Interchangeability of biosimilars: A study of expert views and visions regarding the science and substitution.

Healthcare systems have reached a critical point regarding the question of whether biosimilar substitution should become common practice. To move the discussion forward, the study objective was to investigate the views of experts from medicines agencies and the pharmaceutical industry on the science underpinning interchangeability of biosimilars. We conducted an empirical qualitative study using semi-structured interviews informed by a cross-disciplinary approach encompassing regulatory science, law, and pharmaceutical policy. In total 25 individuals with experience within biologics participated during September 2018-August 2019. Eight participants were EU national medicines authority regulators, and 17 had pharmaceutical industry background: five from two originator-only companies, four from two companies with both biosimilar and originator products, and eight from seven biosimilar-only companies. Two analysts independently conducted inductive content analysis, resulting in data-driven themes capturing the meaning of the data. The participants reported that interchangeability was more than a scientific question of likeness between biosimilar and reference products: it also pertained to regulatory practices and trust. Participants were overall confident in the science behind exchanging biosimilar products for the reference products via switching, i.e., with physician involvement. However, their opinions differed regarding the scientific risk associated with biosimilar substitution, i.e., without physician involvement. Almost all participants saw no need for additional scientific data to support substitution. Moreover, the participants did not believe that switching studies, as required in the US, were appropriate for obtaining scientific certainty due to their small size. It is unclear why biosimilar switching is viewed as scientifically safer than substitution; therefore, we expect greater policy debate on biosimilar substitution in the near future. We urge European and UK policymakers and regulators to clarify their visions for biosimilar substitution; the positions of these two frontrunners are likely to influence other jurisdictions on the future of biosimilar use.

Identifiability of Biologicals: An Analysis Using EudraVigilance, the European Union's Database of Reports of Suspected Adverse Drug Reactions.

The relevance of biological therapies for an increasing number of conditions is on the rise. Following the expiry of the initial period of market exclusivity, many of these successful therapies have seen the arrival of biosimilars on the market. The clear identification of the precise medicine responsible for an adverse drug reaction (ADR) report is an important element for pharmacovigilance, allowing timely detection of potential product-specific safety signals. We looked at the identifiability of biologicals up to the level of commercial product name in ADR reports received from European clinical practice between 2011 and December 2019. A good level of identification (91.5%) was observed overall, but at the same time a downward trend was observed in the last 5 years. This reduction in the level of identifiability of biological products (originators and biosimilars) at the commercial name level in general was driven by five widely used substances, whereas the identification of all other biologics stayed consistent over time (at over 90%). We observed that those five substances were used mostly within oncology. The introduction of the first biosimilar in the market did not appear to affect their identifiability. These results show that although the general level of identification at the commercial product name level in ADRs in Europe is robust and generally stable over time, decreasing trends can be down to a few commonly used substances, which need to be monitored to reverse the trend.

Quality challenges associated with microbial-based cleaning products from the Industry Perspective.

Microbial-based cleaning products (MBCPs) continue to gain popularity in the market as environmentally friendly cleaners. The majority of these products contain spores of various Bacillus species. Although the microorganisms used in MBCPs are subject to regulation in Canada under the Canadian Environmental Protection Act, the products themselves are not. Unlike other types of microbial products such as probiotics and biopesticides, the use, manufacture and quality parameters of MBCPs in Canada and other countries are poorly defined and not specifically subject to any required standards. Due to their complexity and nature, these products feature unique quality challenges. We noted the existing MBCPs we analyzed vary vastly in quality; external microbial contaminants, viability of the spores and the biocompatibility of the ingredients are issues that greatly affect product quality. A proper taxonomic identification of the bacterial species used also seems to be a major challenge for a number of manufacturers. A good understanding of the mechanisms governing these quality challenges and the adoption of good practices for the cultivation, harvesting, formulation, and manufacture of these types of products are essential for achieving high-quality performance standards.

Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates.

The study of medications among pediatric patients has increased worldwide since 1997 in response to new legislation and regulations, but these studies have not yet adequately addressed the therapeutic needs of neonates. Additionally, extant guidance developed by regulatory agencies worldwide does not fully address the specificities of neonatal drug development, especially among extremely premature newborns who currently survive. Consequently, an international consortium from Canada, Europe, Japan, and the United States was organized by the Critical Path Institute to address the content of guidance. This group included neonatologists, neonatal nurses, parents, regulators, ethicists, clinical pharmacologists, specialists in pharmacokinetics, specialists in clinical trials and pediatricians working in the pharmaceutical industry. This group has developed a comprehensive, referenced White Paper to guide neonatal clinical trials of medicines - particularly early phase studies. Key points include: the need to base product development on neonatal physiology and pharmacology while making the most of knowledge acquired in other settings; the central role of families in research; and the value of the whole neonatal team in the design, implementation and interpretation of studies. This White Paper should facilitate successful clinical trials of medicines in neonates by informing regulators, sponsors, and the neonatal community of existing good practice.

Biological agents and biosimilars: Essential information for the internist.

Biologics embrace a wide range of substances synthesized by cells or living organisms by means of different biological processes, including recombinant DNA technology, controlled gene expression, or antibody technologies. A biosimilar establishes similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety, and efficacy based on a comprehensive comparability exercise. Minimizing development costs and accelerating their market access create a convergence of interests between health services, worried about sustainability, and generic manufacturers. While the demonstration of bioequivalence is sufficient for small synthetic molecules, this approach is not scientifically applicable to a copy of biological drug constituted by large and complex molecules, which are similar but not identical to the originator and are also subject to different post-translational processes. Internists should be confident that the development process of biosimilars ensures a comparable risk-to-benefit balance with the originators. On the basis of available evidence and pharmacovigilance network, there are no grounds to believe that the use of a biosimilar carries more risks for the patient than the use of an originator. Since the first biosimilar was authorized in Europe in 2006, no clinical alerts have raised red flags about the established EMA biosimilar pathway. In this article, we discuss some of the most frequent concerns raised by clinicians about biosimilars and try to explains the scientific principles underlying the biosimilar concept established in the EU in order to license biosimilar drugs.

Biosimilar competition in the United States: statutory incentives, payers, and pharmacy benefit managers.

Widespread adoption of generic medications, made possible by the Hatch-Waxman Act of 1984, has contained the cost of small-molecule drugs in the United States. Biologics, however, have yet to face competition from follow-on products and represent the fastest-growing sector of the US pharmaceutical market. We compare the legislative framework governing small-molecule generics to that which regulates follow-on biologics, and we examine management tools that are likely to be most successful in promoting biosimilars' adoption. The Biologics Price Competition and Innovation Act established an abbreviated pathway for follow-on biologics, but weak statutory incentives create barriers to entry. Many authors have raised concerns that competition under the biologics act may be weaker than that posed by small-molecule generics under Hatch-Waxman, in part because of legislative choices such as the absence of market exclusivity for the first biosimilar approved and a requirement that follow-on manufacturers disclose their manufacturing processes to the manufacturer of the reference product. Provider skepticism and limited competition from biosimilars will challenge payers and pharmacy benefit managers to reduce prices and maximize uptake of follow-on biologics. Successful payers and pharmacy benefit managers will employ various strategies, including tiered formularies and innovative fee schedules, that can control spending by promoting uptake of biosimilars across both the pharmacy and medical benefits.

Role of public standards in the safety and efficacy of biologic medicines.

In this report, we emphasize the importance of public monographs with reference materials, coupled with careful process and change control and attention to GMPs, as a means of advancing access to good quality, safe, and effective medicines, with emphasis on available and incoming biologic medicines. With adequate control of articles covered by a monograph, these public standards can form the basis for a global public quality platform that covers reference products, non-interchangeable reference products, biosimilars, and interchangeable biosimilars. Working collaboratively with all stakeholders, new approaches allow these public standards to emerge nationally and globally in a timely way. Yet, there are increasing limitations in the availability of public standards for biologic medicines, which may reverse many decades of progress. Solutions are considered in this report.

[Main direction of harmonization of Russian and international requirements on providing of biological safety when handling pathogenic biological agents].

The actuality of harmonization of Russian and international requirements when handling with pathogenic biological agents (PBA) is caused by the need to ensure biological security on the basis of control of biorisks. One of the basic conditions for harmonization is development and implementation of the Russian standard for biorisk management based on international standard CWA 15793:2008.

Stability studies needed to define the handling and transport conditions of sensitive pharmaceutical or biotechnological products.

Many pharmaceutical or biotechnological products require transport using temperature-controlled systems to keep their therapeutic properties. There are presently no official guidelines for testing pharmaceutical products in order to define suitable transport specifications. After reviewing the current guidance documents, this paper proposes a methodology for testing pharmaceutical products and defining appropriate transport conditions.

Quality control and analytical techniques for biopharmaceuticals.

Biopharmaceuticals are complex products and to ensure their batch-to-batch consistency and continuing quality the use of a combination of complementary analytical tests is required. Regulatory guidelines indicate quality attributes of different product classes to be included in the specifications for product release. Whilst the continuing development of sophisticated physicochemical techniques make them increasingly powerful for defining product identity, integrity, purity and the consistency of the manufacturing process, the results generated are not easily related to the biological activity. Consequently, a bioassay is normally required in the quality control to determine the potency, that is, the quantitative measure of the product's ability to cause a specific biological effect in a defined biological system. A wide, and rapidly increasing, range of bioassay systems exist, each type with particular advantages and disadvantages.

WHO Expert Committee on biological standardization.

This report presents the recommendations of a WHO Expert Committee commissioned to coordinate activities leading to the adoption of international recommendations for the production and control of vaccines and other biologicals and the establishment of international biological reference materials. The report starts with a discussion of general issues brought to the attention of the Committee and provides information on the status and development of reference materials for various antibodies, antigens, blood products and related substances, cytokines, growth factors, and endocrinological substances. The second part of the report, of particular relevance to manufacturers and national regulatory authorities, contains WHO recommendations and guidelines on Japanese encephalitis vaccine (inactivated), human; regulatory preparedness for human pandemic influenza vaccines; and clinical evaluation of meningococcal C conjugate vaccines. Also included are a list of recommendations, guidelines and other documents for biological substances used in medicine, and of international standards and reference reagent for biological substances.

Allergen source materials: state-of-the-art.

A variety of positive outcomes can be realized from validation and risk management activities (see Table 4). They are dependent on the participation of multiple functional groups including the quality unit, regulatory and legal affairs, engineering and production operations, research and development, and sales and marketing. Quality risk management is receiving increased attention in the area of public health, pharmacovigilance, and pharmaceutical manufacturing. Recent examples of its regulatory use in our industry include the assessment of the potential risks of transmissible spongiform encephalopathies (TSE) agents through contaminated products], the risks of precipitates in allergenic extracts, and the revision of the potency limits for standardized dust mite and grass allergen vaccines. Its application to allergen source material process validation activities allowed for a practical strategy, especially in a complex manufacturing environment involving hundreds of products with multiple intended uses. In addition, the use of tools such as FMEA was useful in evaluating proposed changes made to manufacturing procedures and product specifications, new regulatory actions, and customer feedback or complaints. The success of such a quality assurance programs will ultimately be reflected in the elimination or reduction of product failures, improvement in the detection and prediction of potential product failures, and increased confidence in product quality.

Physicochemical characterization of allergens: quantity, identity, purity, aggregation and conformation.

Allergens and allergoids can be characterized by means of physicochemical methods, resulting in a description of the protein on different structural levels. Several techniques are available and their suitability depends on the composition of the particular sample. Current European legislation on allergen products demands characterization of final products in particular focusing on identity, degree of modification (for allergoids) and stability of the composition. Structural parameters of allergens may be used to investigate the stability of an allergen product. The challenge is to identify and optimize techniques that allow determination of protein structure in the context of a formulated pharmaceutical product. As the majority of the products currently marketed are formulated with aluminium hydroxide or aluminium phosphate as a depot, most of the methods and techniques used for protein characterization in solution are not applicable. An additional hurdle is that allergen products are based on natural extracts, comprising a mixture of proteins, both allergens and non-allergens, sometimes in the presence of other uncharacterized components from the raw material. This paper describes which methods are suitable for the different stages of allergen product manufacturing, and how these relate to the current regulatory requirements. Some of the techniques are demonstrated using a model allergen, cod parvalbumin, and a chemically modified form thereof. We conclude that a variety of methods is available for characterization of proteins in solution, and that a limited number of techniques appear to be suitable for modified allergens (allergoids). Adaptation of existing methods, e.g. mass spectroscopy and infrared spectroscopy may be helpful to obtain protein parameters of allergens in a formulated allergen product. By choosing a combination of techniques, including those additional to physicochemical approaches, relevant parameters of allergens in formulated allergen products can be assessed in order to achieve a well-characterized pharmaceutical product.

Reduction of numbers of animals used in the quality control of biologicals.

Laboratory animals are used for the quality control of vaccines. In particular, the potency testing of batches of inactivated vaccine requires large numbers of animals. The possibilities for reduction have been evaluated, and the results are summarised in this paper. Several approaches were studied, including the retrospective analysis of test data, with the objectives of determining the minimum number of animals required per vaccine dilution group, and evaluating the feasibility of a single-dose potency test. Other studies focused on the development of serology-based models and the use of genetically uniform animals. Based on the outcome of these studies, a substantial reduction in the number of animals used for the potency testing of toxoid vaccines has been achieved or will be achieved in the near future. As reduction alternatives can generally be explored in a relatively simpler and less time-consuming way than replacement alternatives, more emphasis should be placed on reduction strategies than at present.