Biosimilar Medicines Research Articles

Variability of Biologics and its Impact on Biosimilar Development

This symposium took place during the International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland, June 2019, and focussed on scientific aspects associated with development and approval of rituximab biosimilars in lymphoma. The symposium began with an overview presented by Dr Cornes detailing the urgent economic need for biosimilars to improve access to these biologic treatments in oncology and other therapy areas. Prof Schellekens, author of the first paper on biosimilars in 2002, discussed how regulatory strategies for biosimilars were shaped, and how these have evolved in the intervening years. Today, the emphasis of biosimilar development is placed on extensive analytical testing to demonstrate a match with the reference medicine at a fundamental level. Clinical testing plays a confirmatory role, removing any residual uncertainty regarding potential clinical differences between biosimilar and reference medicine. Dr Schiestl presented further detail on analytical perspectives on biosimilars. Development of biosimilars is complicated by the inherent variability of biological synthesis techniques employed in the manufacture of biologics. This variability is further increased by ongoing changes to manufacturing processes, which can result in changes in biological activity. Consistent quality is therefore a cornerstone of biosimilar development. Prof Jurczak provided a comprehensive overview of the factors that must be considered during clinical development of a biosimilar. Clinical trials for biosimilars have a confirmatory role in the development process, rather than the pivotal role played by clinical trials for reference medicines. Therefore, these trials have markedly different objectives compared with reference clinical trials, resulting in differences in the chosen endpoints. In biosimilar trials, response endpoints, which provide rapid and sensitive assessments of equivalence, are preferred to survival endpoints, which require large and lengthy trials for adequate evaluation. Prof Jurczak illustrated this using data from the Phase III clinical trials of the Sandoz rituximab biosimilar. In this trial, Sandoz rituximab demonstrated an equivalent response rate to reference rituximab. Increasing economic pressure on healthcare systems means that biosimilars are likely to play an increasing role in the treatment of cancer in coming years, requiring clinicians to increase their familiarity with these important medicines.

Biosimilar Drugs for Multiple Sclerosis: An Unmet International Need or a Regulatory Risk?

Multiple sclerosis (MS) more than any other neurological disorder has experienced a tremendous progress in available evidence-based innovator disease modifying therapies (DMT). These medications include injectable complex nonbiological drugs (CNBD), the injectable biological products β-interferons-1a and -1b, and the infusible monoclonal antibodies (MAB), as well as oral synthetic therapeutic molecules. The degree of efficacy and adverse effects profile is variable. By the end of 2019, all medications have been approved for relapsing forms of MS, including five with indication for clinically isolated syndrome (CIS), two for active secondary progressive MS, and one for primary progressive MS. With the advent of the first generation or “platform” injectable DMT in the 1990s the cost of MS care increased substantially driven basically by the cost of these therapies. As new drugs licensed by health agencies appeared in the global market, the cost of these agents notably increased augmenting the economic gravamen of disease particularly in North America This industrial phenomenon has been promoted by the remarkable profits obtained by the biopharmaceutical companies producing these medications, costs increasing about seven times per patient per year in the span of two decades. The global MS drug market was valued at US$16.3 billion in 2016, expecting to reach US$27.8 billion by 2025. The societal and economic effect of these costs constitute an international concern for health systems which adjudicate an increasing portion of financial resources to MS care. This effect has had a more notorious impact in emerging countries with economies in development. In the early 2000s the industry producers of biosimilar molecules initiated the concept of manufacturing follow-on biosimilar therapeutic options for MS available at a reduced cost without affecting efficacy and safety. Latin American biotechnological companies from Mexico, Argentina and Uruguay, introduced into the regional markets biosimilar β-interferons. These products were licensed by the local regulatory agencies without challenging pharmacological profile and their claims of similarity with the innovator medications. In the licensing process, biosimilar manufactures have typically utilized published literature and phase III clinical trials data previously acquired by the brand medication (“third approval pathway’’). This has raised concerns among local neurological communities and patient organizations in the area. This situation is compounded by the fact that no discernible health cost savings have resulted since their introduction in Latin American countries. In some European countries where the health care system, public and private systems, regulated by Ministries of Health, negotiate with the pharmaceutical industry drug pricing and payment systems. The business scenario has stimulated local industries to produce follow-on biosimilar medications, theoretically to compete or replace the original brands. Countries such as Iran who have experienced a substantial increase in MS prevalence (101.19 per 100,000 inhabitants) has enabled their national Food and Drug Organization (FDO) to license locally produced biosimilar interferon 1-a and 1-b based on somewhat limited clinical studies. The Ministry of Health of the Russian Federation, approved the first biosimilar β-interferon-1a (44 mcg subcutaneous administration) manufactured in the country and developed in accordance to the guidelines of the European Medicine Agency (EMA) for phase I and phase III studies. The EMA, however, along with other international licensing agencies: United States Food and Drug Agency (FDA), Health Canada, the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the UK Medicines and Healthcare Products Regulatory Agency (MHPRA), and others, have produced strict guidelines regulating registration of biosimilar medicines. Thus far these agencies have not approved any interferon or MAB for MS based on these principles. The main obstacles for the approval of biosimilar medications by international health agencies is their consistent inability to demonstrate therapeutic equivalence through physiochemistry, biology, immunogenicity aspects, molecular behavior and clinical studies, preferably through a controlled phase III study, or ideally, utilizing a comparative head-to-head trial with the innovator. Recommendations proposed by experts from the Latin American region to guarantee production quality of biosimilar products, efficacy and safety, include strict application of current regulations; avoid uncontrolled interchangeability; implement strong pharmacovigilance; educate healthcare professionals and regulatory officials on the different issues involved in the biosimilarity concept and use evidence-based decision for therapy selection. The main priority should always be the protection and well-being of the patient irrespectively of therapy availability or pharmacoeconomic issues.

Benefits and drawbacks of moving to biosimilar medicines

The recent introduction of four biosimilars to the anti‐TNF monoclonal antibody adalimumab has raised the prospect of significant cost savings for the NHS. But what are biosimilar medicines, how easy is it to switch patients and how likely is it that large savings will be possible?

How Changes in Reimbursement Practices Influence the Financial Sustainability of Medicine Policy: Lessons Learned from Slovakia.

Objectives: The aim of this study was to review the impact of new reimbursement requirements for medicines in the Slovak Republic based on legislation that came into force in January 2018. Methods: The new legislation was reviewed. The reimbursement dossiers for medicines and health technology assessments and appraisals, justifications for reimbursement decisions, final reimbursement decisions, and all aspects of the appeal mechanisms have been transparently published on the website of the Slovak Ministry of Health and were used for this analysis. Results: Based on the new legislation, there was no need to submit information about relative effectiveness and cost-effectiveness of medicines with less than 1:50,000 eligible patients prior to reimbursement decisions, and the cost-effectiveness threshold has been increased for all other medicines. The estimated impact of the 2-year budget for the 59 medicines submitted for reimbursement without relative effectiveness and cost-effectiveness analysis was €181,273,698, based on the published submission dossiers. The estimated impact of the 2-year budget for the 45 medicines with evidence of relative effectiveness and cost-effectiveness was €178,566,634. In contrast to the easier market access criteria for new original medicines, the new legislation enforces stricter price erosion criteria for generic and biosimilar medicines. Consequently, the number of generic and biosimilar entries was reduced from 242 in 2017 to 224 in 2018. Conclusions: Although some of the new reimbursement applications were not approved by the Ministry of Health, many new medicines were added to the Slovak pharmaceutical reimbursement list based on “balanced assessment” requirements; hence, the system became financially unsustainable. It was necessary to change the legislation from January 2019.

Biosimilars in dermatology: The wind of change.

Biosimilars are new drugs, highly similar copies of biological medicines, equally effective and safe but at lower prices. The aim of this brief review is to provide the current status of biosimilars approved in the European Union for dermatological use. We used PubMed for literature search up to June 2018. The keyword 'biosimilars' was searched and 1,691 items were found. From the 1,691 studies, we included 34 articles in our review. Biologics, biosimilars and generics are different types of drugs. Biosimilars are complex molecules produced by a difficult manufacturing process, and changes in product quality may affect its safety and efficacy. Now, there are 9 biosimilar medicines approved by European Medicines Agency (EMA) for plaque psoriasis and hidradenitis suppurativa: Amgevita, Solymbic, Cyltezo, Imraldi, Benepali, Erelzi, Flixabi, Inflectra and Remsima, and the number is increasing. In 2005, EMA issued the first guidelines for approval of biosimilars. Next-generation biologics, called 'biobetters', have the same target or mechanism of action as previously approved biologics, but they have structural changes and an improved formulation. The debate over the future of biosimilars is far from being finished. The explosive development of biological therapy and the emergence of biosimilars represent a significant success in the effort to provide advanced healthcare to patients all over the world.

Biosimilar medicines: Impact, opportunities and strategies. Twelve years of experience in Europe

Biosimilar medicines: Impact, opportunities and strategies. Twelve years of experience in Europe

The evolution of value with filgrastim in oncology.

The recombinant G-CSF filgrastim was first approved in 1991, and its value has been evolving ever since. Initial health technology assessments suggested low value due to high drug cost and no evidence for significant gain in overall survival. However, more recent meta-analyses of placebo-controlled randomized trial data show falling costs due to biosimilar competition and absolute overall survival gains of 3.2% (95% CI: 2.1-4.2%) from filgrastim support of cytotoxic chemotherapy. The launch of biosimilar alternatives merits a re-evaluation of decisions by health technology assessments and explains the first inclusion of filgrastim in the WHO Essential Drug List for cancer >20years after its original approval in 1991, thus demonstrating the power of biosimilar medicines in transforming healthcare.

Perspectives of Hospital Pharmacists Towards Biosimilar Medicines: A Survey of Polish Pharmacy Practice in General Hospitals.

IntroductionThere has been a significant increase in the volume of biosimilar medicines recently due to the expiries of patent protections of biologic medicines. Biosimilars are considered new medicines, and their usage in therapy is often associated with uncertainty from the perspectives of physicians, pharmacists and patients.ObjectivesThe purpose of this study was to identify hospital pharmacist opinions towards these new medicines and investigate their usage in practice.MethodsA paper-based, self-administered questionnaire was distributed to Polish hospital pharmacists.ResultsBiosimilars were used in 77% of surveyed hospitals, whereas originator biologics were utilised within 90% of settings. The former medicines were found to consist of less than one-third of the entire course of biological pharmacotherapy used within Polish hospitals. A total of 88% of hospital pharmacists were concerned that the new drugs were not identical with the biologic versions, 48% with their immunogenicity and 44% with other pharmacokinetic properties. The majority of respondents (87%) stated that the most important advantage of biosimilars related to decreased costs. Furthermore, according to participants, pharmacist-led substitution is not appropriate.ConclusionDue to the numerous concerns relating to the usage of biosimilars, their introduction into patient therapy requires special attention from healthcare providers. While pharmacists involved in the distribution of biosimilars are conscious of their impact in decreasing costs of therapy, they do not feel comfortable in recommending their substitution without a physician’s permission. There is a need for more precise legal regulations relating to biosimilars, improved communication between physicians and pharmacists, as well as educational initiatives to improve the safe and effective usage of biosimilars.

Harmonization of Pharmacovigilance Regulation in Brazil: Opportunities to Improve Risk Communication

Brazilian pharmacovigilance regulations involve 3 spheres: health services, Marketing Authorization Holders (MAHs), and sanitary agency. Drug tolerability began to be effectively assessed in Brazil after the founding of the National Agency of Sanitary Surveillance, which developed the Sentinel Network Project. The objective of the Sentinel Network Project is to increase the adverse drug reaction (ADR) reporting rate by health care professionals in the hospital setting. Pharmacovigilance practices became mandatory for MAHs, and patient tolerability issues were considered in drug policy in Brazil only as recently as 2000. However, despite recent events, the regulatory advancements in pharmacovigilance in Brazil are only equivalent to international practices (ie, those of the European Union). The pharmacovigilance system in the European Union integrates the national authorities, the European Commission, and the European Medicines Agency, which is responsible for the scientific evaluation, supervision, and safety monitoring of medicines for human and veterinary use in the European Union. Furthermore, ADR patient reporting is included in the new EU pharmacovigilance regulations. Numerous possible ways are available to improve the Brazilian pharmacovigilance system, mainly through regulations of biosimilar, nanotechnology, and veterinary medicines or by training health care professionals and patients to report nonserious cases and quality deviations. It is necessary to encourage and develop strategies for decentralizing pharmacovigilance actions in the whole country, as is common practice in several EU countries. Motivating and considering ADR reports by patients and improving feedback and audit practices in health care services and MAHs are also necessary measures. With the inclusion of Brazil as a member of the International Conference of Harmonization, significant changes in pharmacovigilance regulation are expected; these updates, which will consider international standards, will improve signal detection and risk communication.

Changes in the type and amount of spending disclosed by Australian pharmaceutical companies: an observational study

ObjectivesTo describe and quantify disclosed payments from the pharmaceutical industry to the healthcare sector, and to examine the impact of the 2015 changes to Australia’s self-regulated system of transparency.DesignObservational database...

Safety concerns of biosimilar hormone products

Background: Currently, biotherapeutic medicines are the most effective options for the treatment of many severe and chronic diseases. For faster market entry of biotherapeutic products and their cost reduction, the principles of “biosimilarity” have been developed. Development and licensing of biosimilars is allowed only after the end of patent exclusivity of the original preparation period.Purpose: Characteristics of the main safety parameters of biosimilar hormone preparations licensed by EMA. Methods: This paper analyzes the results demonstrating the similarities and differences between biosimilar and reference hormone products indicated in the EPAR (public assessment report) for the examination of materials presented for the licensing of biosimilar products.Results: During the development of biosimilar hormone medicines, differences in the glycosylation profile between biosimilar and reference preparations are revealed. As biotherapeutical preparations are produced by cells, the differences in glycosylation profile between biosimilar and referent preparation are predictable. While carrying out clinical studies, a high similarity of biosimilar and reference product effectiveness is shown, but some differences between them in the safety profile are revealed.Conclusions: The study of biosimilar product safety has shown the necessity of further improvement in safety and standard approaches for the assessment of the immunogenicity of biosimilar products.

Factors Affecting Health Care Provider Knowledge and Acceptance of Biosimilar Medicines: A Systematic Review.

Newly developed biosimilar agents confer significant cost-saving advantages, yielding the potential to mitigate rising drug costs and expand patient access to care for important biologic therapies. Biosimilar market uptake greatly depends on health care provider willingness to promote, prescribe, and use biosimilars in clinical practice. To perform a systematic review evaluating current U.S. and European health care provider knowledge, perceptions, and prescribing behaviors of biosimilar medicines to assess the need for clinician-directed biosimilar education. An electronic literature search was conducted using journal databases, including PubMed, Embase, and Cochrane Library. Terms related to biosimilar agents, survey questionnaires, and education were used. Two independent reviewers evaluated 158 citations published from January 1, 2014, to March 5, 2018 that were the result of this search. Studies in English were included if they surveyed U.S. or European physician and/or pharmacist knowledge, attitudes, and/or prescribing preferences of biosimilar drugs. Overall trends in prescribing behavior and perceptions were abstracted. A total of 20 studies met inclusion criteria. Three studies originated from the United States and 17 were from Europe. Hospital specialists, gastroenterologists, and rheumatologists were the most frequently surveyed practitioners. The percentage of biosimilar prescribing varied widely between countries and within similar practice fields. If used, biosimilars were predominantly prescribed in biologic treatment-naive patients. An overall lack of biosimilar familiarity in U.S. and European health care settings accompanied concerns about biosimilar safety, efficacy, extrapolation, and interchangeability. Detailed descriptions of biosimilar education programs were lacking within the literature. Findings from this review indicate that U.S. and European health care providers still approach biosimilar medicines with caution, citing limited biosimilar knowledge, low prescribing comfort, and safety and efficacy concerns as main deterrents for biosimilar use. To realize the full cost-saving potential of biosimilar medicines, clinician-directed biosimilar education will be imperative to address gaps in biosimilar knowledge, facilitate prescribing changes, and ultimately increase biosimilar use. No outside funding supported this study. The authors have nothing to disclose.

Hormones, Blood Products, and Therapeutic Enzymes.

Therapeutic uses of biological medicines are diverse and include active substances from different classes. This chapter provides an overview on the clinical applications of biological medicines containing hormones, blood products, and therapeutic enzymes. Currently, therapeutic hormones have 78 approved medicines, including insulin and analogs, glucagon and analogs, growth hormone, gonadotropins (follicle-stimulating hormone, luteinizing hormone, and human chorionic gonadotropin), thyroid-stimulating hormone, and parathyroid hormone. In contrast, recombinant blood products, and particularly blood factors, anticoagulants, and thrombolytic agents, incorporate 49 approved biological medicines. Regarding recombinant therapeutic enzymes, there are 22 approved medicines. Among the referred biological medicines, there are six biosimilar hormones, and no biosimilars have been approved for recombinant blood products and therapeutic enzymes, which is unexpected.Current investigations on recombinant hormones, recombinant blood products, and therapeutic enzymes seem to follow the same directions, searching for alternative non-injectable administration routes, development of new recombinant molecules with improved pharmacokinetic properties and discovering new clinical applications for approved medicines. These approaches are showing positive results and new medicines are expected to reach clinical approval in the coming years. Future prospects also include the approval of more biosimilar medicines.

Biosimilars: Past, Present, and Future

The expiry of patent of biologic medicines emerged the development and manufacturing of biosimilar products worldwide. A number of biologic medicines have successfully been developed and approved over the last one and half decades, enlightening the lives of patients globally. According to the European Medicines Agency (EMA), biosimilar product can be defined as a biological medicine that is highly similar to another biological medicine that has already been authorized for use. Biological medicines contain active substances from a biological source, for example, living cells or organisms (human, animals and microorganisms: bacteria or yeast) and are often manufactured by cutting-edge technology. Most of the biological medicines in current clinical use comprise of active substances made of proteins. Biopharmaceuticals contain a wide-range of products such as vaccines, immunoglobulins, monoclonal antibodies, cell and gene therapy products. The EMA led the way (well ahead of the Food and Drug Administration in the US) in evolving the biosimilar idea, and the type of science-based regulatory framework required to ensure high-quality, safe, and effective biosimilar medicines; the provisions for approval of biosimilars have been in place in Europe since the year 2005. Under these provisions, Omnitrope® (Somatropin-Sandoz-Novartis) was approved by the EMA in the year 2006 as the world’s first biosimilar medicine; the US Food and Drug Administration (US-FDA) approved Zarxio^TM (Filgrastim-Sandoz) for all indications included in the reference product’s label in March 2015. Zarxio^TM (Sandoz-Novartis) is the first biosimilar product approved by US-FDA.

OP45 Biological Drugs And Rheumatoid Arthritis In Brazil: An Overview

IntroductionThe Brazilian Unified Health System (SUS) is known worldwide for ensuring universal assistance to citizens, which includes the supply of medicines free of charge. Biological drugs consume about 40 percent of the public budget for pharmaceutical services in the SUS and Rheumatoid Arthritis (RA) is the largest consumer of these resources, serving about 110,000 patients. Since 2002 there has been a clinical guideline for the care of patients with rheumatoid arthritis in Brazil, currently providing 10 biological drugs for treatment of RA. The objective of this study is to present data about the provision, expenditure and profile of users of biological drugs for rheumatoid arthritis in SUS.MethodsRetrospective and exploratory study, using administrative data regarding the purchase and consumption of biological drugs Infliximab, Etanercept, Adalimumab, Rituximab, Abatacept (intravenous and subcutaneous), Tocilizumab, Golimumab and Certolizumab pegol for the treatment of RA between 2012 and 2017 in SUS.ResultsThere was an expenditure of approximately USD 421.7 million from the Brazilian Ministry of Health with the supply of about 2 million pharmaceutical units of biological drugs for treatment of rheumatoid arthritis, 79 percent of them destined for female users and 89.2 percent for the 40-69 age group. The M05.8 and M.06.0 codes of the International Classification of Diseases (ICD-10) were the most prevalent among the arthritic population served. Adalimumab and Etanercept accounted for 68.3 percent of total expenditure. A reduction in the use of these medicines were observed after the availability of new drugs for the treatment of the disease between 2014 and 2017.ConclusionsBrazil is one of the largest consumers of biological medicines in the world. The use of real-life data allows monitoring trends and costs of the use of these drugs as well as changes with the entry of new therapies and biosimilar medicines.

Cytokines and Growth Factors.

Several cytokines have been used to treat autoimmune diseases, viral infections, and cancer and to regenerate the skin. In particular, interferons (INFs) have been used to treat cancer, hepatitis B and C, and multiple sclerosis, while interleukins (ILs) and tumor necrosis factors (TNFs) have been used in the management of different types of cancer. Concerning the hematopoietic growth factors (HGFs), epoetin has been used for anemia, whereas the colony-stimulating factors (CSFs) have been used for neutropenia. Other growth factors have been extensively explored, although most still need to demonstrate in vivo clinical relevance before reaching the market.This chapter provides an overview on the therapeutic applications of biological medicines containing recombinant cytokines and growth factors (HGFs and others). From this review, we concluded that the clinical relevance of recombinant cytokines has been increasing. Since the 1980s, the European Medicines Agency (EMA) and/or Food and Drug Administration (FDA) have approved 89 biological medicines containing recombinant cytokines. Among these, 18 were withdrawn, 24 are biosimilars, and 18 are orphans.So far, considerable progress has been made in discovering new cytokines, additional cytokine functions, and how they interfere with human diseases. Future prospects include the approval of more biological and biosimilar medicines for different therapeutic applications.

VP71 Barriers To Access Biologic Products: A Rapid Review

IntroductionThe elevated costs with biologic products threaten the sustainability of health services, and, therefore, the access to these medicines in the perspectives of user, health professional, health manager and system. The entry of biosimilar products in the market could be an option to subsidize the search for solutions to those problems.MethodsWe conducted a rapid review using the databases Medline (via PubMed), EMBASE, Cochrane Library and CRD. The eligibility criteria were HTAs, systematic reviews and cross-sectional studies.ResultsLiterature search retrieved 640 registries and, after duplicate removal, screening of titles and abstracts and full text reading, nine cross-sectional studies were selected. From a user's point of view, the following barriers were identified: lack of knowledge about the medicine, distance between the place of living and the health service (especially in the rural area), long waiting periods for service, passivity in regard to treatment. From a health professional's point of view the barriers were: acceptability of the expert in regard to treatment, interchangeability and substitution, the perception of lack of data showing efficacy and safety. Finally, from the payer's (or health manager) point of view, the barriers were: high cost of medicine, problems with reimbursement and bureaucracy. We did not retrieve any barriers from the health system's perspective from the selected studies.ConclusionsThe entry of biosimilar medicines in the market can induce competition and, therefore, reduce prices of biologic treatments. It is necessary to search for potential solutions to the access barriers identified in this rapid review.

Healthcare professionals’ perceptions and perspectives on biosimilar medicines and the barriers and facilitators to their prescribing in UK: a qualitative study

ObjectiveTo investigate UK healthcare professionals’ perceptions and perspectives towards biosimilar infliximab, etanercept and insulin glargine and the potential barriers and facilitators to their prescribing.DesignA cross-sectional qualitative study design was used.SettingFive...

Regulation of biosimilar medicines and current perspectives on interchangeability and policy.

Competition arising from the increasing availability of biosimilar medicines has resulted in healthcare savings and has provided greater patient access to high cost therapeutics in Europe. The biosimilar market in the USA is relatively new so the full impact of biosimilar availability remains to be seen. Educational initiatives relating to the use of biosimilar medicines are currently being undertaken by regulators, policy makers and industry. The debate on biosimilars has moved on from the appropriateness of the regulatory framework which governs their approval, to the practice of interchangeability. Interchangeability is an important issue for healthcare professionals but different definitions and regulatory frameworks exist in the USA and Europe. In the USA, an interchangeable biological product is a biosimilar which may be substituted by a pharmacist, subject to local State policies. The interchangeability of a biosimilar with its reference medicine will be evaluated by the United States Food and Drug Administration (FDA) in cases where approval as an 'interchangeable product' is sought. In contrast, the European Medicines Agency (EMA) does not assess or make recommendations on interchangeability, therefore, in Europe, interchangeability does not mean substitution but is generally physician-led or driven by national policy. This paper provides an overview of the regulation of biosimilar medicines. Challenges associated with the demonstration of interchangeability and practical considerations relating to switching are also discussed. Finally, we present policies that have been adopted to date in several European countries, the USA and Australia, which aim to promote the use of biosimilar medicines.

PHP17 - Cross-National Comparison of Biosimilar Medicines : Market Penetration and Competition with Originators

PHP17 - Cross-National Comparison of Biosimilar Medicines : Market Penetration and Competition with Originators