Biosimilar Market Growth: Lessons From Biosimilar Patent Litigation.

High biologic drug prices have placed substantial strain on the US health care system. The Biologics Price Competition and Innovation Act (BPCIA), passed in 2010 as part of the Affordable Care Act, created an abbreviated approval pathway for biosimilars-versions of "originator" biologic drugs made by different manufacturers-to help address this issue. However, a decade after its passage, the BPCIA has spurred only limited competition. We examined the role that litigation has played in this muted success, reviewing all lawsuits related to the BPCIA filed between its enactment and August 1, 2020. Our review identified two key problems: noncompliance with steps in the complex litigation process established by the BPCIA and large numbers of patents enforced by originator manufacturers. Both actions have contributed to frequent confidential settlements between originator and biosimilar manufacturers that have delayed the availability of biosimilars. To facilitate more timely biosimilar entry, policy makers should consider limits on patent prosecution, compulsory public patent listing, and enhanced antitrust enforcement.

Pegfilgrastim Biosimilars: Where Are We Now?

In 1991, the U.S. Food & Drug Administration (FDA) approved rmetHuGCSF for human use. This recombinant methionyl human granulocyte colony-stimulating factor, or filgrastim, saw use in over 1 million patients in its first 5 years on the market. In 2002, the FDA approved a version of filgrastim with covalent linkage to a monomethoxypolyethylene glycol, increasing the molecular size and half-life to replace multiple days of dosing with a single injection. These medications remained standard of care for neutropenia until the Biologics Price Competition and Innovation Act of 2009 created an abbreviated pathway to licensure for biologic products. Practitioners now have their pick of numerous and expanding options for pegfilgrastim biosimilars.

Regulatory Prototype for Biological Products in the United States

Biological products are used for the treatment of many disease, so the biological application submitted for the approval of products are also increasing. The progress of a biosimilarproduct is more difficult and expensive than a small molecule generic product. Biosimilars are not true generic drugs, but demonstrate a high degree of similarity to the reference biological product. In order to improve access to costly biological treatments, a biosimilar pathway in the US was established under the Biologics Price Competition and Innovation Act of 2009. The study highlighted the “Regulatory prospective for the registration of Biological products in US” and a brief description about the development, Manufacturing and approval process of biosimilar products. This article is also focused on the regulatory framework, Biological License Application, Purple book, and Pharmacovigilance of biological products.

The Biologics Price Competition and Innovation Act 10--A Stocktaking

On March 23, 2010, President Obama signed into law the Biologics Price Competition and Innovation Act (BPCIA) as part of the Patient Protection and Affordable Care Act (“Obamacare”). The purpose of BPCIA was to create for biologics a regime similar to that of the Drug Price Competition and Patent Term Restoration Act (Hatch–Waxman Act) and, in so doing, to open biologics markets to competition and, subsequently, lower the price of these expensive and increasingly important pharmaceuticals. Using original data, this Essay takes stock of the decade that has passed since the enactment of BPCIA. This Essay surveys the state of competition in United States biologics markets, entry of follow-on biologics into these markets, and the effects such entry has had on biologics prices. This Essay’s main findings are that, as of March 23, 2020—exactly ten years since the signing of BPCIA into law—the FDA has approved a total of 26 follow-on biologics deemed biosimilar to 9 original products (ratio: 2.63 follow-on/original products), with only 16 of these deemed biosimilar to 7 original products (ratio: 1.78 follow- on/original products) actually available on the market. None of these follow-on products have been approved as interchangeable with their reference products, which means that substitution of the 7 original products with one of their 16 approved biosimilars cannot be done automatically. The price of these products was 10%–37% lower than the price of the original biologic, with the average price savings being 24% or 27%. All 35 approved follow-on and reference products are owned by a total of 11 pharmaceutical companies. The number of years of market exclusivity of the 9 original biologics before the approval of the first biosimilar ranged between 13.5–28.92 with an average of 18.27 years or 15.33–29.42 with an average of 19.87 years before the launch of the first competing biosimilar. This Essay further puts forward a new method of measuring comparative levels of competition in drug markets by comparing the ratio of total approved follow-on products per total approved original products at certain critical benchmarks. Using this measurement tool, this Essay compares BPCIA’s track record with the levels of competition in small-molecule drugs before and after the Hatch– Waxman Act, showing that that BPCIA significantly underperforms in comparison and fails to instigate levels of competition that would lead to significant price drops and increase access to biologics in the United States. A short survey of the most likely reasons for BPCIA’s underperformance follows. This Essay concludes by presenting the following question: if BPCIA’s current track record is (still) not enough to convince that it is failing to meet its goals, what more would it take to reach such a conclusion, and how much longer should policymakers wait before it is possible to surmise that BPCIA in its current form has failed to significantly increase access to biologics in the United States?

Genentech, Inc. v. Immunex Rhode Island Corp. United States Court of Appeals of the Federal Circuit, 2020 964 F.3d 1109

Genentech, Inc. v. Immunex Rhode Island Corp. United States Court of Appeals of the Federal Circuit, 2020 964 F.3d 1109

Immunex Corp. v. Sandoz Inc. United States Court of Appeals of the Federal Circuit, 2020 964 F.3d 1049

Immunex Corp. v. Sandoz Inc. United States Court of Appeals of the Federal Circuit, 2020 964 F.3d 1049

Update on Biosimilar Insulins: A US Perspective.

The development of biosimilar insulin products has slowly evolved with only two follow-on biologics currently available to patients in the US. Both Basaglar® (insulin glargine) and Admelog® (insulin lispro) have undergone extensive testing, and have gained significant use by patients in the US. Despite the availability of these follow-on products, the price of insulin has remained stubbornly high. New regulatory guidance under the Biologics Price Competition and Innovations Act that came into effect in March 2020 introduced an abbreviated pathway for the approval of biosimilar insulins and introduced the option to apply for interchangeability of the biosimilar insulin with the reference product. This abbreviated clinical testing may open the doors for numerous follow-on insulin products, with unknown supply-chain and fiscal ramifications. This review will highlight the development process of biosimilar insulin in the US and the recent regulatory changes that can aid this process. We will also discuss challenges for prescribers and patients who are navigating this ever-changing landscape. These new regulations for biosimilar insulins will have ramifications for patients, healthcare providers, and third-party payers, though the direction and scope of these changes is unclear.

Do Firms Purposefully Change Capital Structure? Evidence from an Investment-Opportunity Shock to Drug Firms

AbstractWe study the capital structure changes of drug firms after an investment-opportunity shock brought about by the Biologics Price Competition and Innovation Act. Using a difference-in-difference approach, we show that the shock led drug firms to make their capital structures less constraining by decreasing leverage, shortening debt maturity, increasing unsecured debt, and reducing convertible debt. New debt covenants became less restrictive and firms raised equity to preserve borrowing capacity. Our results support the view that firms actively manage their capital structures to bolster financial flexibility and increase debt capacity in response to new investment opportunities.

Biosimilars Regulation in the United States and FDA Approved Biosimilars from 2015-2018

Background: Biological products are the chemicals in the form of medicines that are prepared from the living cells through highly intricate manufacturing techniques that should be handled and managed under favorable conditions. The regulation of the biosimilar products consists of significant challenges, since they are part of the growing sector of the pharmaceutical industry and normally used by human beings. 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. The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed as part of the health reform (Affordable Care Act). Objective: The current manuscript will provide the information regarding the regulation of Biosimilars products with the detail of biosimilar USER fees structure and the list of approved biosimilar by FDA from 2015- 2018. Conclusion: Research is continually developing more biological products that will help treat medical conditions or add some innovation to the existing treatment options. Biosimilars and reference products are generated in the living cells and require trained expertise as well as technology for biologics being usually highly effective compared to small molecule drugs. These are usually specific against the respective target, which generally produces lesser side effects and low toxicity. FDA’s regulatory authority for the approval of biologics is under PHS (Public Health Service Act) which are also suggested to regulate under the Federal Food, Drug and Cosmetics Act (FD&C). Biosimilars can help expand access to high-quality treatment options for doctors and patients, as well as reduce costs for the healthcare system.

Recognizing and addressing challenges to the adoption of trastuzumab biosimilars and HER2-targeted therapies.

Oncology biologics are one of the fastest-growing segments of pharmaceutical development, bringing more options to patients, including those with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The advent of multiple oncology biosimilars is affecting this patient population, as 5 trastuzumab biosimilars had been FDA approved as of the end of 2019; only 2, however, have been commercially marketed. Trastuzumab serves as the foundation for treatment for patients with HER2-positive breast cancer. HER2-targeted antibody-drug conjugates have been developed to enhance efficacy, improve safety, and/or create more convenient administration. Three biologic drug entities have been approved using trastuzumab, including 2 antibody-drug conjugates and a subcutaneous trastuzumab formulation that includes hyaluronidase. More products are being developed, so biosimilars and other HER2-targeted therapies may further disrupt the biologic market. Many challenging questions surround the adoption of oncology biosimilars, including regulatory pathways, efficacy, safety, cost-benefit, and comparability. The Biologics Price Competition and Innovation Act established an abbreviated regulatory approval pathway for biosimilars to create a catalyst for innovation and competition in the biologics market and to lower the costs of biologics. Challenges to adoption of therapeutic oncology biosimilars continue in the United States and include a lack of directed education to providers and patients, residual concerns regarding efficacy and safety, and practices including "pay-for-delay." The uptake of oncology biosimilars is also affected by multiple issues stemming mainly from cost of care, including drug cost, patient access, formulary inclusion, and treatment management algorithms. Managed care organizations and payers need to be familiar with the biosimilar approval process, the concerns of stakeholders (eg, providers and patients), and factors influencing HER2-directed therapies, including the use of biosimilars and antibody-drug conjugates in today's market.

Current and future roles of biosimilars in oncology practice.

Biologics have been used increasingly in the treatment and supportive care of cancer; however, their high cost places a significant burden on healthcare systems. The expiration of patents for biologics has led to the development of biosimilars, with the aim of reducing cost and increasing accessibility to novel treatments, which are affordable for a greater number of patients. Biosimilars are highly similar but not identical to the reference products; therefore, strict regulatory requirements have been formed for their approval. This ensures that there are no clinically meaningful differences compared with respective biologics, with regard to purity, safety and efficacy. In 2003, a regulatory framework for the approval of biosimilars was established in Europe, whereas the USA did not implement a framework until 2009, when the Biologics Price Competition and Innovation Act was formed. A number of biosimilars have currently been approved in oncology and the number is expected to rise in the near future. More than 10 years of evidence has revealed that biosimilars are safe and effective; however healthcare professionals need to be further educated to eliminate potential misconceptions and integrate biosimilars into routine clinical practice. The present review aims to provide an overview of the biosimilars used in Europe and the USA, present their main benefits and challenges, and discuss their current and future roles in medical oncology.

Strategies for Overcoming Barriers to Adopting Biosimilars and Achieving Goals of the Biologics Price Competition and Innovation Act: A Survey of Managed Care and Specialty Pharmacy Professionals.

The Biologics Price Competition and Innovation Act (BPCIA) of 2009, which included pathways for FDA approval of biosimilar products, was designed to promote more affordable, expanded patient access to biologic therapies. Achieving these BPCIA goals depends on overcoming formidable barriers to biosimilar adoption. Managed care and specialty pharmacy professionals are uniquely qualified to inform initiatives to address these barriers. To assess perceptions regarding strategies for overcoming barriers to biosimilar adoption among managed care and specialty pharmacy professionals by conducting a survey study. Invitations to complete the online survey were emailed by the Academy of Managed Care Pharmacy (AMCP) to members and customers and to contacts sourced from a commercial database. In addition to questions on respondent demographics and perceptions of biosimilars, the survey listed 16 strategies for overcoming key barriers to biosimilar adoption. On a 5-point scale, participants rated their opinion on the likelihood that each strategy would have the potential to assist in achieving BPCIA goals. The survey also listed 6 barriers to biosimilar adoption. On a 5-point scale, participants rated their perceived difficulty in overcoming each barrier. The survey concluded with an open-text item that asked participants to list 3 additional strategies for overcoming biosimilar adoption barriers. Response frequencies were calculated to describe participants' ratings of the strategies and barriers. Statistical analyses were conducted to assess whether the ratings differed among respondents grouped by work organization. For the open-text item, we conducted qualitative content analyses to categorize strategies by stakeholder groups that might take primary implementation roles. A total of 300 managed care and specialty pharmacy professionals completed the survey. There was considerable variation in the preferences, policies, and practices regarding biosimilar adoption among respondents' work organizations. Responses to several survey items reflected positive attitudes about the safety and efficacy of biosimilars; for example, 84% agreed or strongly agreed that FDA-approved biosimilars are safe and effective for patients who switch from a reference biologic. Based on pooled percentages for ratings of likely and extremely likely to overcome barriers to biosimilar adoption, the highest-rated strategies were for prescriber education about evidence from switching studies (91%) and FDA guidance on pharmacy-level substitution of reference biologics with biosimilars (90%). The lowest-rated strategies were for requiring therapeutic drug monitoring for patients who switch to biosimilars (39%) and using quotas to incentivize providers to prescribe biosimilars (40%). For the qualitative analysis, the highest numbers of respondents' suggested strategies indicated primary implementation roles of biosimilar manufacturers (40%), the federal government (26%), and managed care organizations (15%). Reflecting the unique knowledge, perspectives, and practices of managed care and specialty pharmacy professionals, the study findings are relevant to informing and advancing initiatives for achieving BPCIA goals. The survey study reported in this article was part of a continuing education program funded by an independent educational grant, which was awarded by Sandoz, a Novartis Division, to PRIME Education. The Academy of Managed Care Pharmacy (AMCP) received grant funding from PRIME to assist in developing the survey and writing the manuscript. The grantor had no role in the study design, execution, analysis, or reporting. Greene and Pardo are employed by PRIME. Singh and Carden are employed by AMCP. Greene, Singh, Carden, and Pardo have no other disclosures. Lichtenstein received an honorarium from PRIME for serving as faculty for the continuing education program and has been a consultant for Pfizer, Cellceutix, and Merck.

The Case for Disclosure of Biologics Manufacturing Information.

Ten years after the enactment of the Biologics Price Competition and Innovation Act (BPCIA), competition in biologics markets remains scant and far from sufficient for lowering prices of biologics to the level of 80-90% price drops seen in generic drug markets. This reality is not a result of one or two cardinal reasons, but many. If lowering the price of biologics is the goal and competition is the means by which we seek to achieve that goal, then there does not seem to be a quick fix to address all of the many impediments to competition that plague biologics markets. Yet, certain changes to how the Food and Drug Administration (FDA) evaluates and approves biologics may go a long way toward the creation of meaningful competition in biologics markets. One such change would be making original biologics' manufacturing information available to follow-on manufacturers. As recognized by several commentators, access to biologics manufacturing information is key to increasing competition in biologics markets. Without access to such information, making follow-on biologics is difficult and expensive, if not outright impossible. This is expected to be especially true for the highly anticipated class of interchangeable biologics, none of which has been approved by the FDA to date. Yet, it has long been the position of the brand-name pharmaceutical industry (Industry) that biologics manufacturing information is proprietary and, thus, may not be shared. Congress has subscribed to the Industry's position, prohibiting the FDA from disclosing regulatory filings submitted by developers of original biologics, including manufacturing information, to third parties. That prohibition not only undermines competition in biologics markets, but is also wasteful, potentially unethical, and poses unnecessary risks to the health and safety of patients. This article makes the case for FDA sharing of original biologics manufacturing information with follow-on biologics developers. It is informed by the similar legal and commercial circumstances in the area of pesticides and the regulatory regime established by Congress in the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), which is administered by the Environmental Protection Agency (EPA). The article reviews the FIFRA regime, including its upholding as constitutional by the United States Supreme Court, and then examines its applicability to the area of biologics. The article concludes with a proposal for a similar regime to be incorporated into the pathway for approval of follow-on biologics as a means of increasing competition in biologics markets.